(ORs) adjusted for age, sex and recruitment site, and their 95% confidence intervals (CIs), using logistic regression models. The models for tobacco smoking were further adjusted for alcohol consumption. Models estimating the effect of alcohol were adjusted for smoking quantity and duration. ORs associated with oral HPV were adjusted for smoking quantity, duration, and alcohol consumption. Two-way interaction on a multiplicative scale was assessed by estimating Ψ, the multiplicative interaction parameter as follows, Ψ=OR11/(OR01*OR10). The 95% CI for Ψ was determined using the CI for the interaction term in the multivariate model. Two-way interaction on an additive scale was assessed using the Relative Excess Risk due to Interaction (RERI), RERI= OR11-OR10-OR01+1. Asymptotic 95% CI were calculated for the RERI as described elsewhere [21]. We also conducted analyses by cancer site (oropharynx/ non oropharynx). We grouped oral cavity, hypopharynx and larynx because of sample size constraints.

HPV status was missing for 147 (27%) subjects (53 cases and 94 controls) that refused to provide a saliva sample, and for three controls for whom the quality of the specimen was considered inadequate for HPV detection. In addition, missing data were observed for smoking status (one case) smoking quantity (19 cases, 3 controls), smoking duration (6 cases, 1 control) and alcohol quantity (4 controls). We used multiple imputations by chained equations (MICE) to deal with missing data [22]. The imputation model contained all the basic characteristics of the study subjects (age, sex recruitment site and education level), variables related to alcohol and smoking (ever daily alcohol drinking, quantity of alcohol, smoking status, smoking duration, and smoking quantity), HPV status (low-risk, probable high-risk, high-risk, and other HPV types) and the case-control status. All variables in the imputation model which had missing values were imputed for our analyses. We generated 20 datasets. We also performed a complete case analysis, on a dataset containing only observed data. Results were similar to those from the imputed datasets, despite wider confidence
intervals (See supplementary material). Statistical analysis was performed using SAS 9.4
software (SAS Institute, Carry, NC USA).

## Results

### Characteristics of study population

Table 1 shows socio-demographic characteristics of HNSCC cases and controls. The majority of subjects in our study were between 55 and 64 years old and were men. A little under half of the cases had only primary school education (42.8%) compared to 23.2% of the controls.

### Tobacco, Alcohol, Oral HPV and HNSCC risk

Table 2 shows multivariate ORs of HNSCC and 95% CI associated with tobacco smoking, alcohol drinking and oral HPV. Current smokers were significantly 11 times more likely to develop HNSCC compared to never smokers. Ex-smokers were only twice as likely to develop a HNSCC compared to never smokers. The risk increased with the quantity and duration of tobacco smoking. Significant increases in risk by more than 10-fold were observed for more than 20 cigarettes/day, and for more than 30 years. We studied as well the combination between smoking quantity and duration. We observed that duration had a greater role in HNSCC aetiology than the quantity. Persons who smoked for shorter periods of time (less than 30 years) had a lower risk for developing HNSCC regardless of the quantity of cigarettes smoked per day.

Compared to never smokers, the risk of HNSCC was slightly greater for the persons who smoked only black tobacco than blond tobacco alone (OR=5.97, 95%CI=2.80-12.73; OR=4.67, 95%CI=2.55-8.54 respectively) (data not shown). The ORs were higher for those who inhaled deeply cigarette fumes (OR=5.20, 95%CI=2.94-9.18) than for those who never inhaled (OR=3.76, 95%CI=1.57-8.96) or inhaled a little (OR=3.53, 95%CI=1.85-6.75) (data not shown). Cigarette without filters (2.5%), hand-rolled cigarettes (2.8%), pipe (5.0%) and cigars (3.6%) were uncommon in our study population and were not associated with the risk
of HNSCC (data not shown). It should be noted that all cigar smokers and all pipe smokers
but one case had also smoked cigarettes. No subject had chewed tobacco and only one case
had snuffed.

We observed a significant inverse association for those persons who drank less than one glass per day in relation to HNSCC, when compared to non-drinkers. On the other hand, we found that drinking more than 5 glasses of alcohol per day increases the risk of HNSCC by two fold.
We observed as well an increase, although not significant, in HNSCC risk for person who drank between 1 and 5 glasses per day.

Rum was the most frequently consumed alcoholic beverage in our study population regardless of case-control status. The daily consumption of rum and beer increased the risk significantly by two fold compared to the persons who never drank rum or beer daily. In contrast, daily consumption of wine and other strong spirits did not increase the risk significantly compared to non-daily drinkers.

In terms of oral HPV infections, no significant association with HNSCC was found for
persons tested positive for HPV when compared to HPV-negative subjects. Non-high-risk
HPV types as well did not show any significant difference in risk to HPV-negative subjects.
On the other hand, subjects positive for Hr-HPV types were twice as likely to develop
HNSCC compared to Hr-HPV-negative subjects.

We analysed tobacco, alcohol and oral HPV risk among oropharyngeal and non-
oropharyngeal subsites separately; these results did not change in terms of direction of the
association observed in the analyses with all HNSCC cases (data not shown).

Joint effect of risk factors and HNSCC risk

Table 3 shows the multivariate ORs, their 95% CIs, and measures of two-way interaction for combined exposures to risk factors, for HNSCC and by subsite. Compared to never smokers and non-drinkers, never smokers who drank alcohol daily had a non-significant increase in
HNSCC risk (OR=2.01, 95%CI=0.87-4.61) whereas smokers who did not drink alcohol were 3 times more likely to have HNSCC (OR=3.57, 95%CI=1.89-6.74). The joint effect of tobacco and alcohol was more than multiplicative but not significant for HNSCC (Ψ=2.01, 95%CI=0.75-5.37). However, a significant interaction was observed on the additive scale for tobacco and alcohol (RERI=9.82, 95%CI=3.06 to 16.57). Never smokers positive for Hr-HPV were significantly more likely to have HNSCC when compared with Hr-HPV-negative never smokers (OR=4.74, 95%CI=1.45-15.50). Moreover, Hr-HPV-negative ever smokers had an even greater risk of HNSCC (OR=6.30, 95%CI=3.44-11.52). Negative interactions, although not significant, between Hr-HPV and smoking were observed on both the multiplicative (Ψ=0.30, 95%CI=0.07-1.24) and the additive scale (RERI=-1.07, 95%CI=-8.28 to 6.15). Hr-HPV-positive non-drinkers and Hr-HPV-Negative drinkers were both significantly more likely to have HNSCC than Hr-HPV-negative non-drinkers. The joint effect of alcohol and Hr-HPV on HNSCC risk was less than additive (RERI=-3.30, 95%CI=-8.01 to 1.42) and significantly less than multiplicative (Ψ=0.24, 95%CI=0.06-0.99). Negative interactions involving oral Hr-HPV were consistently more marked for alcohol than tobacco. We also performed the above interaction analyses on oropharyngeal and non-oropharyngeal squamous cell carcinomas separately. Although the difference in effect size and trends did not differ significantly between subsites, the effect of all the studied risk factors appeared to be of greater magnitude for the oropharynx than the non-oropharynx cases. In particular, oral Hr-HPV in never smokers and in non-drinkers was found to be significant for only oropharyngeal cancer

Table 4 shows the associations for combined exposures to tobacco smoking and alcohol drinking, stratified by Hr-HPV status. In the Hr-HPV-negative subgroup, the trend was similar to the effect sizes and the measures of interaction for all study participants together.
The Hr-HPV-Positive subgroup on the other hand had overall lower effect sizes for the tobacco-alcohol profiles compared to their Hr-HPV-negative counterparts.

Discussion

Our findings provide new insight on the role of tobacco, alcohol and oral HPV infection and their combined effects on the occurrence of HNSCC in the FWI.

Similarly, to other studies, we found that the risk of HNSCC increased with the duration and intensity of smoking, and the duration had a greater effect than the average number of cigarettes/day [3,23]. Rum was found to be the beverage which conferred the greatest risk of HNSCC compared to other alcoholic beverages. This observed association for rum is likely to result from it being the most frequently consumed alcoholic beverage in the FWI rather than an independent effect of the alcohol concentration [24]. The inverse association we found for light alcohol drinking (<1 glass/day) was consistent with a French study [25]; however, a recent meta-analysis reported pooled estimates that suggested rather a non-significant positive association between light alcohol drinking and head and neck cancer [26]. Although not significant we observed a more than multiplicative effect of the combined of exposure to tobacco and alcohol on HNSCC risk which was of similar magnitude to a study conducted within the INHANCE Consortium [2]. The few studies assessing the additive interaction for tobacco and alcohol conducted their analysis in individual HNSCC subsites and reported super-additive interactions of varying degrees [27–29].

Oral Hr-HPV infections were significantly associated with HNSCC, regardless of Hr-HPV genotype. A study conducted in Canada did not find any significant association with HNSCC and Hr-HPV types excluding HPV16 [10]. In our study, only four cases and two controls were positive for HPV16, and the effect of Hr-HPV on HNSCC was maintained after removing HPV16-positive subjects. These results could be suggestive of a greater role of non-
HPV16 high risk types in HNSCC carcinogenesis in the FWI compared to other populations, as also suggested for cervical infections [30].

Concerning the joint effect of tobacco and HPV, and alcohol and HPV, we found some evidence of a negative interaction on both the additive and multiplicative scale. In particular, the combined effect of alcohol and HPV was significantly less than multiplicative. In other words, the effect of tobacco, alcohol and of the combined exposure of tobacco and alcohol were substantially lower in HPV-positive than in HPV-negative HNSCC, which is indicative of a more pre-dominant role of tobacco and alcohol in HPV-negative HNSCC as described in previous studies which investigated HPV16 specifically [5,7,8]. In contrast, other studies found that tobacco and alcohol increased the risk of both HPV-positive and HPV-negative HNSCC [11,31,32].

Analyses by subsite did not reveal important differences with regards to the effects of tobacco and alcohol; although point estimates were higher in oropharyngeal cancer than in non- oropharyngeal cancer, the confidence intervals were wide and the effect of traditional risk factors was similar in both subsites, as previously shown [9].

Our data on the joint effect of tobacco, alcohol and Hr-HPV on the occurrence of oropharyngeal cancer were supported by previous reports [9,10]. We found that Hr-HPV was associated with a significant increase in risk of oropharyngeal cancer in never smokers and in non-drinkers. These significant associations were not present in the non-oropharyngeal cases. In addition, the measures of interaction for the joint exposure with each of the risk factors and oral Hr-HPV-Positive infections were more marked in the oropharyngeal cases than the non- oropharyngeal cases. Furthermore, the significant sub-multiplicative interaction between alcohol and Hr-HPV was observed exclusively in the oropharynx. These observations support an aetiological role of oral Hr-HPV specific to oropharyngeal cancer, as in previous studies [7,8,31,32]. We demonstrated that alcohol alone did not play a role in Hr-HPV-positive
oropharyngeal cancer as described previously [9,10]. On the other hand, our results did not provide strong evidence for a role of tobacco in oropharyngeal carcinogenesis regardless of HPV status, contrarily to a recent study which emphasised the existence of a positive association in HPV16-related oropharyngeal cancer [9].

Our study presents some limitations. We had a relatively small sample size which limited the detail in our analyses. In particular, we were not able to assess three-way interactions by subsite as we would have liked with tobacco, alcohol and Hr-HPV. We had 27% missing data for HPV in our sample. To handle missing data, we used a multiple imputation procedure that has been shown to result in less biased and more precise estimates than the exclusion of individuals with missing data [22]. The case-control design coupled with the lack of temporal sequence in HPV data made it difficult to put forward a more precise mechanism between the risk factors and HPV in HNSCC risk. We had very few subjects infected with HPV16, which made comparisons with other studies difficult [7–10]. Furthermore, the use of oral HPV detection to assess the HPV status may have resulted in misclassification, which is however likely to be non-differential. Oral HPV detection has been shown to have good specificity but moderate sensitivity for HPV-positive HNSCC tumours [33]. Despite the limitations imposed by oral HPV detection, this method is indicative of the site of infections compared to HPV serology which is not site-specific.

Selection bias may not be excluded but is thought to be minimal in the present study. The distribution by sex, age and cancer sites of the cases included in our study was similar to that of the cases in the local cancer registries. Our study population can thus be considered representative of the HNSCC cases. The method used to select the control group was previously demonstrated to yield unbiased samples and the controls could be considered representative of the general population of similar age and sex [20]. We confirmed the
representativeness of the tobacco and alcohol distribution in our control group to FWI population after comparison with the data from a national health survey [12].

**Conclusion**

This is the first case-control study to investigate the role of tobacco smoking, alcohol drinking and oral HPV infection in an Afro-Caribbean population. Overall, we showed that these risk factors have significant independent effects on the occurrence of HNSCC. our findings suggest a less important role of tobacco and alcohol in Hr-HPV-positive HNSCC. The precise mechanisms driving these interactions on HNSCC risk are yet to be elucidated and further investigations are warranted notably on the interaction of these three risk factors simultaneously.
References

[1] J Ferlay, Ervik M, Lam F, Soerjomataram I, Bray F, Colombet M, et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. International Agency for Research on Cancer 2018. https://gco.iarc.fr/today (accessed August 5, 2019).

[2] Hashibe M, Brennan P, Chuang S-C, Boccia S, Castellsague X, Chen C, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev 2009;18:541–50. doi:10.1158/1055-9965.EPI-08-0347.

[3] Di Credico G, Edefonti V, Polesel J, Pauli F, Torelli N, Serraino D, et al. Joint effects of intensity and duration of cigarette smoking on the risk of head and neck cancer: A bivariate spline model approach. Oral Oncol 2019;94:47–57. doi:10.1016/j.oraloncology.2019.05.006.

[4] Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, et al. Evidence for a Causal Association Between Human Papillomavirus and a Subset of Head and Neck Cancers. JNCI J Natl Cancer Inst 2000;92:709–20. doi:10.1093/jnci/92.9.709.

[5] D'Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356:1944–56. doi:10.1056/NEJMoa065497.

[6] Gillison ML, Alemany L, Snijders PJF, Chaturvedi A, Steinberg BM, Schwartz S, et al. Human Papillomavirus and Diseases of the Upper Airway: Head and Neck Cancer and Respiratory Papillomatosis. Vaccine 2012;30:F34–54. doi:10.1016/j.vaccine.2012.05.070.

[7] Gillison ML, D'Souza G, Westra W, Sugar E, Xiao W, Begum S, et al. Distinct Risk Factor Profiles for Human Papillomavirus Type 16-Positive and Human Papillomavirus Type 16-Negative Head and Neck Cancers. J Natl Cancer Inst 2008;100:407–20. doi:10.1093/jnci/djn025.
[8] Applebaum KM, Furniss CS, Zeka A, Posner MR, Smith JF, Bryan J, et al. Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. J Natl Cancer Inst 2007;99:1801-10. doi:10.1093/jnci/djm233.

[9] Anantharaman D, Muller DC, Lagiou P, Ahrens W, Holcátová I, Merletti F, et al. Combined effects of smoking and HPV16 in oropharyngeal cancer. Int J Epidemiol 2016;45:752-61. doi:10.1093/ije/dyw069.

[10] Farsi NJ, Rousseau M-C, Schlecht N, Castonguay G, Allison P, Nguyen-Tan PF, et al. Aetiological heterogeneity of head and neck squamous cell carcinomas: the role of human papillomavirus infections, smoking and alcohol. Carcinogenesis 2017;38:1188-95. doi:10.1093/carcin/bgx106.

[11] Smith EM, Rubenstein LM, Haugen TH, Hamsikova E, Turek LP. Tobacco and alcohol use increases the risk of both HPV-associated and HPV-independent head and neck cancers. Cancer Causes Control 2010;21:1369-78. doi:10.1007/s10552-010-9564-z.

[12] Richard J-B. Premiers résultats du Baromètre Santé DOM 2014- Résultats détaillés selon mle DOM, l'âge et le sexe. Saint-Maurice (Fra): Santé publique France; 2015.

[13] Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review. Cancer Epidemiol Biomarkers Prev 2005;14:467-75. doi:10.1158/1055-9965.EPI-04-0551.

[14] Termine N, Panzarella V, Falaschini S, Russo A, Matranga D, Lo Muzio L, et al. HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988-2007). Ann Oncol 2008;19:1681-90. doi:10.1093/annonc/mdn372.

[15] Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer—systematic review and meta-analysis of trends by time and region. Head Neck 2013;35:747-55. doi:10.1002/hed.22015.
[16] Ndiaye C, Mena M, Alemany L, Arbyn M, Castellsagué X, Laporte L, et al. HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. The Lancet Oncology 2014;15:1319–31. doi:10.1016/S1470-2045(14)70471-1.

[17] Ragin C, Liu JC, Jones G, Shoyele O, Sowunmi B, Kennett R, et al. Prevalence of HPV infection in racial-ethnic subgroups of head and neck cancer patients. Carcinogenesis 2017;38:218–29. doi:10.1093/carcin/bgw203.

[18] Voltzke KJ, Lee Y-CA, Zhang Z-F, Zevallos JP, Yu G-P, Winn DM, et al. Racial differences in the relationship between tobacco, alcohol, and the risk of head and neck cancer: Pooled analysis of US studies in the INHANCE Consortium. Cancer Causes Control 2018;29:619–30. doi:10.1007/s10552-018-1026-z.

[19] Auguste A, Gaëte S, Herrmann-Storck C, Michineau L, Joachim C, Deloumeaux J, et al. Prevalence of oral HPV infection among healthy individuals and head and neck cancer cases in the French West Indies. Cancer Causes Control 2017;28:1333–40. doi:10.1007/s10552-017-0966-z.

[20] Luce D, Stücker I, ICARE Study Group. Investigation of occupational and environmental causes of respiratory cancers (ICARE): a multicenter, population-based case-control study in France. BMC Public Health 2011;11:928. doi:10.1186/1471-2458-11-928.

[21] VanderWeele TJ, Knol MJ. A Tutorial on Interaction. Epidemiologic Methods 2014;3:33–72. doi:10.1515/em-2013-0005.

[22] Azur MJ, Stuart EA, Frangakis C, Leaf PJ. Multiple imputation by chained equations: what is it and how does it work? Int J Methods Psychiatr Res 2011;20:40–9. doi:10.1002/mpr.329.
[23] Lubin JH, Purdue M, Kelsey K, Zhang Z-F, Winn D, Wei Q, et al. Total exposure and exposure rate effects for alcohol and smoking and risk of head and neck cancer: a pooled analysis of case-control studies. Am J Epidemiol 2009;170:937-47. doi:10.1093/aje/kwp222.

[24] Kawakita D, Matsuo K. Alcohol and head and neck cancer. Cancer Metastasis Rev 2017;36:425-34. doi:10.1007/s10555-017-9690-0.

[25] Radoï L, Paget-Bailly S, Cyr D, Papadopoulos A, Guida F, Schmaus A, et al. Tobacco smoking, alcohol drinking and risk of oral cavity cancer by subsite: results of a French population-based case-control study, the ICARE study. Eur J Cancer Prev 2013;22:268-76. doi:10.1097/CEJ.0b013e3283592cce.

[26] Choi Y-J, Myung S-K, Lee J-H. Light Alcohol Drinking and Risk of Cancer: A Meta-Analysis of Cohort Studies. Cancer Res Treat 2018;50:474-87. doi:10.4143/crt.2017.094.

[27] Menvielle G, Fayossé A, Radoï L, Guida F, Sanchez M, Carton M, et al. The joint effect of asbestos exposure, tobacco smoking and alcohol drinking on laryngeal cancer risk: evidence from the French population-based case-control study, ICARE. Occup Environ Med 2016;73:28-33. doi:10.1136/oemed-2015-102954.

[28] Petti S, Masood M, Scully C. The Magnitude of Tobacco Smoking-Betel Quid Chewing-Alcohol Drinking Interaction Effect on Oral Cancer in South-East Asia. A Meta-Analysis of Observational Studies. PLoS One 2013;8. doi:10.1371/journal.pone.0078999.

[29] Chen F, He B-C, Yan L-J, Liu F-P, Huang J-F, Hu Z-J, et al. Tea consumption and its interactions with tobacco smoking and alcohol drinking on oral cancer in southeast China. Eur J Clin Nutr 2017;71:481-5. doi:10.1038/ejcn.2016.208.

[30] Cordel N, Ragin C, Trival M, Tressières B, Janky E. High-risk human papillomavirus cervical infections among healthy women in Guadeloupe. International Journal of Infectious Diseases 2015;41:13-6. doi:10.1016/j.ijid.2015.10.012.
[31] Smith EM, Ritchie JM, Summersgill KF, Hoffman HT, Wang DH, Haugen TH, et al. Human Papillomavirus in Oral Exfoliated Cells and Risk of Head and Neck Cancer. JNCI Journal of the National Cancer Institute 2004;96:449-55. doi:10.1093/jnci/djh074.

[32] Herrero R, Castellsagué X, Pawlita M, Lissowska J, Kee F, Balaram P, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003;95:1772-83. doi:10.1093/jnci/djg107.

[33] Gipson BJ, Robbins HA, Fakhry C, D'Souza G. Sensitivity and specificity of oral HPV detection for HPV-positive head and neck cancer. Oral Oncol 2018;77:52-6. doi:10.1016/j.oraloncology.2017.12.008.
<table><caption>**Table 1:** Socio-demographic characteristics of HNSCC cases and controls</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Cases</th><th colspan="2">Controls</th></tr><tr><th>n=145</th><th>col%</th><th>n=405</th><th>col%</th></tr></thead><tbody><tr><td><strong>Age (years)</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;45</td><td>3</td><td>(2.1)</td><td>62</td><td>(15.3)</td></tr><tr><td>45-54</td><td>40</td><td>(27.6)</td><td>107</td><td>(26.4)</td></tr><tr><td>55-64</td><td>61</td><td>(42.1)</td><td>129</td><td>(31.9)</td></tr><tr><td>&gt;65</td><td>41</td><td>(28.3)</td><td>107</td><td>(26.4)</td></tr><tr><td><strong>Sex</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Women</td><td>18</td><td>(12.4)</td><td>99</td><td>(24.4)</td></tr><tr><td>Men</td><td>127</td><td>(87.6)</td><td>306</td><td>(75.6)</td></tr><tr><td><strong>Recruitment site</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Guadeloupe</td><td>95</td><td>(65.5)</td><td>245</td><td>(60.5)</td></tr><tr><td>Martinique</td><td>50</td><td>(34.5)</td><td>160</td><td>(39.5)</td></tr><tr><td><strong>Education level</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Primary school</td><td>62</td><td>(42.8)</td><td>94</td><td>(23.2)</td></tr><tr><td>Secondary school</td><td>51</td><td>(35.2)</td><td>161</td><td>(39.8)</td></tr><tr><td>High school diploma</td><td>17</td><td>(11.7)</td><td>53</td><td>(13.0)</td></tr><tr><td>Tertiary education</td><td>15</td><td>(10.3)</td><td>97</td><td>(24.0)</td></tr></tbody></table>

French West Indies, 2013-2016
<table><caption>**Table 2:** Multivariate OR of HNSCC and 95% CI associated with tobacco smoking, alcohol drinking, oral HPV infection and HNSCC.</caption><thead><tr><th>Risk factor</th><th>Cases<br>n=145</th><th>col%</th><th>Controls<br>n=405</th><th>col%</th><th>OR<sup>†</sup></th><th>95%CI</th></tr></thead><tbody><tr><td><strong>Tobacco smoking<sup>a</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never smoker</td><td>30</td><td>(21.8)</td><td>263</td><td>(64.9)</td><td>1</td><td>ref</td></tr><tr><td><strong>Smoking status</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Current smoker</td><td>88</td><td>(61.1)</td><td>52</td><td>(12.8)</td><td>11.59</td><td>(6.69-20.08)</td></tr><tr><td>Former smoker</td><td>26</td><td>(18.1)</td><td>90</td><td>(22.2)</td><td>2.28</td><td>(1.24-4.17)</td></tr><tr><td>Missing</td><td>1</td><td></td><td>0</td><td></td><td></td><td></td></tr><tr><td><strong>Quantity (cigarette/day)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 to 10</td><td>35</td><td>(27.8)</td><td>71</td><td>(17.7)</td><td>4.17</td><td>(2.33-7.46)</td></tr><tr><td>11 to 20</td><td>35</td><td>(27.8)</td><td>51</td><td>(12.7)</td><td>6.11</td><td>(3.39-11.04)</td></tr><tr><td>>20</td><td>26</td><td>(20.6)</td><td>17</td><td>(4.2)</td><td>10.69</td><td>(4.89-23.41)</td></tr><tr><td>Missing</td><td>19</td><td></td><td>3</td><td></td><td></td><td></td></tr><tr><td><strong>Duration (years)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 to 20</td><td>9</td><td>(6.5)</td><td>57</td><td>(14.1)</td><td>1.43</td><td>(0.64-3.23)</td></tr><tr><td>21 to 30</td><td>17</td><td>(12.2)</td><td>37</td><td>(9.2)</td><td>3.94</td><td>(1.92-8.07)</td></tr><tr><td>31 to 40</td><td>42</td><td>(30.2)</td><td>23</td><td>(5.7)</td><td>12.25</td><td>(6.16-24.37)</td></tr><tr><td>> 40</td><td>41</td><td>(29.5)</td><td>24</td><td>(5.9)</td><td>13.28</td><td>(6.61-26.68)</td></tr><tr><td>Missing</td><td>6</td><td></td><td>1</td><td></td><td></td><td></td></tr><tr><td><strong>&le; 20 cigarettes/day</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>during &le; 30 years</td><td>16</td><td>(12.8)</td><td>84</td><td>(21.0)</td><td>2.00</td><td>(1.05-3.81)</td></tr><tr><td>during &gt;30 years</td><td>53</td><td>(42.4)</td><td>37</td><td>(9.2)</td><td>12.19</td><td>(6.68-22.24)</td></tr><tr><td><strong>&gt; 20 cigarettes/day</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>during &le; 30 years</td><td>6</td><td>(4.8)</td><td>7</td><td>(1.8)</td><td>7.10</td><td>(2.13-23.70)</td></tr><tr><td>during &gt; 30 years</td><td>20</td><td>(16.0)</td><td>10</td><td>(2.5)</td><td>15.38</td><td>(6.03-39.19)</td></tr><tr><td>Missing</td><td>20</td><td></td><td>4</td><td></td><td></td><td></td></tr><tr><td><strong>Alcohol quantity<sup>b</sup> (glasses/day)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never or occasionally</td><td>51</td><td>(35.2)</td><td>216</td><td>(53.9)</td><td>1</td><td>ref</td></tr><tr><td>&lt;1 glass/day</td><td>8</td><td>(5.5)</td><td>73</td><td>(18.2)</td><td>0.40</td><td>(0.17-0.93)</td></tr><tr><td>1 to 5 glasses/day</td><td>45</td><td>(31.0)</td><td>84</td><td>(21.0)</td><td>1.24</td><td>(0.70-2.20)</td></tr><tr><td>>5 glasses/days</td><td>41</td><td>(28.3)</td><td>28</td><td>(7.0)</td><td>2.36</td><td>(1.18-4.73)</td></tr><tr><td>Missing</td><td>0</td><td></td><td>4</td><td></td><td></td><td></td></tr><tr><td><strong>Type of beverage (daily drinking)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Wine</td><td>38</td><td>(26.2)</td><td>54</td><td>(13.3)</td><td>1.35</td><td>(0.76-2.39)</td></tr><tr><td>Beer</td><td>34</td><td>(23.5)</td><td>35</td><td>(8.6)</td><td>1.83</td><td>(0.98-3.42)</td></tr><tr><td>Rum</td><td>75</td><td>(51.7)</td><td>61</td><td>(15.1)</td><td>2.90</td><td>(1.74-4.84)</td></tr><tr><td>Other strong spirits</td><td>13</td><td>(9.0)</td><td>12</td><td>(3.0)</td><td>1.82</td><td>(0.68-4.89)</td></tr><tr><td><strong>Oral HPV status<sup>c</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HPV-Negative</td><td>60</td><td>(65.2)</td><td>228</td><td>(73.9)</td><td></td><td>ref</td></tr><tr><td>Any HPV</td><td>32</td><td>(34.8)</td><td>80</td><td>(26.1)</td><td>1.44</td><td>(0.82-2.53)</td></tr><tr><td>HPV-Non-high risk</td><td>13</td><td>(14.1)</td><td>50</td><td>(16.3)</td><td>0.80</td><td>(0.35-1.83)</td></tr></tbody></table>
<table><tr><td>HPV-High risk</td><td>19</td><td>(20.7)</td><td>30</td><td>(9.8)</td><td>2.37</td><td>(1.13-4.97)</td></tr><tr><td>Missing</td><td>53</td><td></td><td>97</td><td></td><td></td><td></td></tr></table>

French West Indies, 2013-2016

a: Model adjusted for age, sex, recruitment site, alcohol consumption (glasses/day)

b: Model adjusted for age, sex, recruitment site, tobacco smoking as the combination of quantity (cigarettes/day) and duration (years)

c: Model adjusted for age, sex, recruitment site, tobacco smoking status, alcohol consumption (glasses/day)
<table><caption>**Table 3:** Multivariate OR, their 95% CI, and measures of two-way interactions between risk factors for HNSCC, and by subsite.</caption><thead><tr><th rowspan="2">Risk factor combinations</th><th colspan="2">All cases</th><th colspan="2">Oropharynx</th><th colspan="2">Non-Oropharynx</th></tr><tr><th>OR</th><th>(95%CI)</th><th>OR</th><th>(95%CI)</th><th>OR</th><th>(95%CI)</th></tr></thead><tbody><tr><td colspan="7"><strong>Smoking and Alcohol<sup>a</sup></strong></td></tr><tr><td>Never Smoker-Non Drinker</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td></tr><tr><td>Never Smoker-Drinker</td><td>2.01</td><td>(0.87-4.61)</td><td>2.81</td><td>(0.75-10.48)</td><td>1.79</td><td>(0.64-5.01)</td></tr><tr><td>Ever smoker-Non drinker</td><td>3.57</td><td>(1.89-6.74)</td><td>5.59</td><td>(2.06-15.20)</td><td>2.75</td><td>(1.24-6.11)</td></tr><tr><td>Ever Smoker-Drinker</td><td>14.39</td><td>(8.02-25.82)</td><td>19.37</td><td>(7.56-49.61)</td><td>13.23</td><td>(6.62-26.45)</td></tr><tr><td>Ψ (95%CI)</td><td>2.01</td><td>(0.75-5.37)</td><td>1.23</td><td>(0.28-5.67)</td><td>2.69</td><td>(0.80-9.11)</td></tr><tr><td>RERI (95% CI)</td><td>9.82</td><td>(3.06 to 16.57)</td><td>11.96</td><td>(-1.32 to 25.24)</td><td>9.69</td><td>(2.25 to 17.13)</td></tr><tr><td colspan="7"><strong>Smoking and Hr-HPV<sup>b</sup></strong></td></tr><tr><td>Never Smoker-Hr-HPV-</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td></tr><tr><td>Never Smoker-Hr-HPV+</td><td>4.74</td><td>(1.45-15.50)</td><td>5.23</td><td>(1.10-24.86)</td><td>3.26</td><td>(0.64-16.60)</td></tr><tr><td>Ever smoker-Hr-HPV-</td><td>6.30</td><td>(3.44-11.52)</td><td>8.82</td><td>(3.47-22.38)</td><td>5.11</td><td>(2.46-10.61)</td></tr><tr><td>Ever Smoker-Hr-HPV+</td><td>8.98</td><td>(3.85-20.94)</td><td>10.09</td><td>(2.94-34.56)</td><td>7.53</td><td>(2.77-20.43)</td></tr><tr><td>Ψ (95%CI)</td><td>0.30</td><td>(0.07-1.24)</td><td>0.22</td><td>(0.03-1.38)</td><td>0.45</td><td>(0.07-2.94)</td></tr><tr><td>RERI (95% CI)</td><td>-1.07</td><td>(-8.28 to 6.15)</td><td>-2.97</td><td>(-14.35 to 8.42)</td><td>0.16</td><td>(-6.67 to 6.99)</td></tr><tr><td colspan="7"><strong>Alcohol and Hr-HPV<sup>c</sup></strong></td></tr><tr><td>Non Drinker-Hr-HPV-</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td></tr><tr><td>Non Drinker-Hr-HPV+</td><td>4.43</td><td>(1.50-13.11)</td><td>4.76</td><td>(1.31-17.32)</td><td>3.39</td><td>(0.69-16.78)</td></tr><tr><td>Drinker-Hr-HPV-</td><td>3.20</td><td>(1.76-5.82)</td><td>3.85</td><td>(1.65-8.97)</td><td>3.06</td><td>(1.47-6.39)</td></tr><tr><td>Drinker-Hr-HPV+</td><td>3.33</td><td>(1.27-8.73)</td><td>2.40</td><td>(0.62-9.30)</td><td>3.70</td><td>(1.24-11.09)</td></tr><tr><td>Ψ (95%CI)</td><td>0.24</td><td>(0.06-0.99)</td><td>0.13</td><td>(0.02-0.80)</td><td>0.36</td><td>(0.05-2.40)</td></tr><tr><td>RERI (95% CI)</td><td>-3.30</td><td>(-8.01 to 1.42)</td><td>-5.21</td><td>(-11.93 to 1.52)</td><td>-1.75</td><td>(-6.93 to 3.43)</td></tr></tbody></table>

French West Indies, 2013-2016

a: Model adjusted for age, sex, recruitment site

b: Model adjusted for age, sex, recruitment site and ever daily alcohol consumption

c: Model adjusted for age, sex, recruitment site, tobacco smoking as the combination of quantity (cigarettes/day) and duration (years)

Ψ: Phi, measure of interaction on a multiplicative scale (interaction term)

RERI: Relative Excess Risk due to Interaction
<table><caption>**Table 4:** Multivariate OR, their 95% CI, and measures of two-way interaction of combined exposure to tobacco smoking and alcohol drinking on HNSCC risk stratified by Hr-HPV status.</caption><thead><tr><th rowspan="2">Risk factor combinations</th><th colspan="2">HPV-Hr-Negative</th><th colspan="2">HPV-Hr-Positive</th></tr><tr><th>OR</th><th>95% CI</th><th>OR</th><th>95% CI</th></tr></thead><tbody><tr><td><strong>Smoking and Alcohol<sup>a</sup></strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Never Smoker -Non Drinker</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td></tr><tr><td>Never Smoker -Drinker</td><td>3.09</td><td>(1.03-9.22)</td><td>0.56</td><td>(0.05-6.72)</td></tr><tr><td>Ever smoker- Non drinker</td><td>4.89</td><td>(1.99-12.03)</td><td>1.41</td><td>(0.27-7.32)</td></tr><tr><td>Ever Smoker- Drinker</td><td>23.43</td><td>(10.11-54.30)</td><td>3.57</td><td>(0.88-14.48)</td></tr><tr><td>Ψ (95%CI)</td><td>1.55</td><td>(0.43-5.58)</td><td>4.52</td><td>(0.21-97.84)</td></tr><tr><td>RERI (95% CI)</td><td>16.45</td><td>(1.76 to 31.16)</td><td>2.59</td><td>(-1.65 to 6.84)</td></tr></tbody></table>

French West Indies, 2013-2016

a: Model adjusted for age, sex, recruitment site

Ψ: multiplicative interaction parameter

RERI: Relative Excess Risk due to Interaction
## Supplementary Materials

Multivariate logistic regression analyses performed on observed data

<table><caption>**Supplementary table 1:** Multivariate OR of HNSCC and 95%CI associated with tobacco smoking, alcohol drinking and oral (observed data).</caption><thead><tr><th rowspan="2">Risk factor</th><th colspan="2">Cases</th><th colspan="2">Controls</th><th rowspan="2">OR<sup>†</sup></th><th rowspan="2">95%CI</th></tr><tr><th>n=145</th><th>col%</th><th>n=405</th><th>col%</th></tr></thead><tbody><tr><td><strong>Tobacco smoking<sup>a</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never smoker</td><td>30</td><td>(21.8)</td><td>263</td><td>(64.9)</td><td>1</td><td>ref</td></tr><tr><td><strong>Smoking status</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Current smoker</td><td>88</td><td>(61.1)</td><td>52</td><td>(12.8)</td><td>9.04</td><td>(5.13-15.92)</td></tr><tr><td>Former smoker</td><td>26</td><td>(18.1)</td><td>90</td><td>(22.2)</td><td>1.97</td><td>(1.05-3.68)</td></tr><tr><td>Missing</td><td>1</td><td></td><td>0</td><td></td><td></td><td></td></tr><tr><td><strong>Quantity (cigarette/day)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 to 10</td><td>35</td><td>(27.8)</td><td>71</td><td>(17.7)</td><td>3.63</td><td>(2.01-6.57)</td></tr><tr><td>11 to 20</td><td>35</td><td>(27.8)</td><td>51</td><td>(12.7)</td><td>4.71</td><td>(2.56-11.04)</td></tr><tr><td>>20</td><td>26</td><td>(20.6)</td><td>17</td><td>(4.2)</td><td>7.79</td><td>(3.58-16.95)</td></tr><tr><td>Missing</td><td>19</td><td></td><td>3</td><td></td><td></td><td></td></tr><tr><td><strong>Duration (years)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 to 20</td><td>9</td><td>(6.5)</td><td>57</td><td>(14.1)</td><td>1.06</td><td>(0.43-2.59)</td></tr><tr><td>21 to 30</td><td>17</td><td>(12.2)</td><td>37</td><td>(9.2)</td><td>3.19</td><td>(1.51-6.76)</td></tr><tr><td>31 to 40</td><td>42</td><td>(30.2)</td><td>23</td><td>(5.7)</td><td>8.89</td><td>(4.39-18.04)</td></tr><tr><td>> 40</td><td>41</td><td>(29.5)</td><td>24</td><td>(5.9)</td><td>10.84</td><td>(5.33-22.05)</td></tr><tr><td>Missing</td><td>6</td><td></td><td>1</td><td></td><td></td><td></td></tr><tr><td><strong>≤ 20 cigarettes/day</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>during ≤ 30 years</td><td>16</td><td>(12.8)</td><td>84</td><td>(21.0)</td><td>1.56</td><td>(0.79-3.09)</td></tr><tr><td>during >30 years</td><td>53</td><td>(42.4)</td><td>37</td><td>(9.2)</td><td>9.76</td><td>(5.29-18.02)</td></tr><tr><td><strong>> 20 cigarettes/day</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>during ≤ 30 years</td><td>6</td><td>(4.8)</td><td>7</td><td>(1.8)</td><td>6.03</td><td>(1.80-20.23)</td></tr><tr><td>during > 30 years</td><td>20</td><td>(16.0)</td><td>10</td><td>(2.5)</td><td>10.27</td><td>(4.10-25.71)</td></tr><tr><td>Missing</td><td>20</td><td></td><td>4</td><td></td><td></td><td></td></tr><tr><td><strong>Alcohol quantity (glasses/day)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never or occasionally</td><td>51</td><td>(35.2)</td><td>216</td><td>(53.9)</td><td>1</td><td>ref</td></tr><tr><td>&lt;1 glass/day or &lt;7 glasses/week</td><td>8</td><td>(5.5)</td><td>73</td><td>(18.2)</td><td>0.50</td><td>(0.21-1.19)</td></tr><tr><td>1 to 5 glasses/day</td><td>45</td><td>(31.0)</td><td>84</td><td>(21.0)</td><td>1.61</td><td>(0.88-2.96)</td></tr><tr><td>>5 glasses/days</td><td>41</td><td>(28.3)</td><td>28</td><td>(7.0)</td><td>2.50</td><td>(1.18-5.29)</td></tr><tr><td>Missing</td><td>0</td><td></td><td>4</td><td></td><td></td><td></td></tr><tr><td><strong>Type of beverage (daily drinking)<sup>b</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Wine</td><td>38</td><td>(26.2)</td><td>54</td><td>(13.3)</td><td>1.43</td><td>(0.78-2.64)</td></tr><tr><td>Beer</td><td>34</td><td>(23.5)</td><td>35</td><td>(8.6)</td><td>2.02</td><td>(1.06-3.83)</td></tr><tr><td>Rum</td><td>75</td><td>(51.7)</td><td>61</td><td>(15.1)</td><td>3.01</td><td>(1.76-5.17)</td></tr><tr><td>Other strong spirits</td><td>13</td><td>(9.0)</td><td>12</td><td>(3.0)</td><td>1.73</td><td>(0.64-4.70)</td></tr><tr><td><strong>Oral HPV Status<sup>c</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HPV-Negative</td><td>60</td><td>(65.2)</td><td>228</td><td>(73.9)</td><td>ref</td><td></td></tr></tbody></table>
<table><tr><td>Any HPV</td><td>32</td><td>(34.8)</td><td>80</td><td>(26.1)</td><td>1.23</td><td>(0.66-2.30)</td></tr><tr><td>HPV-Non-high risk</td><td>13</td><td>(14.1)</td><td>50</td><td>(16.3)</td><td>0.74</td><td>(0.33-1.70)</td></tr><tr><td>HPV-High risk</td><td>19</td><td>(20.7)</td><td>30</td><td>(9.8)</td><td>2.10</td><td>(0.95-4.88)</td></tr><tr><td>Missing</td><td>53</td><td></td><td>97</td><td></td><td></td><td></td></tr></table>

French West Indies, 2013-2016

a: Model adjusted for age, sex, recruitment site, alcohol consumption (glasses/day)

b: Model adjusted for age, sex, recruitment site, Tobacco smoking as the combination of quantity (cigarettes/day) and duration (years)

c: Model adjusted for age, sex, recruitment site, Tobacco smoking status, alcohol consumption (glasses/day)
<table><caption>**Supplementary table 2:** Multivariate ORs, their 95% CI, and measures of two-way interactions between risk factors for HNSCC, and by subsite (observed data).</caption><thead><tr><th rowspan="2">Risk factor combinations</th><th colspan="2">All cases</th><th colspan="2">Oropharynx</th><th colspan="2">Non-Oropharynx</th></tr><tr><th>OR</th><th>(95%CI)</th><th>OR</th><th>(95%CI)</th><th>OR</th><th>(95%CI)</th></tr></thead><tbody><tr><td colspan="7"><strong>Smoking and Alcohol<sup>a</sup></strong></td></tr><tr><td>Never Smoker-Non Drinker</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td></tr><tr><td>Never Smoker-Drinker</td><td>1.97</td><td>(0.86-4.52)</td><td>2.69</td><td>(0.72-10.05)</td><td>1.79</td><td>(0.64-5.01)</td></tr><tr><td>Ever smoker-Non drinker</td><td>3.57</td><td>(1.89-6.74)</td><td>5.59</td><td>(2.06-15.21)</td><td>2.75</td><td>(1.24-6.11)</td></tr><tr><td>Ever Smoker-Drinker</td><td>14.31</td><td>(7.97-25.68)</td><td>19.13</td><td>(7.46-49.08)</td><td>13.23</td><td>(6.62-26.45)</td></tr><tr><td>Ψ (95%CI)</td><td>2.04</td><td>(0.76-5.45)</td><td>1.27</td><td>(0.29-5.66)</td><td>2.69</td><td>(0.80-9.11)</td></tr><tr><td>RERI (95% CI)</td><td>9.77</td><td>(3.06 to 16.49)</td><td>11.85</td><td>(-1.29 to 25.00)</td><td>9.69</td><td>(2.25 to 17.13)</td></tr><tr><td colspan="7"><strong>Smoking and Hr-HPV<sup>b</sup></strong></td></tr><tr><td>Never Smoker-Hr-HPV-</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td></tr><tr><td>Never Smoker-Hr-HPV+</td><td>7.81</td><td>(2.35-25.88)</td><td>9.86</td><td>(1.86-52.36)</td><td>3.30</td><td>(0.60-18.03)</td></tr><tr><td>Ever smoker-Hr-HPV-</td><td>6.67</td><td>(3.29-13.49)</td><td>9.66</td><td>(3.19-29.23)</td><td>5.22</td><td>(2.22-12.26)</td></tr><tr><td>Ever Smoker-Hr-HPV+</td><td>6.70</td><td>(2.39-18.76)</td><td>7.91</td><td>(1.76-35.64)</td><td>5.53</td><td>(1.66-18.46)</td></tr><tr><td>Ψ (95%CI)</td><td>0.13</td><td>(0.03-0.57)</td><td>0.08</td><td>(0.01-0.64)</td><td>0.32</td><td>(0.05-2.52)</td></tr><tr><td>RERI (95% CI)</td><td>-6.78</td><td>(-17.86 to 4.30)</td><td>-10.61</td><td>(-30.61 to 9.40)</td><td>-1.99</td><td>(-9.88 to 5.91)</td></tr><tr><td colspan="7"><strong>Alcohol and Hr-HPV<sup>c</sup></strong></td></tr><tr><td>Non Drinker-Hr-HPV-</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td></tr><tr><td>Non Drinker-Hr-HPV+</td><td>6.54</td><td>(2.12-20.15)</td><td>7.83</td><td>(1.73-35.38)</td><td>3.03</td><td>(0.55-16.68)</td></tr><tr><td>Drinker-Hr-HPV-</td><td>5.32</td><td>(2.60-10.91)</td><td>7.92</td><td>(2.79-22.52)</td><td>4.30</td><td>(1.78-10.41)</td></tr><tr><td>Drinker-Hr-HPV+</td><td>4.18</td><td>(1.38-12.61)</td><td>4.95</td><td>(1.01-24.40)</td><td>3.40</td><td>(0.96-12.10)</td></tr><tr><td>Ψ (95%CI)</td><td>0.12</td><td>(0.03-0.56)</td><td>0.08</td><td>(0.01-0.60)</td><td>0.26</td><td>(0.05-2.62)</td></tr><tr><td>RERI (95% CI)</td><td>-6.68</td><td>(-15.65 to 2.28)</td><td>-9.80</td><td>(-25.66 to 4.94)</td><td>-2.93</td><td>(-9.89 to 4.04)</td></tr></tbody></table>

French West Indies, 2013-2016

a: Model adjusted for age, sex, recruitment site

b: Model adjusted for age, sex, recruitment site and ever daily alcohol consumption

c: Model adjusted for age, sex, recruitment site, Tobacco smoking as the combination of quantity (cigarettes/day) and duration (years)

Ψ: Phi, measure of interaction on a multiplicative scale (interaction term)

RERI: Relative Excess Risk due to Interaction
<table><caption>**Supplementary table 3:** Multivariate ORs, their 95% CI, and measures of two-way interaction of combined exposures to tobacco smoking and alcohol drinking for HNSCC stratified by Hr-HPV status (observed data).</caption><thead><tr><th rowspan="2">Risk factor combinations</th><th colspan="2">HPV-Hr-Negative</th><th colspan="2">HPV-Hr-Positive</th></tr><tr><th>OR</th><th>95% CI</th><th>OR</th><th>95% CI</th></tr></thead><tbody><tr><td><strong>Smoking and Alcohol<sup>a</sup></strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Never Smoker –Non Drinker</td><td>1</td><td>(ref)</td><td>1</td><td>(ref)</td></tr><tr><td>Never Smoker -Drinker</td><td>6.71</td><td>(1.95-23.09)</td><td>0.40</td><td>(0.03-4.83)</td></tr><tr><td>Ever smoker- Non drinker</td><td>6.49</td><td>(2.14-19.75)</td><td>0.40</td><td>(0.05-3.22)</td></tr><tr><td>Ever Smoker- Drinker</td><td>43.66</td><td>(15.43-123.54)</td><td>1.94</td><td>(0.44-8.57)</td></tr><tr><td>Ψ (95%CI)</td><td>1.00</td><td>(0.23-4.28)</td><td>12.25</td><td>(0.47-319.23)</td></tr><tr><td>RERI (95% CI)</td><td>31.46</td><td>(10.09-52.83)</td><td>2.14</td><td>(1.23-3.06)</td></tr></tbody></table>

French West Indies, 2013-2016

a: Model adjusted for age, sex, recruitment site

Ψ: multiplicative interaction parameter

RERI: Relative Excess Risk due to Interaction
4.4 Population attributable fractions of head and neck cancer risk factors in the
French West Indies

Submitted for publication
**Population attributable fractions of head and neck cancer risk factors in the French West Indies.**

**Authors:** Aviane Auguste<sup>a</sup>, Clarisse Joachim<sup>b</sup> Jacqueline Deloumeaux<sup>c,d</sup>, Stanie Gaete<sup>d</sup>, Leah Michineau<sup>a</sup>, Cécile Herrmann-Storck<sup>e</sup>, Suzy Duflo<sup>f</sup>, Danièle Luce *<sup>a</sup>

**Affiliations**

**Author's e-mail addresses:**

Aviane Auguste: aviane.auguste@inserm.fr

Stanie Gaete: stanie.gaete@chu-guadeloupe.fr

Cécile Herrmann-Storck: cecile.herrmann@chu-guadeloupe.fr

Léah Michineau: leah.michineau@inserm.fr

Clarisse Joachim: clarisse.joachim@chu-martinique.fr

Jacqueline Deloumeaux: jacqueline.deloumeaux@chu-guadeloupe.fr

Suzy Duflo: suzy.duflo@chu-guadeloupe.fr

Danièle Luce: daniele.luce@inserm.fr

Danièle Luce, PhD
Inserm U 1085 - Irset
Faculté de Médecine
Campus de Fouillole
BP 145
97154 Pointe-à-Pitre
E-mail: daniele.luce@inserm.fr

Words count for the main-text: 3399

Word count of abstract: 239

<footnote><sup>a</sup>Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) -UMR_S 1085, F-97100 Pointe-à-Pitre, France</footnote>

<footnote><sup>b</sup>Martinique Cancer Registry, UF 1441 Registre des cancers, Pôle de Cancérologie Hématologie Urologie Pathologie, University Hospital of Martinique, Fort-de-France, Martinique, France</footnote>

<footnote><sup>c</sup>General Cancer Registry of Guadeloupe, University Hospital of Guadeloupe, Pointe-à-Pitre, Guadeloupe, France</footnote>

<footnote><sup>d</sup>Centre de Ressources Biologiques de Guadeloupe, Pointe-à-Pitre, Guadeloupe, France</footnote>

<footnote><sup>e</sup>Laboratory of Microbiology, University Hospital of Guadeloupe, Pointe-à-Pitre, Guadeloupe</footnote>

<footnote><sup>f</sup>Department of Oto-Rhino-Laryngology and Head and Neck Surgery, University Hospital of Guadeloupe, Pointe-à-Pitre, Guadeloupe, France</footnote>

<footnote>*Correspondence and requests for reprints to:</footnote>
**Abstract**

**Objectives:** To assess population attributable fractions (PAF) of a selection of head and neck squamous cell carcinoma (HNSCC) risk factors in the French West Indian population, in the Caribbean. In addition, we compared these PAFs among different subgroups.

**Materials and Methods:** We conducted a population-based case-control study (145 cases and 405 controls). We used logistic regression models to estimate adjusted odds-ratios (OR), PAFs and their 95% confidence intervals (CI).

**Results:** The overall PAF to all risk factors combined was 90.1% (95% CI=81.1-94.8). The majority of HNSCC cases (62.5% and 55.4%) were attributable to tobacco smoking and alcohol. These PAFs were considerably larger in men (72.7% and 60.4%) than in women (21.4% and 23.6%). The PAFs for the remaining risk factors were 7% for family history of HNSCC, 13.7% for High-risk HPV, 11.4% for low BMI and 27% for occupations. The combined PAFs by sex were significantly greater in men (93.9% 95% CI=85.8-97.4) than in women (64.6% 95% CI=13.1-85.6). After taking into account late age at menarche, we were able to further explain up to 91.1% of female cases (95% CI= 41.5-98.7).

**Conclusion:** Tobacco and alcohol appeared to have the greatest impact on HNSCC incidence among the studied risk factors, especially among men. Female cases, on the other hand, were rather affected by late age at menarche and other hormonal factors. Prevention programs for HNSCC in the FWI should target tobacco and alcohol cessation, particularly in men and younger persons. Future research on HNSCC should emphasise on the role of hormonal factors to better understand this disease in women.

**Keywords:** Head and neck cancer; Population attributable fraction; tobacco smoking; alcohol drinking; oral HPV; Family history; Body mass index; Occupational health; French West Indies;
Introduction

Head and neck cancer is a public health concern across the world, counting 700,000 new cases every year [1]. Tobacco smoking and alcohol drinking are the major risk factors. However, in Guadeloupe and Martinique, two French overseas territories in the French West Indies (FWI), the prevalence of these risk factors is relatively low whereas incidence rates of HNC among men are among the highest in Latin America and the Caribbean [2]. Thus, other risk factors known or suspected to be associated with an increased risk of HNC may be contributing actively to the cancer burden in these regions. Risk factors that have been previously found to be associated with an increased risk of head and neck cancer are infection with human papillomavirus (HPV), low vegetable and fruit consumption, low body mass index, occupational exposures and family history of HNC [3–14]. We previously demonstrated that in this population high-risk oral human papillomavirus (Hr-HPV) infections were associated with an increase in head and neck squamous cell carcinoma risk (HNSCC) [15].

Estimating population attributable fractions (PAF) of the different risk factors of HNSCC could be used to attain a better understanding of the public health impact of the various HNSCC risk factors in a given population. This knowledge could have substantial implications for the prevention of head and neck cancers in the FWI. In particular, identify specific situations for which primary prevention or screening programs could be subsequently implemented, and will provide useful data to assess the potential impact of HPV vaccination on HNC. in the FWI.

Previous studies have looked at the population attributable risks for various risk factors [16–20]. In particular, tobacco and alcohol were found to be responsible for 72% of these cancers in an international pooled analysis [18]. The results from PAF are dependent on socio-cultural
context and thus, subject to geographic variation. The studies having reported data on HNSCC risk factors have been performed in populations of European and/or of Asian descent. Although the effects of tobacco and alcohol on HNSCC risk have been reported in black populations [21, 22], data on their public health impact and that of other HNC risk factors are still scarce in populations of African descent [23]. This is the first study to investigate the impact of known or suspected risk factors of HNSCC in an Afro-Caribbean population. We aimed to assess the role and impact of a selection of HNSCC risk factors (tobacco, alcohol, family history of HNC, diet, low BMI, Hr-HPV and at-risk occupations) in the French West Indian population. We estimated population attributable fractions and we compared these PAFs in different subgroups of the study population.

## Methods

### *Study population, data and specimen collection*

We conducted a population-based case-control study in Martinique and Guadeloupe. The study is an extension of a large nationwide case-control study, the ICARE study, which has already been conducted in ten French regions covered by a cancer registry [24]. The study in the FWI used the same protocol and questionnaire, described in details elsewhere [24], with some adaptations to the local context. Eligible cases were patients residing in the FWI, suffering from a primary, malignant tumour of the oral cavity, pharynx, sinonasal cavities and larynx of any histological type, aged between 18 and 75 years old at diagnosis, newly diagnosed and histologically confirmed between April 1, 2013 and June 30, 2016. The control group was selected from the general population by random digit dialling, using incidence density sampling method. Controls were frequency matched to the cases by sex, age and region. Additional stratification was used to achieve a distribution by socioeconomic status among the controls comparable to that of the general population.
Cases and controls were interviewed face-to-face with a standardized questionnaire. The questionnaire consisted of the following items: sociodemographic characteristics (age, gender, birth country, education level, marital status), residential history, personal medical history, familial history of cancer, detailed tobacco and alcohol consumption (quantity, duration, type of product, age at starting, time since cessation), non-alcoholic beverage consumption (coffee, tea), diet (food frequency questionnaire), anthropometric variables (height, weight at interview, 2 years before the interview and at age 30), hormonal factors, detailed lifelong occupational history, and sexual behaviour.

Participants were also asked to provide a saliva sample, using the Oragene® OG-500 kit (DNA Genotek).

Among 257 cases identified as potentially eligible, 192 (74.7%) agreed to participate and were interviewed. Among them, after diagnosis review, 22 did not meet the inclusion criteria. Among the remaining 170 cases, 114 (72.3%) provided a saliva sample. Among the 497 eligible controls, 405 (81.5%) answered the questionnaire and among them 311 (76.2%) provided a saliva sample.

## HPV detection and genotyping

The detection of HPV-integrated DNA from saliva samples was performed with the INNO-LiPA ® kit, according to the manufacturer's instructions (INNO-LiPA HPV Genotyping Extra; Innogenetics, Ghent, Belgium). The INNO-LiPA HPV genotyping assay allows the detection of the following genotypes: HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, HPV68 (High-risk), HPV26, HPV53, HPV66, HPV70, HPV73, HPV82 (Probable high-risk), HPV06, HPV11, HPV40, HPV42, HPV43, HPV44, HPV54, HPV61, HPV81 (Low-risk), HPV62, HPV67, HPV83, HPV89 (Other). The full details on the method for HPV detection has been described elsewhere [15].
Exposure variables

Ever cigarette smokers were defined as persons who smoked at least 100 cigarettes in their lifetime. Ever daily alcohol drinking was defined as at least one glass per day during at least one year.

To ascertain the family history of HNC cancer, subjects were first asked to indicate whether any of their first-degree relatives (biological mother and father, and full brothers or sisters) were diagnosed with head and neck cancer. No verification of the cancer diagnosis in the relatives was performed.

We examined the relationship between BMI at different time points (at interview, 2 years before the interview and at age 30). BMI was computed as weight (kg) divided by height squared (m²). In relation to BMI, the study population was divided into four categories according to the World Health Organization (WHO) international classification [25]: underweight subjects (BMI < 18.5 kg/m²), subjects with normal weight (18.5 kg/m² ≥ BMI < 24.9 kg/m²), overweight subjects (25.0 kg/m² ≥ BMI < 29.9 kg/m²), and obese subjects (BMI ≥ 30 kg/m²).

Oral Hr-HPV status was assessed as high-risk-HPV-positive versus high-risk-HPV-negative, the latter category grouping HPV-negative and non-high-risk-HPV genotypes. Participants were as defined Hr-HPV-positive when at least one high-risk HPV type was detected in the saliva sample that they provided.

Occupational exposures were ascertained by collecting detailed lifetime job history during the interview. The international Standard Classification of Occupations (ISCO) and the French Nomenclature of Activities (NAF) were used by a trained coder to blindly code occupations and branches of the industry, independently of the case-control status of the participants [26, 27].
Information on diet was collected using a food frequency questionnaire [28]. We developed beforehand a list of food items pertinent to our research question and/or consumed regularly in the French West Indies. Participants were asked whether or not they consumed one of the foods in the list, then they were asked to specify the usual frequency at which they consumed those foods.

Information on menstruation, menopause, reproductive characteristics (pregnancies, live births, miscarriages and abortions), lifelong use of oral contraceptives, and hormone replacement therapy (HRT) were recorded exclusively for female participants. HRT was defined as hormone therapy intended to treat menopausal symptoms.

## Statistical analysis

The current analysis was restricted to squamous cell carcinomas of the oral cavity (International Classification of Diseases 10th revision codes C00.3-C00.9, C02.0-C02.3, C03.0, C03.1, C03.9, C04.1, C04.8, C04.9, C05.0, C06.0-C06.2, C06.8 and C06.9, n=35), the oropharynx (ICD-10 codes C01.9, C02.4, C05.1, C05.2, C09, C10, C14.2, n=58), the hypopharynx (ICD-10 codes C12-C13, n=19) and the larynx (ICD-10 codes C32, n=32). Our analysis included 145 cases and 405 controls. The associations between the various risk factors and the occurrence of HNSCC were assessed by estimating odds ratios (ORs) and their 95% confidence intervals (CIs), using logistic regression models. An analysis on the job history of subjects were conducted beforehand to assess the association between the occurrence of HNSCC and having held a certain occupation at least once in the participant's lifetime regardless of the duration. We then created a single variable to take into account the overall risk associated with occupation. Someone who had an at-risk occupational activity was defined as someone who held a job at least once during his/her lifetime in one or more of the occupations which were significantly associated with HNSCC risk based on our analyses,
and evidence in the literature. The occupations and sectors selected to construct this variable
were: cook (ISCO 53130), banana plantation worker (ISCO 62210 and NAF 01.1F), mason,
carpenter, and other construction workers (ISCO 95), labourers (ISCO 99) and workers in the
manufacture of metal products (NAF 28). The ORs for the associations between HNSCC and
the occupations and sector used to construct the at-risk occupational activity variable are
available in the supplementary table 1.

The association between HNSCC and known risk factors were assessed prior to the final
logistic regression model to calculate the PAFs. Each risk factor was regressed individually
adjusting for age, sex, region, tobacco and alcohol. Another logistic regression model was
then fit with all the significant risk factors as binary variables simultaneously, and the PAFs
as well as their 95 % CI were calculated using the aflogit procedure available in STATA
software version 13.0 (StataCorp, Texas, USA). This procedure is based on a method
described by Greenland and Drescher elsewhere [29].

The PAFs were also calculated in different subgroups: in men and in women, in
oropharyngeal and non-oropharyngeal cancer, and in persons <59 years and ≥59 years.

HPV status was missing for 27% of the subjects, who were excluded from the main analysis.
We conducted a supplementary analysis to determine the extent to which the removal of these
subjects affected estimates for other risk factors. We excluded Hr-HPV status from our final
model, and ran this model in the restricted sample used in our primary analysis (excluding
subjects with missing values for Hr-HPV) and in the complete dataset (including subjects
with missing values for Hr-HPV). We then compared ORs and PAFs for the other risk factors
estimated in the two datasets.

## Results

### Characteristics of study population
The majority of subjects in our study were between 55 and 64 years old and were men. A little under half of the cases have had only primary school education (42.8%) whereas the population controls had mostly secondary school education. Great disparities were observed in tertiary education; cases had less frequently tertiary education compared to controls (10% vs. 24% respectively).

## Population attributable fractions of HNSCC

We found no significant association between HNSCC risk and the consumption of fruits and/or vegetables. The highest OR was found among those who consumed fruits and vegetables less than once a week (OR=1.46 95%CI=0.61-3.51), compared to a consumption of at least once a week. This variable did not reach statistical significance and was not included in the final model.

Table 1 shows ORs and PAFs for HNSCC associated with the other risk factors, overall and by subgroups. Overall, more than half of the HNSCC cases (62.5% and 55.4% respectively) were attributable to ever tobacco smoking and daily alcohol drinking. The estimates for the PAF produced large confidence intervals and it was difficult to evaluate significant differences between strata. Nevertheless, notable sex differences in PAFs to individual factors were observed. In comparison to women, a significant larger proportion of cases in men were due to ever cigarette smoking (72.7% vs. 21.4%). Similarly, 60.4% of male cases were due to alcohol drinking versus only 23% of cases in women. Compared to older participants (≥59) the proportion of cases attributable to ever smoking was notably greater among persons under 59 years (78.7% vs. 47.6%).

Family history of HNC was associated with a four-fold increase in HNSCC risk and 7.4% of the cases overall were attributable to this risk factor. Although no significant differences were
observed between subgroups, greater PAFs were found for non-oropharyngeal cancers, women and older persons.

Overall, 11.4% of cases were attributable to low BMI. Greater PAFs were noted for non-oropharyngeal cases, men and persons of younger age.

Overall, 14% of cases were attributable to Hr-HPV. Although non-significant, a greater proportion of cases in younger age group (17.9%) was attributable to Hr-HPV compared to the others (8.3%). The PAF was slightly higher for oropharyngeal cases (12.7%) than for non-oropharyngeal cases (9.8%).

Overall, 27.0% of cases were attributable to at-risk occupational activity. The PAF was 20.3% for oropharyngeal cancer and 30.4% in non-oropharyngeal cancers, 27.9% in men compared to only 10.3% of women.

The PAF for all risk factors combined (Table 2) was 90.1% (95% CI=81.1-94.8). The PAF by sex was significantly greater in men (93.9% 95% CI=85.8-97.4) than in women (64.6% 95% CI=13.1-85.6). PAF were slightly more elevated in younger person (93.6%). On the other hand, no difference was found by subsite.

ORs estimates and PAFs for tobacco, alcohol, family history, BMI and occupation remained virtually unchanged when Hr-HPV status was not included in the model. PAFs estimates from the full dataset were slightly lower for tobacco, alcohol and BMI, slightly higher for family history and similar for occupation, but overall were on the same order of magnitude (Supplementary Table 2).

## Role of hormonal factors in female HNSCC

We performed an analysis on the hormonal factors on the occurrence of HNSCC on a subgroup of 117 women (18 cases and 99 controls). Although the measures of association
were not systematically significant, exogenous and endogenous exposure hormonal factors
were found to be consistently associated with a decreased risk of HNSCC in women.
Compared to women who used oral contraceptives for more than two years, never users and
users for two years and less were found to be at a greater risk for HNSCC. Shorter lifetime
menstruation (begin after 13 and end ≤ 50) was observed to be significantly associated with
an increase in HNSCC risk compared to longer periods of lifetime menstruation (OR=26.49,
95% CI= 3.69-189.93). In terms of reproductive factors, giving birth to no children or only
one child was significantly associated with an increase in risk of HNSCC compared to those
who had 2 or more (OR=8.34 95%CI= 1.74-40.06). Women who never miscarried a child
were also at a greater risk for HNSCC (Supplementary table 3). The PAFs for all risk factors
combined were recalculated for women after introducing the binary variable “menarche after
13 years old” into the regression model and it was accountable for 63.8% (95% CI= 4.3-86.3)
of the female cases. After taking into account age at menarche, we were able to explain 91.1%
(95% CI= 41.5-98.7) of the female cases (Supplementary table 4).

Discussion

This is the first study to investigate the impact of known or suspected risk factors of HNSCC
in an Afro-Caribbean population. We were able to attribute 90% of the HNSCC cases to the
studied risk factors in this paper, and highlight the predominant impact of tobacco smoking
and alcohol on HNSCC incidence across all subgroups studied, except in women.

Overall 62.5% and 55.4% of cases were attributable to ever tobacco smoking and alcohol
drinking respectively. These two risk factors accounted for the largest proportion of cases
regardless of the stratification on different characteristics. The multiplicative interaction for
the joint effect between ever tobacco smokers and daily drinkers on HNSCC was non-
significant, and thus, we did not assess the PAF for the joint effect or the cross-product term
in our analysis. Nevertheless, despite a low prevalence of tobacco and alcohol in the FWI [2]
our results for individual impacts of tobacco and alcohol were consistent with other studies
which showed that the majority of cases were attributable to tobacco smoking, alcohol and
their joint effect [16–18, 30, 31].

In terms of the other HNSCC risk factors, the overall PAFs ranged from 7% to 27%. Previous
studies investigated mainly PAF for tobacco and alcohol; however, those who looked at other
risk factors reported PAFs which were of similar order of magnitude to ours [16, 19].
Occupational exposure accounted for 27% of the cases in our sample, and this PAF was
greater than what was estimated previously in an international study [32]. The proportion of
cases attributable to family history of HNC in the FWI was higher than what was reported by
a pooled analysis from the INHANCE consortium and two European studies [16, 19, 33].

The PAF for oral Hr-HPV was overall 13%. Other studies reported global attributable
fractions for Hr-HPV which were consistently greater for the oropharynx (between 21.3 and
30.8%) than the other the other subsites separately [20, 34, 35]. Our results, on the hand,
showed no major differences by subsites (12% for oropharynx and 9% for non-oropharyngeal
subsites together) and the PAFs for Hr-HPV in the oropharynx was lower than in other
studies. Although the etiological fraction of Hr-HPV in the FWI was not as substantial as that
of tobacco and alcohol, a noteworthy proportion of cases could be attributed to Hr-HPV
infections and therefore, this population could still draw considerable benefits from primary
cancer prevention through HPV vaccination [36].

Similarly, to previous studies, great sex disparities were observed in the proportion of cases
explained by all the factors studied initially (93.6% in men and 64.0% in women) [16, 17].
This difference is due to the low prevalence of tobacco and alcohol in women, as well as
weaker associations. We were able to further explain female HNSCC in our population by up
to 91% by adding menarche after 13 years old to our regression model. Our results on
hormonal factors in women coincide with previous studies which show that exposure to
estrogen reduces the risk of HNSCC [37–39].

PAFs are conventionally calculated for risk factors with an established causal link with the
disease. In addition, we acknowledge that some of the factors studied are indeed non-
modifiable and may not provide many avenues for prevention and control, especially in
regards to BMI, and the underlying health concerns which may arise from recommending
weight gain in the population. However, looking at known or suspected risk factors could
contribute towards a better understanding of the etiology of HNSCC in the FWI population
and assist in decision-making for public health interventions.

Our study presents several limitations. We had a small sample size and we were not able to
perform analyses by all anatomical subsites individually. The risk factors were ascertained
mostly by using self-reported measures and may have induced misclassification bias. We
cannot disregard the possibility of a recall bias due to the retrospective study design.
However, it was shown that participants in case-control studies tend to report accurately
information on cancer in first-degree relatives [40, 41]. Furthermore, BMI from two years
prior to the interview was used to avoid underestimating the BMI due to weight loss
associated with head and neck cancer diagnosis. In our study we were able to investigate a
large number of known or suspected risk factors of HNSCC that were studied in previous
reports [16–18, 30, 31]. Consequently, we were able to explore various areas such as
hormonal factors to explain a greater proportion of female HNSCC. Occupational exposures
were assessed collectively as one variable based on occupation and thus, we are unable to
produce any information for etiological fractions for specific occupational exposures.
We had 27% missing data for HPV in our sample which imposed the removal of a large
proportion of subjects from our regression analysis and thus, contributed to a loss of statistical
power. However, sensitivity analysis showed that the removal of these subjects did not
change markedly the point estimates for our analyses (supplementary table 2). Furthermore,
the use of oral HPV detection to assess the HPV status may have resulted in misclassification,
which is however likely to be non-differential. Oral HPV detection has been shown to have
good specificity but moderate sensitivity for HPV-positive HNSCC tumours [42].

Selection bias may not be excluded but is thought to be kept to minimum in the current study.
The distribution by sex, age and cancer sites of the cases included in our study was similar to
that of the cases in the local cancer registries. Our study population can thus be considered
representative of the HNSCC cases. The method used to select the control group was
previously demonstrated to yield unbiased samples and the controls could be considered
representative of the general population of similar age and sex [24]. We confirmed the
representativeness of the tobacco and alcohol distribution in our control group to FWI
population after comparison with the data from a national health survey [43]. We were able to
explain close to 90% of HNSCC and missing 10% could be attributable to residual risk
factors that were not taken into account for our study. Factors like gene-environment
interactions and medical history were not studied and could bring further clarification to
HNSCC aetiology in the FWI.

Conclusion

Overall, we were able to explain 90.1% of HNSCC in the FWI based on the risk factors
studied in this report. Tobacco and alcohol appeared to have the greatest impact on HNSCC
incidence among the other risk factors (62.5% and 55.4% respectively). Female cases, on the
other hand, were rather concerned by menarche after 13 years (63.4% of cases). Given the
large attributable fraction for occupational risk factors (27.0%) the public health impact could be considerable if we reduced these exposures. Special attention should be given to tobacco and alcohol cessation in particular in men and younger persons, when considering prevention programs for HNSCC in the FWI. More in-depth analyses are warranted on occupational exposures in the FWI, and future research on HNSCC should emphasise on the role of hormonal factors to better understand this disease in women.

**Conflict of interest statement**

The authors have no conflict of interest

**Acknowledgements**

We would like to thank our clinical research associates Lucina Lipau and Audrey Pomier for their help in data collection. Aviane Auguste was supported by a grant from the "Ligue contre le Cancer, comité d'Ile-et-Vilaine" for this work.

**Funding sources**

This study was funded by the French National Cancer Institute (Institut National du Cancer) and the Cancéropôle Ile-de-France. The funding bodies had no involvement in the preparation of this article.

**Ethical approval**

French Data Protection Authority (CNIL, Commission Nationale de l'Informatique et des Libertés) n° DR-2015-2027; IRB INSERM n°01-036
References

1. J Ferlay, Ervik M, Lam F, et al (2018) Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. In: International Agency for Research on Cancer. https://gco.iarc.fr/today. Accessed 5 Aug 2019

2. Jean-Baptiste Richard (2015) Premiers résultats du Baromètre santé DOM 2014 - Résultats détaillés selon le DOM, l'âge et le sexe - 2015. Santé publique France, Saint-Maurice (Fra)

3. Radoï L, Paget-Bailly S, Menvielle G, et al (2013) Tea and coffee consumption and risk of oral cavity cancer: results of a large population-based case-control study, the ICARE study. Cancer Epidemiol 37:284-289. https://doi.org/10.1016/j.canep.2013.02.001

4. Radoï L, Paget-Bailly S, Cyr D, et al (2013) Body mass index, body mass change, and risk of oral cavity cancer: results of a large population-based case-control study, the ICARE study. Cancer Causes Control 24:1437-1448. https://doi.org/10.1007/s10552-013-0223-z

5. Radoï L, Paget-Bailly S, Cyr D, et al (2013) Tobacco smoking, alcohol drinking and risk of oral cavity cancer by subsite: results of a French population-based case-control study, the ICARE study. Eur J Cancer Prev 22:268-276. https://doi.org/10.1097/CEJ.0b013e3283592cce

6. Menvielle G, Fayossé A, Radoï L, et al (2016) The joint effect of asbestos exposure, tobacco smoking and alcohol drinking on laryngeal cancer risk: evidence from the French population-based case-control study, ICARE. Occup Environ Med 73:28-33. https://doi.org/10.1136/oemed-2015-102954

7. Barul C, Fayossé A, Carton M, et al (2017) Occupational exposure to chlorinated solvents and risk of head and neck cancer in men: a population-based case-control study in France. Environ Health 16:77. https://doi.org/10.1186/s12940-017-0286-5

8. Carton M, Barul C, Menvielle G, et al (2017) Occupational exposure to solvents and risk of head and neck cancer in women: a population-based case-control study in France. BMJ Open 7:e012833. https://doi.org/10.1136/bmjopen-2016-012833

9. Maasland DHE, van den Brandt PA, Kremer B, Schouten LJ (2015) Body mass index and risk of subtypes of head-neck cancer: the Netherlands Cohort Study. Sci Rep 5:17744. https://doi.org/10.1038/srep17744

10. Huang Y-HJ, Lee Y-CA, Li Q, et al (2015) Family History of Cancer and Head and Neck Cancer Risk in a Chinese Population. Asian Pac J Cancer Prev 16:8003-8008

11. Radoï L, Paget-Bailly S, Guida F, et al (2013) Family history of cancer, personal history of medical conditions and risk of oral cavity cancer in France: the ICARE study. BMC Cancer 13:560. https://doi.org/10.1186/1471-2407-13-560

12. Gaudet MM, Olshan AF, Chuang S-C, et al (2010) Body mass index and risk of head and neck cancer in a pooled analysis of case-control studies in the International Head
and Neck Cancer Epidemiology (INHANCE) Consortium. Int J Epidemiol 39:1091–1102. https://doi.org/10.1093/ije/dyp380

13. Kawakita D, Lee Y-CA, Turati F, et al (2017) Dietary fiber intake and head and neck cancer risk: A pooled analysis in the International Head and Neck Cancer Epidemiology consortium. Int J Cancer 141:1811–1821. https://doi.org/10.1002/ijc.30886

14. Bryere J, Menvielle G, Dejardin O, et al (2017) Neighborhood deprivation and risk of head and neck cancer: A multilevel analysis from France. Oral Oncol 71:144–149. https://doi.org/10.1016/j.oraloncology.2017.06.014

15. Auguste A, Gaëte S, Herrmann-Storck C, et al (2017) Prevalence of oral HPV infection among healthy individuals and head and neck cancer cases in the French West Indies. Cancer Causes Control 28:1333–1340. https://doi.org/10.1007/s10552-017-0966-z

16. Radoï L, Menvielle G, Cyr D, et al (2015) Population attributable risks of oral cavity cancer to behavioral and medical risk factors in France: results of a large population-based case-control study, the ICARE study. BMC Cancer 15:827. https://doi.org/10.1186/s12885-015-1841-5

17. Anantharaman D, Marron M, Lagiou P, et al (2011) Population attributable risk of tobacco and alcohol for upper aerodigestive tract cancer. Oral Oncol 47:725–731. https://doi.org/10.1016/j.oraloncology.2011.05.004

18. Hashibe M, Brennan P, Chuang S-C, et al (2009) Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev 18:541–550. https://doi.org/10.1158/1055-9965.EPI-08-0347

19. Negri E, Boffetta P, Berthiller J, et al (2009) Family history of cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Int J Cancer 124:394–401. https://doi.org/10.1002/ijc.23848

20. Castellsagué X, Alemany L, Quer M, et al (2016) HPV Involvement in Head and Neck Cancers: Comprehensive Assessment of Biomarkers in 3680 Patients. J Natl Cancer Inst 108:djv403. https://doi.org/10.1093/jnci/djv403

21. Voltzke KJ, Lee Y-CA, Zhang Z-F, et al (2018) Racial differences in the relationship between tobacco, alcohol, and the risk of head and neck cancer: pooled analysis of US studies in the INHANCE Consortium. Cancer Causes Control 29:619–630. https://doi.org/10.1007/s10552-018-1026-z

22. Stingone JA, Funkhouser WK, Weissler MC, et al (2013) Racial differences in the relationship between tobacco, alcohol and squamous cell carcinoma of the head and neck. Cancer Causes Control 24:649–664. https://doi.org/10.1007/s10552-012-9999-5

23. Day GL, Blot WJ, Austin DF, et al (1993) Racial differences in risk of oral and pharyngeal cancer: alcohol, tobacco, and other determinants. J Natl Cancer Inst 85:465–473. https://doi.org/10.1093/jnci/85.6.465

24. Luce D, Stücker I, ICARE Study Group (2011) Investigation of occupational and environmental causes of respiratory cancers (ICARE): a multicenter, population-based
case-control study in France. BMC Public Health 11:928. https://doi.org/10.1186/1471-2458-11-928

25. World Health Organization (2000) Obesity: preventing and managing the global epidemic. Report of a WHO Consultation. WHO Technical Report Series 894 Geneva: World Health Organization. In: WHO. http://www.who.int/entity/nutrition/publications/obesity/WHO_TRS_894/en/index.html. Accessed 18 Aug 2019

26. International Labour Office (1968) International Standard Classification of Occupations (ISCO)

27. INSEE (2000) Institut National de la Statistique et des Etudes Economiques. Nomenclature d'activités française

28. Shim J-S, Oh K, Kim HC (2014) Dietary assessment methods in epidemiologic studies. Epidemiol Health 36: https://doi.org/10.4178/epih/e2014009

29. Greenland S, Drescher K (1993) Maximum likelihood estimation of the attributable fraction from logistic models. Biometrics 49:865-872

30. Szymańska K, Hung RJ, Wünsch-Filho V, et al (2011) Alcohol and tobacco, and the risk of cancers of the upper aerodigestive tract in Latin America: a case-control study. Cancer Causes Control 22:1037-1046. https://doi.org/10.1007/s10552-011-9779-7

31. Kfouri SA, Eluf Neto J, Koifman S, et al (2018) Fraction of head and neck cancer attributable to tobacco and alcohol in cities of three Brazilian regions. Rev Bras Epidemiol 21:e180005. https://doi.org/10.1590/1980-549720180005

32. Khetan P, Boffetta P, Luce D, et al (2019) Occupations and the Risk of Head and Neck Cancer: A Pooled Analysis of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. J Occup Environ Med 61:397-404. https://doi.org/10.1097/JOM.0000000000001563

33. Li X, Hemminki K (2003) Familial upper aerodigestive tract cancers: incidence trends, familial clustering and subsequent cancers. Oral Oncol 39:232-239

34. de Martel C, Plummer M, Vignat J, Franceschi S (2017) Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 141:664-670. https://doi.org/10.1002/ijc.30716

35. de Sanjosé S, Serrano B, Tous S, et al (2018) Burden of Human Papillomavirus (HPV)-Related Cancers Attributable to HPVs 6/11/16/18/31/33/45/52 and 58. JNCI Cancer Spectr 2: https://doi.org/10.1093/jncics/pky045

36. Gillison ML, Alemany L, Snijders PJF, et al (2012) Human Papillomavirus and Diseases of the Upper Airway: Head and Neck Cancer and Respiratory Papillomatosis. Vaccine 30:F34-F54. https://doi.org/10.1016/j.vaccine.2012.05.070

37. Hashim D, Sartori S, Vecchia CL, et al (2017) Hormone factors play a favorable role in female head and neck cancer risk. Cancer Med 6:1998-2007. https://doi.org/10.1002/cam4.1136
38. Singh HP, Kumar P, Goel R, Kumar A (2012) Sex hormones in head and neck cancer: Current knowledge and perspectives. Clinical Cancer Investigation Journal 1:2. https://doi.org/10.4103/2278-0513.95011

39. Langevin SM, Grandis JR, Taioli E (2011) Female hormonal and reproductive factors and head and neck squamous cell carcinoma risk. Cancer Lett 310:216-221. https://doi.org/10.1016/j.canlet.2011.07.007

40. Kerber RA, Slattery ML (1997) Comparison of self-reported and database-linked family history of cancer data in a case-control study. Am J Epidemiol 146:244-248. https://doi.org/10.1093/oxfordjournals.aje.a009259

41. Love RR, Evans AM, Josten DM (1985) The accuracy of patient reports of a family history of cancer. J Chronic Dis 38:289-293

42. Gipson BJ, Robbins HA, Fakhry C, D'Souza G (2018) Sensitivity and specificity of oral HPV detection for HPV-positive head and neck cancer. Oral Oncol 77:52-56. https://doi.org/10.1016/j.oraloncology.2017.12.008

43. Richard J-B (2015) Premiers résultats du Baromètre Santé DOM 2014- Résultats détaillés selon le DOM, l'âge et le sexe. Santé publique France, Saint-Maurice (Fra)
<table><caption>**Table 1:** Adjusted odds ratios (OR), population attributable fractions (PAF) and 95% confidence intervals (CI) for HNSCC associated with tobacco, alcohol, family history of HNC, low BMI, Hr-HPV and at-risk occupations, overall and by subgroups.</caption><thead><tr><th>Risk factor</th><th>Cases</th><th>Controls</th><th>OR<sup>†</sup></th><th>95% CI</th><th>PAF</th><th>95% CI</th></tr></thead><tbody><tr><td><strong>Tobacco smoking (ever vs never smoker)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HNSCC</td><td>114</td><td>142</td><td>4.94</td><td>(2.52-9.66)</td><td>62.5%</td><td>(41.3-76.0)</td></tr><tr><td>By subsite</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Oropharynx</td><td>47</td><td>142</td><td>5.82</td><td>(2.29-14.80)</td><td>67.2%</td><td>(34.1-83.6)</td></tr><tr><td>Non-oropharynx</td><td>67</td><td>142</td><td>4.30</td><td>(1.82-10.12)</td><td>59.7%</td><td>(26.9-77.8)</td></tr><tr><td>By Sex</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Men</td><td>106</td><td>121</td><td>7.02</td><td>(3.20-15.43)</td><td>72.7%</td><td>(51.2-84.7)</td></tr><tr><td>Women</td><td>8</td><td>21</td><td>2.50</td><td>(0.36-17.13)</td><td>21.4%</td><td>(-39.1-55.6)</td></tr><tr><td>By age</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;59</td><td>60</td><td>68</td><td>9.99</td><td>(3.30-30.22)</td><td>78.7%</td><td>(50.2-90.9)</td></tr><tr><td>&ge;59</td><td>54</td><td>74</td><td>3.14</td><td>(1.26-7.86)</td><td>47.6%</td><td>(10.5-69.3)</td></tr><tr><td><strong>Daily alcohol (ever vs non-daily drinkers)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HNSCC</td><td>96</td><td>112</td><td>4.29</td><td>(2.28-8.07)</td><td>55.4%</td><td>(34.7-69.6)</td></tr><tr><td>By subsite</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Oropharynx</td><td>38</td><td>112</td><td>4.74</td><td>(2.00-11.20)</td><td>57.6%</td><td>(25.7-75.8)</td></tr><tr><td>Non-oropharynx</td><td>58</td><td>112</td><td>4.76</td><td>(2.08-10.86)</td><td>57.9%</td><td>(29.1-75.0)</td></tr><tr><td>By Sex</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Men</td><td>90</td><td>97</td><td>4.79</td><td>(2.34-9.79)</td><td>60.4%</td><td>(37.6-74.9)</td></tr><tr><td>Women</td><td>6</td><td>15</td><td>2.09</td><td>(0.35-12.44)</td><td>23.6%</td><td>(-54.4-62.2)</td></tr><tr><td>By age</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;59</td><td>42</td><td>35</td><td>4.72</td><td>(1.86-11.97)</td><td>53.2%</td><td>(23.3-71.4)</td></tr><tr><td>&ge;59</td><td>54</td><td>77</td><td>4.39</td><td>(1.75-11.04)</td><td>59.3%</td><td>(25.8-77.7)</td></tr><tr><td><strong>Family history of HNC cancer (yes vs no)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HNSCC</td><td>13</td><td>14</td><td>4.29</td><td>(1.30-14.17)</td><td>7.4%</td><td>(-3.2-16.9)</td></tr><tr><td>By subsite</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Oropharynx</td><td>4</td><td>14</td><td>2.11</td><td>(0.36-12.49)</td><td>2.9%</td><td>(-12.5-16.1)</td></tr><tr><td>Non-oropharynx</td><td>9</td><td>14</td><td>6.67</td><td>(1.81-24.60)</td><td>11.3%</td><td>(-3.7-24.2)</td></tr><tr><td>By Sex</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Men</td><td>11</td><td>10</td><td>3.94</td><td>(0.94-16.49)</td><td>6.2%</td><td>(-5.2-16.4)</td></tr><tr><td>Women</td><td>2</td><td>4</td><td>8.50</td><td>(0.78-92.78)</td><td>15.9%</td><td>(-18.5-40.4)</td></tr><tr><td>By age</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;59</td><td>6</td><td>7</td><td>3.17</td><td>(0.47-21.17)</td><td>5.1%</td><td>(-11.4-19.2)</td></tr><tr><td>&ge;59</td><td>7</td><td>7</td><td>4.72</td><td>(0.94-23.70)</td><td>9.2%</td><td>(-5.3-21.7)</td></tr><tr><td><strong>Low BMI (BMI&lt; 18.5 vs BMI&ge; 18.5)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HNSCC</td><td>12</td><td>10</td><td>6.96</td><td>(1.98-24.52)</td><td>11.4%</td><td>(0.7-20.8)</td></tr><tr><td>By subsite</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Oropharynx</td><td>4</td><td>10</td><td>5.83</td><td>(1.13-30.10)</td><td>9.0%</td><td>(-6.6-22.3)</td></tr><tr><td>Non-oropharynx</td><td>8</td><td>10</td><td>8.15</td><td>(1.87-35.50)</td><td>13.7%</td><td>(-1.4-26.5)</td></tr><tr><td>By Sex</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Men</td><td>11</td><td>9</td><td>7.32</td><td>(1.67-32.12)</td><td>12.0%</td><td>(0.5-22.1)</td></tr><tr><td>Women</td><td>1</td><td>1</td><td>51.99</td><td>(1.42-1902.37)</td><td>8.9%</td><td>(-21.2-31.6)</td></tr><tr><td>By age</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;59</td><td>8</td><td>5</td><td>11.36</td><td>(1.85-69.81)</td><td>16.0%</td><td>(-0.2-29.5)</td></tr><tr><td>&ge;59</td><td>4</td><td>5</td><td>4.70</td><td>(0.65-34.11)</td><td>7.3%</td><td>(-6.7-19.5)</td></tr><tr><td><strong>Oral HPV Status (Hr-HPV+ vs Hr-HPV-)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HNSCC</td><td>19</td><td>30</td><td>2.49</td><td>(1.16-5.35)</td><td>13.7%</td><td>(-0.5-26.0)</td></tr><tr><td>By subsite</td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>
<table><tbody><tr><td>Oropharynx</td><td>8</td><td>30</td><td>2.41</td><td>(0.88-6.63)</td><td>12.7%</td><td>(-8.2-29.5)</td></tr><tr><td>Non-oropharynx</td><td>11</td><td>30</td><td>1.79</td><td>(0.69-4.61)</td><td>9.8%</td><td>(-11.7-27.1)</td></tr><tr><td>By Sex</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Men</td><td>17</td><td>28</td><td>2.10</td><td>(0.91-4.83)</td><td>12.4%</td><td>(-4.4-26.4)</td></tr><tr><td>Women</td><td>2</td><td>2</td><td>6.11</td><td>(0.51-73.23)</td><td>14.1%</td><td>(-23.6-40.4)</td></tr><tr><td>By age</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;59</td><td>12</td><td>13</td><td>2.49</td><td>(0.75-8.28)</td><td>17.9%</td><td>(-8.2-37.8)</td></tr><tr><td>≥59</td><td>7</td><td>17</td><td>2.04</td><td>(0.70-5.99)</td><td>8.3%</td><td>(-9.6-23.3)</td></tr><tr><td>At-risk occupational activity (yes vs no)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HNSCC</td><td>56</td><td>87</td><td>2.94</td><td>(1.52-5.68)</td><td>27.0%</td><td>(9.7-41.0)</td></tr><tr><td>By subsite</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Oropharynx</td><td>19</td><td>87</td><td>2.37</td><td>(0.96-5.81)</td><td>20.3%</td><td>(-5.8-40.0)</td></tr><tr><td>Non-oropharynx</td><td>37</td><td>87</td><td>3.17</td><td>(1.41-7.13)</td><td>30.4%</td><td>(6.2-48.4)</td></tr><tr><td>By Sex</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Men</td><td>53</td><td>80</td><td>2.85</td><td>(1.38-5.86)</td><td>27.9%</td><td>(8.3-43.4)</td></tr><tr><td>Women</td><td>3</td><td>7</td><td>2.30</td><td>(0.22-23.68)</td><td>10.3%</td><td>(-30.3-48.6)</td></tr><tr><td>By age</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;59</td><td>27</td><td>48</td><td>2.41</td><td>(0.88-6.61)</td><td>24.9%</td><td>(-5.9-46.7)</td></tr><tr><td>≥59</td><td>29</td><td>39</td><td>3.26</td><td>(1.30-8.19)</td><td>27.4%</td><td>(4.2-45.0)</td></tr></tbody></table>

<footnote>†: Adjusted for age, sex, region and all the risk factors in the table</footnote>
<table><caption>**Table 2:** Population attributable fractions (PAF) and 95% confidence intervals (CI) of all risk factors combined for HNSCC, overall and by subgroups.</caption><thead><tr><th></th><th>Ca</th><th>Co</th><th>PAF</th><th>95% CI</th></tr></thead><tbody><tr><td>HNSCC</td><td></td><td></td><td>90.1%</td><td>(81.1-94.8)</td></tr><tr><td>By subsite</td><td></td><td></td><td></td><td></td></tr><tr><td>Oropharynx</td><td>58</td><td>405</td><td>90.2%</td><td>(74.7-96.2)</td></tr><tr><td>Non-oropharynx</td><td>86</td><td>405</td><td>90.9%</td><td>(78.2-96.2)</td></tr><tr><td>By Sex</td><td></td><td></td><td></td><td></td></tr><tr><td>Men</td><td>127</td><td>306</td><td>93.9%</td><td>(85.8-97.4)</td></tr><tr><td>Women</td><td>18</td><td>99</td><td>64.6%</td><td>(13.1-85.6)</td></tr><tr><td>By age</td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;59</td><td>67</td><td>203</td><td>93.9%</td><td>(81.3-98.0)</td></tr><tr><td>≥59</td><td>78</td><td>202</td><td>86.8%</td><td>(69.5-94.3)</td></tr></tbody></table>
**Title:** Population attributable fractions of head and neck cancer risk factors in the French West Indies.

**Supplementary Materials**

<table><caption>**Supplementary table 1:** Adjusted ORs for the individual occupations and sectors used to construct the occupational exposure variable.</caption><thead><tr><th>ISCO code</th><th>NAF code</th><th>Title</th><th>Cases n=145</th><th>Controls n=405</th><th>OR<sup>†</sup></th><th>95% CI</th></tr></thead><tbody><tr><td></td><td></td><td><strong>At-risk occupational activity</strong></td><td>56</td><td>87</td><td>2.74</td><td>(1.61-4.67)</td></tr><tr><td></td><td></td><td><em>Occupation</em></td><td></td><td></td><td></td><td></td></tr><tr><td>53130</td><td>Any</td><td>Cook, except private service</td><td>7</td><td>8</td><td>5.22</td><td>(1.64-16.67)</td></tr><tr><td>62210</td><td>01.1F</td><td>Banana plantation workers</td><td>9</td><td>6</td><td>3.89</td><td>(0.96-15.74)</td></tr><tr><td>95</td><td>Any</td><td>Bricklayers, Carpenters and Other Construction Workers</td><td>35</td><td>58</td><td>1.87</td><td>(1.02-3.44)</td></tr><tr><td>99</td><td>Any</td><td>Labourer</td><td>14</td><td>22</td><td>2.34</td><td>(0.98-5.61)</td></tr><tr><td></td><td></td><td><strong>NAF</strong></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td><em>Sector</em></td><td></td><td></td><td></td><td></td></tr><tr><td>Any</td><td>28</td><td>Manufacture of fabricated metal products, except machinery and equipment</td><td>7</td><td>6</td><td>6.52</td><td>(1.69-25.14)</td></tr></tbody></table>

<footnote>†: Adjusted for age, sex, region, the combination of cigarette smoking duration and intensity (cigarette/day), and daily alcohol drinking</footnote>
<table><caption>**Supplementary table 2:** Comparison of the results with and without exclusion of subjects with missing values for HPV</caption><thead><tr><th rowspan="3">Covariates in model</th><th colspan="6">Restricted sample (exclusion of subjects with missing values for HPV)</th><th colspan="4">Full dataset (including subjects with missing values for HPV)</th></tr><tr><th colspan="3">Model 1</th><th colspan="3">Model 2</th><th colspan="3">Model 2</th></tr><tr><th>OR<br>(95% CI)</th><th>PAF<br>(95% CI)</th><th>OR</th><th>95% CI</th><th>PAF<br>(95% CI)</th><th>OR</th><th>95% CI</th><th>PAF<br>(95% CI)</th></tr></thead><tbody><tr><td>Ever smoker</td><td>4.94 (2.53-9.65)</td><td>62.5% (41.3-76.0)</td><td>4.94</td><td>2.56</td><td>9.57</td><td>62.5 (41.5-75.9)</td><td>4.36</td><td>2.56</td><td>7.54</td><td>58.1 (40.8-0.3)</td></tr><tr><td>Daily drinking</td><td>4.29 (2.28-8.07)</td><td>55.4% (34.7-69.6)</td><td>4.42</td><td>2.37</td><td>8.28</td><td>56.0 (35.6-69.9)</td><td>3.64</td><td>2.18</td><td>6.07</td><td>49.6 (32.2-62.5)</td></tr><tr><td>Family history</td><td>4.29 (1.29-14.17)</td><td>7.4% (-3.2-16.9)</td><td>4.76</td><td>1.43</td><td>15.80</td><td>7.6 (-2.8-17.0)</td><td>5.10</td><td>1.96</td><td>13.26</td><td>8.9 (0.4-16.7)</td></tr><tr><td>BMI &lt; 18.5 kg/m<sup>2</sup></td><td>6.96 (1.98-24.52)</td><td>11.4% (0.7-0.8)</td><td>6.56</td><td>1.86</td><td>23.17</td><td>11.2 (0.06-20.6)</td><td>4.48</td><td>1.46</td><td>13.71</td><td>7.3 (1.2-15.1)</td></tr><tr><td>High-risk HPV</td><td>2.49 (1.16-5.35)</td><td>13.7% (-0.5-6.0)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>At-risk occupation</td><td>2.94 (1.52-5.67)</td><td>27.0% (9.7-1.0)</td><td>2.77</td><td>1.45</td><td>5.29</td><td>26.2 (8.6-40.4)</td><td>2.91</td><td>1.70</td><td>4.96</td><td>26.3 (12.5-38.0)</td></tr></tbody></table>

All the models in this table have been adjusted for age, sex and region

NA: covariate not introduced in to the regression model
<table><caption>**Supplementary table 3:** Adjusted odds ratios (OR) and 95% confidence intervals (CI) for HNSCC associated with hormonal factors</caption><thead><tr><th rowspan="2">Hormonal factor</th><th colspan="2">Case</th><th colspan="2">Control</th><th rowspan="2">OR<sup>†</sup></th><th rowspan="2">95% CI</th></tr><tr><th>n</th><th>col%</th><th>n</th><th>col%</th></tr></thead><tbody><tr><td colspan="7"><em>Exogeneous factors</em></td></tr><tr><td><strong>Oral contraceptive use</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>9</td><td>(64.3)</td><td>83</td><td>(84.7)</td><td>1</td><td>ref</td></tr><tr><td>Never</td><td>5</td><td>(35.7)</td><td>15</td><td>(15.3)</td><td>2.27</td><td>(0.60-8.64)</td></tr><tr><td>Missing</td><td>4</td><td></td><td>1</td><td></td><td></td><td></td></tr><tr><td><strong>Duration of oral contraception (years)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never used oral contraception</td><td>5</td><td>(35.7)</td><td>15</td><td>(15.3)</td><td>2.75</td><td>(0.55-13.62)</td></tr><tr><td>≤ 2</td><td>5</td><td>(35.7)</td><td>42</td><td>(42.9)</td><td>1.41</td><td>(0.31-6.40)</td></tr><tr><td>2</td><td>4</td><td>(28.6)</td><td>41</td><td>(41.8)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>4</td><td></td><td>1</td><td></td><td></td><td></td></tr><tr><td><strong>Hormone replacement therapy (HRT)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>1</td><td>(7.7)</td><td>23</td><td>(35.9)</td><td>1</td><td>ref</td></tr><tr><td>Never</td><td>12</td><td>(92.3)</td><td>41</td><td>(64.1)</td><td>5.39</td><td>(0.61-47.54)</td></tr><tr><td>Missing</td><td>5</td><td></td><td>35</td><td></td><td></td><td></td></tr><tr><td colspan="7"><em>Endogeneous factors</em></td></tr><tr><td><strong>Age at Menarche</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 13</td><td>5</td><td>(35.7)</td><td>67</td><td>(68.4)</td><td>1</td><td>ref</td></tr><tr><td>over 13</td><td>9</td><td>(64.3)</td><td>31</td><td>(31.6)</td><td>4.95</td><td>(1.30-18.92)</td></tr><tr><td>Missing</td><td>4</td><td></td><td>1</td><td></td><td></td><td></td></tr><tr><td><strong>Menopause</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>13</td><td>(92.9)</td><td>61</td><td>(67.8)</td><td>9.25</td><td>(0.71-120.49)</td></tr><tr><td>No</td><td>1</td><td>(7.1)</td><td>29</td><td>(32.2)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>4</td><td></td><td>9</td><td></td><td></td><td></td></tr><tr><td><strong>Menopause age (years)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 50</td><td>12</td><td>(92.3)</td><td>39</td><td>(66.1)</td><td>18.51</td><td>(1.37-249.83)</td></tr><tr><td>Over 50</td><td>1</td><td>(7.7)</td><td>20</td><td>(33.9)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>5</td><td></td><td>40</td><td></td><td></td><td></td></tr><tr><td><strong>Menopause age (years)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never menopause</td><td>1</td><td>(7.1)</td><td>29</td><td>(33.0)</td><td>1</td><td>ref</td></tr><tr><td>≤ 50</td><td>12</td><td>(85.7)</td><td>39</td><td>(44.3)</td><td>14.84</td><td>(1.04-211.34)</td></tr><tr><td>over 50</td><td>1</td><td>(7.1)</td><td>20</td><td>(22.7)</td><td>1.11</td><td>(0.04-29.00)</td></tr><tr><td>Missing</td><td>4</td><td></td><td>11</td><td></td><td></td><td></td></tr><tr><td><strong>Lifetime menstruation</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Begin after 13 – end ≤ 50</td><td>8</td><td>(61.5)</td><td>12</td><td>(20.3)</td><td>1</td><td>ref</td></tr><tr><td>Begin ≤ 13 – end ≤ 50</td><td>4</td><td>(30.8)</td><td>27</td><td>(45.8)</td><td>0.07</td><td>(0.01-0.53)</td></tr><tr><td>Begin after 13 – end after 50</td><td>1</td><td>(7.7)</td><td>8</td><td>(13.6)</td><td>0.04</td><td>(0.00-1.26)</td></tr><tr><td>Begin ≤ 13 – end after 50</td><td>0</td><td>(0.0)</td><td>12</td><td>(20.3)</td><td>NA</td><td>NA</td></tr><tr><td>Missing</td><td>5</td><td></td><td>40</td><td></td><td></td><td></td></tr></tbody></table>
## Lifetime menstruation (binary)

<table><tr><td>Begin after 13 – end ≤ 50</td><td>8</td><td>(61.5)</td><td>12</td><td>(20.3)</td><td>26.49</td><td>(3.69-189.93)</td></tr><tr><td>Other scenarios</td><td>5</td><td>(37.8)</td><td>47</td><td>(79.7)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>5</td><td></td><td>40</td><td></td><td></td><td></td></tr></table>

## Ever Pregnant

<table><tr><td>Yes</td><td>9</td><td>(75.0)</td><td>91</td><td>(93.8)</td><td>1</td><td>ref</td></tr><tr><td>No</td><td>3</td><td>(25.0)</td><td>6</td><td>(6.2)</td><td>5.92</td><td>(0.88-39.88)</td></tr><tr><td>Missing</td><td>6</td><td></td><td>2</td><td></td><td></td><td></td></tr></table>

## Number of pregnancies

<table><tr><td>Never pregnant</td><td>3</td><td>(21.4)</td><td>6</td><td>(6.1)</td><td>5.25</td><td>(0.73-37.50)</td></tr><tr><td>Once</td><td>1</td><td>(7.1)</td><td>11</td><td>(11.2)</td><td>0.95</td><td>(0.07-13.83)</td></tr><tr><td>Twice</td><td>3</td><td>(21.4)</td><td>15</td><td>(15.3)</td><td>4.24</td><td>(0.77-23.24)</td></tr><tr><td>&gt; 2</td><td>7</td><td>(50.0)</td><td>66</td><td>(67.4)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>4</td><td></td><td>1</td><td></td><td></td><td></td></tr></table>

## Parity

<table><tr><td>Never pregnant</td><td>3</td><td>(23.1)</td><td>6</td><td>(6.4)</td><td>8.23</td><td>(0.96-70.50)</td></tr><tr><td>1 child</td><td>3</td><td>(23.1)</td><td>15</td><td>(16.0)</td><td>8.75</td><td>(1.13-67.71)</td></tr><tr><td>2 children</td><td>3</td><td>(23.1)</td><td>28</td><td>(29.8)</td><td>1.53</td><td>(0.26-8.99)</td></tr><tr><td>&gt; 2 children</td><td>4</td><td>(30.8)</td><td>45</td><td>(47.9)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>5</td><td></td><td>5</td><td></td><td></td><td></td></tr></table>

## Miscarriage

<table><tr><td>Ever</td><td>2</td><td>(16.7)</td><td>38</td><td>(41.3)</td><td>1</td><td>ref</td></tr><tr><td>Never</td><td>10</td><td>(83.3)</td><td>54</td><td>(58.7)</td><td>3.94</td><td>(0.68-22.84)</td></tr><tr><td>Missing</td><td>6</td><td></td><td>7</td><td></td><td></td><td></td></tr></table>

## Number of miscarriages

<table><tr><td>Never miscarried</td><td>10</td><td>(83.3)</td><td>54</td><td>(59.3)</td><td>2.17</td><td>(0.35-13.37)</td></tr><tr><td>Once</td><td>2</td><td>(16.7)</td><td>22</td><td>(24.2)</td><td>1</td><td>ref</td></tr><tr><td>&gt; 1</td><td>0</td><td>(0.0)</td><td>15</td><td>(16.5)</td><td>NA</td><td>NA</td></tr><tr><td>Missing</td><td>6</td><td></td><td>8</td><td></td><td></td><td></td></tr></table>

<footnote>†: Adjusted for age, sex, region, smoking status (current/former), daily alcohol drinking</footnote>
<table><caption>**Supplementary table 4:** Population attributable fractions (PAF) and 95% confidence intervals (CI) of all risk factors individually and combined for female HNSCC only</caption><thead><tr><th rowspan="2">Risk factor</th><th>Cases</th><th>Controls</th><th rowspan="2">OR<sup>†</sup></th><th rowspan="2">95% CI</th><th rowspan="2">PAF</th><th rowspan="2">95% CI</th></tr><tr><th>n=18</th><th>n=99</th></tr></thead><tbody><tr><td>Female HNSCC</td><td></td><td></td><td></td><td></td><td>91.1%</td><td>(41.5-98.7)</td></tr><tr><td>Ever Smoker</td><td>8</td><td>21</td><td>3.74</td><td>(0.36-38.56)</td><td>29.3%</td><td>(-31.4-62.0)</td></tr><tr><td>Ever daily drinker</td><td>6</td><td>15</td><td>3.23</td><td>(0.33-31.82)</td><td>34.5%</td><td>(-46.1-70.7)</td></tr><tr><td>Family history of HNC cancer</td><td>2</td><td>4</td><td>24.76</td><td>(1.20-511.45)</td><td>19.2%</td><td>(-17.3-44.3)</td></tr><tr><td>Leanness</td><td>1</td><td>1</td><td>24.98</td><td>(0.62-1010.6)</td><td>9.6%</td><td>(-25.2-34.7)</td></tr><tr><td>Hr-HPV-positive</td><td>2</td><td>2</td><td>3.98</td><td>(0.09-182.27)</td><td>15.0%</td><td>(-33.3-45.8)</td></tr><tr><td>At-risk occupational activity</td><td>3</td><td>7</td><td>2.85</td><td>(0.09-91.10)</td><td>19.5%</td><td>(-52.5-57.5)</td></tr><tr><td>Menarche after 13 years</td><td>9</td><td>31</td><td>11.36</td><td>(1.22-105.73)</td><td>63.8%</td><td>(4.3-86.3)</td></tr></tbody></table>

<footnote>†: Adjusted for age, sex, region and all the risk factors in the table</footnote>
4.5 Association between Sexual Behaviour and Head and neck cancer in the French
West Indies

The following is a presentation of preliminary results on sexual behaviour and Head and neck
cancer. Although the results are presented using the structure of a research article,
complementary work is necessary before submitting this manuscript.
**Association between sexual behaviour and head and neck cancer in the French West Indies**

**Words count for the main-text:** 3397

**Keywords:** Head and neck cancer; Sexual behaviour; Condom use; HPV; Sexually transmitted infection; Caribbean; French West Indies;

**Introduction**

Head and neck cancer is a public health concern across the world, counting 700,000 new cases every year [1]. Guadeloupe and Martinique are two French overseas territories in the French West Indies (FWI). In 2018, age-standardized (world) incidence rates of head and neck cancer per 100,000 were estimated to be 8.1 in Guadeloupe (men: 15.5; women: 2.1) and 5.7 in Martinique (men: 12.1; women: 0.6). Though tobacco smoking and alcohol drinking prevalence of these risk factors are relatively low in Guadeloupe and Martinique, incidence rate of these two French overseas territories are one of the highest of HNC among men in Latin America and the Caribbean [2]. Oral HPV infections are emerging as a prominent risk factor especially in oropharyngeal cancer [1, 2]. The incidence of HPV-positive HNSCC has increased as of recent and was observed during that same period decline of 50% in HPV-negative HNSCC cancer which driven by chronic tobacco and alcohol consumption [3]. We have previously demonstrated a significant association between oral Hr-HPV and HNSCC in the French West Indies (FWI) [4]. Knowing the involvement of Hr-HPV in HNSCC, it is imperative that we acquire a solid understanding of the natural history in this virus in HNSCC development. In spite of the biological similarities to cervical cancer, the etiological pathway in regards to sexual behaviour and oral HPV infection is less clear in HNSCC [6, 7]. Sexual behaviour, including oral sex and other at risk and promiscuous behaviour have been consistently regarded as plausible drivers of oral HPV infection which in turn provoke HNSCC [8–11]. However, results from previous studies are sometimes
conflicting and few data exist on this topic in populations of African descent [12]. In the current paper we proposed an analysis investigating the association between sexual behaviour and the occurrence of head and neck in the FWI and the role of oral Hr-HPV in this association. To our knowledge, this is first study addressing this topic in an Afro-Caribbean population.

## Method

### Study population, data and specimen collection

We conducted a population-based case-control study in Martinique and Guadeloupe. The study is an extension of a large nationwide case-control study, the ICARE study, which has already been conducted in ten French regions covered by a cancer registry [13]. The study in the FWI used the same protocol and questionnaire, described in details elsewhere [13], with some adaptations to the local context. Eligible cases were patients residing in the FWI, suffering from a primary, malignant tumour of the oral cavity, pharynx, sinonasal cavities and larynx of any histological type, aged between 18 and 75 years old at diagnosis, newly diagnosed and histologically confirmed between April 1, 2013 and June 30, 2016. The control group was selected from the general population by random digit dialling, using incidence density sampling method. Controls were frequency matched to the cases by sex, age and region. Additional stratification was used to achieve a distribution by socioeconomic status among the controls comparable to that of the general population.

Cases and controls were interviewed face-to-face with a standardized questionnaire including in particular sociodemographic characteristics, lifetime tobacco and alcohol consumption and sexual behavior. Participants were also asked to provide a saliva sample, using the Oragene® OG-500 kit (DNA Genotek).

Among 257 cases identified as potentially eligible, 192 (74.7%) agreed to participate and were interviewed. Among them, after diagnosis review, 22 did not meet the inclusion criteria.
Among the remaining 170 cases, 114 (72.3%) provided a saliva sample. Among the 497 eligible controls, 405 (81.5%) answered the questionnaire and among them 311 (76.2%) provided a saliva sample. Each subject included in the study gave a written and informed consent. The study was approved by the Institutional Review Board of the French National Institute of Health and Medical Research (IRB INSERM n°01-036) and by the French Data Protection Authority (n° DR-2015-2027).

## HPV detection and genotyping

The detection of HPV-integrated DNA from saliva samples was performed with the INNO-LiPA ® kit, according to the manufacturer's instructions (INNO-LiPA HPV Genotyping Extra; Innogenetics, Ghent, Belgium). The INNO-LiPA HPV genotyping assay allows the detection of the following genotypes: HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, HPV68 (High-risk), HPV26, HPV53, HPV66, HPV70, HPV73, HPV82 (Probable high-risk), HPV06, HPV11, HPV40, HPV42, HPV43, HPV44, HPV54, HPV61, HPV81 (Low-risk), HPV62, HPV67, HPV83, HPV89 (Other). The full details on the method for HPV detection has been described elsewhere [4].

## Collection of data on sexual behaviour

Lifetime sexual behavior was ascertained during the face-to-face interviews. The questionnaire included questions pertaining to the number of lifetime sex partners, sexual orientation and whether or not the last sexual intercourse took place in the last 6 months prior to the interview. Participants were asked if they ever performed certain sexual practices and the frequency at which they did them. These variables were condom use, oral sex practice, whether or not the participants had ever received sperm in their mouth, and the age at which these acts were last practiced was also noted. Information on having multiple partners, sexual intercourse in exchange for money and sexually transmitted infections (STI) also collected. Oral sex was defined as the contact between the participant's mouth and their partner's
genitalia. Having multiple partners was defined as having several sexual partners during the same period. When the frequency of an activity was requested, 4 responses were possible: just once, sometimes, often, always or almost always.

## Statistical analysis

We restricted the current analysis to squamous cell carcinomas of the oral cavity (International Classification of Diseases 10th revision codes C00.3-C00.9, C02.0-C02.3, C03.0, C03.1, C03.9, C04.1, C04.8, C04.9, C05.0, C06.0-C06.2, C06.8 and C06.9, n=35), the oropharynx (ICD-10 codes C01.9, C02.4, C05.1, C05.2, C09, C10, C14.2, n=58), the hypopharynx (ICD-10 codes C12-C13, n=19) and the larynx (ICD-10 codes C32, n=32). Our analysis included 145 cases and 405 controls. The effect of sexual behaviour variables on the occurrence of HNSCC, and oral Hr-HPV infection was assessed by estimating odds ratios (ORs) and their 95% confidence intervals (CIs), using logistic regression models. Regression analyses were adjusted for age, sex and recruitment site, tobacco, alcohol and education level. Tobacco was accounted as one variable combining the quantity (the average number of cigarettes per day over one's lifetime,) and the duration of lifetime smoking. This smoking variable was divided into 4 categories (≤20 cigarettes/day during ≤ 30 years, ≤20 cigarettes/day during >30 years, >20 cigarettes/day during ≤ 30 years and >20 cigarettes/day during > 30 years). Alcohol drinking was accounted for as the average number of glasses per day was over a lifetime, regardless of the type of beverage, and was categorised into 3 groups (<1 glass/day, 1 to 5 glasses/day and >5 glasses per day). Level of education was evaluated as the highest level of formal education obtained and was divided into four categories (primary school, secondary school, high school diploma, tertiary education).

In order to assess the role of HPV as a mediator in the relationship between sexual behaviour and HNSCC we performed logistic regressions with Hr-HPV as a covariate as well as reproducing the initial analyses by Hr-HPV subgroups (Hr-HPV-negative and Hr-HPV-
positive). Oral Hr-HPV status was assessed as high-risk-HPV-positive versus high-risk-HPV-negative, the latter category grouping HPV-negative and non-high-risk-HPV genotypes. Assuming that Hr-HPV is on the causal pathway to head and neck cancer, we considered HPV as a mediator when the association between sexual behaviour and HNSCC dissipated in the Hr-HPV-positive subgroup. Hr-HPV was also regarded as a mediator when the adjustment for Hr-HPV resulted in the loss of the initial significant association.

We also studied the associations between sexual behaviour and oral Hr-HPV infection separately among population controls and HNSCC cases.

## Results

### Sexual behaviour and Head and neck cancer

Table 1 shows the association between sexual behaviour and HNSCC. Last intercourse beyond 6 months preceding the interview was positively associated with the occurrence of HNSCC. Having sexual intercourse after the age of 18 year was associated with 60% reduction of HNSCC risk, compared to those who began before 15 years. Similarly, HNSCC risk was significantly reduced by 50% among persons who used condoms at least occasionally (once, sometimes). In addition, after adjustment for main confounding variables, condom users were twice as likely to have engaged in sexual intercourse in the 6 month prior to their interview (OR=2.52, 95% CI=1.51-4.18) (Data not shown). Although non-significant compared to persons who never practiced oral sex, those who had practiced at least occasionally were less likely to have HNSCC. Receiving money for performing sexual intercourse was uncommon in our study, there were only 6 controls who responded “yes”, and represented 1% of the general population. Lifetime sex partners, sexual orientation, paying for sex, and having multiple partners were not associated with HNSCC.
We were interested in the role of Hr-HPV in the mediation of the associations between sexual
behaviour and HNSCC from our analyses. Table 2 shows association between age at first
intercourse, time since last intercourse, condom use, oral sex and HNSCC after stratification
and adjustment for Hr-HPV. The associations observed for age at intercourse were
unchanged after adjusting for Oral Hr-HPV and stratification. However, the associations for
time since last intercourse, ever condom use and oral sex were accentuated following the
adjustment for Hr-HPV. In addition, the significant effects of condom use and time since last
intercourse on HNSCC appeared only in Hr-HPV-negative HNSCC whereas the association
with oral sex remained non-significant regardless of HPV status.

We were then interested in the link between significantly associated sexual behaviour
variables in regards to HNSCC risk. Table 3 shows the effect of age at sexual debut on
HNSCC adjusted for ever condom use and stratified by condom use frequency. Age at first
intercourse remained significantly associated with an increase in HNSCC risk but only
among persons who used condoms inconsistently (once or sometimes) or not all. Similarly,
the significant association disappeared following the adjustment on ever condom use. When
compared to having few lifetime sexual partners (1 to 5), higher numbers of partners were
neither associated with HNSCC in the subgroup of regular oral sex (6 to 20, OR=0.34
95%CI=0.06-1.88; >20, OR=0.62 95%CI=0.12-3.22) nor in the subgroup practicing oral sex
sparingly (once or sometimes) or never (6 to 20, OR=0.52 95%CI=0.25-1.09; >20, OR=0.68
95%CI=0.26-1.78) (Table 4).

We also examined the effect of Hr-HPV on HNSCC risk taking into account significant
sexual behaviour variables individually and in different combinations as covariates in the
multivariate model (Table 5). Adjustment for ever condom use, and/or oral sex tended to
increase slightly the effect of Hr-HPV on HNSCC risk (relative variation=15-26%) contrarily
to age at first sexual intercourse which caused a slight decrease. Overall, the association
between Hr-HPV and HNSCC was not markedly changed after adjustment for sexual
behaviour variables.

Oral HPV and sexual behaviour in population controls and in HNSCC cases

Table 6 shows the association between sexual behaviour and oral Hr-HPV infection in population controls and among HNSCC cases. After adjusting for confounding factors, none of the sexual behaviour variables studied in the current paper were significantly associated with oral HPV infections in controls, who may be considered as representative of the general FWI population. However, oral Hr-HPV was non-significantly associated with an increase in the frequency of oral sex. Although not significant, first intercourse before 15 years appeared to occur more frequently in Hr-HPV-positive controls compared to persons who began intercourse after 18 years. Likewise, Hr-HPV-positive controls were non-significantly more likely to use condoms at least once, and have repeated sexually transmitted infections when compared to control who never had an STI.

In contrast, the associations between sexual behaviour and oral Hr-HPV infections were consistently more apparent in HNSCC cases. Cases who had a sexual debut between the ages of 15-18 years were significantly less likely to be positive for Hr-HPV. A fewer number lifetime sex partners was more frequent among Hr-HPV-negative cases compared to their Hr-HPV-positive counterparts (51% vs. 35%). Non-heterosexual cases were significantly more likely to have an oral Hr-HPV infection when compared to heterosexuals. Practicing oral sex regularly (often or always) was associated with Hr-HPV positivity when compared to cases who never practiced. In addition, recent oral sex encounters (<1 year) preceding the interview were more frequent among the Hr-HPV-positive cases than their Hr-HPV-negative counterparts. The use of condoms was associated with a non-significant increase in the likelihood of a case having an oral Hr-HPV infection. Cases were significantly more likely to
be positive for Hr-HPV when they had multiple sexual partners simultaneously from more
than 5 years preceding the interview

Discussion

The data from our study revealed significant associations between age at first intercourse
condom use, time since last sexual intercourse, and HNSCC risk. We found no clear
association in the population controls with any of the indicators studied. Case-to-case
comparisons however, yielded evidence that is in favour of an association between risky
sexual behaviour and oral Hr-HPV infection.

Ever oral sex did not reach statistical significance but it was inversely associated with HNSCC, similarly to results from other studies, including a large pooled analysis from the INHANCE consortium [8, 14]. On the contrary, these results opposed findings which highlight rather a positive association with ever oral sex and head and neck cancer [15-17].

Our study did not provide any evidence of an association between the number of lifetime
intercourse partners and HNSCC which was concordant with previous findings [9, 17, 18].

We stratified the number of lifetime sex partner by oral sex frequency in an attempt to
produce a proxy for oral sex partners. Even in persons who perform oral sex often or always,
the number of lifetime oral sex partners did not yield any significant association with HNSCC
risk which corresponded to previous reports on number of oral sex partners [17, 18].

In regards to oral Hr-HPV infections in the control group, we unable to highlight any clear
association with sexual behaviour based on the variables we studied. Although non-
significant, oral sex appeared to increase the risk of Hr-HPV infections in population controls
which coincided with a previous study [16]. Given the absence of significant association with
sexual behaviour and Hr-HPV in population controls, other factors such as fomites or self-
inoculation could be considered as means of contamination in the general population [19].
Despite the lack of the putative effects of oral sex, and number of sexual partners [8, 15, 16, 20, 21] on HPV transmission and HNSCC in our study, we were able to highlight associations with other sexual behaviour indicators. We found that persons who had their first sexual intercourse at a younger age were at a greater risk of HNSCC compared to a sexual debut after the age of 18. These findings coincided with other studies [9, 18]; however, summary estimates from a meta-analysis suggest that overall, age at first intercourse did not affect HNSCC risk significantly [15]. In terms of this association between sexual behaviour and oral Hr-HPV infection, our positive association for sexual intercourse debut between 15-18 years among HNSCC cases was consistent with another study [22] but discordant with the non-significant association described in previous reports [20, 23, 24]. The positive associations we observed for oral sex and oral HPV infections among cases were consistent with previous reports [8, 20, 23] whereas same-sex contact was discordant in a study having done a similar analysis [23]. Data on multiple partners and HPV positivity in HNSCC cases was less frequent but our results were consistent with reports which mentioned that women with multiple partners were at higher risk for cervical cancer [6].

Regarding the use of condoms, we observed a significant protective effect for ever condom use on HNSCC, similarly to another case-control study on oropharyngeal cancer [9]. The observed association with age at first intercourse disappeared after adjusting for ever condom use, and in subgroup analysis among persons who used condoms regularly (often or always). On the other hand, this significant association was maintained in the subgroup of person who used condoms very inconsistently or not at all; thus, reinforcing the evidence that association between age at sexual debut and HNSCC is mediated by risky sexual habits [25].

Despite the associations observed between sexual behaviour and HNSCC, we did not find any evidence of an association mediated by oral Hr-HPV infections. Indeed, ever condom use was significantly associated with a reduction in HNSCC risk; however, this effect was neither
attenuated after adjusting for Hr-HPV nor in HPV-negative subject alone. Furthermore, the association between condom use and oral Hr-HPV in both control and cases was non-significantly negative. Contrarily to a Canadian study [16], our results allude to a risk reduction by condom use which is independent of oral Hr-HPV infections.

Subjects who had their last sexual intercourse from more than 6 months from their interview were significantly more likely to have HNSCC. There were not any studies which looked at this particular indicator [26] but this difference could have arisen from bodily changes linked to their illness which could have reduced their desire to initiate in sexual intercourse [27].

Information on HIV seropositivity, which has been shown to influence sexual behaviour [28, 29] was not available. Moreover, HIV-seropositivity is known to be associated with greater HPV prevalence and can potentiate the carcinogenic activity of an HPV infection and thus, would clarify the differences in HPV transmission through sexual behaviour between cases and controls [30–35].

Our study presents several limitations. Our findings are exposed to the possibility of a recall bias due to the retrospective nature of the case-control Furthermore, we had a small sample size and we were not able to perform analyses by anatomical subsite. In addition, sexual behaviour in the Caribbean is regarded as a taboo [36] and could induce misclassification bias, in particular in regards to number of sexual partners. Our sample comprising mainly of men, the average number of sexual partners may be more likely to be overestimated [37]. In terms of sexual orientation, homosexuality is thought to be underestimated in our sample because of discrimination faced by this group in the FWI [38]. Furthermore, the use of oral HPV detection to assess the HPV status may have caused misclassification. Oral HPV detection has been shown to have good specificity but moderate sensitivity for HPV-positive HNSCC tumours [39].
Selection bias may not be ruled out but is thought to be kept to minimum in the present
analysis. There were more missing data in cases than in controls; however, we do not believe
that omission of this part of the question was linked to sexual behaviour. In addition, the
questions pertaining to sexual behaviour were at the end of the questionnaire and cases
tended to stop the interview prior to those questions more often than controls due to fatigue.
27% of the data for HPV was missing in our sample which imposed the removal of a large
proportion of subjects from our regression analysis and thus, resulted in a reduction in
statistical power in our analyses involving HPV. Nevertheless, the distribution by sex, age
and cancer sites of the cases included in our study was similar to that of the cases in the local
cancer registries. Our study population can thus be considered representative of the HNSCC
cases. The method used to select the control group was previously demonstrated to yield
unbiased samples and the controls could be considered representative of the general
population of similar age and sex [24]. We confirmed the representativeness of sexual
behaviour distribution in our control group to FWI population after comparison with the data
from a regional KABP survey [40]. During our study, we did not collect any information on
HIV status which is a factor suspected to modify the natural history of HPV in head and neck
cancer [34] and could provide clues to link between sexual behaviour and head and neck
cancer considering that the prevalence of HIV is high in the FWI [41, 42]. Future studies on
sexual behaviour should take into account HIV and other viral agents to better understand the
biological mechanism between sexual behaviour and neck cancer.

Conclusion

This is the first study to investigate the role of sexual behaviour in the occurrence of head and
neck in an Afro-Caribbean population while taking into account oral HPV infections. In light
of our analyses, first intercourse before 15, time interval since last intercourse and never
condom use were positively associated with HNSCC independently of oral Hr-HPV infection. Oral Hr-HPV infections were associated with riskier sexual behaviour in HNSCC cases but not in population controls. These results do not provide any strong evidence of Hr-HPV as a mediator of these observed associations, in particular with condom use. However, other sources of contamination such as fomites, as well as HIV infections could play a role in the causal pathway to HNSCC. Further investigation on this topic in the FWI is warranted and special attention should be given to the interaction between viral factors to better substantiate the natural history of HPV in HNSCC thus, providing additional prospects for prevention.
References

1. Gillison ML, Broutian T, Pickard RKL, et al (2012) Prevalence of oral HPV infection in the United States, 2009-2010. JAMA 307:693-703.
https://doi.org/10.1001/jama.2012.101

2. Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C (2015) Epidemiology of Human Papillomavirus-Positive Head and Neck Squamous Cell Carcinoma. J Clin Oncol 33:3235-3242. https://doi.org/10.1200/JCO.2015.61.6995

3. Chaturvedi AK, Engels EA, Pfeiffer RM, et al (2011) Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States. J Clin Oncol 29:4294-4301.
https://doi.org/10.1200/JCO.2011.36.4596

4. Auguste A, Gaëte S, Herrmann-Storck C, et al (2017) Prevalence of oral HPV infection among healthy individuals and head and neck cancer cases in the French West Indies. Cancer Causes Control 28:1333-1340. https://doi.org/10.1007/s10552-017-0966-z

5. Castellsagué X, Alemany L, Quer M, et al (2016) HPV Involvement in Head and Neck Cancers: Comprehensive Assessment of Biomarkers in 3680 Patients. J Natl Cancer Inst 108:djv403. https://doi.org/10.1093/jnci/djv403

6. Alexander ER (1973) Possible Etiologies of Cancer of the Cervix Other Than Herpesvirus. Cancer Res 33:1485-1490

7. Gillison ML, Alemany L, Snijders PJF, et al (2012) Human Papillomavirus and Diseases of the Upper Airway: Head and Neck Cancer and Respiratory Papillomatosis. Vaccine 30:F34-F54. https://doi.org/10.1016/j.vaccine.2012.05.070

8. Heck JE, Berthiller J, Vaccarella S, et al (2010) Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol 39:166-181.
https://doi.org/10.1093/ije/dyp350

9. D'Souza G, Kreimer AR, Viscidi R, et al (2007) Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356:1944-1956.
https://doi.org/10.1056/NEJMoa065497

10. Dahlstrom KR, Burchell AN, Ramanakumar AV, et al (2014) Sexual transmission of oral human papillomavirus infection among men. Cancer Epidemiol Biomarkers Prev 23:2959-2964. https://doi.org/10.1158/1055-9965.EPI-14-0386

11. D'Souza G, Agrawal Y, Halpern J, et al (2009) Oral Sexual Behaviors Associated with Prevalent Oral Human Papillomavirus Infection. J Infect Dis 199:1263-1269.
https://doi.org/10.1086/597755

12. Garrote LF, Herrero R, Reyes RM, et al (2001) Risk factors for cancer of the oral cavity and oro-pharynx in Cuba. Br J Cancer 85:46-54. https://doi.org/10.1054/bjoc.2000.1825

13. Luce D, Stücker I, ICARE Study Group (2011) Investigation of occupational and environmental causes of respiratory cancers (ICARE): a multicenter, population-based
case-control study in France. BMC Public Health 11:928. https://doi.org/10.1186/1471-2458-11-928

14. Maden C, Beckmann AM, Thomas DB, et al (1992) Human Papillomaviruses, Herpes Simplex Viruses, and the Risk of Oral Cancer in Men. Am J Epidemiol 135:1093-1102.
https://doi.org/10.1093/oxfordjournals.aje.a116209

15. Farsi NJ, El-Zein M, Gaied H, et al (2015) Sexual behaviours and head and neck cancer: A systematic review and meta-analysis. Cancer Epidemiol 39:1036-1046.
https://doi.org/10.1016/j.canep.2015.08.010

16. Laprise C, Madathil SA, Schlecht NF, et al (2019) Increased risk of oropharyngeal cancers mediated by oral human papillomavirus infection: Results from a Canadian study. Head Neck 41:678-685. https://doi.org/10.1002/hed.25436

17. Rajkumar T, Sridhar H, Balaram P, et al (2003) Oral cancer in Southern India: the influence of body size, diet, infections and sexual practices. European Journal of Cancer Prevention 12:135-143

18. Schwartz SM, Daling JR, Doody DR, et al (1998) Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst 90:1626-1636

19. Ryndock EJ, Meyers C (2014) A risk for non-sexual transmission of human papillomavirus? Expert Review of Anti-infective Therapy 12:1165-1170.
https://doi.org/10.1586/14787210.2014.959497

20. Dahlstrom KR, Li G, Tortolero - Luna G, et al (2011) Differences in history of sexual behavior between patients with oropharyngeal squamous cell carcinoma and patients with squamous cell carcinoma at other head and neck sites. Head & Neck 33:847-855.
https://doi.org/10.1002/hed.21550

21. Castellsagué X (2008) Natural history and epidemiology of HPV infection and cervical cancer. Gynecol Oncol 110:S4-7. https://doi.org/10.1016/j.ygyno.2008.07.045

22. Anaya-Saavedra G, Ramírez-Amador V, Irigoyen-Camacho MaE, et al (2008) High Association of Human Papillomavirus Infection with Oral Cancer: A Case-Control Study. Archives of Medical Research 39:189-197.
https://doi.org/10.1016/j.arcmed.2007.08.003

23. Bahl A, Kumar P, Dar L, et al (2014) Prevalence and trends of human papillomavirus in oropharyngeal cancer in a predominantly north Indian population. Head & Neck 36:505-510. https://doi.org/10.1002/hed.23317

24. Baumeister P, Reiter M, Welz C, et al (2014) Surgically treated oropharyngeal cancer: risk factors and tumor characteristics. J Cancer Res Clin Oncol 140:1011-1019.
https://doi.org/10.1007/s00432-014-1631-5

25. Kahn JA, Rosenthal SL, Succop PA, et al (2002) Mediators of the association between age of first sexual intercourse and subsequent human papillomavirus infection. Pediatrics 109:E5. https://doi.org/10.1542/peds.109.1.e5
26. Chancellor JA, Ioannides SJ, Elwood JM (2016) Oral and oropharyngeal cancer and the role of sexual behaviour: a systematic review. Community Dent Oral Epidemiol. https://doi.org/10.1111/cdoe.12255

27. Stanton AM, Handy AB, Meston CM (2018) Sexual function in adolescents and young adults diagnosed with cancer: A systematic review. J Cancer Surviv 12:47–63. https://doi.org/10.1007/s11764-017-0643-y

28. Eaton LA, Kalichman SC (2009) Changes in Transmission Risk Behaviors Across Stages of HIV Disease among People Living with HIV/AIDS. J Assoc Nurses AIDS Care 20:39–49. https://doi.org/10.1016/j.jana.2008.10.005

29. Poon CM, Wong NS, Kwan TH, et al (2018) Changes of sexual risk behaviors and sexual connections among HIV-positive men who have sex with men along their HIV care continuum. PLOS ONE 13:e0209008. https://doi.org/10.1371/journal.pone.0209008

30. Strickler HD, Burk RD, Fazzari M, et al (2005) Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst 97:577–586. https://doi.org/10.1093/jnci/dji073

31. Massad LS, Ahdieh L, Benning L, et al (2001) Evolution of cervical abnormalities among women with HIV-1: evidence from surveillance cytology in the women’s interagency HIV study. J Acquir Immune Defic Syndr 27:432–442. https://doi.org/10.1097/00126334-200108150-00003

32. Kreimer AR, Alberg AJ, Daniel R, et al (2004) Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 189:686–698. https://doi.org/10.1086/381504

33. Beachler DC, D'Souza G (2013) Oral HPV infection and head and neck cancers in HIV-infected individuals. Curr Opin Oncol 25:503–510. https://doi.org/10.1097/CCO.0b013e32836242b4

34. Beachler DC, Weber KM, Margolick JB, et al (2012) Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults. Cancer Epidemiol Biomarkers Prev 21:122–133. https://doi.org/10.1158/1055-9965.EPI-11-0734

35. Abel S, Najioullah F, Voluménie J-L, et al (2019) High prevalence of human papillomavirus infection in HIV-infected women living in French Antilles and French Guiana. PLOS ONE 14:e0221334. https://doi.org/10.1371/journal.pone.0221334

36. Sharpe J, Pinto S (2006) The Sweetest Taboo: Studies of Caribbean Sexualities; A Review Essay. Signs: Journal of Women in Culture and Society 32:247–274. https://doi.org/10.1086/505541

37. Smith TW (1992) Discrepancies between men and women in reporting number of sexual partners: a summary from four countries. Soc Biol 39:203–211

38. Chadee D, Joseph C, Peters C, et al (2013) Religiosity, and Attitudes Towards Homosexuals in a Caribbean Environment. Social and Economic Studies 62:1–28
39. Gipson BJ, Robbins HA, Fakhry C, D'Souza G (2018) Sensitivity and specificity of oral HPV detection for HPV-positive head and neck cancer. Oral Oncol 77:52-56.
https://doi.org/10.1016/j.oraloncology.2017.12.008

40. Halfen S, Lydié N (2014) Les habitants des Antilles et de la Guyane face au VIH/SIDA et à d'autres risques sexuels. Observatoire régional de santé d'île-de-France, Paris

41. Elenga N, Georger-Sow M-T, Messiaen T, et al (2013) Incidence and Risk Factors for Follow-Up Interruption of HIV-Infected Patients in Guadeloupe

42. Géodes - Santé publique France - Indicateurs : cartes, données et graphiques.
https://geodes.santepubliquefrance.fr/#c=indicator&selcgeo=971&view=map2.
Accessed 4 Oct 2019
<table><caption>**Table 1:** Association between sexual behaviour and HNSCC</caption><thead><tr><th></th><th>Case<br>n (col%)</th><th>Control<br>n (col%)</th><th>OR</th><th>95% CI</th></tr></thead><tbody><tr><td><strong>Age at first sexual intercourse (years)</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 15</td><td>39 (33.9)</td><td>71 (17.9)</td><td>1</td><td>ref</td></tr><tr><td>15 - 18</td><td>61 (53.0)</td><td>217 (54.8)</td><td>0.58</td><td>(0.31-1.06)</td></tr><tr><td>&gt; 18</td><td>15 (13.0)</td><td>108 (27.3)</td><td>0.41</td><td>(0.19-0.91)</td></tr><tr><td>Missing</td><td>30</td><td>9</td><td></td><td></td></tr><tr><td><strong>Time since last intercourse (months)</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 6</td><td>61 (56.5)</td><td>309 (79.2)</td><td>1</td><td>ref</td></tr><tr><td>&gt; 6</td><td>47 (43.5)</td><td>81 (20.8)</td><td>2.35</td><td>(1.32-4.18)</td></tr><tr><td>Missing</td><td>37</td><td>15</td><td></td><td></td></tr><tr><td><strong>Number of lifetime partners</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>10 (9.3)</td><td>36 (9.2)</td><td>1</td><td>ref</td></tr><tr><td>2 to 5</td><td>37 (34.3)</td><td>141 (36.1)</td><td>1,59</td><td>(0.55-4.59)</td></tr><tr><td>6 to 9</td><td>16 (14.8)</td><td>58 (14.8)</td><td>1,34</td><td>(0.39-4.58)</td></tr><tr><td>10 to 20</td><td>17 (15.7)</td><td>96 (24.6)</td><td>0,58</td><td>(0.18-1.89)</td></tr><tr><td>20 to 50</td><td>17 (15.7)</td><td>34 (8.7)</td><td>1,41</td><td>(0.40-4.97)</td></tr><tr><td>50 to 100</td><td>6 (5.6)</td><td>15 (3.8)</td><td>0,69</td><td>(0.15-3.16)</td></tr><tr><td>&gt; 100</td><td>5 (4.6)</td><td>9 (2.3)</td><td>2,02</td><td>(0.39-10.51)</td></tr><tr><td>Missing</td><td>37</td><td>16</td><td></td><td></td></tr><tr><td><strong>Number of lifetime partners</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>1 to 5</td><td>47 (43.5)</td><td>177 (45.5)</td><td>1</td><td>ref</td></tr><tr><td>6 to 20</td><td>33 (30.6)</td><td>154 (39.6)</td><td>0.56</td><td>(0.29-1.07)</td></tr><tr><td>&gt; 20</td><td>28 (25.9)</td><td>58 (14.9)</td><td>0.87</td><td>(0.41-1.85)</td></tr><tr><td>Missing</td><td>37</td><td>16</td><td></td><td></td></tr><tr><td><strong>Sexual orientation</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Heterosexual</td><td>89 (80.9)</td><td>345 (88.7)</td><td>1</td><td>ref</td></tr><tr><td>Non-Heterosexual</td><td>21 (19.1)</td><td>44 (11.3)</td><td>1.77</td><td>(0.86-3.67)</td></tr><tr><td>Missing</td><td>35</td><td>16</td><td></td><td></td></tr><tr><td><strong>Condom use</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>61 (57.0)</td><td>303 (77.3)</td><td>0.51</td><td>(0.28-0.93)</td></tr><tr><td>Never</td><td>46 (43.0)</td><td>89 (22.7)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>38</td><td>13</td><td></td><td></td></tr><tr><td><strong>Condom use, frequency</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>46 (43.0)</td><td>89 (22.6)</td><td>1</td><td>ref</td></tr><tr><td>Once, sometimes</td><td>40 (37.4)</td><td>183 (46.5)</td><td>0.51</td><td>(0.27-0.97)</td></tr><tr><td>Often, always or almost always</td><td>21 (19.6)</td><td>122 (31.0)</td><td>0.51</td><td>(0.24-1.08)</td></tr><tr><td>Missing</td><td>38</td><td>11</td><td></td><td></td></tr><tr><td><strong>Oral sex</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>69 (63.3)</td><td>288 (72.4)</td><td>0.76</td><td>(0.42-1.38)</td></tr><tr><td>Never</td><td>40 (36.7)</td><td>106 (26.6)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>36</td><td>11</td><td></td><td></td></tr><tr><td><strong>Oral sex, frequency</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>40 (37.0)</td><td>106 (27.4)</td><td>1</td><td>ref</td></tr><tr><td>Once, sometimes</td><td>39 (36.1)</td><td>201 (51.9)</td><td>0.67</td><td>(0.35-1.27)</td></tr><tr><td>Often, always or almost always</td><td>29 (26.9)</td><td>80 (20.7)</td><td>0.88</td><td>(0.41-1.89)</td></tr><tr><td>Missing</td><td>37</td><td>18</td><td></td><td></td></tr><tr><td><strong>Received sperm in mouth</strong></td><td></td><td></td><td></td><td></td></tr></tbody></table>
<table><tbody><tr><td>Never oral sex, never sperm, just once</td><td>66 (90.4)</td><td>233 (91.4)</td><td>1</td><td>ref</td></tr><tr><td>Sometimes, often, always or almost always</td><td>7 (9.6)</td><td>22 (8.6)</td><td>1.81</td><td>(0.56-5.92)</td></tr><tr><td>Missing</td><td>72</td><td>150</td><td></td><td></td></tr><tr><td><strong>Paid for sex</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>27 (24.1)</td><td>95 (23.9)</td><td>1</td><td>ref</td></tr><tr><td>Never</td><td>85 (75.9)</td><td>302 (76.1)</td><td>1.54</td><td>(0.82-2.86)</td></tr><tr><td>Missing</td><td>33</td><td>8</td><td></td><td></td></tr><tr><td><strong>STI, Frequency</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>75 (68.8)</td><td>248 (63.1)</td><td>1</td><td>ref</td></tr><tr><td>Once</td><td>11 (10.1)</td><td>60 (15.3)</td><td>0.51</td><td>(0.19-1.18)</td></tr><tr><td>More than once</td><td>23 (21.1)</td><td>85 (21.6)</td><td>0.88</td><td>(0.44-1.74)</td></tr><tr><td>Missing</td><td>36</td><td>12</td><td></td><td></td></tr><tr><td><strong>Recent multiple partners</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Never multiple partners</td><td>68 (61.3)</td><td>244 (61.8)</td><td>1</td><td>ref-</td></tr><tr><td>≤ 5 years</td><td>12 (10.8)</td><td>42 (10.3)</td><td>0.93</td><td>(0.39-2.22)</td></tr><tr><td>> 5 years</td><td>31 (27.9)</td><td>109 (27.6)</td><td>0.81</td><td>(0.40-1.48)</td></tr><tr><td>Missing</td><td>34</td><td>10</td><td></td><td></td></tr></tbody></table>

a: OR adjusted for age, sex, recruitment site, cigarette quantity and duration combined, alcohol quantity and level of education
<table><caption>**Table 2:** Association between age at first intercourse, condom use, oral sex and HNSCC after adjusting for Hr-HPV and stratification on Hr-HPV status</caption><thead><tr><th></th><th>Ca</th><th>Co</th><th>Univariate<br>OR<sup>a</sup> (95% CI)</th><th>Conf<br>OR<sup>b</sup> (95% CI)</th><th>Conf+Hr-HPV<br>OR<sup>c</sup> (95% CI)</th><th>Hr-HPV-<br>OR<sup>b</sup> (95% CI)</th><th>Hr-HPV+<br>OR<sup>b</sup> (95% CI)</th></tr></thead><tbody><tr><td><strong>Age at first sexual intercourse</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 15</td><td>39</td><td>71</td><td>3.44 (1.73-6.85)</td><td>2.42 (1.09-5.33)</td><td>2.32 (0.92-5.28)</td><td>2.60 (0.90-7.49)</td><td>NA</td></tr><tr><td>15 - 18</td><td>61</td><td>217</td><td>1.87 (1.01-3.49)</td><td>1.38 (0.68-2.78)</td><td>1.34 (0.59-3.05)</td><td>1.20 (0.47-3.05)</td><td>NA</td></tr><tr><td>&gt; 18</td><td>15</td><td>108</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td></tr><tr><td><strong>Time since last intercourse</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 6</td><td>69</td><td>288</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td></tr><tr><td>&gt; 6</td><td>40</td><td>106</td><td>3.34 (2.07-5.39)</td><td>2.37 (1.33-4.22)</td><td>3.09 (1.53-6.25)</td><td>2.39 (1.11-5.13)</td><td>10.90 (0.72-165.34)</td></tr><tr><td><strong>Condom use</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>61</td><td>303</td><td>0.32 (0.20-0.52)</td><td>0.51 (0.28-0.93)</td><td>0.33 (0.16-7.0)</td><td>0.30 (0.13-7.0)</td><td>0.56 (0.08-4.01)</td></tr><tr><td>Never</td><td>46</td><td>89</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td></tr><tr><td><strong>Oral sex</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>69</td><td>288</td><td>0.56 (0.35-0.90)</td><td>0.76 (0.42-1.38)</td><td>0.49 (0.24-0.99)</td><td>0.56 (0.25-1.23)</td><td>0.22 (0.02-2.58)</td></tr><tr><td>Never</td><td>40</td><td>106</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td><td>1 (ref)</td></tr></tbody></table>

Conf: confounders

a: OR adjusted for age, sex, recruitment site

b: OR adjusted for age, sex, recruitment site, cigarette quantity and duration combined, alcohol quantity and level of education

c: OR adjusted for age, sex, recruitment site, cigarette quantity and duration combined, alcohol quantity and level of education and high-risk HPV status

NA: Estimates were not computed because of convergence issues in the regression model due to few subjects.
<table><caption>**Table 3:** Association between Age at first intercourse and head and neck cancer stratified by Frequency of condom use</caption><thead><tr><th rowspan="2">Age at first sexual intercourse</th><th colspan="2">All subjects</th><th colspan="6">Condom use</th></tr><tr><th>OR<sup>b</sup></th><th>(95% CI)</th><th>Ca</th><th>Co</th><th>Often, Always</th><th>Ca</th><th>Co</th><th>Never, Once, Sometimes</th></tr></thead><tbody><tr><td>&lt;15</td><td>2.01</td><td>(0.87-4.65)</td><td>9</td><td>18</td><td>0.78</td><td>(0.07-9.23)</td><td>23</td><td>50</td><td>4.00</td><td>(0.97-16.48)</td></tr><tr><td>15-18</td><td>1.53</td><td>(0.73-3.20)</td><td>17</td><td>50</td><td>0.46</td><td>(0.05-4.22)</td><td>42</td><td>161</td><td>2.92</td><td>(0.80-10.70)</td></tr><tr><td>&gt;18</td><td>1</td><td>ref</td><td>3</td><td>12</td><td>1</td><td>ref</td><td>12</td><td>94</td><td>1</td><td>ref</td></tr></tbody></table>

a: OR adjusted for age, sexe, recruitment site, cigarette quantity and duration combined, alcohol quantity and level of education

b: Model from “a” further adjusted for ever condom use

<table><caption>**Table 4:** Number of lifetime sexual partners stratified by oral sex frequency</caption><thead><tr><th rowspan="3">Number of lifetime partners</th><th colspan="4">Oral sex frequency</th></tr><tr><th colspan="2">Often or always</th><th colspan="2">Never, Once, Sometimes</th></tr><tr><th>OR</th><th>95% CI</th><th>OR</th><th>95% CI</th></tr></thead><tbody><tr><td>1 to 5</td><td>1.00</td><td>ref</td><td></td><td>ref</td></tr><tr><td>6 to 20</td><td>0.34</td><td>(0.06-1.88)</td><td>0.52</td><td>(0.25-1.09)</td></tr><tr><td>&gt; 20</td><td>0.62</td><td>(0.12-3.22)</td><td>0.68</td><td>(0.26-1.78)</td></tr></tbody></table>
<table><caption>**Table 5:** Association between Hr-HPV and HNSCC risk after adjusting for age at first intercourse, condom use and oral sex</caption><thead><tr><th>Covariate(s)</th><th>Hr-HPV-</th><th>OR</th><th>(95% CI)</th></tr></thead><tbody><tr><td>Univariate<sup>a</sup></td><td>Hr-HPV+</td><td>2.23</td><td>(1.17-4.25)</td></tr><tr><td>Univariate+Confounders<sup>b</sup></td><td>Hr-HPV+</td><td>2.23</td><td>(0.98-5.11)</td></tr><tr><td>Univariate+Confounders<sup>b+</sup>:</td><td>Hr-HPV+</td><td></td><td></td></tr><tr><td>Age at first sexual intercourse</td><td>Hr-HPV+</td><td>2.00</td><td>(0.86-4.70)</td></tr><tr><td>Condom use</td><td>Hr-HPV+</td><td>2.69</td><td>(1.13-6.39)</td></tr><tr><td>Oral sex</td><td>Hr-HPV+</td><td>2.57</td><td>(1.11-5.96)</td></tr><tr><td>Condom use+ Oral sex</td><td>Hr-HPV+</td><td>2.80</td><td>(1.18-6.64)</td></tr><tr><td>Age at first sexual intercourse+Condom use</td><td>Hr-HPV+</td><td>2.46</td><td>(1.02-5.93)</td></tr><tr><td>Age at first sexual intercourse+Oral sex</td><td>Hr-HPV+</td><td>2.41</td><td>(1.02-5.67)</td></tr><tr><td>Age at first sexual intercourse+Condom use+ Oral sex</td><td>Hr-HPV+</td><td>2.59</td><td>(1.08-6.23)</td></tr></tbody></table>

a: OR adjusted for age, sexe, recruitment site

b: OR adjusted for age, sex, recruitment site, cigarette quantity and duration combined, alcohol quantity and level of education
<table><caption>**Table 6:** Association between sexual behaviour and Oral HPV infection in population controls and HNSCC cases</caption><thead><tr><th rowspan="2"></th><th colspan="4">Controls</th><th colspan="4">Cases</th></tr><tr><th>Hr-HPV-<br>n (col%)</th><th>Hr-HPV+<br>n (col%)</th><th>OR<sup>a</sup></th><th>95% CI</th><th>Hr-HPV-<br>n (col%)</th><th>Hr-HPV+<br>n (col%)</th><th>OR<sup>a</sup></th><th>95% CI</th></tr></thead><tbody><tr><td><strong>Age at first sexual intercourse (years)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 15</td><td>45 (16.6)</td><td>7 (23.3)</td><td>1</td><td>ref</td><td>21 (31.3)</td><td>9 (50.0)</td><td>1</td><td>ref</td></tr><tr><td>15 - 18</td><td>149 (55.0)</td><td>18 (60.0)</td><td>1.05</td><td>(0.38-2.91)</td><td>36 (53.7)</td><td>7 (38.9)</td><td>0.15</td><td>(0.03-0.85)</td></tr><tr><td>&gt; 18</td><td>77 (28.4)</td><td>5 (16.7)</td><td>0.65</td><td>(0.18-2.36)</td><td>10 (14.9)</td><td>2 (11.1)</td><td>0.10</td><td>(0.01-1.44)</td></tr><tr><td>Missing</td><td>6</td><td>0</td><td></td><td></td><td>6</td><td>1</td><td></td><td></td></tr><tr><td><strong>Time since last intercourse (months)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 6</td><td>213 (79.5)</td><td>27 (93.1)</td><td>1</td><td>ref</td><td>34 (54.0)</td><td>11 (64.7)</td><td>1</td><td>ref</td></tr><tr><td>&gt; 6</td><td>55 (20.5)</td><td>2 (6.9)</td><td>0.26</td><td>(0.05-1.27)</td><td>29 (46.0)</td><td>6 (35.3)</td><td>0.93</td><td>(0.20-4.31)</td></tr><tr><td>Missing</td><td>8</td><td>2</td><td></td><td></td><td>10</td><td>2</td><td></td><td></td></tr><tr><td><strong>Number of lifetime partners</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 to 5</td><td>124 (46.8)</td><td>8 (27.6)</td><td>1</td><td>ref</td><td>33 (51.6)</td><td>6 (35.3)</td><td>1</td><td>ref</td></tr><tr><td>6 to 20</td><td>106 (40.0)</td><td>15 (51.7)</td><td>1.89</td><td>(0.69-5.16)</td><td>17 (26.6)</td><td>6 (35.3)</td><td>3.88*</td><td>(0.32-46.74)</td></tr><tr><td>&gt; 20</td><td>35 (13.2)</td><td>6 (20.7)</td><td>1.27</td><td>(0.34-4.70)</td><td>14 (21.9)</td><td>5 (29.4)</td><td>8.59*</td><td>(0.86-85.66)</td></tr><tr><td>Missing</td><td>12</td><td>1</td><td></td><td></td><td>9</td><td>2</td><td></td><td></td></tr><tr><td><strong>Sexual orientation</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Heterosexual</td><td>237 (89.1)</td><td>26 (86.7)</td><td>1</td><td>ref</td><td>51 (86.7)</td><td>9 (50.0)</td><td>1</td><td>ref</td></tr><tr><td>Non-Heterosexual</td><td>29 (10.9)</td><td>4 (13.3)</td><td>0.78</td><td>(0.23-2.67)</td><td>12 (13.3)</td><td>9 (50.0)</td><td>6.37</td><td>(1.23-33.04)</td></tr><tr><td>Missing</td><td>11</td><td>0</td><td></td><td></td><td>10</td><td>1</td><td></td><td></td></tr><tr><td><strong>Condom use</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>208 (78.3)</td><td>26 (86.7)</td><td>1.54</td><td>(0.45-5.27)</td><td>33 (54.1)</td><td>12 (66.7)</td><td>2.82</td><td>(0.56-14.41)</td></tr><tr><td>Never</td><td>61 (21.7)</td><td>4 (13.3)</td><td>1</td><td>ref</td><td>28 (45.9)</td><td>6 (33.3)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>8</td><td>0</td><td></td><td></td><td>12</td><td>1</td><td></td><td></td></tr><tr><td><strong>Condom use, frequency</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>61 (22.7)</td><td>4 (13.3)</td><td>1</td><td>ref</td><td>28 (45.9)</td><td>6 (33.3)</td><td>1</td><td>ref</td></tr></tbody></table>
<table><tbody><tr><td>Once, sometimes</td><td>120 (44.6)</td><td>19 (63.3)</td><td>1.98</td><td>(0.57-6.83)</td><td>22 (36.1)</td><td>8 (44.4)</td><td>3.41</td><td>(0.57-20.22)</td></tr><tr><td>Often, always or almost always</td><td>88 (32.7)</td><td>7 (23.3)</td><td>0.79</td><td>(0.19-3.35)</td><td>11 (18.0)</td><td>4 (22.2)</td><td>2.10</td><td>(0.29-15.20)</td></tr><tr><td>Missing</td><td>8</td><td>0</td><td></td><td></td><td>12</td><td>1</td><td></td><td></td></tr><tr><td><strong>Oral sex</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>196 (72.9)</td><td>26 (86.7)</td><td>1.73</td><td>(0.52-5.79)</td><td>37 (57.8)</td><td>13 (72.2)</td><td>0.09</td><td>(0.01-1.75)</td></tr><tr><td>Never</td><td>73 (27.1)</td><td>4 (13.3)</td><td>1</td><td>ref</td><td>27 (42.2)</td><td>5 (27.8)</td><td>1</td><td>ref</td></tr><tr><td>Missing</td><td>8</td><td>0</td><td></td><td></td><td>9</td><td>1</td><td></td><td></td></tr><tr><td><strong>Oral sex, frequency</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>73 (27.9)</td><td>4 (13.3)</td><td>1</td><td>ref</td><td>27 (42.2)</td><td>5 (27.8)</td><td>1</td><td>ref</td></tr><tr><td>Once, sometimes</td><td>140 (53.4)</td><td>15 (50.0)</td><td>1.52</td><td>(0.44-5.28)</td><td>25 (39.1)</td><td>5 (27.8)</td><td>0.46</td><td>(0.05-3.85)</td></tr><tr><td>Often, always or almost always</td><td>49 (18.7)</td><td>11 (36.7)</td><td>2.72</td><td>(0.69-10.76)</td><td>12 (18.8)</td><td>8 (44.4)</td><td>11.06</td><td>(1.12-109.06)</td></tr><tr><td>Missing</td><td>14</td><td>1</td><td></td><td></td><td>9</td><td>1</td><td></td><td></td></tr><tr><td><strong>Years since last oral sex</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never oral sex</td><td>73 (28.2)</td><td>4 (13.8)</td><td>1</td><td>ref</td><td>27 (44.3)</td><td>5 (31.3)</td><td>1</td><td>ref</td></tr><tr><td>&lt;1</td><td>105 (40.5)</td><td>19 (65.5)</td><td>2.67</td><td>(0.74-9.60)</td><td>10 (16.4)</td><td>9 (56.3)</td><td>6.69</td><td>(0.79-56.63)</td></tr><tr><td>1-10</td><td>57 (22.0)</td><td>5 (17.2)</td><td>1.13</td><td>(0.26-4.93)</td><td>15 (24.6)</td><td>2 (12.5)</td><td>0.29</td><td>(0.02-5.12)</td></tr><tr><td>&gt; 10</td><td>24 (9.3)</td><td>1 (3.5)</td><td>0.57</td><td>(0.06-5.85)</td><td>9 (14.8)</td><td>0 (0.0)</td><td>NA</td><td>NA</td></tr><tr><td>Missing</td><td>18</td><td>1</td><td></td><td></td><td>12</td><td>3</td><td></td><td></td></tr><tr><td><strong>Received sperm in mouth</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never oral sex, never sperm, just once</td><td>164 (91.6)</td><td>12 (85.7)</td><td>1</td><td>ref</td><td>45 (90.0)</td><td>5 (71.4)</td><td>1</td><td>ref</td></tr><tr><td>Sometimes, often, always or almost always</td><td>15 (8.4)</td><td>2 (14.3)</td><td>9.84</td><td>(0.47-207.68)</td><td>5 (10.0)</td><td>2 (28.6)</td><td>4.91<sup>†</sup></td><td>(0.10-239.62)</td></tr><tr><td>Missing</td><td>98</td><td>16</td><td></td><td></td><td>23</td><td>12</td><td></td><td></td></tr><tr><td><strong>Paid for sex</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ever</td><td>62 (22.8)</td><td>10 (33.3)</td><td>1</td><td>ref</td><td>14 (21.5)</td><td>6 (33.3)</td><td>1</td><td>ref</td></tr><tr><td>Never</td><td>210 (77.2)</td><td>20 (66.7)</td><td>1.20</td><td>(0.49-2.95)</td><td>51 (78.5)</td><td>12 (66.7)</td><td>0.58</td><td>(0.13-2.62)</td></tr><tr><td>Missing</td><td>5</td><td>0</td><td></td><td></td><td>8</td><td>1</td><td></td><td></td></tr><tr><td><strong>STI, Frequency</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>176 (65.4)</td><td>15 (51.7)</td><td>1</td><td>ref</td><td>45 (71.4)</td><td>14 (82.4)</td><td>1</td><td>ref</td></tr></tbody></table>
<table><tbody><tr><td>Once</td><td>43 (16.0)</td><td>7 (24.1)</td><td>0.63</td><td>(0.12-3.23)</td><td>6 (9.5)</td><td>0 (0.0)</td><td>NA</td><td>NA</td></tr><tr><td>More than once</td><td>50 (18.6)</td><td>7 (24.1)</td><td>1.82</td><td>(0.70-4.72)</td><td>12 (19.1)</td><td>3 (17.7)</td><td>0.41</td><td>(0.05-3.17)</td></tr><tr><td>Missing</td><td>8</td><td>1</td><td></td><td></td><td>10</td><td>2</td><td></td><td></td></tr><tr><td><strong>Recent multiple partners</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never multiple partners</td><td>172 (63.5)</td><td>16 (53.3)</td><td>1</td><td>ref</td><td>43 (67.2)</td><td>10 (55.6)</td><td>1</td><td>ref</td></tr><tr><td>≤ 5 years</td><td>27 (10.0)</td><td>3 (10.0)</td><td>0.73</td><td>(0.18-3.07)</td><td>4 (6.3)</td><td>1 (5.6)</td><td>2.18</td><td>(0.07-70.68)</td></tr><tr><td>> 5 years</td><td>72 (26.6)</td><td>11 (36.7)</td><td>1.15</td><td>(0.47-2.84)</td><td>17 (26.6)</td><td>7 (38.9)</td><td>6.07</td><td>(1.05-35.28)</td></tr><tr><td>Missing</td><td>6</td><td>0</td><td></td><td></td><td>9</td><td>1</td><td></td><td></td></tr></tbody></table>

a: OR adjusted for age, sex, recruitment site, cigarette quantity and duration combined, alcohol quantity and level of education

*: Level of education accounted for as three categories instead of four.

†: OR adjusted for age, sex, recruitment site, cigarette quantity and duration, alcohol quantity and level of education in three categories
## 4.6 Supplementary results

### 4.6.1 Fruits and vegetable consumption and head and neck cancer

Analyses for this risk factor are still ongoing and complementary studies are necessary before beginning a draft for an original research manuscript. The following is a presentation of main results on fruit and vegetable consumption and head and neck cancer in the French West Indies.
<table><caption>**Table 5:** Association between fruits and vegetable consumption and HNSCC</caption><thead><tr><th rowspan="2"></th><th colspan="2">HNSCC</th><th colspan="2">Control</th><th rowspan="2">OR<sup>a</sup></th><th rowspan="2">95%CI</th><th rowspan="2">OR<sup>b</sup></th><th rowspan="2">95%CI</th></tr><tr><th>n</th><th>col%</th><th>n</th><th>col%</th></tr></thead><tbody><tr><td><strong>Fruits and Vegetables</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never or exceptionally, occasionally</td><td>16</td><td>(13.1)</td><td>22</td><td>(5.5)</td><td>2.62</td><td>(1.33-5.17)</td><td>1.46</td><td>(0.61-3.51)</td></tr><tr><td>At least once per week or per day</td><td>106</td><td>(86.9)</td><td>382</td><td>(94.6)</td><td>1</td><td>ref</td><td>1</td><td>ref</td></tr><tr><td><strong>Fruits and Vegetables</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never or exceptionally, occasionally, at least once per week</td><td>49</td><td>(40.2)</td><td>137</td><td>(33.9)</td><td>1.31</td><td>(0.86-1.98)</td><td>0.86</td><td>(0.52-1.42)</td></tr><tr><td>At least once per day</td><td>73</td><td>(59.8)</td><td>267</td><td>(66.1)</td><td>1</td><td>ref</td><td>1</td><td>ref</td></tr><tr><td><strong>Fruits and Vegetables</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never or exceptionally</td><td>1</td><td>(0.8)</td><td>1</td><td>(0.3)</td><td>3.66</td><td>(0.23-59.18)</td><td>0.86</td><td>(0.02-41.72)</td></tr><tr><td>Occasionally</td><td>15</td><td>(12.3)</td><td>21</td><td>(5.2)</td><td>2.61</td><td>(1.28-5.32)</td><td>1.52</td><td>(0.63-3.63)</td></tr><tr><td>At least once per week</td><td>33</td><td>(27.1)</td><td>115</td><td>(28.5)</td><td>1.05</td><td>(0.66-1.67)</td><td>0.73</td><td>(0.42-1.27)</td></tr><tr><td>At least once per day</td><td>73</td><td>(59.8)</td><td>267</td><td>(66.1)</td><td>1</td><td>ref</td><td>1</td><td>ref</td></tr></tbody></table>

a: Crude odds ratio, no adjustment on matching variable or confounding factors

b: Model adjusted for age, sex, recruitment site, combination of cigarette quantity and duration, quantity of alcohol
<table><caption>**Table 6:** Association between fruits and vegetable consumption and ever tobacco smoking</caption><thead><tr><th rowspan="3"></th><th colspan="6">Tobacco smoking</th></tr><tr><th colspan="2">Never</th><th colspan="2">Ever</th><th rowspan="2">OR<sup>a</sup></th><th rowspan="2">95%CI</th></tr><tr><th>n</th><th>col%</th><th>n</th><th>col%</th></tr></thead><tbody><tr><td colspan="7"><strong>Fruits and Vegetables</strong></td></tr><tr><td>Never or exceptionally, occasionally</td><td>14</td><td>(4.8)</td><td>24</td><td>(10.2)</td><td>1.58</td><td>(0.75-3.31)</td></tr><tr><td>At least once per week or per day</td><td>277</td><td>(95.2)</td><td>211</td><td>(89.8)</td><td>1</td><td>ref</td></tr><tr><td colspan="7"><strong>Fruits and Vegetables</strong></td></tr><tr><td>Never or exceptionally</td><td>1</td><td>(0.3)</td><td>1</td><td>(0.4)</td><td>0.80</td><td>(0.04-16.75)</td></tr><tr><td>Occasionally</td><td>13</td><td>(4.5)</td><td>23</td><td>(9.8)</td><td>2.00</td><td>(0.92-4.33)</td></tr><tr><td>At least once per week</td><td>69</td><td>(23.7)</td><td>79</td><td>(33.6)</td><td>1.80</td><td>(1.17-2.76)</td></tr><tr><td>At least once per day</td><td>208</td><td>(71.5)</td><td>132</td><td>(56.2)</td><td>1</td><td>ref</td></tr></tbody></table>

a: Model adjusted for age, sex, recruitment site, and case-control status

<table><caption>**Table 7:** Association between fruits and vegetable consumption and daily alcohol drinking</caption><thead><tr><th rowspan="3"></th><th colspan="6">Daily alcohol drinking</th></tr><tr><th colspan="2">Never</th><th colspan="2">Ever</th><th rowspan="2">OR<sup>a</sup></th><th rowspan="2">95%CI</th></tr><tr><th>n</th><th>col%</th><th>n</th><th>col%</th></tr></thead><tbody><tr><td colspan="7"><strong>Fruits and Vegetables</strong></td></tr><tr><td>Never or exceptionally, occasionally.</td><td>13</td><td>(4.0)</td><td>25</td><td>(12.5)</td><td>2.83</td><td>(1.31-6.14)</td></tr><tr><td>At least once per week or per day</td><td>313</td><td>(96.0)</td><td>175</td><td>(87.5)</td><td>1</td><td>ref</td></tr><tr><td colspan="7"><strong>Fruits and Vegetables</strong></td></tr><tr><td>Never or exceptionally</td><td>0</td><td>(0.0)</td><td>2</td><td>(1.0)</td><td>NA</td><td>NA</td></tr><tr><td>Occasionally</td><td>13</td><td>(4.0)</td><td>23</td><td>(11.5)</td><td>2.95</td><td>(1.32-6.59)</td></tr><tr><td>At least once per week</td><td>89</td><td>(27.3)</td><td>59</td><td>(29.5)</td><td>1.39</td><td>(0.88-2.18)</td></tr><tr><td>At least once per day</td><td>224</td><td>(68.7)</td><td>116</td><td>(58.0)</td><td>1</td><td>ref</td></tr></tbody></table>

a: Model adjusted for age, sex, recruitment site, and case-control status
<table><caption>**Table 8:** Association between fruits and vegetable consumption and HNSCC stratified by daily alcohol drinking</caption><thead><tr><th rowspan="2">Fruits and Vegetables</th><th>HNSCC</th><th>Control</th><th colspan="2">Never daily alcohol drinking</th><th>HNSCC</th><th>Control</th><th colspan="2">Ever daily alcohol drinking</th><th rowspan="2">P<sub>inter</sub></th></tr><tr><th>n</th><th>n</th><th>OR<sup>a</sup></th><th>95%CI</th><th>n</th><th>n</th><th>OR<sup>a</sup></th><th>95%CI</th></tr></thead><tbody><tr><td>Never or exceptionally, occasionally</td><td>4</td><td>9</td><td>4.81</td><td>(1.32-17.51)</td><td>12</td><td>13</td><td>0.83</td><td>(0.32-2.14)</td><td>0.061</td></tr><tr><td>At least once per week or At least once per week</td><td>30</td><td>283</td><td>1</td><td>ref</td><td>76</td><td>99</td><td>1</td><td>ref</td><td></td></tr></tbody></table>

a: Model adjusted for age, sex, recruitment site, combination of cigarette quantity and duration,
P<sub>inter</sub>: Statistical test assessing the multiplicative interaction between frequency of fruit and vegetable consumption and daily alcohol drinking
4.6.2 Tea, coffee and juice/soda consumption and head and neck cancer

<table><caption>**Table 9:** Association between tea,coffee and juice/soda consumption and HNSCC</caption><thead><tr><th>Beverage quantity</th><th>Crude OR</th><th>95%CI</th><th>OR<sup>a</sup></th><th>95%CI</th></tr></thead><tbody><tr><td><strong>Coffee</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Never or occasionally</td><td>1</td><td>ref</td><td>1</td><td>ref</td></tr><tr><td>&lt;1 cup/day</td><td>0.34</td><td>(0.15-0.74)</td><td>1.17</td><td>(0.41-3.34)</td></tr><tr><td>1-5 cups/day</td><td>0.33</td><td>(0.20-0.54))</td><td>0.53</td><td>(0.25-1.12)</td></tr><tr><td>&gt; 5 cups/day</td><td>1.01</td><td>(0.34-3.04)</td><td>0.64</td><td>(0.14-2.97)</td></tr><tr><td><strong>Tea</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Never or occasionally</td><td>1</td><td>ref</td><td>1</td><td>ref</td></tr><tr><td>&lt;1 cup/day</td><td>0.18</td><td>(0.07-0.47)</td><td>0.53</td><td>(0.18-1.59)</td></tr><tr><td>1-5 cups/day</td><td>0.35</td><td>(0.18-0.71)</td><td>0.84</td><td>(0.34-2.05)</td></tr><tr><td>&gt; 5 cups/day</td><td>0.66</td><td>(0.07-6.39)</td><td>0.86</td><td>(0.03-23.32)</td></tr><tr><td><strong>Juice or soda</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Never or occasionally</td><td>1</td><td>ref</td><td>1</td><td>ref</td></tr><tr><td>&lt;1 glass/day</td><td>0.12</td><td>(0.05-0.28)</td><td>0.42</td><td>(0.15-1.18)</td></tr><tr><td>1-5 glasses/day</td><td>0.31</td><td>(0.18-0.53)</td><td>0.52</td><td>(0.25-1.12)</td></tr><tr><td>&gt; 5 glasses/day</td><td>0.44</td><td>(0.15-1.26)</td><td>0.77</td><td>(0.20-3.04)</td></tr></tbody></table>

a: Adjusted for age, sex, recruitment site, tobacco smoking status, cigarette quantity, smoking duration and quantity of alcohol
4.6.3 Occupational exposures and head and neck cancer in the French West Indies

Preliminary results for occupational risk factors were accepted for a poster presentation at the Aderest symposium in Toulouse, France in November 2019. Analyses are still ongoing and complementary studies are necessary before beginning a draft for an original research manuscript. The following is a presentation of main results occupational risk factors and head and neck cancer in the French West Indies.
<table><caption>**Table 10:** Association between occupations and HNSCC using major occupational groups</caption><thead><tr><th rowspan="2">Major occupation groups</th><th rowspan="2">ISCO code</th><th colspan="2">Case</th><th colspan="2">Control</th><th rowspan="2">OR<sup>a</sup></th><th rowspan="2">IC95%</th></tr><tr><th>n</th><th>%col</th><th>n</th><th>%col</th></tr></thead><tbody><tr><td>Professional, technical and related workers</td><td>0/1</td><td>24</td><td>16.6</td><td>122</td><td>30.1</td><td>0.47</td><td>0.26 0.86</td></tr><tr><td>Administrative and managerial workers</td><td>2</td><td>8</td><td>5.5</td><td>21</td><td>5.2</td><td>0.72</td><td>0.26 1.96</td></tr><tr><td>Clerical and related workers</td><td>3</td><td>21</td><td>14.5</td><td>119</td><td>29.4</td><td>0.36</td><td>0.19 0.66</td></tr><tr><td>Sales workers</td><td>4</td><td>26</td><td>17.9</td><td>72</td><td>17.8</td><td>0.82</td><td>0.43 1.55</td></tr><tr><td>Service workers</td><td>5</td><td>32</td><td>22.1</td><td>106</td><td>26.2</td><td>1.17</td><td>0.63 2.17</td></tr><tr><td>Agricultural, animal husbandry and forestry workers, fishermen and hunters</td><td>6</td><td>45</td><td>31.0</td><td>78</td><td>19.3</td><td>1.35</td><td>0.78 2.34</td></tr><tr><td>Production and related workers, transport equipment operators and labourers</td><td>7/8/9</td><td>90</td><td>62.1</td><td>192</td><td>47.4</td><td>1.50</td><td>0.89 2.54</td></tr></tbody></table>

a: Age, sex, recruitment site, smoking quantity and duration combined and daily alcohol drinking
<table><caption>**Table 11:** Association between occupations and HNSCC using two-digit ISCO codes</caption><thead><tr><th>Occupation title</th><th>ISCO code</th><th>Case</th><th>Control</th><th>OR<sup>a</sup></th><th>95%CI</th></tr></thead><tbody><tr><td>Architects, Engineers and Related Technicians</td><td>03</td><td>7</td><td>18</td><td>0.94</td><td>0.32 2.79</td></tr><tr><td>Aircraft and Ships' Officers</td><td>04</td><td>1</td><td>1</td><td>2.88</td><td>0.07 115.31</td></tr><tr><td>Medical, Dental, Veterinary and Related Workers</td><td>06</td><td>1</td><td>6</td><td>0.70</td><td>0.06 8.75</td></tr><tr><td>Medical, Dental, Veterinary and Related Workers</td><td>07</td><td>3</td><td>16</td><td><strong>0.24</strong></td><td><strong>0.06 0.98</strong></td></tr><tr><td>Statisticians, Mathematicians, Systems Analysts and Related Technicians</td><td>08</td><td>1</td><td>6</td><td>0.31</td><td>0.03 3.27</td></tr><tr><td>Teachers</td><td>13</td><td>10</td><td>53</td><td>0.67</td><td>0.29 1.55</td></tr><tr><td>Professional, Technical and Related Workers Not Elsewhere Classified</td><td>19</td><td>5</td><td>14</td><td>1.98</td><td>0.54 7.23</td></tr><tr><td>Managers</td><td>21</td><td>6</td><td>21</td><td>0.57</td><td>0.19 1.68</td></tr><tr><td>Government Executive Officials</td><td>31</td><td>5</td><td>25</td><td>0.63</td><td>0.2 2.00</td></tr><tr><td>Stenographers, Typists and Card- and Tape-Punching Machine Operators</td><td>32</td><td>3</td><td>21</td><td>0.28</td><td>0.05 1.43</td></tr><tr><td>Bookkeepers, Cashiers and Related Workers</td><td>33</td><td>5</td><td>32</td><td><strong>0.33</strong></td><td><strong>0.11 0.99</strong></td></tr><tr><td>Mail Distribution Clerks</td><td>37</td><td>1</td><td>15</td><td>0.16</td><td>0.02 1.42</td></tr><tr><td>Clerical and Related Workers Not Elsewhere Classified</td><td>39</td><td>8</td><td>43</td><td>0.55</td><td>0.22 1.36</td></tr><tr><td>Managers (Wholesale and Retail Trade)</td><td>40</td><td>2</td><td>2</td><td>1.81</td><td>0.17 19.25</td></tr><tr><td>Sales Supervisors and Buyers</td><td>42</td><td>12</td><td>2</td><td>0.58</td><td>0.1 3.31</td></tr><tr><td>Technical Salesman, Commercial Travellers and Manufacturers' Agents</td><td>43</td><td>3</td><td>8</td><td>0.65</td><td>0.14 3.02</td></tr><tr><td>Insurance Real Estate, Securities and Business Services Salesmen and Auctioneers</td><td>44</td><td>2</td><td>11</td><td>0.30</td><td>0.05 1.77</td></tr><tr><td>Salesmen, Shop Assistants and Related Workers</td><td>45</td><td>17</td><td>47</td><td>0.84</td><td>0.39 1.80</td></tr><tr><td>Working Proprietors (Catering and Lodging Services)</td><td>51</td><td>3</td><td>3</td><td>0.90</td><td>0.12 6.7</td></tr><tr><td>Cooks, Waiters, Bartenders and Related Workers</td><td>53</td><td>12</td><td>28</td><td>1.40</td><td>0.55 3.57</td></tr><tr><td>Maids and Related Housekeeping Service Workers Not Elsewhere Classified</td><td>54</td><td>5</td><td>36</td><td>1.16</td><td>0.34 3.94</td></tr><tr><td>Building Caretakers, Charworkers, Cleaners and Related Workers</td><td>55</td><td>4</td><td>27</td><td>1.00</td><td>0.31 3.25</td></tr><tr><td>Launderers, Dry-Cleaners and Pressers</td><td>56</td><td>1</td><td>1</td><td>12.11</td><td>0.73 201.34</td></tr><tr><td>Hairdressers, Barbers, Beauticians and Related Workers</td><td>57</td><td>1</td><td>3</td><td>0.39</td><td>0.03 5.71</td></tr><tr><td>Protective Service Workers</td><td>58</td><td>6</td><td>14</td><td>1.55</td><td>0.48 5.06</td></tr><tr><td>Service Workers Not Elsewhere Classified</td><td>59</td><td>6</td><td>13</td><td>1.40</td><td>0.41 4.78</td></tr><tr><td>Farmers</td><td>61</td><td>5</td><td>23</td><td>0.58</td><td>0.17 1.96</td></tr><tr><td>Agricultural and Animal Husbandry Workers</td><td>62</td><td>33</td><td>54</td><td>1.31</td><td>0.71 2.41</td></tr><tr><td>Fishermen, Hunters and Related Workers</td><td>64</td><td>8</td><td>8</td><td>2.53</td><td>0.65 9.75</td></tr><tr><td>Production Supervisors and General Foremen</td><td>70</td><td>2</td><td>18</td><td>0.19</td><td>0.02 1.74</td></tr><tr><td>Miners, Quarrymen, Well Drillers and Related Workers</td><td>71</td><td>1</td><td>2</td><td>1.19</td><td>0.09 16.3</td></tr><tr><td>Chemical Processors and Related Workers</td><td>74</td><td>1</td><td>2</td><td>0.93</td><td>0.05 16.32</td></tr><tr><td>Food and Beverage Processors</td><td>77</td><td>6</td><td>11</td><td>0.89</td><td>0.25 3.24</td></tr></tbody></table>
<table><tr><td>Tailors, Dressmakers, Sewers, Upholsterers and Related Workers</td><td>79</td><td>1</td><td>7</td><td>1.24</td><td>0.14</td><td>10.72</td></tr><tr><td>Cabinetmakers and Related Woodworkers</td><td>81</td><td>3</td><td>6</td><td>1.23</td><td>0.23</td><td>6.55</td></tr><tr><td>Blacksmiths, Toolmakers and Machine Tool Operators</td><td>83</td><td>3</td><td>9</td><td>1.49</td><td>0.31</td><td>7.29</td></tr><tr><td>Machinery Fitters, Machine Assemblers and Precision-Instrument Makers (except Electri)</td><td>84</td><td>11</td><td>24</td><td>1.31</td><td>0.52</td><td>3.36</td></tr><tr><td>Electrical Fitters and Related Electrical and Electronics Workers</td><td>85</td><td>6</td><td>22</td><td>0.73</td><td>0.23</td><td>2.29</td></tr><tr><td>Broadcasting Station and Sound-Equipment Operators and Cinema Projectionists</td><td>86</td><td>1</td><td>3</td><td>2.01</td><td>0.16</td><td>24.67</td></tr><tr><td>Plumbers, Welders, Sheet-Metal and Structural Metal Preparers and Erectors</td><td>87</td><td>12</td><td>22</td><td>0.98</td><td>0.38</td><td>2.51</td></tr><tr><td>Painters</td><td>93</td><td>10</td><td>13</td><td>0.99</td><td>0.35</td><td>2.85</td></tr><tr><td>Production and Related Workers Not Elsewhere Classified</td><td>94</td><td>1</td><td>3</td><td>1.34</td><td>0.08</td><td>22.62</td></tr><tr><td>Bricklayers, Carpenters and Other Construction Workers</td><td>95</td><td>35</td><td>58</td><td><strong>1.87</strong></td><td><strong>1.02</strong></td><td><strong>3.44</strong></td></tr><tr><td>Material Handling and Related Equipment Operators, Dockers and Freight Handlers</td><td>97</td><td>16</td><td>30</td><td>1.51</td><td>0.69</td><td>3.29</td></tr><tr><td>Transport Equipment Operators</td><td>98</td><td>18</td><td>47</td><td>0.94</td><td>0.46</td><td>1.91</td></tr><tr><td>Labourers Not Elsewhere Classified</td><td>99</td><td>14</td><td>22</td><td><strong>2.34</strong></td><td><strong>0.98</strong></td><td><strong>5.61</strong></td></tr></table>

a: Age, sex, recruitment site, smoking quantity and duration combined and daily alcohol drinking
<table><caption>**Table 12.** Association between occupations and HNSCC using five-digit ISCO codes</caption><thead><tr><th>Occupation title</th><th>ISCO code</th><th>Case</th><th>Control</th><th>OR<sup>a</sup></th><th>95% CI</th></tr></thead><tbody><tr><td>Telecommunications technician</td><td>03430</td><td>2</td><td>5</td><td>0.69</td><td>0.10 4.65</td></tr><tr><td>Mechanical engineering technician (motors and engines)</td><td>03520</td><td>1</td><td>1</td><td>2.54</td><td>0.05 119.45</td></tr><tr><td>Other engineering technicians</td><td>03990</td><td>1</td><td>1</td><td>12.11</td><td>0.73 201.34</td></tr><tr><td>General physician</td><td>06105</td><td>1</td><td>1</td><td>2.56</td><td>0.06 116.99</td></tr><tr><td>Professional nurse (general)</td><td>07110</td><td>1</td><td>4</td><td>0.30</td><td>0.03 3.44</td></tr><tr><td>Medical X-ray technician</td><td>07710</td><td>1</td><td>3</td><td>0.41</td><td>0.03 4.79</td></tr><tr><td>Computer programmer</td><td>08420</td><td>1</td><td>4</td><td>0.37</td><td>0.03 4.22</td></tr><tr><td>Other university and higher education teachers</td><td>13190</td><td>1</td><td>2</td><td>1.09</td><td>0.08 15.61</td></tr><tr><td>Languages and literature teacher (second level)</td><td>13215</td><td>2</td><td>5</td><td>1.11</td><td>0.17 7.45</td></tr><tr><td>Mathematics teacher (second level)</td><td>13220</td><td>1</td><td>6</td><td>0.70</td><td>0.06 8.00</td></tr><tr><td>Technical education teacher (second level)</td><td>13280</td><td>2</td><td>5</td><td>0.82</td><td>0.06 10.46</td></tr><tr><td>First-level education teacher</td><td>13320</td><td>3</td><td>9</td><td>2.08</td><td>0.45 9.58</td></tr><tr><td>Head teacher</td><td>13940</td><td>1</td><td>5</td><td>0.76</td><td>0.06 9.81</td></tr><tr><td>Other teachers</td><td>13990</td><td>1</td><td>9</td><td>0.48</td><td>0.05 5.07</td></tr><tr><td>Social welfare worker</td><td>19320</td><td>1</td><td>2</td><td>2.67</td><td>0.16 45.2</td></tr><tr><td>Culture centre worker</td><td>19330</td><td>1</td><td>2</td><td>5.43</td><td>0.46 63.55</td></tr><tr><td>Interpreter</td><td>19540</td><td>1</td><td>1</td><td>2.54</td><td>0.05 119.45</td></tr><tr><td>General manager</td><td>21110</td><td>3</td><td>8</td><td>0.61</td><td>0.12 3.06</td></tr><tr><td>Industrial relations and personnel manager</td><td>21980</td><td>1</td><td>1</td><td>1.15</td><td>0.04 30.57</td></tr><tr><td>Other managers</td><td>21990</td><td>3</td><td>9</td><td>0.69</td><td>0.15 3.07</td></tr><tr><td>Government executive official</td><td>31010</td><td>5</td><td>25</td><td>0.63</td><td>0.20 2.00</td></tr><tr><td>Bookkeeper (general)</td><td>33110</td><td>2</td><td>10</td><td>0.48</td><td>0.08 2.96</td></tr><tr><td>Bank teller</td><td>33140</td><td>1</td><td>3</td><td>0.60</td><td>0.05 7.39</td></tr><tr><td>Other bookkeepers, cashiers and related workers</td><td>33990</td><td>1</td><td>3</td><td>1.10</td><td>0.05 23.60</td></tr><tr><td>Postman</td><td>37030</td><td>1</td><td>3</td><td>1.05</td><td>0.07 15.62</td></tr><tr><td>Storeroom clerk</td><td>39140</td><td>4</td><td>18</td><td>0.72</td><td>0.20 2.64</td></tr><tr><td>Office clerk (general)</td><td>39310</td><td>2</td><td>10</td><td>0.35</td><td>0.06 1.96</td></tr><tr><td>Other receptionists and travel agency clerks</td><td>39490</td><td>1</td><td>1</td><td>5.23</td><td>0.27 102.48</td></tr><tr><td>Manager, wholesale trade</td><td>40020</td><td>1</td><td>1</td><td>2.44</td><td>0.07 82.27</td></tr><tr><td>Manager, retail trade</td><td>40030</td><td>1</td><td>1</td><td>1.42</td><td>0.06 34.26</td></tr><tr><td>Sales supervisor (retail trade)</td><td>42130</td><td>2</td><td>8</td><td>1.29</td><td>0.21 8.09</td></tr><tr><td>Technical salesman</td><td>43120</td><td>2</td><td>3</td><td>1.27</td><td>0.17 9.29</td></tr><tr><td>Commercial traveller</td><td>43220</td><td>1</td><td>4</td><td>0.33</td><td>0.03 3.72</td></tr><tr><td>Insurance salesman</td><td>44120</td><td>1</td><td>1</td><td>1.26</td><td>0.06 27.00</td></tr><tr><td>Advertising salesman</td><td>44230</td><td>1</td><td>2</td><td>0.44</td><td>0.03 6.31</td></tr><tr><td>Retail trade salesman</td><td>45130</td><td>9</td><td>33</td><td>0.59</td><td>0.24 1.49</td></tr><tr><td>Other salesmen, shop assistants demonstrators</td><td>45190</td><td>5</td><td>8</td><td>3.19</td><td>0.78 13.00</td></tr><tr><td>Street vendor</td><td>45220</td><td>3</td><td>4</td><td>0.75</td><td>0.08 6.73</td></tr><tr><td>Working proprietor (restaurant)</td><td>51030</td><td>2</td><td>2</td><td>1.93</td><td>0.22 17.41</td></tr><tr><td>Cook, except private service</td><td>53130</td><td>7</td><td>8</td><td><strong>5.22</strong></td><td><strong>1.64</strong> <strong>16.67</strong></td></tr><tr><td>Waiter, general</td><td>53210</td><td>3</td><td>11</td><td>0.48</td><td>0.08 2.93</td></tr></tbody></table>
<table><tr><td>Bartender</td><td>53250</td><td>2</td><td>2</td><td>0.43</td><td>0.03</td><td>7.03</td></tr><tr><td>Nursemaid</td><td>54035</td><td>3</td><td>12</td><td>2.41</td><td>0.51</td><td>11.47</td></tr><tr><td>Other maids and related housekeeping, service workers</td><td>54090</td><td>2</td><td>9</td><td>2.51</td><td>0.46</td><td>13.64</td></tr><tr><td>Concierge (apartment house)</td><td>55120</td><td>1</td><td>2</td><td>3.38</td><td>0.28</td><td>41.34</td></tr><tr><td>Charworker</td><td>55220</td><td>2</td><td>20</td><td>1.00</td><td>0.22</td><td>4.64</td></tr><tr><td>Other charworkers, cleaners and related workers</td><td>55290</td><td>1</td><td>1</td><td>4.29</td><td>0.16</td><td>115.99</td></tr><tr><td>Policeman</td><td>58220</td><td>1</td><td>5</td><td>0.39</td><td>0.03</td><td>4.50</td></tr><tr><td>Private police guard</td><td>58240</td><td>2</td><td>1</td><td>11.17</td><td>0.76</td><td>165.05</td></tr><tr><td>Watchman</td><td>58940</td><td>1</td><td>2</td><td>6.17</td><td>0.53</td><td>72.23</td></tr><tr><td>Other protective service workers</td><td>58990</td><td>1</td><td>1</td><td>1.77</td><td>0.06</td><td>53.96</td></tr><tr><td>Sightseeing guide</td><td>59130</td><td>2</td><td>2</td><td>3.37</td><td>0.27</td><td>41.67</td></tr><tr><td>Nursing aid</td><td>59940</td><td>2</td><td>9</td><td>0.71</td><td>0.12</td><td>4.19</td></tr><tr><td>Other service workers not elsewhere classified</td><td>59990</td><td>1</td><td>1</td><td>2.90</td><td>0.16</td><td>53.45</td></tr><tr><td>General farmer</td><td>61110</td><td>1</td><td>4</td><td>0.88</td><td>0.08</td><td>9.87</td></tr><tr><td>Field crop farmer</td><td>61220</td><td>4</td><td>14</td><td>0.71</td><td>0.16</td><td>3.1</td></tr><tr><td>Farm helper (general)</td><td>62110</td><td>4</td><td>12</td><td>0.43</td><td>0.12</td><td>1.59</td></tr><tr><td>Field crop farm worker (general)</td><td>62210</td><td>10</td><td>8</td><td><strong>3.90</strong></td><td><strong>1.13</strong></td><td><strong>13.4</strong></td></tr><tr><td>Sugar-cane farm worker</td><td>62260</td><td>10</td><td>18</td><td>1.48</td><td>0.53</td><td>4.09</td></tr><tr><td>Other field crop and vegetable farm workers</td><td>62290</td><td>1</td><td>1</td><td>11.66</td><td>0.69</td><td>196.76</td></tr><tr><td>Other livestock workers</td><td>62490</td><td>1</td><td>1</td><td>1.50</td><td>0.06</td><td>35.44</td></tr><tr><td>Gardener</td><td>62740</td><td>11</td><td>14</td><td>1.60</td><td>0.57</td><td>4.49</td></tr><tr><td>Motorised farm equipment operator</td><td>62820</td><td>2</td><td>4</td><td>0.38</td><td>0.06</td><td>2.39</td></tr><tr><td>Groundsman</td><td>62960</td><td>1</td><td>4</td><td>0.43</td><td>0.04</td><td>5.00</td></tr><tr><td>Inland and coastal waters fisherman</td><td>64130</td><td>8</td><td>7</td><td>2.96</td><td>0.74</td><td>11.9</td></tr><tr><td>Supervisor and general foreman, construction work</td><td>70075</td><td>1</td><td>13</td><td>0.23</td><td>0.02</td><td>2.28</td></tr><tr><td>Charcoal burner</td><td>74930</td><td>1</td><td>1</td><td>1.18</td><td>0.05</td><td>27.59</td></tr><tr><td>Butcher, general</td><td>77310</td><td>1</td><td>1</td><td>2.56</td><td>0.07</td><td>89.4</td></tr><tr><td>Baker, general</td><td>77610</td><td>1</td><td>1</td><td>1.94</td><td>0.06</td><td>65.07</td></tr><tr><td>Bread baker</td><td>77620</td><td>2</td><td>6</td><td>0.39</td><td>0.03</td><td>4.52</td></tr><tr><td>Pastry maker</td><td>77630</td><td>2</td><td>2</td><td>1.59</td><td>0.16</td><td>16.29</td></tr><tr><td>Cabinetmaker</td><td>81120</td><td>3</td><td>3</td><td>1.61</td><td>0.25</td><td>10.23</td></tr><tr><td>Blacksmith (general)</td><td>83110</td><td>1</td><td>2</td><td>0.98</td><td>0.05</td><td>18.55</td></tr><tr><td>Machine-tool operator (general)</td><td>83410</td><td>1</td><td>2</td><td>1.48</td><td>0.07</td><td>32.79</td></tr><tr><td>Automobile mechanic</td><td>84320</td><td>6</td><td>14</td><td>1.40</td><td>0.42</td><td>4.66</td></tr><tr><td>Other motor-vehicle mechanics</td><td>84390</td><td>1</td><td>1</td><td>3.10</td><td>0.08</td><td>116.32</td></tr><tr><td>Machinery mechanic (general)</td><td>84910</td><td>1</td><td>1</td><td>1.37</td><td>0.06</td><td>29.33</td></tr><tr><td>Agricultural machinery mechanic</td><td>84955</td><td>1</td><td>2</td><td>6.67</td><td>0.57</td><td>78.14</td></tr><tr><td>Maintenance electrician</td><td>85560</td><td>1</td><td>1</td><td>0.79</td><td>0.04</td><td>14.13</td></tr><tr><td>Plumber (general)</td><td>87105</td><td>5</td><td>9</td><td>0.84</td><td>0.22</td><td>3.18</td></tr><tr><td>Pipe fitter (general)</td><td>87110</td><td>4</td><td>5</td><td>0.93</td><td>0.18</td><td>4.98</td></tr><tr><td>Gas and electric welder (general)</td><td>87210</td><td>2</td><td>5</td><td>1.06</td><td>0.14</td><td>8.07</td></tr><tr><td>Vehicle sheet-metal worker</td><td>87370</td><td>2</td><td>1</td><td>2.33</td><td>0.06</td><td>94.98</td></tr><tr><td>Building painter</td><td>93120</td><td>6</td><td>13</td><td>0.45</td><td>0.13</td><td>1.52</td></tr><tr><td>Quality inspector</td><td>94980</td><td>1</td><td>1</td><td>2.56</td><td>0.07</td><td>89.4</td></tr></table>
<table><tr><td>Tile setter</td><td>95150</td><td>1</td><td>5</td><td>0.69</td><td>0.05</td><td>8.70</td></tr><tr><td>Reinforced concreter (general)</td><td>95210</td><td>22</td><td>36</td><td>1.70</td><td>0.82</td><td>3.53</td></tr><tr><td>Concrete shutterer</td><td>95220</td><td>1</td><td>5</td><td>1.15</td><td>0.12</td><td>10.78</td></tr><tr><td>Reinforcing iron worker</td><td>95230</td><td>2</td><td>2</td><td>1.81</td><td>0.16</td><td>21.15</td></tr><tr><td>Carpenter, general</td><td>95410</td><td>2</td><td>1</td><td>3.83</td><td>0.15</td><td>100.36</td></tr><tr><td>Construction carpenter</td><td>95415</td><td>1</td><td>2</td><td>0.91</td><td>0.05</td><td>17.08</td></tr><tr><td>Construction joiner</td><td>95420</td><td>1</td><td>5</td><td>1.64</td><td>0.18</td><td>15.00</td></tr><tr><td>Bench carpenter</td><td>95470</td><td>1</td><td>2</td><td>1.65</td><td>0.07</td><td>36.94</td></tr><tr><td>Housebuilder (general)</td><td>95910</td><td>3</td><td>5</td><td>0.68</td><td>0.10</td><td>4.62</td></tr><tr><td>Other construction workers</td><td>95990</td><td>2</td><td>1</td><td><strong>15.56</strong></td><td><strong>0.99</strong></td><td><strong>244.54</strong></td></tr><tr><td>Dockers</td><td>97120</td><td>1</td><td>4</td><td>0.28</td><td>0.03</td><td>2.77</td></tr><tr><td>Warehouse porter</td><td>97145</td><td>8</td><td>11</td><td><strong>2.50</strong></td><td><strong>0.8</strong></td><td><strong>7.81</strong></td></tr><tr><td>Hand packer</td><td>97150</td><td>1</td><td>4</td><td>1.08</td><td>0.08</td><td>15.59</td></tr><tr><td>Machine packer</td><td>97155</td><td>1</td><td>3</td><td>1.65</td><td>0.14</td><td>19.15</td></tr><tr><td>Other Dockers and freight handlers</td><td>97190</td><td>2</td><td>3</td><td>1.53</td><td>0.20</td><td>11.49</td></tr><tr><td>Lifting-truck operator</td><td>97920</td><td>3</td><td>4</td><td><strong>5.13</strong></td><td><strong>0.99</strong></td><td><strong>26.52</strong></td></tr><tr><td>Taxi driver</td><td>98530</td><td>2</td><td>3</td><td>0.75</td><td>0.09</td><td>6.18</td></tr><tr><td>Motor bus driver</td><td>98540</td><td>2</td><td>10</td><td>0.76</td><td>0.13</td><td>4.32</td></tr><tr><td>Lorry and van driver (local transport)</td><td>98550</td><td>12</td><td>29</td><td>1.10</td><td>0.46</td><td>2.62</td></tr><tr><td>Lorry and van driver (long-distance transport)</td><td>98560</td><td>1</td><td>3</td><td>0.88</td><td>0.06</td><td>14.12</td></tr><tr><td>Labourer</td><td>99910</td><td>14</td><td>22</td><td><strong>2.34</strong></td><td><strong>0.98</strong></td><td><strong>5.61</strong></td></tr></table>

a: Age, sex, recruitment site, smoking quantity and duration combined and daily alcohol drinking
<table><caption>**Table 13:** Association between industries and HNSCC using two-digit NAF codes</caption><thead><tr><th>Industry title</th><th>Code NAF</th><th>Case</th><th>Control</th><th>OR<sup>a</sup></th><th>95%CI</th></tr></thead><tbody><tr><td>Agriculture, hunting and related service activities</td><td>01</td><td>28</td><td>54</td><td>1.34</td><td>0.70 2.56</td></tr><tr><td>Fishing, fish farming and related service activities</td><td>05</td><td>8</td><td>8</td><td>2.62</td><td>0.68 10.09</td></tr><tr><td></td><td>14</td><td>1</td><td>5</td><td>0.40</td><td>0.03 4.75</td></tr><tr><td>Manufacture of food products, beverages and tobacco</td><td>15</td><td>20</td><td>44</td><td>1.05</td><td>0.51 2.19</td></tr><tr><td>Manufacture of wearing apparel; dressing and dyeing of fur</td><td>18</td><td>1</td><td>3</td><td>3.02</td><td>0.28 32.58</td></tr><tr><td>Manufacture of wood and of products of wood and cork, except furniture; manufacture of articles of straw and plaiting materials</td><td>20</td><td>3</td><td>6</td><td>1.87</td><td>0.35 10.10</td></tr><tr><td>Publishing, printing and reproduction of recorded media</td><td>22</td><td>2</td><td>6</td><td>0.57</td><td>0.09 3.60</td></tr><tr><td>Chemical industry</td><td>24</td><td>3</td><td>8</td><td>0.79</td><td>0.16 3.86</td></tr><tr><td>Manufacture of rubber products</td><td>25</td><td>2</td><td>1</td><td>2.10</td><td>0.17 25.42</td></tr><tr><td>Manufacture of fabricated metal products, except machinery and equipment</td><td>28</td><td>7</td><td>6</td><td><strong>6.52</strong></td><td><strong>1.69 25.14</strong></td></tr><tr><td>Manufacture of machinery and equipment n.e.c.</td><td>29</td><td>2</td><td>5</td><td>0.93</td><td>0.11 7.68</td></tr><tr><td>Manufacture of medical, precision and optical instruments, watches and clocks</td><td>33</td><td>1</td><td>5</td><td>1.62</td><td>0.18 14.91</td></tr><tr><td>Manufacture of motor vehicles, trailers and semi-trailers</td><td>34</td><td>2</td><td>2</td><td>1.40</td><td>0.14 14.38</td></tr><tr><td>Manufacture of other transport equipment</td><td>35</td><td>2</td><td>4</td><td>2.28</td><td>0.30 17.48</td></tr><tr><td>Manufacture of furniture; manufacturing n.e.c.</td><td>36</td><td>4</td><td>7</td><td>1.94</td><td>0.38 9.79</td></tr><tr><td>Electricity, gas, steam and hot water supply</td><td>40</td><td>1</td><td>9</td><td>0.54</td><td>0.05 5.39</td></tr><tr><td>Construction</td><td>45</td><td>42</td><td>100</td><td>0.95</td><td>0.55 1.63</td></tr><tr><td>Sale, maintenance and repair of motor vehicles and motorcycles; retail sale of automotive fuel</td><td>50</td><td>14</td><td>33</td><td>1.26</td><td>0.54 2.90</td></tr><tr><td>Wholesale trade and commission trade, except of motor vehicles and motorcycles</td><td>51</td><td>5</td><td>20</td><td>0.57</td><td>0.16 2.07</td></tr><tr><td>Retail trade, except of motor vehicles and motorcycles and personal and household goods</td><td>52</td><td>20</td><td>67</td><td>0.67</td><td>0.33 1.33</td></tr><tr><td>Hotels and restaurants</td><td>55</td><td>13</td><td>32</td><td>1.03</td><td>0.43 2.47</td></tr><tr><td>Land transport; transport via pipelines</td><td>60</td><td>9</td><td>33</td><td>0.47</td><td>0.19 1.15</td></tr><tr><td>Water transport</td><td>61</td><td>2</td><td>1</td><td>3.51</td><td>0.18 67.63</td></tr><tr><td>Air transport</td><td>62</td><td>2</td><td>3</td><td>1.28</td><td>0.14 11.39</td></tr><tr><td>Supporting and auxiliary transport activities; activities of travel agencies</td><td>63</td><td>9</td><td>17</td><td>1.25</td><td>0.47 3.36</td></tr><tr><td>Post and telecommunications</td><td>64</td><td>4</td><td>30</td><td>0.34</td><td>0.10 1.10</td></tr><tr><td>"Financial intermediation"<br>intermediation, except insurance and pension funding</td><td>65</td><td>1</td><td>14</td><td>0.13</td><td>0.02 1.16</td></tr><tr><td>Insurance and pension funding, except compulsory social security</td><td>66</td><td>1</td><td>6</td><td>0.28</td><td>0.03 3.23</td></tr><tr><td>Real estate activities</td><td>70</td><td>2</td><td>15</td><td>0.30</td><td>0.06 1.57</td></tr><tr><td>Rental without operator</td><td>71</td><td>1</td><td>5</td><td>0.52</td><td>0.05 5.86</td></tr><tr><td>Computer and related activities</td><td>72</td><td>3</td><td>3</td><td>0.72</td><td>0.09 5.90</td></tr><tr><td>Research and development</td><td>73</td><td>1</td><td>3</td><td>0.39</td><td>0.03 4.95</td></tr></tbody></table>
<table><tr><td>Other business activities</td><td>74</td><td>9</td><td>37</td><td>0.50</td><td>0.19</td><td>1.30</td></tr><tr><td>Public administration and defence; compulsory social security</td><td>75</td><td>48</td><td>147</td><td>0.76</td><td>0.46</td><td>1.27</td></tr><tr><td>Education</td><td>80</td><td>18</td><td>109</td><td>0.54</td><td>0.29</td><td>1.03</td></tr><tr><td>Health and social work</td><td>85</td><td>7</td><td>53</td><td><strong>0.29</strong></td><td><strong>0.11</strong></td><td><strong>0.76</strong></td></tr><tr><td>Activities of membership organizations n.e.c.</td><td>91</td><td>1</td><td>19</td><td>0.22</td><td>0.03</td><td>1.92</td></tr><tr><td>Recreational, cultural and sporting activities</td><td>92</td><td>4</td><td>25</td><td><strong>0.25</strong></td><td><strong>0.06</strong></td><td><strong>0.96</strong></td></tr><tr><td>Other service activities</td><td>93</td><td>4</td><td>7</td><td>2.38</td><td>0.49</td><td>11.66</td></tr><tr><td>Domestic services</td><td>95</td><td>17</td><td>37</td><td>2.12</td><td>0.96</td><td>4.68</td></tr></table>

a: age, sex, recruitment site, smoking quantity and duration combined and daily alcohol drinking
## 5.1 Background

This doctoral thesis investigated at a wide panel of suspected and known HNC risk factors in an attempt to better understand the aetiology of these cancers in the French West Indies. This current work revealed new information on HNC epidemiology and clues for further investigations and prevention. This thesis was based on the first case-control study looking at these cancers in the French West Indies and therefore, we focused our analyses on the classical risk factors, tobacco and alcohol, and we had a particular interest in the role of HPV.

The population of the French West Indies presents an interesting framework for study for HNC in terms of risk factor distribution and ethno-geographic origins. HNC incidence is elevated in this region considering the smoking and alcohol drinking prevalence which is lower when compared to countries with similar incidence rates. In addition, the population comprises mostly persons of African descent and very few studies have investigated HNC epidemiology in this ethnic group, and to our knowledge this is the first study conducted in an Afro-Caribbean population. Furthermore, the participation of the local cancer registries further added to the methodological robustness of our study and ensured a representative capture of the cases.

## 5.2 Main findings

Regarding the secondary analysis on the data from the Baromètre Santé DOM survey, we were able to describe finely the distribution of tobacco, alcohol and obesity in the population and highlight significant social disparities. The intention of this investigation was to explain the particularities of HNSCC epidemiology in the FWI through the distribution of common cancer risk factors and produce data on a topic which was rarely studied in the Caribbean region. We found that the prevalence of tobacco smoking was significantly greater in women
of higher SES. Furthermore, harmful chronic alcohol use in men was significantly greater in the lower SES strata. Likewise, the prevalence of obesity was greater in both men and women of lower SES. Overall, the social distributions of risk factors observed for both sexes in the FWI coincided partially with previous studies from the Caribbean and mainland France [86–89]. Indeed, the previously described descriptive statistics on cancer incidence showed distinct trends between the French West Indies and mainland France despite having similar health care system [67]. In light of this current work, we have seen that this specific cancer epidemiology in the French West Indies is also reflected in the risk factor distribution and could be attributed to their economic development and the culture being midway between the Caribbean and mainland France [90].

Considering that this is first time that any aetiological research on HNC of this magnitude has been conducted in the FWI, a thorough investigation on the tobacco and alcohol was conducted initially to confirm their role in this population. Then the other risk factors were examined, notably oral HPV infection which was a key focus of my research in addition to traditional risk factors.

Concerning the results from the case-control study in the FWI, tobacco and alcohol indeed play a considerable role in HNSCC etiology and the majority of the cases in the FWI were attributable these factors. These findings were concordant with other studies which attributed more than 60% of cases to these two risk factors [19, 91, 92]. Analysis by HNSCC subsites did not reveal any significant difference in the effects of tobacco, alcohol contrarily to other reports which attribute greater role of tobacco and alcohol to the larynx [5].

The overall HPV prevalence in the general population was 26% and was higher than what was reported previously in other countries (4.7 to 17.3%) [30, 93–99]. Likewise, the prevalence by sex was also higher than reports from other countries. However, the HPV
distribution by sociodemographics coincided with other studies; HPV was more prevalent among men, persons between 45 and 65 years [96, 99]. Among HNSCC cases, the HPV prevalence was 36% and was similar to regions of Central and Latin America (33%) according to a recent meta-analysis [100] but notably higher than pooled estimates for populations of African descent (17%) [101]. We found that oral HPV infections were more frequent among cases who were never smoker or non-drinkers. The reverse trend was observed in the control group; the prevalence was greater in smokers and daily drinkers. These data on HPV prevalence were further supported by the detailed analysis we performed on the interactions with tobacco and alcohol. The analyses on oral HPV genotype are indicative of an ethno-geographic particularity of the HPV distribution. Unlike most studies which showed an elevated risk for HPV16 solely [102], we found that the other high-risk types were also very involved in HNC in the FWI [103]. The findings are consistent with a study on in Guadeloupe which highlighted a higher prevalence of Hr-HPV types other than HPV16 and HPV18 in the cervix of healthy women [70]. The viral factors linked to HNSCC presents opportunities for cancer prevention, notably because of the availability of the HPV vaccine [27].

HNSCC was associated high-risk oral HPV infections and 13% of the cases were attributable to these infections. Furthermore, the data on interaction between tobacco, alcohol and HPV from previous studies are inconclusive [30, 102, 104–107]. Our results are in favour of a less important role of tobacco and alcohol in Hr-HPV-positive HNSCC. In addition, we were able to show evidence of significant negative interactions with alcohol on both the additive and multiplicative scale. These negative interactions were consistent with previous studies including a large study from IARC [106, 108]. However, despite non-significant negative interaction we found between tobacco and Hr-HPV, we cannot exclude tobacco as an independent risk factor in Hr-HPV-positive HNSCC as was suggested in another study [106].
Likewise, the effect of Hr-HPV was similar across the subsites; in contrast to previously described associations which were exclusively for the oropharynx [102, 106]. Indeed, despite inconsistency in the association related to HPV, we cannot completely rule out the involvement of Hr-HPV in the other subsites in this population.

Sexual behavior is thought to be involved in the causal pathway between oral HPV infection and the development of HNSCC; however previous work studying the association between sexual behavior and HNSCC have shown conflicting results [13, 30, 94, 108–113]. Therefore, we were interested in exploring sexual behavior as a risk factor of HNSCC. Our preliminary analyses revealed that condom use was significantly associated with a reduction in HNSCC risk. Contrarily to another study [114] our results did not allude to a mediating role of oral HPV infection in the effect of sexual behavior on HNSCC but rather an independent relationship. Given the risky behavior associated to HPV-positivity in cases and the lack of association among controls, we suspect there are other factors driving the causal pathway to HNSCC, such as HIV infections. In light of our findings, we believe that the underlying mechanism between sexual behavior and HNSCC in the French West Indies are yet to be elucidated and require further studies.

Family history, BMI and occupational exposures were also significantly associated to HNSCC and accounted for a smaller proportion of cases compared to tobacco and alcohol. Other studies which investigated these risk factors produced similar results in regards to their effect and their impact on HNC [32, 33, 58, 59, 115]. We found associations between HNSCC and some occupations and industries which were previously described in the literature. Cooks, construction workers, labourer and workers in the metal industry were significantly more likely to have HNSCC than persons who never worked in those occupations or industries [116–118]. The increased HNSCC risk among banana plantations workers is a new finding, as this occupation can only be investigated in a limited number of