# Risk of incident cancer in patients with Inflammatory Bowel Disease with prior breast cancer: a multicenter cohort study

Guillaume Le Cosquer, Julien Kirchgesner, Cyrielle Gilletta de Saint Joseph, Philippe Seksik, Aurélien Amiot, David Laharie, Maria Nachury, Cléa Rouillon, Vered Abitbol, Alexandre Nuzzo, et al.

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## ► To cite this version:

Guillaume Le Cosquer, Julien Kirchgesner, Cyrielle Gilletta de Saint Joseph, Philippe Seksik, Aurélien Amiot, et al. Risk of incident cancer in patients with Inflammatory Bowel Disease with prior breast cancer: a multicenter cohort study. Clinical Gastroenterology and Hepatology, 2025, 23 (10), pp.1824-1833.e3. 10.1016/j.cgh.2024.09.034. hal-04766650

HAL Id: hal-04766650

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Submitted on 19 May 2025

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# Risk of Incident Cancer in Patients with Inflammatory Bowel Disease with Prior Breast Cancer: A Multicenter Cohort Study

Guillaume Le Cosquer,¹ Julien Kirchgesner,² Cyrielle Gilletta De Saint Joseph,¹
Philippe Seksik,² Aurélien Amiot,³,⁴ David Laharie,⁵ Maria Nachury,⁶ Cléa Rouillon,⁷
Vered Abitbol,⁸ Alexandre Nuzzo,⁹ Stéphane Nancey,¹⁰ Mathurin Fumery,¹¹
Amélie Biron,¹² Nicolas Richard,¹³ Romain Altwegg,¹⁴ Driffa Moussata,¹⁵
Benedicte Caron,¹⁶ Mathias Vidon,¹⁷ Catherine Reenaers,¹⁸ Mathieu Uzzan,³
Jean-Marie Reimund,¹⁹ Mélanie Serrero,²⁰ Marion Simon,²¹ Alban Benezech,²²
Félix Goutorbe,²³ Anne-Laure Pelletier,²⁴ Ludovic Caillo,²⁵ Charlotte Vaysse,²⁶ and
Florian Poullenot,⁴ and the GETAID

¹Department of Gastroenterology and Pancreatology, Toulouse University Hospital, Toulouse, France; ²Sorbonne Université, Institut Pierre Louis d'Epidémiologie et de Santé Publique, INSERM UMRS-938, Centre de Recherche Saint-Antoine, CRSA, Hôpital Saint-Antoine, Department of Gastroenterology, Paris, France; ³Department of Gastroenterology, Hôpitaux Universitaires Henri Mondor Hospital, AP-HP, Université Paris Est Creteil, Creteil, France; ⁴Department of Gastroenterology, Bicêtre University Hospital, AP-HP, Université Paris Saclay, INSERM CESP, Le Kremlin Bicêtre, Le Kremlin Bicêtre, France; ⁵CHU de Bordeaux, Centre Medico-chirurgical Magellan, Hôpital Haut-Lévêque, Gastroenterology Department; Université de Bordeaux; INSERM CIC 1401; Bordeaux, France; ⁶University Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France; ⁷Hepato-gastroenterology Department, CHU Caen, Caen, France; ⁸Hôpital Cochin AP-HP Gastro-entérologie, and Université de Paris Cité, Paris, France; ⁹Department of Gastroenterology, IBD and Intestinal Failure, Beaujon Hospital, APHP, Nord, Paris Cité University, INSERM U1148, Paris, France; ¹⁰Department of Gastroenterology, CHU, Lyon, France; ¹¹Department of Gastroenterology, CHU, Amiens, et Unité Peritox UMRI-01, Université de Picardie Jules Verne, Amiens, France; ¹²Department of Hepato-Gastro-Enterology and Digestive Oncology, Robert Debré Hospital, Reims, France; ¹³Department of Gastroenterology, Rouen University Hospital, University of Rouen Normandy, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen, France; ¹⁴Department of Gastroenterology, Saint-Eloi Hospital, Montpellier, France; ¹⁵Hepato-gastroenterology Department, CHRU Tours-TROUSSEAU Hospital, Tours, France; ¹⁶Department of Gastroenterology, Nancy University Hospital, INFINY Institute, FHU-CURE, INSERM, NGERE, University of Lorraine, Vandœuvre-lès-Nancy, Nancy, France; ¹⁷Departement of Gastroenterology, Hôpital Intercommunal de Créteil, Créteil, France; ¹⁸Hepato-gastroenterology Department, CHU Sart Tilman, Liège University, Liège, Belgium; ¹⁹Service d'Hépato-Gastroentérologie et d'Assistance Nutritive, Hôpitaux Universitaires de Strasbourg et INSERM U1113, Université de Strasbourg, Strasbourg, France; ²⁰Department of Gastroenterology, CHU Hopital Nord, AP-HM, Université Aix Marseille, Marseille, France; ²¹Hepato-gastroenterology Department, Insititut Mutualiste Montsouris, Paris, France; ²²Department of Gastroenterology, Centre Hospitalier Avignon, Avignon, France; ²³Department of Gastroenterology, Hospital of Bayonne, Bayonne, France; ²⁴Department of Hepato-Gastroenterology and Digestive Oncology, Bichat Claude Bernard University Hospital, Paris, France; ²⁵Department of Gastroenterology, Nimes University Hospital, Nimes, France; and ²⁶Department of Surgical Oncology, University Hospital Center Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
# Risk of incident cancer in patients with Inflammatory Bowel Disease with prior breast cancer: a multicenter cohort study

207 IBD patients from 24 institutions

Median follow-up 71 months

Multivariate analysis (incident cancer risk)

- Stage T4d (p=0.036)

- Triple negative tumor (p=0.016)

- Follow-up of less than 71 months (p=0.005)

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**BACKGROUND & AIMS:** Breast cancer is the most common malignancy observed in patients with inflammatory bowel diseases (IBD). The aim of our study was to evaluate incident cancer rate (recurrence or new-onset cancer) in a cohort of patients with IBD with a history of breast cancer according to the subsequent IBD treatment provided.

**METHODS:** A multicenter retrospective study included consecutive patients with IBD with prior breast cancer. The inclusion date corresponded to the diagnosis of index malignancy. Follow-up lasted from cancer diagnosis until the occurrence of incident cancer.

**RESULTS:** Among 207 patients included (median disease duration, 13 years [interquartile range, 6-21]), first-line treatment (median interval of 28 months [interquartile range, 7-64]) was a conventional immunosuppressant in 19.3% of patients, anti-tumor necrosis factor in 19.8%, vedolizumab in 7.2%, and ustekinumab in 1.9%. After a median follow-up of 71 months (interquartile range, 34-148), 42 (20%) incident cancers were observed (34 breast cancer recurrences). Adjusted incidence rates per 1000 person-years were 10.2 (95% confidence interval, 6.0-16.4) for the untreated arm and 28.9 (95% confidence interval, 11.6-59.6) for exposed patients (P = .0519). There was no significant difference between treated patients and control subjects regarding incident cancer-free survival rates (P = .4796). In multivariable analysis, factors associated with incident cancer were stage T4d (P = .036), triple negative tumor (P = .016), and follow-up of less than 71 months (P = .005).

**CONCLUSIONS:** We did not find a statistically significant increase in incident breast cancer related to IBD treatment beyond the already known poor prognostic factors of breast cancer.

Keywords: Breast Cancer; IBD; Incident Cancer; Biologics.

Inflammatory bowel diseases (IBD) are lifelong inflammatory disorders which management has dramatically changed in the last decades. Recent IBD guidelines recommend earlier use of advanced therapies in the disease course and drug de-escalation exit strategies.¹,² Therefore, for 2 decades patients have been exposed to immunosuppressive drugs for longer periods. One of the most dreaded side effects of these drugs is an increase in the risk of malignancies (notably skin, urinary tract, uterine and cervical cancer, and lymphoma).³,⁴ Patients with a history of cancer and a theoretical risk of reactivation of dormant micrometastasis are another concern.⁵,⁶

Previous studies suggest that conventional immunosuppressants (thiopurines and methotrexate), anti-tumor necrosis factor (TNF), and vedolizumab have no impact on the risk of incident cancer (recurrence or new-onset cancer) in patients with IBD and prior nondigestive malignancy.⁷⁻¹¹ Yet, recently published ECCO guidelines state that data are insufficient to make recommendations regarding the safety of methotrexate use in patients with prior malignancies and vedolizumab and ustekinumab use in patients with active malignancy.¹² Regarding anti-TNFs, individual cancer types, and the timing of treatment, data required to recommend precise use in patients with prior or active malignancy are lacking.
Breast cancer is the most common cancer diagnosed in women, and it affects 1 in 8 women.¹³ According to the World Health Organization, 2.3 million women were diagnosed with breast cancer and 685,000 cases resulted in deaths in 2020.¹⁴ Regarding patients with IBD, breast cancer is the most common extradigestive malignancy (approximately 25% of cancers) unrelated to the disease or its treatment.⁷ Previous studies in posttransplant immunosuppressed patients show that breast cancer has a moderate risk of recurrence (11%-25%) according to Penn's classification.¹⁵ In patients with IBD, medical management of subjects with a history of breast cancer is a frequent and unresolved problem for clinicians. Therefore, we conducted a cohort study aimed at assessing the rate of incident cancer (recurrence or new onset) in patients with IBD with a history of breast cancer, according to the medications used.

## Materials and Methods

### Study Design and Population

This was an extension study from a multicenter retrospective cohort study including consecutive patients with IBD from May 2016 to December 2019 with prior cancer recruited among 24 French and Belgian centers affiliated with Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID).⁷ Patients were included when they had a confirmed diagnosis of prior cancer (based on the pathology or oncology records) excluding digestive and biliary tract cancers.⁷ Patients diagnosed with IBD after a cancer diagnosis could be recruited.

In this study, only patients from the initial cohort with a confirmed diagnosis of breast cancer, excluding lymphoma or skin cancers with breast localization, were included. Additional patients from the participating centers were included from May 2019 to August 2023. To ensure that all consecutive patients were included, cases were identified by extracting patient files with the Crohn's disease (CD) or ulcerative colitis coding according to the 10th revision of the International Classification of Diseases (ICD 10 code: K50 and K51) and the breast cancer coding (ICD 10 code: C50).

### Data Collection

The data for each patient included were anonymously recorded on an electronic Case Report Form in an Excel file. The data was collected retrospectively by consulting the electronic patient records.

The following patient characteristics at inclusion were retrospectively reviewed and collected: gender, age, smoking status, age at IBD diagnosis, subtype, localization, and behavior of IBD,¹⁶ and the presence of extraintestinal manifestations. Data were collected on the prior treatment lines (ie, before breast cancer index diagnosis).

## What You Need to Know

### Background

Management of IBD patients with prior breast cancer is a common unresolved problem due to the theoretical risk of reactivating dormant micrometastasis under immunosuppressants and biologics.

### Findings

In our study, the risk of incident cancer was related to established poor breast cancer prognostic factors, but not to IBD therapy.

### Implications for patient care

Immunosuppressants and biologics in IBD patients with prior breast cancer can be considered after multidisciplinary discussion, considering the established poor prognostic factors of breast cancer and IBD behavior.

The following data were collected on breast cancer: date of diagnosis, presence of BRCA mutation, tumor laterality, histologic type (ductal, lobular, or papillary carcinoma in situ or invasive behavior), pathologic staging (tumor size, number of positive axillary nodes, lymphovascular emboli), grade (low, medium, or high), progesterone and estrogen receptor status, human epidermal growth factor receptor 2 (HER2) status, the TNM cancer staging system, and previous and current cancer treatments (including surgery, chemotherapy, radiotherapy, hormonotherapy, and specific targeted therapy).

Follow-up started from the date of the cancer diagnosis and ended at the diagnosis of incident cancer, which corresponds to cancer recurrence or the occurrence of a new cancer, death, or the last date of news in patients who experienced no event. Breast cancer recurrence was defined as local (same side) or distant (nodes or metastasis).

During the follow-up period, data on IBD treatment were collected: type, date of the first administration, and need for discontinuation. Patients were categorized according to whether an immunosuppressive drug (thiopurines, methotrexate, anti-TNF, vedolizumab, ustekinumab) was used.

For each incident cancer, the date of diagnosis, management, and status at the end of follow-up (remission, palliative, under treatment, or death) were recorded.

## Outcome Measures

The main objective of this study was to evaluate the crude incidence rate (per 1000 person-years) of incident cancer according to whether a treatment was used after cancer diagnosis.

Secondary objectives were to (1) compare the adjusted incidence rate of incident cancers between
patients exposed to treatment and those who were not; (2) compare incident cancer-free survival rates between patients exposed to conventional immunosuppressants, biologics, and no treatment; and (3) determine factors related to IBD and prior breast cancer associated with incident cancer.

## Statistical Analysis

Continuous variables were reported as medians and ranges and compared using the Student *t*-test (or the Mann-Whitney Wilcoxon test for variables with an abnormal distribution). Categorical variables were indicated as proportions and percentages and comparison was drawn using a chi-square test (or Fisher exact tests when appropriate).

Regarding the crude incidence rate calculation in the treatment arm, the follow-up time was calculated from the first treatment administration after the cancer index to the last follow-up visit. To avoid immortal time bias, patients in the treated group contributed to the untreated group during their "unexposed time" (before drug exposure [ie, from the time of breast cancer diagnosis to the first treatment administration]). For patients who did not receive IBD treatment during the follow-up period, the follow-up time started at the time of breast cancer diagnosis and ended at the last follow-up visit. We evaluated crude cancer incidence rates in both groups. To evaluate the confounding effect of subsequent treatments on the first treatment received, a sensitivity analysis was done that censored the follow-up after the first treatment was stopped.

Considering that introducing a treatment after breast cancer diagnosis could have been influenced by patients' baseline characteristics, propensity score matching was performed to establish comparable groups. The following variables were a priori determined and included in the propensity score model: age, lymph node and metastasis extension, and tumor grade. Patients were matched 1:1 with no replacement by a Mahalanobis matching algorithm based on the propensity score using XLSTAT software (version 2022.5.1). The comparability of baseline characteristics between matched groups was verified using chi-square tests for categorical variables and t-tests for continuous variables. We evaluated adjusted cancer incidence rates of matched groups.

Cumulative survival rates without incident cancer were calculated with a Kaplan-Meier method and compared using a Cox model with time-varying covariates that accounts for time on a drug and changes in "exposed" status for each patient.

We investigated risk factors for incident cancer among the following variables: gender, age at cancer diagnosis, IBD subtype, first treatment administered after the cancer index diagnosis, lymph node and metastasis extension, tumor grade and size, lymphovascular emboli, stage T4d (inflammatory breast cancer), estrogen, progesterone receptor, and HER2 expression and

follow-up time after cancer diagnosis. Continuous variables were dichotomized at the median. Variables with a *P* < .25 in univariate regression (univariable Cox regression) were included in a multivariable Cox regression model. Manual stepwise elimination was performed to find the best suitable model of factors that predict incident cancer risk. Results are presented as hazard ratio with 95% confidence intervals (95% CI). A multivariable model including only the patients who received a treatment after the cancer index diagnosis was also applied to highlight specific drug effect and the impact of the delay between cancer diagnosis and the first dose of treatment.

Two-sided statistical tests were used for all analyses and a *P* < .05 was considered significant. The statistical analyses were performed with Jamovi (version 2.3.18) and STATA (version 18.5) software.

## Ethical Considerations

The entire study was conducted in accordance with the principles of good clinical practice and the declaration of Helsinki. The use of all the data collected complies with the modified French Data Protection Act of June 1, 1998, and the General Data Protection Regulation. The study design was approved by the French Data Protection Agency (CNIL, registration number: 2210131) and the investigational review board of each center. All patients were informed of their participation by written notice.

## Results

### Patient Characteristics

A total of 207 patients (202 women, 5 men) were included: 126 (60.8%) patients with CD, 78 (37.7%) with ulcerative colitis, and 3 (1.5%) with unclassified IBD. The median age at IBD diagnosis was 38 years (interquartile range [IQR], 30–50 years). IBD was diagnosed after the breast cancer index diagnosis in 38 patients (18.4%) in the entire cohort. In the others, median IBD duration at index breast cancer diagnosis was 167 (74–259) months. Before inclusion, 86 (51%) patients had been exposed to conventional immunosuppressants, 73 (43%) to anti-TNF, 10 (6%) to vedolizumab, and 6 (3.6%) to ustekinumab. Patient characteristics at inclusion are summarized in Table 1.

### Breast Cancer Characteristics

Mean age at breast cancer index diagnosis was 50 years (IQR, 42–60 years). The presence of BRCA 1/2 mutation was detected in 4 (1.9%) patients. At cancer diagnosis, 52 (25.1%) patients had lymph node involvement and 15 (7.2%) a metastatic extension. Among the 196 patients who underwent surgery
<table><caption>Table 1. Patient IBD Characteristics</caption><thead><tr><th></th><th>Whole cohort<br>(N = 207)</th><th>Patients without<br>incident cancer (n = 165)</th><th>Patients with<br>incident cancer (n = 42)</th><th>P value</th></tr></thead><tbody><tr><td>Age at diagnosis<sup>a</sup></td><td></td><td></td><td></td><td>.884</td></tr><tr><td>A1</td><td>6 (2.9)</td><td>5 (3)</td><td>1 (2.4)</td><td></td></tr><tr><td>A2</td><td>114 (55)</td><td>92 (55.8)</td><td>22 (52.4)</td><td></td></tr><tr><td>A3</td><td>87 (42)</td><td>68 (41.2)</td><td>19 (45.2)</td><td></td></tr><tr><td>Crohn's disease (n = 126)</td><td></td><td></td><td></td><td>.170</td></tr><tr><td>Location<sup>a,b</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>L1</td><td>38 (30.2)</td><td>29 (28.2)</td><td>9 (39.1)</td><td></td></tr><tr><td>L2</td><td>29 (23)</td><td>25 (24.3)</td><td>4 (17.4)</td><td></td></tr><tr><td>L3</td><td>55 (43.7)</td><td>46 (44.7)</td><td>9 (39.1)</td><td></td></tr><tr><td>L4</td><td>3 (2.4)</td><td>3 (2.9)</td><td>0 (0)</td><td></td></tr><tr><td>Behavior<sup>a</sup></td><td></td><td></td><td></td><td>.938</td></tr><tr><td>B1</td><td>68 (54)</td><td>56 (54.4)</td><td>12 (52.2)</td><td></td></tr><tr><td>B2</td><td>40 (31.7)</td><td>32 (31.1)</td><td>8 (34.8)</td><td></td></tr><tr><td>B3</td><td>18 (14.3)</td><td>15 (14.6)</td><td>3 (13)</td><td></td></tr><tr><td>Perianal disease</td><td>34 (27.2)</td><td>27 (26.2)</td><td>7 (30.4)</td><td>.680</td></tr><tr><td>Ulcerative colitis (n = 78)</td><td></td><td></td><td></td><td>.782</td></tr><tr><td>Extension<sup>a</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>E1</td><td>15 (19.2)</td><td>12 (19.7)</td><td>3 (17.6)</td><td></td></tr><tr><td>E2</td><td>18 (23.1)</td><td>15 (24.6)</td><td>3 (17.6)</td><td></td></tr><tr><td>E3</td><td>45 (57.7)</td><td>34 (55.7)</td><td>11 (64.8)</td><td></td></tr><tr><td>Extraintestinal manifestations</td><td>34 (16.4)</td><td>25 (16.8)</td><td>9 (23.7)</td><td>.325</td></tr><tr><td>Smoking status</td><td></td><td></td><td></td><td>.016</td></tr><tr><td>Former</td><td>44 (21.3)</td><td>38 (23)</td><td>6 (14.3)</td><td></td></tr><tr><td>Never</td><td>136 (65.7)</td><td>101 (61.2)</td><td>35 (83.3)</td><td></td></tr><tr><td>Active</td><td>27 (13)</td><td>26 (15.8)</td><td>1 (2.4)</td><td></td></tr><tr><td>Bowel resection, prior cancer diagnosis</td><td>51 (24.6)</td><td>38 (23)</td><td>13 (31)</td><td>.287</td></tr></tbody></table>

NOTE. Data are presented as n (%).

<sup>a</sup>According to the Montreal classification.

<sup>b</sup>One patient had only perianal disease (incident cancer group).

(94.7%), 78 (39.8%) had breast-conserving surgery and 70 (35.7%) a mastectomy (no data available for 48 patients). A sentinel lymph node biopsy was performed in 59 (30.1) patients, and 65 (33.2) patients had an axillary lymph node dissection (no data available for 72 patients). All cancer characteristics are indicated in Table 2. A comparison of cancer characteristics between patients exposed to conventional immunosuppressants, biologics, and no treatment is provided in Supplementary Table 1.

## Follow-Up and Incident Cancer Risk

After a median follow-up of 71 months (IQR, 34–148), 42 (20.2%) incident cancers were observed: 34 (80.9%) recurrences of prior breast cancer and 8 (19.1%) new cancers (sites shown in Supplementary Table 2). Seven (3.4%) patients died from cancer-related causes during follow-up. Concerning treatments after the breast cancer index, 107 (51.6%) patients received no treatment, 22 (10.6%) were treated with thiopurines, 18 (8.7%) with methotrexate, 41 (19.8%) with anti-TNF, 15 (7.2%) with vedolizumab, and 4 (1.9%) with ustekinumab. Treatments were initiated at a median interval of 28 months (IQR, 7–64) after the breast cancer index.

Crude incidence rates per 1000 person-years were 5.18 (95% CI, 3.53–7.36) for the untreated arm and 11.8 (95% CI, 5.88–21.12) for exposed patients (P = .0417). After matching for age, lymph node and metastasis extension, and tumor grade using a propensity score analysis with a 1:1 ratio, adjusted crude incidence rates per 1000 person-years were 10.2 (95% CI, 6.0–16.4) for the untreated arm and 28.9 (95% CI, 11.6–59.6), respectively (P = .0519).

In the overall population, survival without incident cancer at 1, 3, and 5 years was 97.9%, 90.3%, and 80.4%, respectively. There was no significant difference between treated patients and control subjects regarding incident cancer-free survival rates (P = .4796) (Figure 1). Incident cancer-free survival rates were not different between patients receiving immunosuppressants and biologics when analyzed separately (Figure 2). Crude incidence rates per 1000 person-years were 16.67 for patients exposed to immunosuppressants (95% CI, 3.44–48.71) and 22.06 for patients exposed to biologics (95% CI, 4.55–64.47; P = .7305) in the sensitivity analysis (which censored the follow-up after the first treatment following the cancer index diagnosis was stopped) (Supplementary Table 3).
<table><caption>**Table 2.** Breast Cancer Characteristics</caption><thead><tr><th>Characteristics</th><th>n</th><th>N = 207</th></tr></thead><tbody><tr><td>Tumor laterality</td><td>173</td><td></td></tr><tr><td>Left</td><td></td><td>90 (52)</td></tr><tr><td>Right</td><td></td><td>78 (45.1)</td></tr><tr><td>Bilateral</td><td></td><td>5 (2.9)</td></tr><tr><td>Histologic type</td><td>153</td><td></td></tr><tr><td>In situ ductal carcinoma</td><td></td><td>25 (16.3)</td></tr><tr><td>Invasive ductal carcinoma</td><td></td><td>96 (62.7)</td></tr><tr><td>Ductal carcinoma (without precision)</td><td></td><td>1 (0.7)</td></tr><tr><td>In situ lobular carcinoma</td><td></td><td>11 (7.2)</td></tr><tr><td>Invasive lobular carcinoma</td><td></td><td>13 (8.5)</td></tr><tr><td>Lobular carcinoma (without precision)</td><td></td><td>1 (0.7)</td></tr><tr><td>Papillary carcinoma</td><td></td><td>1 (0.7)</td></tr><tr><td>Tubular carcinoma</td><td></td><td>1 (0.7)</td></tr><tr><td>Carcinoma not otherwise specified</td><td></td><td>4 (2.5)</td></tr><tr><td>Tumor size, mm</td><td>103</td><td>18 (2–120)</td></tr><tr><td>Tumor grade</td><td>117</td><td></td></tr><tr><td>Low</td><td></td><td>14 (12)</td></tr><tr><td>Medium</td><td></td><td>67 (57.3)</td></tr><tr><td>High</td><td></td><td>36 (30.7)</td></tr><tr><td>Presence of lymphovascular emboli</td><td>68</td><td>17 (25)</td></tr><tr><td>Presence of lymph node capsular rupture</td><td>55</td><td>6 (10.9)</td></tr><tr><td>Progesterone receptor status</td><td>111</td><td></td></tr><tr><td>Absence</td><td></td><td>29 (26.1)</td></tr><tr><td>+</td><td></td><td>21 (18.9)</td></tr><tr><td>++</td><td></td><td>14 (12.6)</td></tr><tr><td>+++</td><td></td><td>47 (42.4)</td></tr><tr><td>Estrogen receptor status</td><td>109</td><td></td></tr><tr><td>Absence</td><td></td><td>19 (17.4)</td></tr><tr><td>+</td><td></td><td>15 (13.8)</td></tr><tr><td>++</td><td></td><td>13 (11.9)</td></tr><tr><td>+++</td><td></td><td>62 (56.9)</td></tr><tr><td>Human epidermal growth factor<br/>receptor 2 (HER2) status</td><td>109</td><td></td></tr><tr><td>Absence</td><td></td><td>82 (75.2)</td></tr><tr><td>+</td><td></td><td>4 (3.7)</td></tr><tr><td>++</td><td></td><td>6 (5.5)</td></tr><tr><td>+++</td><td></td><td>17 (15.6)</td></tr><tr><td>Triple negative tumor</td><td>103</td><td>13 (12.6)</td></tr><tr><td>TNM cancer staging system</td><td>114</td><td></td></tr><tr><td>Tis</td><td></td><td>5 (4.4)</td></tr><tr><td>T1</td><td></td><td>62 (54.4)</td></tr><tr><td>T2</td><td></td><td>32 (28.1)</td></tr><tr><td>T3</td><td></td><td>8 (7)</td></tr><tr><td>T4</td><td></td><td>5 (4.4)</td></tr><tr><td>T4d</td><td></td><td>3 (2.6)</td></tr><tr><td>N1</td><td></td><td>32 (28.1)</td></tr><tr><td>N2</td><td></td><td>3 (2.6)</td></tr><tr><td>N3</td><td></td><td>3 (2.6)</td></tr><tr><td>M1</td><td></td><td>7 (6.1)</td></tr><tr><td>Cancer treatment</td><td></td><td></td></tr><tr><td>Surgery</td><td>207</td><td>196 (94.7)</td></tr><tr><td>Adjuvant chemotherapy</td><td>187</td><td>109 (58.3)</td></tr><tr><td>Radiation therapy</td><td>193</td><td>157 (81.3)</td></tr><tr><td>Hormonal therapy<sup>a</sup></td><td>163</td><td>109 (66.8)</td></tr><tr><td>Aromatase inhibitors</td><td></td><td>28 (17.2)</td></tr><tr><td>Tamoxifen</td><td></td><td>56 (34.4)</td></tr></tbody></table>

<table><caption>**Table 2.** Continued</caption><thead><tr><th>Characteristics</th><th>n</th><th>N = 207</th></tr></thead><tbody><tr><td>Tamoxifen and switch to<br/>aromatase inhibitors</td><td></td><td>7 (4.3)</td></tr><tr><td>HER2-directed therapy</td><td>94</td><td>16 (17)</td></tr></tbody></table>

NOTE. Data are represented as median (range) for continuous variables and n (%) for categorical variables.

Stage T4d, triple negative tumor, and follow-up of less than 71 months after cancer diagnosis were independently associated with lower survival rates without incident cancer in the multivariable analysis. Results from the univariate and multivariable Cox model analyses are presented in Table 3.

In the multivariable model including only the 100 patients having received a treatment after the cancer index diagnosis, the type of treatment was not associated with the risk of incident cancer. A follow-up of less than 71 months after cancer diagnosis was independently associated with an increased risk of incident cancer (hazard ratio, 5.13; 95% CI, 1.09–24.21; P = .039) (Supplementary Table 4).

Discussion

In this large international multicenter retrospective study with long-term follow-up, no statistically significant association was found between IBD therapies and the risk of incident cancer in patients with IBD with a history of breast cancer. Managing patients with IBD with a history of breast cancer, which may recur decades after the initial diagnosis, poses a significant clinical challenge. Our findings will help clinicians to make decisions in multidisciplinary meetings to start immunosuppressants or biologics in case of IBD flare-up in these patients.

Although no increase in the risk of breast cancer was shown in patients with IBD,¹⁷,¹⁸ a recent Danish registry reported that the survival of patients with breast cancer with CD treated with chemotherapy was poorer compared with survival in patients without IBD.¹⁹ In our study, we found no difference based on IBD type (ulcerative colitis vs CD). The Danish results should be interpreted with caution because of the overrepresentation of chemotherapy use in patients with CD in their study, possibly indicating a poorer prognosis at inclusion. On the other hand, Axelrad et al²⁰ showed that hormonal therapy may increase the risk of IBD relapse. This suggests that the increase in relapse rate partially explains the use of immunosuppressant in these patients. We found no increase in the need for IBD treatments in hormonal therapy-treated patients in our study (data not shown).

<footnote>aNot otherwise specified for 18 patients.</footnote>
<figure><img src="image_4.png" /><figcaption>**Figure 1.** Survival without incident cancer. Survival curves without incident cancer for patients receiving IBD treatments (red curve) and control subjects (blue curve) calculated with the Kaplan-Meier method and compared using a Cox model with time-varying covariates.</figcaption></figure>

Prospective safety data of biologics in patients with IBD and cancer are limited because these patients are excluded from clinical trials. In the coming years, large ongoing prospective studies (eg, the French I-CARE and US SAPPHIRE registries) will help to identify potential IBD risk factors associated with the worst outcomes.²¹,²² In the meantime, our results concur with those of previous retrospective studies and the recently published interim analysis of the SAPPHIRE registry.¹⁰,²³⁻²⁸ While those works have design limitations, the major strength of our work is that it is the first to focus on the most frequent cancer (breast cancer) in patients with IBD only, with the longest follow-up after breast cancer in patients with IBD ever published (median follow up of 71 months).

The absolutely low number of patients in each treatment subgroup did not allow separate analysis of the distinct effect of individual IBD treatment (notably in multivariable analysis). Findings similar to ours were noted in a retrospective analysis of US Medicare data on the risk of breast cancer recurrence, which showed no

increased risk with the use of methotrexate, thiopurines, or anti-TNF in patients suffering from IBD and rheumatoid arthritis.²³ Yet, the median duration of follow-up was shorter (2.4–3.4 years) and anti-TNFs were started at a mean time of 9.4 years after breast cancer. Regarding anti-TNFs, a Swedish study on 240 matched patients with rheumatoid arthritis and a history of breast cancer found no increased risk of breast cancer recurrence.²⁴

Data on vedolizumab and ustekinumab are even more limited. One study merging different cancers highlighted no impact of those treatments on incident cancer risks.²⁵ However, this study included only 37 patients exposed to vedolizumab and 14 to ustekinumab and merged different cancers. Similarly, in their study Hasan et al²⁶ showed that neither exposure to ustekinumab (27 patients) nor exposure to vedolizumab (34 patients) are associated with an increased risk of incident cancer in patients with prior malignancy compared with patients not receiving treatment. Interestingly, Holmer et al²⁷ compared the risk of cancer recurrence between patients with IBD with a recent prior cancer treated with

<figure><img src="image_5.png" /><figcaption>**Figure 2.** Comparison of incident cancer-free survival between control, immunosuppressants, and biologics cohorts. Survival curves without incident cancer for patients receiving no treatment (blue curve), conventional immunosuppressants (red curve), and biologics (green curve) calculated with the Kaplan-Meier method and compared using a Cox model with time-varying covariates.</figcaption></figure>
<table><caption>**Table 3.** Incident Cancer Risk Factors</caption><thead><tr><th rowspan="2">Factors</th><th colspan="3">Univariate analysis</th><th colspan="3">Multivariable analysis</th></tr><tr><th>HR</th><th>95% CI</th><th><i>P</i> value</th><th>HR</th><th>95% CI</th><th><i>P</i> value</th></tr></thead><tbody><tr><td>Male gender</td><td>0.64</td><td>0.09-4.65</td><td>.655</td><td></td><td></td><td></td></tr><tr><td>Age ≥50 y at inclusion</td><td>1.67</td><td>0.44-6.3</td><td>.450</td><td></td><td></td><td></td></tr><tr><td>Ulcerative colitis<sup>a</sup></td><td>0.46</td><td>0.1-2.19</td><td>.331</td><td></td><td></td><td></td></tr><tr><td>Lymph node extension</td><td>0.67</td><td>0.17-2.7</td><td>.575</td><td></td><td></td><td></td></tr><tr><td>Metastatic extension</td><td>0.85</td><td>0.1-6.91</td><td>.875</td><td></td><td></td><td></td></tr><tr><td>First treatment after cancer diagnosis<sup>b</sup></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Anti-TNF</td><td>0</td><td>0-infinity</td><td>.999</td><td></td><td></td><td></td></tr><tr><td>Methotrexate</td><td>1.02</td><td>0.24-4.31</td><td>.981</td><td></td><td></td><td></td></tr><tr><td>Thiopurines</td><td>0</td><td>0-infinity</td><td>.999</td><td></td><td></td><td></td></tr><tr><td>Vedolizumab</td><td>0</td><td>0-infinity</td><td>.999</td><td></td><td></td><td></td></tr><tr><td>Ustekinumab</td><td>N/A<sup>c</sup></td><td>N/A<sup>c</sup></td><td>.999</td><td></td><td></td><td></td></tr><tr><td>High grade<sup>d</sup></td><td>1.52</td><td>0.42-5.45</td><td>.524</td><td></td><td></td><td></td></tr><tr><td>Tumor size >18 mm</td><td>1.84</td><td>0.51-6.6</td><td>.348</td><td></td><td></td><td></td></tr><tr><td>Lymphovascular emboli</td><td>0.61</td><td>0.13-2.98</td><td>.543</td><td></td><td></td><td></td></tr><tr><td>Stage T4d</td><td>3.53</td><td>0.43-29.36</td><td><strong>.242</strong></td><td>10.84</td><td>1.17-100.26</td><td><strong>.036</strong></td></tr><tr><td>Triple negative</td><td>4.1</td><td>0.81-20.72</td><td><strong>.087</strong></td><td>3.88</td><td>1.29-11.74</td><td><strong>.016</strong></td></tr><tr><td>Follow-up after cancer diagnosis <71 mo</td><td>7.35</td><td>0.8-67.489</td><td><strong>.078</strong></td><td>5.93</td><td>1.73-20.35</td><td><strong>.005</strong></td></tr></tbody></table>

NOTE. Bold characters highlight results with *P* < .05.

CI, confidence intervals; HR, hazard ratio; N/A, not applicable; TNF, tumor necrosis factor.

<sup>a</sup>Versus Crohn's disease.

<sup>b</sup>Versus none.

<sup>c</sup>Nonapplicable. There was no recurrence in patients with tubular carcinoma (n = 1) and those treated with ustekinumab (n = 3).

<sup>d</sup>Versus low and medium grade.

anti-TNFs and non-anti-TNF biologics (ustekinumab, vedolizumab). Although their results were limited by the small samples (78 patients received anti-TNF, 51 vedolizumab, and 15 ustekinumab), they found no significant differences between the 2 groups. Their results concur with 2 other retrospective studies that compared the impact of vedolizumab and anti-TNF on incident cancer in patients with prior malignancy.<sup>7,10</sup>

As previously described, we confirmed the poor prognosis of inflammatory breast cancer and triple negative tumor,<sup>29,30</sup> thereby providing strong external validation for the robustness of our cohort. Indeed, triple negative tumors (15%-20% of breast cancer) are described in the literature as the subtype with the worst prognosis with higher locoregional and metastatic recurrence rates.<sup>31</sup> However, our findings on the impact of inflammatory breast cancer are limited by the low number of patients concerned in our cohort. Furthermore, we identified a shorter follow-up as a risk factor for incident cancer. This result can be partially explained by the fact that patients with a poor prognosis are more likely to be lost to follow-up as they receive palliative care and avoid unnecessary medical visits. On the other hand, we found no impact of previous IBD therapies on the incident cancer risk (data not shown).

We acknowledge that our study has several limitations. First, the retrospective design introduces recall bias with missing data and unmeasured confounders that might have influenced the results. Yet, the high standardization of the medical records in our IBD units (referral centers) and in specialized oncologic centers restricted this. Unfortunately, one-third of all cancers (diagnosed before 2010) had limited data available. Second, the tumor stage could be a potential confounder because clinicians might have been less confident about starting a treatment in patients with higher stage cancers. We considered this limitation by matching groups for age, lymph node and metastasis extension, and tumor grade using a propensity score analysis. Finally, the generalizability of our results is limited by the small absolute number of events and patients.

In conclusion, immunosuppressants and biologics use in selected patients with IBD with prior breast cancer does not seem to increase the risk of incident cancer. In the near future, large prospective studies will help to identify potential IBD risk factors associated with the worst outcomes. Meanwhile, each clinician should make decisions after multidisciplinary discussion with oncologists and the patient, considering the poor prognostic factors of established breast cancer and IBD behavior.
Supplementary Material

Note: To access the supplementary material accompanying this article, visit the online version of *Clinical Gastroenterology and Hepatology* at www.cghjournal.org, and at https://doi.org/10.1016/j.cgh.2024.09.034.

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**Correspondence**

Address correspondence to: Guillaume Le Cosquer, MD, Department of Gastroenterology and Pancreatology, Toulouse Rangueil University Hospital, 1 Avenue Jean Poulhès, TSA 50032, 31059, Toulouse Cedex 9, Toulouse, France. e-mail: lecosquer.g@chu-toulouse.fr.

**Acknowledgments**

GETAID centers collaborators includes Barbara Bournet (CHU Toulouse), Samira Denguir (Saint Antoine, APHP), Frank Zerbib and Pauline Rivière (CHU Bordeaux), Charlotte Gagnière and Julie Assaraf (Hôpital Henri Mondor), Guillaume Cadiot and Hedia Brixi (CHU de Reims), Guillaume Savoye (Rouen), Clara Yzet and Franck Brazier (Amiens), and Laurent Peyrin-Biroulet (Nancy). Collaborators from Cancer Centers includes Mellie Heinemann (Centre Léon Bérard, Lyon) and Nicolas Vigneron (Centre François Baclesse, Caen). GETAID CRO, which participated in data collection, includes Marie Coisnon, Justine Amaro, Mira Raad, and Charlotte Mailhat. The authors thank Jason Shourick (CHU Toulouse) for his help in statistical analysis.

**CRediT Authorship Contributions**

Guillaume Le Cosquer, MD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Validation: Lead; Writing – original draft: Lead; Writing – review & editing: Lead)

Julien Kirchgesner (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Cyrielle Gilletta (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Philippe Seksik (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Aurélien Amiot (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

David Laharie (Conceptualization: Supporting; Formal analysis: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Equal; Validation: Equal; Writing – review & editing: Equal)

Maria Nachury (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Cléa Rouillon (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Vered Abitbol (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Alexandre Nuzzo (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Stéphane Nancey (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Mathurin Fumery (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Amélie Biron (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Nicolas Richard (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Romain Altwegg (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Driffa Moussata (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Benedicte Caron (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Mathias Vidon (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Catherine Reenaers (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Mathieu Uzzan (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Jean-Marie Reimund (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Mélanie Serrero (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Marion Simon (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Alban Benezech (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Félix Goutorbe (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Anne-Laure Pelletier (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Ludovic Caillo (Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Charlotte Vaysse (Conceptualization: Supporting; Investigation: Equal; Validation: Equal; Writing – review & editing: Equal)

Florian Poulenot (Conceptualization: Lead; Formal analysis: Supporting; Investigation: Lead; Methodology: Lead; Supervision: Lead; Validation: Lead; Writing – original draft: Supporting; Writing – review & editing: Lead)

**Conflicts of interest**

These authors disclose the following: Guillaume Le Cosquer declares lecture, transports, or fees from AbbVie, Janssen, Takeda, and Pfizer. Julien Kirchgesner declares lecture fees from Janssen and Lilly; and consulting fees from Roche, Pfizer, Janssen, AbbVie, Takeda, Lilly, Celltrion, Tillots, and Galapagos. Cyrielle Gilletta declares consulting/lecture fees from AbbVie, Celltrion, Ferring, Fresenius, Janssen, MSD, Pfizer, and Takeda. Philippe Seksik declares consulting fees from Pfizer, Astellas, Janssen, Fresenius Kabi, Takeda, AbbVie, Merck-MSD, Pilège, Lilly, Celltrion, and Biocodex; and grants from Biocodex and Janssen. Aurélien Amiot declares consulting fees from AbbVie, Pfizer, Takeda, Tillotts Pharma, Janssen, and Sandoz; and lecture fees and travel accommodations from AbbVie, Janssen, Pfizer, Takeda, Biogen, Fresenius Kabi, Amgen, and Celltrion. David Laharie declares counseling, boards, transports, or fees from AbbVie, Amgen, Biogen, Celltrion, Ferring, Galapagos, Janssen, Pfizer, MSD, Pfizer, Prometheus, Roche, Takeda, and Theradiag. Maria Nachury declares board membership, consultancy, or lecture fees from AbbVie, Amgen, Biogen, Celltrion, Ferring, Fresenius-Kabi, Galapagos, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Pfizer, Takeda, and Viatris. Cléa Rouillon declares boards or lecture fees from AbbVie, Celltrion, Biogen, Janssen, Lilly, and Galapagos. Vered Abitbol declares board or lectures fees from Takeda, Amgen, Viatris, Sandoz, Janssen, Tillotts, Celltrion, Pfizer, Galapagos, Nordic Pharma, AbbVie, Lilly, and Ferring. Alexandre Nuzzo declares consulting/lecture fees from AbbVie, Janssen, Celltrion, and Amgen. Stéphane Nancey declares board or lectures fees from AbbVie, Janssen, Pfizer, Takeda, Celltrion, Amgen, Galapagos, Sandoz, Amgen, Ferring, Lilly, and Medac. Mathurin Fumery declares consulting/lecture fees from AbbVie, Amgen, Arena, Biogen, Celltrion, CTMA, Galapagos, Janssen, MSD, Pfizer, Takeda, Nordic-Pharma, Viatris, Fresenius-Kabi, Tillotts, Lilly, MSD, Gilead, Celgene, Sandoz, and Ferring. Amélie Biron declares consultant fees from AbbVie, Amgen, Celltrion, Ferring, Galapagos, and Takeda. Nicolas Richard declares lecture/consultant fees from AbbVie and Takeda. Romain Altwegg declares counseling, boards, transports, or fees from AbbVie, Amgen, Biogen, Celltrion, Galapagos, Janssen, Lilly, Pfizer, and Takeda. Driffa Moussata declares consulting fees from AbbVie, Amgen, Sanofi, Takeda, Galapagos, and Pfizer. Benedicte Caron declares lecture and/or consulting fees from AbbVie, Amgen, Celltrion, Ferring, Galapagos, Janssen, Lilly, Pfizer, and Takeda. Catherine Reenaers declares consulting/lectures fees from AbbVie, Janssen, Pfizer, Takeda, Celltrion, Ffresenius-Kabi, Lilly, BMS, Ferring, and Galapagos. Mathieu Uzzan declares board or lectures fees from AbbVie, Janssen, Pfizer, Takeda, Celltrion, Amgen, and Ferring. Jean-Marie Reimund declares counseling, boards, transports, or fees from Hospira, Pfizer, AbbVie, Biocodex, Ferring, Janssen Cilag, Takeda, and MSD. Mélanie Serrero declares board or lecture fees from AbbVie, Janssen, Takeda, Galapagos, Amgen, and Celltrion. Marion Simon declares transports or lecture fees from AbbVie, Amgen, Takeda, Celltrion, and Galapagos. Alban Benezech received board or lectures fees from AbbVie, Janssen, Takeda, Ferring, Galapagos, Amgen, and Fresenius. Félix Goutorbe declares counseling, boards, transports, or lectures fees from AbbVie, Amgen, Biogen, Celltrion, Janssen, Lilly, MSD, Pfizer, and Takeda. Anne-Laure Pelletier declares counseling, boards, transports, or fees from Janssen, Amgen, and Sandoz. Ludovic Caillo declares board or lectures fees from AbbVie, Janssen, Pfizer, Takeda, Celltrion, Amgen, and Sandoz. Florian Poulenot declares counseling, boards, transports, or fees from AbbVie, MSD, Takeda, Ferring, Janssen, and Pfizer. The remaining authors disclose no conflicts.
<table><caption>Supplementary Table 1. Cancer Characteristics</caption><thead><tr><th>Characteristics</th><th>No treatment<br>(n = 107)</th><th>Immunosuppressants<br>(n = 40)</th><th>Biologics<br>(n = 60)</th><th>P value</th></tr></thead><tbody><tr><td>Tumor laterality</td><td></td><td></td><td></td><td>.074</td></tr><tr><td>Left</td><td>49/94 (52.1)</td><td>20/33 (60.6)</td><td>21/46 (45.7)</td><td></td></tr><tr><td>Right</td><td>44/94 (46.8)</td><td>13/33 (39.4)</td><td>21/46 (45.7)</td><td></td></tr><tr><td>Bilateral</td><td>1 (1.1)</td><td>0/33 (0)</td><td>4/46 (8.6)</td><td></td></tr><tr><td>Histologic type</td><td></td><td></td><td></td><td>.073</td></tr><tr><td>In situ ductal carcinoma</td><td>13/79 (16.5)</td><td>8/29 (27.6)</td><td>4/45 (8.9)</td><td></td></tr><tr><td>Invasive ductal carcinoma</td><td>52/79 (65.8)</td><td>15/29 (51.7)</td><td>29/45 (64.4)</td><td></td></tr><tr><td>Ductal carcinoma (without precision)</td><td>1/79 (1.3)</td><td>0/29 (0)</td><td>0/45 (0)</td><td></td></tr><tr><td>In situ lobular carcinoma</td><td>6/79 (7.6)</td><td>2/29 (6.9)</td><td>3/45 (6.7)</td><td></td></tr><tr><td>Invasive lobular carcinoma</td><td>2/79 (2.5)</td><td>3/29 (6.9)</td><td>8/45 (17.8)</td><td></td></tr><tr><td>Lobular carcinoma (without precision)</td><td>1/79 (1.3)</td><td>0/29 (0)</td><td>0/45 (0)</td><td></td></tr><tr><td>Papillary carcinoma</td><td>0/79 (0)</td><td>0/29 (0)</td><td>1/45 (2.2)</td><td></td></tr><tr><td>Tubular carcinoma</td><td>0/79 (0)</td><td>1/29 (3.4)</td><td>0/45 (0)</td><td></td></tr><tr><td>Carcinoma not otherwise specified</td><td>4 (5.1)</td><td>0/29 (0)</td><td>0/45 (0)</td><td></td></tr><tr><td>Tumor size, mm</td><td>19 (3–120)</td><td>13 (2–50)</td><td>19 (4–60)</td><td>.157</td></tr><tr><td>Tumor grade</td><td></td><td></td><td></td><td>.363</td></tr><tr><td>Low</td><td>8/65 (12.3)</td><td>1/18 (5.6)</td><td>5/34 (14.7)</td><td></td></tr><tr><td>Medium</td><td>41/65 (63.1)</td><td>11/18 (61.1)</td><td>15/34 (44.1)</td><td></td></tr><tr><td>High</td><td>16/65 (24.6)</td><td>6/18 (33.3)</td><td>14/34 (41.2)</td><td></td></tr><tr><td>Presence of lymphovascular emboli</td><td>11/39 (28.2)</td><td>2/11 (18.2)</td><td>4/18 (22.2)</td><td>.756</td></tr><tr><td>Presence of lymph node capsular rupture</td><td>4/32 (12.5)</td><td>0/10 (0)</td><td>2/13 (15.4)</td><td>.455</td></tr><tr><td>Progesterone receptor status</td><td></td><td></td><td></td><td>.717</td></tr><tr><td>Absence</td><td>14/61 (23)</td><td>5/18 (27.8)</td><td>10/32 (31.3)</td><td></td></tr><tr><td>+</td><td>11/61 (18)</td><td>3/18 (16.7)</td><td>7/32 (21.9)</td><td></td></tr><tr><td>++</td><td>8/61 (13.1)</td><td>4/18 (22.2)</td><td>2/32 (6.3)</td><td></td></tr><tr><td>+++</td><td>28/61 (45.9)</td><td>6/18 (33.3)</td><td>13/32 (40.6)</td><td></td></tr><tr><td>Estrogen receptor status</td><td></td><td></td><td></td><td>.670</td></tr><tr><td>Absence</td><td>10/60 (16.7)</td><td>2/17 (11.8)</td><td>7/32 (21.9)</td><td></td></tr><tr><td>+</td><td>6/60 (10)</td><td>3/17 (17.6)</td><td>6/32 (18.8)</td><td></td></tr><tr><td>++</td><td>6/60 (10)</td><td>2/17 (11.8)</td><td>5/32 (15.6)</td><td></td></tr><tr><td>+++</td><td>38/60 (63.3)</td><td>10/17 (58.8)</td><td>14/32 (43.8)</td><td></td></tr><tr><td>Human Epidermal growth factor Receptor 2 (HER2) status</td><td></td><td></td><td></td><td>.593</td></tr><tr><td>Absence</td><td>44/58 (75.9)</td><td>16/18 (88.9)</td><td>22/33 (66.7)</td><td></td></tr><tr><td>+</td><td>3/58 (5.2)</td><td>0/18 (0)</td><td>1/33 (3)</td><td></td></tr><tr><td>++</td><td>3/58 (5.2)</td><td>0/18 (0)</td><td>3/33 (9.1)</td><td></td></tr><tr><td>+++</td><td>8/58 (13.8)</td><td>2/18 (11.1)</td><td>7/33 (21.2)</td><td></td></tr><tr><td>Triple negative tumor</td><td>9/55 (16.4)</td><td>1/16 (6.3)</td><td>3/32 (9.4)</td><td>.451</td></tr><tr><td>TNM cancer staging system</td><td></td><td></td><td></td><td>.359</td></tr><tr><td>Tumor staging</td><td></td><td></td><td></td><td>.359</td></tr><tr><td>Tis</td><td>3/60 (5)</td><td>1/22 (4.5)</td><td>1/30 (3.3)</td><td></td></tr><tr><td>T1</td><td>29/60 (54.4)</td><td>14/22 (63.6)</td><td>19/30 (63.3)</td><td></td></tr><tr><td>T2</td><td>20/60 (33.3)</td><td>7/22 (31.8)</td><td>5/30 (16.7)</td><td></td></tr><tr><td>T3</td><td>6/60 (10)</td><td>0/22 (0)</td><td>2/30 (6.7)</td><td></td></tr><tr><td>T4</td><td>2/60 (3.3)</td><td>0/22 (0)</td><td>3/30 (10)</td><td></td></tr><tr><td>T4d</td><td>1/60 (1.7)</td><td>0/22 (0)</td><td>2/30 (6.7)</td><td></td></tr><tr><td>Node staging</td><td></td><td></td><td></td><td>.153</td></tr><tr><td>N1</td><td>17/66 (25.8)</td><td>7/25 (28)</td><td>8/34 (23.5)</td><td></td></tr><tr><td>N2</td><td>0/66 (0)</td><td>0/25 (0)</td><td>3/34 (8.8)</td><td></td></tr><tr><td>N3</td><td>2/66 (3)</td><td>1/25 (4)</td><td>0/34 (0)</td><td></td></tr><tr><td>Metastasis staging</td><td></td><td></td><td></td><td>.363</td></tr><tr><td>M1</td><td>4/64 (6.3)</td><td>0/24 (0)</td><td>3/35 (8.6)</td><td></td></tr><tr><td>Cancer treatment</td><td></td><td></td><td></td><td>.184</td></tr><tr><td>Surgery</td><td>100/103 (97.1)</td><td>40/40 (100)</td><td>56/60 (93.3)</td><td></td></tr><tr><td>Adjuvant chemotherapy</td><td>60/95 (63.2)</td><td>15/35 (42.9)</td><td>34/57 (59.6)</td><td>.111</td></tr><tr><td>Radiation therapy</td><td>81/100 (81)</td><td>30/36 (83.3)</td><td>46/57 (80.7)</td><td>.943</td></tr><tr><td>Hormonal therapy<sup>a</sup></td><td>58/89 (65.2)</td><td>21/31 (67.7)</td><td>30/43 (69.8)</td><td>.865</td></tr></tbody></table>
<table><caption>**Supplementary Table 1. Continued**</caption><thead><tr><th>Characteristics</th><th>No treatment<br>(n = 107)</th><th>Immunosuppressants<br>(n = 40)</th><th>Biologics<br>(n = 60)</th><th>P value</th></tr></thead><tbody><tr><td>Aromatase inhibitors</td><td>17/48 (35.4)</td><td>2/18 (11.1)</td><td>9/25 (36)</td><td></td></tr><tr><td>Tamoxifen</td><td>30/48 (62.5)</td><td>14/18 (77.8)</td><td>12/25 (48)</td><td></td></tr><tr><td>Tamoxifen and switch to aromatase inhibitors</td><td>1/48 (2.1)</td><td>2/18 (11.1)</td><td>4/35 (16)</td><td></td></tr><tr><td>HER2-directed therapy</td><td>10/47 (21.3)</td><td>1/22 (4.5)</td><td>5/25 (20)</td><td>.204</td></tr></tbody></table>

NOTE. Data are represented as median (range) for continuous variables and n/N (%) for categorical variables, with n = number of patients with data available.

<table><caption>**Supplementary Table 2.** New Incident Cancer Sites (n = 8)</caption><thead><tr><th>Location</th><th>n (%)</th></tr></thead><tbody><tr><td>Melanoma skin cancer</td><td>3 (37.5)</td></tr><tr><td>Colorectal cancer</td><td>2 (25)</td></tr><tr><td>Waldenstrom macroglobulinemia</td><td>1 (12.5)</td></tr><tr><td>Cholangiocarcinoma</td><td>1 (12.5)</td></tr><tr><td>Pleural cancer</td><td>1 (12.5)</td></tr><tr><td>Basal cell carcinoma</td><td>1 (12.5)</td></tr></tbody></table>

NOTE. One patient subsequently had a melanoma and basal cell carcinoma.

<footnote>ªNot otherwise specified for 18 patients.</footnote>
<table><caption>**Supplementary Table 3.** Details of the Crude Cancer Incidence Rate Calculation Accounting for Discontinuation of the First Treatment after the Cancer Index Diagnosis</caption><thead><tr><th rowspan="2"></th><th colspan="2">Total follow-up</th><th colspan="2">Follow-up before stopping first treatment</th></tr><tr><th>Follow-up in person-years</th><th>Number of incident cancers</th><th>Follow-up in person-years</th><th>Number of incident cancers</th></tr></thead><tbody><tr><td>Immunosuppressants</td><td>335</td><td>4</td><td>180</td><td>3</td></tr><tr><td>Biologics</td><td>245</td><td>7</td><td>136</td><td>3</td></tr></tbody></table>

<table><caption>**Supplementary Table 4.** Incident Cancer Risk Factors in a Multivariate Cox Model Analysis Including Only Patients Having Received an IBD Treatment after Cancer Index Diagnosis (n = 100)</caption><thead><tr><th rowspan="2">Factors</th><th colspan="3">Multivariate analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P value</th></tr></thead><tbody><tr><td>Delay between cancer diagnosis and first IBD treatment dose &gt;28 months</td><td></td><td></td><td>.056</td></tr><tr><td>Metastasis extension</td><td></td><td></td><td>.276</td></tr><tr><td>First IBD treatment after cancer diagnosis<sup>a</sup></td><td></td><td></td><td></td></tr><tr><td>Methotrexate</td><td></td><td></td><td>.453</td></tr><tr><td>Thiopurines</td><td></td><td></td><td>.998</td></tr><tr><td>Vedolizumab</td><td></td><td></td><td>.842</td></tr><tr><td>Ustekinumab</td><td></td><td></td><td>.079</td></tr><tr><td>Follow-up after cancer diagnosis &lt;71 months</td><td>5.13</td><td>1.09-24.21</td><td><strong>.039</strong></td></tr></tbody></table>

NOTE. Bold characters highlight results with *P* < .05.

95% CI, 95% confidence intervals; HR, hazard ratio; IBD, inflammatory bowel disease.

<sup>a</sup>Versus anti-tumor necrosis factor.