bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Metformin for Reducing Racial/Ethnic Difference in Prostate Cancer Incidence for Men with Type II Diabetes
Authors: Wang Chen-Pin , Lehman Donna M. , Lam Yui-Wing F. , Kuhn John G. , Mahalingam Devalingam , Weitman Steven , Lorenzo Carlos , Downs John R. , Stuart Elizabeth A. , Hernandez Javier , Thompson Ian M. , Ramirez Amelie G.
Published: March 2024

Abstract
Racial/ethnic disparity in prostate cancer is under studied in men with diabetes who are at a higher risk of aggressive prostate cancer. This study assessed the race/ethnic disparity in prostate cancer incidence for men with type II diabetes (T2D) and whether the impact of metformin on prostate cancer incidence varied by race/ethnicity. We conducted a retrospective study in 76,733 male veterans with T2D during 2003 to 2012. Cox proportional hazards model adjusting for covariates and propensity scores of metformin use and race/ethnic group membership was utilized to compute the HR of prostate cancer incidence associated with race/ethnicity and compare HR associated with metformin use between race/ethnic groups. Mean follow-up was 6.4 ± 2.8 years; 7% were Hispanics; 17% were African Americans (AA); mean age was 67.8 ± 9.8 years; 5.2% developed prostate cancer; and 38.9% used metformin. Among these diabetic men without metformin use, prostate cancer incidence was higher in Hispanics and AA than in non-Hispanic White (NHW). Use of metformin alone or metformin + statins was associated with a greater prostate cancer incidence reduction in Hispanics compared with NHW, but not between AA and NHW. Use of metformin + finasteride was associated with a greater prostate cancer incidence reduction in Hispanics and AA compared with NHW. Our results suggested that metformin treatment could be a potential strategy to reduce prostate cancer incidence in the minority populations who are at high risk for fatal prostate cancer. It will be important to further examine the pleiotropic effects of metformin in multi-race/ethnic prospective studies to better inform clinical management and potentially reduce racial/ethnic disparity in prostate cancer incidence among diabetic men. Cancer Prev Res; 9(10); 779–87. ©2016 AACR.
Data from Case-only Methods Identified Genetic Loci Predicting a Subgroup of Men with Reduced Risk of High-grade Prostate Cancer by Finasteride
Authors: Dai James Y. , LeBlanc Michael , Goodman Phyllis J. , Lucia M. Scott , Thompson Ian M. , Tangen Catherine M.
Published: March 2024

Abstract
In the Prostate Cancer Prevention Trial (PCPT), genotypes that may modify the effect of finasteride on the risk of prostate cancer have not been identified. Germline genetic data from 1,157 prostate cancer cases in PCPT were analyzed by case-only methods. Genotypes included 357 SNPs from 83 candidate genes in androgen metabolism, inflammation, circadian rhythm, and other pathways. Univariate case-only analysis was conducted to evaluate whether individual SNPs modified the finasteride effect on the risk of high-grade and low-grade prostate cancer. Case-only classification trees and random forests, which are powerful machine learning methods with resampling-based controls for model complexity, were employed to identify a predictive signature for genotype-specific treatment effects. Accounting for multiple testing, a single SNP in SRD5A1 gene (rs472402) significantly modified the finasteride effect on high-grade prostate cancer (Gleason score > 6) in PCPT (family-wise error rate < 0.05). Men carrying GG genotype at this locus had a 55% reduction of the risk in developing high-grade cancer when assigned to finasteride (RR = 0.45; 95% confidence interval, 0.27–0.75). Additional effect-modifying SNPs with moderate statistical significance were identified by case-only trees and random forests. A prediction model built by the case-only random forest method with 28 selected SNPs classified 37% of PCPT men to have reduced risk of high-grade prostate cancer when taking finasteride, while the others have increased risk. In conclusion, case-only methods identified SNPs that modified the effect of finasteride on the risk of high-grade prostate cancer and predicted a subgroup of men who had reduced cancer risk by finasteride.
Data from Transcriptomic Response to Calcium in Normal Colon Organoids is Impacted by Colon Location and Sex
Authors: Devall Matthew A.M. , Dampier Christopher H. , Eaton Stephen , Ali Mourad Wagdy , Plummer Sarah J. , Bryant Jennifer , Gauderman W. James , Peters Ulrike , Powell Steven M. , Casey Graham
Published: March 2024

Abstract
Observational studies indicate that calcium supplementation may protect against colorectal cancer. Stratified analyses suggest that this protective effect may differ based on anatomic subsite and sex, but these hypotheses have been difficult to test experimentally. Here, we exposed 36 patient-derived organoid lines derived from normal colon biopsies (21 right colons, 15 left colons) of unrelated subjects (18 female, 18 male) to moderate (1.66 mmol/L) or high (5.0 mmol/L) concentrations of calcium for 72 hours. We performed bulk RNA-sequencing to measure gene expression, and cell composition was inferred using single-cell deconvolution in CIBERSORTx. We tested for significant differences in gene expression using generalized linear models in DESeq2. Exposure to higher levels of calcium was associated with changes in cell composition (P < 0.05), most notably increased goblet and reduced stem cell populations, and differential expression of 485 genes (FDR < 0.05). We found that 40 of these differentially expressed genes mapped to genomic loci identified through colorectal cancer genome-wide association studies, suggesting a potential biologic overlap between calcium supplementation and inherited colorectal cancer risk. Stratified analyses identified more differentially expressed genes in colon organoids derived from right sided colon and male subjects than those derived from left sided colon and female subjects. We confirmed the presence of a stronger right-sided effect for one of these genes, HSD17B2 using qPCR in a subset of matched right and left colon organoids (n = 4). By relating our findings to genetic data, we provide new insights into how nutritional and genetic factors may interact to influence colorectal cancer risk.
Prevention Relevance:
A chemopreventive role for calcium in colorectal cancer is still unclear. Here, we identify mechanisms through which calcium supplementation may reduce risk. Calcium supplementation increased differentiation and altered expression of colorectal cancer-related genes in a large study of patient-derived colon organoids. These findings were influenced by colon location and sex.
Data from The Role of Forkhead Box Q1 Transcription Factor in Anticancer Effects of Withaferin A in Breast Cancer
Authors: Kim Su-Hyeong , Singh Krishna B. , Hahm Eun-Ryeong , Singh Shivendra V.
Published: March 2024

Abstract
Elimination of both rapidly dividing epithelial mammary cancer cells as well as breast cancer stem-like cells (bCSC) is essential for maximizing antitumor response. Withaferin A (WA), a small molecule derived from a medicinal plant (Withania somnifera), is highly effective in reducing burden and/or incidence of breast cancer in vivo in various preclinical models. We have shown previously that suppression of breast cancer incidence by WA administration in a rat model is associated with a decrease in self-renewal of bCSC but the underlying mechanism is still elusive. This study investigated the role of forkhead box Q1 (FoxQ1) transcription factor in antitumor responses to WA. Exposure of MDA-MB-231 and SUM159 cells to WA resulted in downregulation of protein and mRNA levels of FoxQ1 as well as inhibition of its transcriptional activity. FoxQ1 overexpression in SUM159 and MCF-7 cells resulted in a marked protection against WA-mediated inhibition of bCSC as judged by flow cytometric analysis of CD49fhigh population and mammosphere assay. RNA-sequencing analysis revealed upregulation of many bCSC-associated genes by FoxQ1 overexpression in SUM159 cells, including IL8 whose expression was decreased by WA treatment in SUM159 and MCF-7 cells. FoxQ1 was recruited to the promoter of IL8 that was inhibited significantly by WA treatment. On the other hand, WA-mediated inhibition of cell proliferation or migration was not affected by FoxQ1 overexpression. The FoxQ1 overexpression partially attenuated WA-mediated G2–M phase cell cycle arrest in SUM159 cells only. These results indicate that FoxQ1 is a target of WA for inhibition of bCSC fraction.
Prevention Relevance:
Withaferin A (WA) is highly effective in reducing burden and/or incidence of breast cancer in various preclinical models. However, the mechanism underlying breast cancer prevention by WA is not fully understood. This study shows a role for FoxQ1 in antitumor response to WA.
Data from Association Between Baseline C-Reactive Protein and the Risk of Lung Cancer: A Prospective Population-Based Cohort Study
Authors: Yin Jian , Wang Gang , Wu Zheng , Lyu Zhangyan , Su Kai , Li Fang , Feng Xiaoshuang , Guo Lan-Wei , Chen Yuheng , Xie Shuanghua , Cui Hong , Li Jiang , Ren Jiansong , Shi Ju-Fang , Chen Shuohua , Wu Shouling , Dai Min , Li Ni , He Jie
Published: March 2024

Abstract
C-reactive protein (CRP), a systemic marker of diagnosing chronic inflammation, has been associated with the incidence of multiple types of cancer. However, little is known about the impact of CRP on lung cancer incidence in Chinese population. A total of 97,950 participants without cancer at baseline (2006–2007) of the Kailuan Cohort Study were followed up. The concentration of plasma high-sensitivity CRP (hsCRP) was tested for all participants at baseline interview. Multivariable Cox proportional hazards regression models were used to assess the association between levels of hsCRP and incident lung cancer. During 8.7-year follow-up, 890 incident lung cancer cases occurred and were divided into three groups according to the level of hsCRP. The risk of incident lung cancer was significantly increased with elevated levels of hsCRP [HRMedium/Low, 1.21; 95% confidence interval (CI), 1.03–1.42; HRHigh/Low, 1.42, 95% CI, 1.20–1.68; Ptrend < 0.001], compared with the low group after adjusting confounders. Moreover, after stratifying by BMI, the significantly positive associations between the hsCRP level and the risk of lung cancer were found among those with BMI < 24 (HRHigh/Low, 1.51; 95% CI, 1.18–1.94; Ptrend = 0.001) and BMI = 24–28 (HRHigh/Low, 1.47; 95% CI, 1.13–1.92; Ptrend = 0.003), but not among those with BMI ≥ 28 (HRHigh/Low, 1.01; 95% CI, 0.64–1.57; Ptrend = 0.991). There was an antagonistic interaction between hsCRP levels and BMI that contributed to development of lung cancer (Pinteraction = 0.049). In conclusion, these findings indicate a dose-dependent relationship between hsCRP and lung cancer risk among Chinese population, especially in nonobese participants, suggesting that CRP could serve as a potential biomarker for prediction of lung cancer risk and identification of high-risk population.
Prevention Relevance:
In this prospective population-based cohort study, we found an association between higher plasma hsCRP and an increased risk of developing lung cancer, with stronger associations observed among nonobese participants.
Data from ERβ Expression and Breast Cancer Risk Prediction for Women with Atypias
Authors: Hieken Tina J. , Carter Jodi M. , Hawse John R. , Hoskin Tanya L. , Bois Melanie , Frost Marlene , Hartmann Lynn C. , Radisky Derek C. , Visscher Daniel W. , Degnim Amy C.
Published: March 2024

Abstract
Estrogen receptor (ER) β is highly expressed in normal breast epithelium and a putative tumor suppressor. Atypical hyperplasia substantially increases breast cancer risk, but identification of biomarkers to further improve risk stratification is needed. We evaluated ERβ expression in breast tissues from women with atypical hyperplasia and association with subsequent breast cancer risk. ERβ expression was examined by immunohistochemistry in a well-characterized 171-women cohort with atypical hyperplasia diagnosed 1967–1991. Nuclear ERβ percent and intensity was scored in the atypia and adjacent normal lobules. An ERβ sum score (percent + intensity) was calculated and grouped as low, moderate, or high. Competing risks regression was used to assess associations of ERβ expression with breast cancer risk. After 15-year median follow-up, 36 women developed breast cancer. ERβ expression was lower in atypia lobules in than normal lobules, by percent staining and intensity (both P < 0.001). Higher ERβ expression in the atypia or normal lobules, evaluated by percent staining, intensity or sum score, decreased the risk of subsequent breast cancer by 2-fold (P = 0.04) and 2.5-fold (P = 0.006). High normal lobule ERβ expression conferred the strongest protective effect in premenopausal women: the 20-year cumulative incidence of breast cancer was 0% for women younger than 45 years with high versus 31% for low–moderate ERβ expression (P = 0.0008). High ERβ expression was associated with a significantly decreased risk of breast cancer in women with atypical hyperplasia. These data suggest that ERβ may be a useful biomarker for risk stratification and a novel therapeutic target for breast cancer risk reduction. Cancer Prev Res; 8(11); 1084–92. ©2015 AACR.
Data from The Association of Predicted Resting Energy Expenditure with Risk of Breast Cancer among Postmenopausal Women in the Women's Health Initiative Cohort
Authors: Arthur Rhonda S. , Mossavar-Rahmani Yasmin , Prentice Ross L. , Shadyab Aladdin H. , Luo Juhua , Sattari Maryam , Xue Xiaonan , Kamensky Victor , Chen Guo-Chong , Qi Qibin , Anderson Garnet L. , Wassertheil-Smoller Sylvia , Neuhouser Marian L. , Rohan Thomas E.
Published: March 2024

Abstract
Obesity and obesity-related metabolic disorders, such as diabetes and chronic inflammation, have been positively associated both with postmenopausal breast cancer and with resting energy expenditure (REE). However, there is limited epidemiologic evidence on the associations between REE and risk of postmenopausal breast cancer. We used multivariable Cox proportional hazards models to examine the association between predicted REE (calculated using the Ikeda, Livingston, and Mifflin equations) and risk of postmenopausal breast cancer overall and by subtypes, and by level of body fat) among 137,283 postmenopausal women in the Women's Health Initiative (WHI). All predicted REEs were positively associated with risk of invasive breast cancer [HRq5 vs. q1 = 1.69; 95% confidence interval (CI), 1.57–1.81; HR = 1.69; 95% CI, 1.57–1.82; and HR = 1.68; 95% CI, 1.56–1.80 for Ikeda, Livingston, and Mifflin, respectively]. These positive associations were observed irrespective of the hormone receptor subtype, grade, and stage of the tumors, but were most pronounced for estrogen receptor–positive/progesterone receptor–positive tumors. After additional adjustment for body mass index (BMI), the associations were mostly attenuated and remained statistically significant for most of the outcomes. We also observed an interaction between the predicted REEs and BMI, with the associations being somewhat stronger among normal weight and overweight women than among obese women (Pinteractions < 0.05). Our findings indicate that relatively high REE is associated with increased risk of invasive breast cancer among postmenopausal women (particularly for the obesity-related tumor subtypes), irrespective of the equation used. Further studies using more objective measures of REE are, however, needed to confirm our findings.
Prevention Relevance:
This study showed that higher resting energy expenditure (REE) was associated with higher postmenopausal breast cancer risk. REE provides energy to support cancer-associated disorders such as obesity and inflammation. Thus, studies on its association with breast cancer can help to improve our understanding of the pathophysiology of breast cancer.
Data from Association between Statins and Incidence of Cancer in Patients with Dyslipidemia Using Large-Scale Health Insurance Claims Data
Authors: Maeda-Minami Ayako , Takagi Masayuki , Mano Yasunari , Ishikawa Hideki , Matsuyama Yutaka , Mutoh Michihiro
Published: March 2024

Abstract
Recent experimental studies have examined the efficacy of statins in preventing cancer, but the findings of clinical studies are inconsistent, and studies on Japanese patients are limited. This study aimed to clarify the association between statins and cancer risk among Japanese patients. We conducted a large population-based retrospective cohort study using the Japanese health insurance claims database, including patients newly diagnosed with dyslipidemia between 2005 and 2015. Patients who were on newly prescribed statins during the study period were designated as statin users. They were matched 1:1 with randomly selected drug nonusers who were not prescribed drugs for dyslipidemia according to age, sex, and year of first diagnosis of dyslipidemia. There were 23,746 patients in each group. The mean duration of follow-up for statin users and drug nonusers was approximately 2 years. Using a Cox proportional hazards model, significant reduction in cancer risk was observed in statin users compared with that in drug nonusers [adjusted HR = 0.84; 95% confidence interval (CI), 0.72–0.97; adjusted for patient background factors]. The results of subgroup analyses suggested that prescribed statins reduced the incidence of cancer of the digestive organs (adjusted HR = 0.79; 95% CI, 0.63–0.99) as well as reduced cancer risk in patients with nonsmokers (adjusted HR = 0.78, 95% CI = 0.65–0.92). Our results suggest that statin use may reduce cancer risk in patients with dyslipidemia.
Prevention Relevance:
This study clarified the relationship between statin use and cancer risk in patients with dyslipidemia. Our study will contribute to medicine selection in patients with hypercholesterolemia level.

See related Spotlight, p. 1
Data from Genome-wide Association Analysis of Proinflammatory Cytokines and Gene–lifestyle Interaction for Invasive Breast Cancer Risk: The WHI dbGaP Study
Authors: Jung Su Yon , Scott Peter A. , Papp Jeanette C. , Sobel Eric M. , Pellegrini Matteo , Yu Herbert , Han Sihao , Zhang Zuo-Feng
Published: March 2024

Abstract
Immune-related etiologic pathways to influence invasive breast cancer risk may interact with lifestyle factors, but the interrelated molecular genetic pathways are incompletely characterized. We used data from the Women's Health Initiative Database for Genotypes and Phenotypes Study including 16,088 postmenopausal women, a population highly susceptible to inflammation, obesity, and increased risk for breast cancer. With 21,784,812 common autosomal single-nucleotide polymorphisms (SNP), we conducted a genome-wide association (GWA) gene–environment interaction (G × E) analysis in six independent GWA Studies for proinflammatory cytokines [IL6 and C-reactive protein (CRP)] and their gene–lifestyle interactions. Subsequently, we tested for the association of the GWA SNPs with breast cancer risk. In women overall and stratified by obesity status (body mass index, waist circumference, and waist-to-hip ratio) and obesity-related lifestyle factors (exercise and high-fat diet), 88 GWA SNPs in 10 loci were associated with proinflammatory cytokines: 3 associated with IL6 (1 index SNP in MAPK1 and 1 independent SNP in DEC1); 85 with CRP (3 index SNPs in CRPP1, CRP, RP11–419N10.5, HNF1A-AS1, HNF1A, and C1q2orf43; and two independent SNPs in APOE and APOC1). Of those, 27 in HNF1A-AS1, HNF1A, and C1q2orf43 displayed significantly increased risk for breast cancer. We found a number of novel top markers for CRP and IL6, which interacted with obesity factors. A substantial proportion of those SNPs' susceptibility influenced breast cancer risk. Our findings may contribute to better understanding of genetic associations between pro-inflammation and cancer and suggest intervention strategies for women who carry the risk genotypes, reducing breast cancer risk.
Prevention Relevance:
The top GWA-SNPs associated with pro-inflammatory biomarkers have implications for breast carcinogenesis by interacting with obesity factors. Our findings may suggest interventions for women who carry the inflammatory-risk genotypes to reduce breast cancer risk.
Data from Oral Microbiome Profiling in Smokers with and without Head and Neck Cancer Reveals Variations Between Health and Disease
Authors: Sharma Ashok Kumar , DeBusk William T. , Stepanov Irina , Gomez Andres , Khariwala Samir S.
Published: March 2024

Abstract
While smoking is inextricably linked to oral/head and neck cancer (HNSCC), only a small fraction of smokers develop HNSCC. Thus, we have sought to identify other factors, which may influence the development of HNSCC in smokers including microbiology. To determine microbial associations with HNSCC among tobacco users, we characterized oral microbiome composition in smokers with and without HNSCC. 16S rRNA MiSeq sequencing was used to examine the oral mucosa microbiome of 27 smokers with (cases) and 24 without HNSCC (controls). In addition, we correlated previously reported levels of DNA damage with the microbiome data. Smokers with HNSCC showed lower microbiome richness compared with controls (q = 0.012). Beta-diversity analyses, assessed as UniFrac (weighted and unweighted) and Bray–Curtis distances, showed significant differences in oral mucosal microbiome signatures between cases and controls (r2 = 0.03; P = 0.03) and higher interindividual microbiome heterogeneity in the former (q ≤ 0.01). Higher relative abundance of Stenotrophomonas and Comamonadaceae and predicted bacterial pathways mainly involved in xenobiotic and amine degradation were found in cases compared with controls. The latter, in contrast, exhibited higher abundance of common oral commensals and predicted sugar degradation pathways. Finally, levels of DNA damage in the oral cavity were correlated with the microbiome profiles above. Oral microbiome traits differ in smokers with and without HNSCC, potentially informing the risk of eventual HNSCC and shedding light into possible microbially mediated mechanisms of disease. These findings present data that may be useful in screening efforts for HNSCC among smokers who are unable to quit.
Data from A National Bowel Cancer Screening Programme using FIT: Achievements and Challenges
Authors: O'Donoghue Diarmuid , Sheahan Kieran , MacMathuna Padraic , Stephens Richard B. , Fenlon Helen , Morrin Martina , Mooney Jenny , Fahy Lorraine E. , Mooney Therese , Smith Alan
Published: March 2024

Abstract
Colorectal cancer accounts for 11% of all cancer-related deaths in Ireland. With the aim of diagnosing these cancers at an earlier stage, and detecting premalignant lesions, the National Screening Service (NSS) offered a fecal immunochemical test (FIT) to all individuals aged 60 to 69. All individuals in the age range were contacted by post and invited to participate in the programme. Those with a positive FIT result were offered a colonoscopy in an internationally accredited unit. From an eligible population of 488,628, 196,238 individuals participated giving an uptake of 40.2%. Commencing at a FIT threshold of 20 μg Hg/g feces, the positivity rate was 8.6%, which overwhelmed colonoscopy capacity and, thus, the threshold was increased to 45 μg, resulting in an overall 5% positivity rate. A total of 520 individuals had cancer detected (68.3% stage I or II), of which 104 were removed endoscopically (pT1s). Adenomas were present in 54.2% of all colonoscopies, 17.4% deemed high risk. Despite a lower uptake, males were twice as likely to have colorectal cancers as females and had a 59% increased rate of high-risk adenomas diagnosed. Challenges facing the programme include increasing participation, especially among males, and increasing colonoscopy capacity. The ability to alter the sensitivity of FIT to match colonoscopy capacity is a valuable option for such a programme as it ensures that the maximum public health benefit can be achieved within available resources.
Data from Prevention of Colorectal Carcinogenesis by DNA-Binding Small-Molecule Curaxin CBL0137 Involves Suppression of Wnt Signaling
Authors: Kirsanov Kirill , Fetisov Timur , Lesovaya Ekaterina A. , Maksimova Varvara , Trukhanova Lubov , Antoshina Elena , Gor'kova Tatiana , Morozova Olga , Safina Alfiya , Fleyshman Daria , Salimov Ramiz , Shipaeva Elena , Ivanov Roman , Leonov Andrey , Purmal Andrei A. , Belitsky Gennady A. , Gudkov Andrei V. , Gurova Katerina V. , Yakubovskaya Marianna G.
Published: March 2024

Abstract
Chemoprevention is considered a valid approach to reduce the incidence of colorectal cancer, one of the most common malignancies worldwide. Here, we investigated the tumor-preventive activity of curaxin CBL0137. This compound represents a new class of nonmutagenic DNA-binding small molecules that alter chromatin stability and inhibit the function of the histone chaperone FACT. Among downstream effects of CBL0137 treatment are activation of p53 and type I interferons and inhibition of NFκB, HSF1, and MYC. In addition, our data show that in both human and mouse colorectal cancer cells in vitro, CBL0137 inhibits the APC/WNT/β-catenin signaling pathway, which plays a key role in colon carcinogenesis. Using quantitative RT-PCR and microarray hybridization, we have demonstrated decreased expression of multiple components and downstream targets of the WNT pathway in colon cancer cells treated with CBL0137. At the same time, CBL0137 induced expression of WNT antagonists. Inhibition of WNT signaling activity by CBL0137 was also confirmed by luciferase reporter assay. Tumor-preventive activity of CBL0137 in vivo was tested in a murine model of colorectal carcinogenesis induced by 1,2-dimethylhydrazine (DMH), which is known to involve WNT pathway dysregulation. After DMH subcutaneous treatment, mice were administered CBL0137 in drinking water. Efficacy of CBL0137 in suppressing development of colorectal cancer in this model was evidenced by reduced incidence of adenocarcinomas and adenomas in both males and females and decrease in tumor multiplicity. These data support the prospective use of CBL0137 in chemoprevention of colorectal cancer as well as of other malignances associated with activated WNT signaling.
Data from Risk of Skin Cancer Associated with Metformin Use: A Meta-Analysis of Randomized Controlled Trials and Observational Studies
Authors: Chang Michael S. , Hartman Rebecca I. , Xue Junchao , Giovannucci Edward L. , Nan Hongmei , Yang Keming
Published: March 2024

Abstract
Previous studies demonstrate mixed evidence regarding the association between metformin and skin cancer risk. To synthesize prior evidence and evaluate the association between metformin and skin cancer risk in patients with diabetes/prediabetes, we conducted a meta-analysis. A systematic literature search was performed up to March 23, 2020 to identify randomized controlled trials (RCT) and observational studies of metformin that reported any event of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. In a meta-analysis of 6 trials involving 8,541 patients (Peto method), compared with controls, metformin was not significantly associated with decreased risk of melanoma [OR, 0.82; 95% confidence interval (CI), 0.27–2.43], BCC (OR, 0.75; 95% CI, 0.36–1.57), SCC (OR, 0.98; 95% CI, 0.06–15.60), total nonmelanoma skin cancer (NMSC; OR, 0.69; 95% CI, 0.38–1.24), or total skin cancer (OR, 0.71; 95% CI, 0.42–1.20). This nonsignificant association pattern was consistent with the random-effects meta-analysis of 4 cohort studies with 354,746 patients (melanoma: RR, 0.91; 95% CI, 0.62–1.33; NMSC: RR, 0.65; 95% CI, 0.35–1.18; total skin cancer: RR, 0.83; 95% CI, 0.59–1.16). In conclusion, meta-analyses of both RCT and cohort studies showed no statistically significant association between metformin and skin cancer risks, although suggestive evidence of modestly reduced risks of skin cancer among metformin users was observed. Further studies are needed.
Prevention Relevance:
Meta-analyses of RCT and cohort studies showed no significant association between metformin and skin cancer, although suggestive evidence of modestly reduced skin cancer risks among metformin users was observed. These findings suggest metformin use should not influence current medical decision making for diabetes patients at risk of developing skin cancer.
Data from The Relationship Between Breast Density Change During Menopause and the Risk of Breast Cancer in Korean Women
Authors: Kang Danbee , Kim Ji-Yeon , Kim Ji-Young , Mun Han Song , Yoon Sook Ja , Lee Jieun , Han Gayeon , Im Young-Hyuck , Shin Soo-Young , Lee Se Kyung , Yu Jong-Han , Lee Kyung-Hyun , Kim Mincheol , Park Dohyun , Choi Yoon-Ho , Jeong Ok Soon , Lee Jean Hyoung , Jekal Se Yong , Choi Jong Soo , Guallar Eliseo , Chang Yoosoo , Ryu Seungho , Cho Juhee , Kang Mira
Published: March 2024

AbstractBackground:
The aim of this study was to investigate the relationship between changes in breast density during menopause and breast cancer risk.
Methods:
This study was a retrospective, longitudinal cohort study for women over 30 years of age who had undergone breast mammography serially at baseline and postmenopause during regular health checkups at Samsung Medical Center. None of the participants had been diagnosed with breast cancer at baseline. Mammographic breast density was measured using the American College of Radiology Breast Imaging Reporting and Data System.
Results:
During 18,615 person-years of follow-up (median follow-up 4.8 years; interquartile range 2.8–7.5 years), 45 participants were diagnosed with breast cancer. The prevalence of dense breasts was higher in those who were younger, underweight, had low parity or using contraceptives. The cumulative incidence of breast cancer increased 4 years after menopause in participants, and the consistently extremely dense group had a significantly higher cumulative incidence (CI) of breast cancer compared with other groups [CI of extremely dense vs. others (incidence rate per 100,000 person-years): 375 vs. 203, P < 0.01].
Conclusion:
Korean women whose breast density was extremely dense before menopause and who maintained this density after menopause were at two-fold greater risk of breast cancer.
Prevention Relevance:
Extremely dense breast density that is maintained persistently from premenopause to postmenopause increases risk of breast cancer two fold in Korean women. Therefore, women having risk factors should receive mammography frequently and if persistently extremely dense breast had been detected, additional modalities of BC screening could be considered.
Data from Variant Identification in BARD1, PRDM9, RCC1, and RECQL in Patients with Ovarian Cancer by Targeted Next-generation Sequencing of DNA Pools
Authors: Suszynska Malwina , Ratajska Magdalena , Galka-Marciniak Paulina , Ryszkowska Aleksandra , Wydra Dariusz , Debniak Jaroslaw , Jasiak Anna , Wasag Bartosz , Cybulski Cezary , Kozlowski Piotr
Published: March 2024

Abstract
Several ovarian cancer susceptibility genes have been discovered, but more are likely to exist. In this study, we aimed to analyze knowledge-based selected genes, that is, BARD1, PRDM9, RCC1, and RECQL, in which pathogenic germline variants have been reported in patients with breast and/or ovarian cancer. As deep sequencing of DNA samples remains costly, targeted next-generation sequencing of DNA pools was utilized to screen the exons of BARD1, PRDM9, RCC1, and RECQL in approximately 400 Polish ovarian cancer cases. A total of 25 pools of 16 samples (including several duplicated samples with known variants) were sequenced on the NovaSeq6000 and analyzed with SureCall (Agilent) application. The set of variants was filtrated to exclude spurious variants, and, subsequently, the identified rare genetic variants were validated using Sanger sequencing. No pathogenic mutation was found within the analyzed cohort of patients with ovarian cancer. Validation genotyping of filtered rare silent and missense variants revealed that the majority of them were true alterations, especially those with a higher mutation quality value. The high concordance (R2 = 0.95) of population allele frequency for 44 common SNPs in the European control population (gnomAD) and our experiment confirmed the reliability of pooled sequencing. Mutations in BARD1, PRDM9, RCC1, and RECQL do not contribute substantially to the risk of ovarian cancer. Pooled DNA sequencing is a cost-effective and reliable method for the initial screening of candidate genes; however, it still requires validation of identified rare variants.
Prevention Relevance:
BARD1, PRDM9, RCC1, and RECQL are not high/moderate-risk ovarian cancer susceptibility genes. Pooled sequencing is a reliable and cost-effective method to detect rare variants in candidate genes.
Data from Risk versus Benefit of Chemoprevention among Raloxifene and Tamoxifen Users with a Family History of Breast Cancer
Authors: Anderson Chelsea , Nichols Hazel B. , House Melissa , Sandler Dale P.
Published: March 2024

Abstract
Tamoxifen and raloxifene have been approved for the primary prevention of breast cancer in high-risk women, but are associated with an increased risk of serious side effects. Few studies have characterized risk–benefit profiles for chemoprevention among women who initiate tamoxifen or raloxifene outside of a clinical trial setting. Use of raloxifene and tamoxifen for chemoprevention was self-reported in 2014 to 2016 by participants in The Sister Study, a prospective cohort of women with a sister who had been diagnosed with breast cancer. After exclusions, 432 current raloxifene users and 96 current tamoxifen users were matched to 4,307 and 953 nonusers, respectively, on age and year of cohort enrollment. Conditional logistic regression was used to evaluate characteristics associated with chemoprevention use. Risk–benefit profiles were examined using published indices that assess the level of evidence (none, moderate, strong) that the benefits of chemoprevention outweigh the risk of serious side effects. Among current chemoprevention users, 44% of tamoxifen users and 5% of raloxifene users had no evidence of a net benefit. In analyses of factors associated with chemoprevention use, having strong evidence of benefit was a significant predictor of raloxifene use, but not of tamoxifen use. In our sample of women with a first-degree family history of breast cancer, raloxifene was more commonly used for breast cancer prevention than tamoxifen. Most raloxifene users, but <60% of tamoxifen users, were likely to benefit. Use of risk–benefit tables can help women and their healthcare providers make an informed decision about breast cancer chemoprevention.
Data from Urgent Need for Novel Investigations of Treatments to Quit E-cigarettes: Findings from a Systematic Review
Authors: Palmer Amanda M. , Price Sarah N. , Foster Madeline G. , Sanford Brandon T. , Fucito Lisa M. , Toll Benjamin A.
Published: March 2024

Abstract
E-cigarette use has been increasing globally over the past decade. Many use e-cigarettes as an alternative or method to quit cigarette smoking, whereas others use these products recreationally. As technology has advanced, many individuals have reported symptoms of dependence on these products and continue to use them beyond achieving abstinence from smoking. Despite individuals reporting interest in quitting, little is known about e-cigarette cessation. This systematic review sought to identify and evaluate all human subjects literature published on the outcome of e-cigarette cessation through September 2021. Of the 79 articles identified, 56 were cross-sectional, 6 were qualitative, 5 were cohort studies, 3 were experimental, 2 were mixed methods, and 7 reported intervention or case studies of e-cigarette cessation. Results showed youth generally had high intent to quit e-cigarettes, whereas results were mixed with adult samples. Youth were motivated to quit e-cigarettes by health concerns, whereas adults were motivated to quit e-cigarettes by cost, lack of satisfaction, and psychologic factors. Adults were more likely to report past e-cigarette quit attempts, most commonly “cold turkey.” Few interventions tested strategies for e-cigarette cessation, with a majority targeted for youth. Given the lack of information on e-cigarette cessation, recommendations for future studies are outlined.
Data from Dietary Weight Loss, Exercise, and Oxidative Stress in Postmenopausal Women: A Randomized Controlled Trial
Authors: Duggan Catherine , Tapsoba Jean de Dieu , Wang Ching-Yun , Campbell Kristin L. , Foster-Schubert Karen , Gross Myron D. , McTiernan Anne
Published: March 2024

Abstract
Oxidative stress, a potential mechanism linking obesity and cancer, results from an imbalance between activation/inactivation of reactive oxygen species, byproducts of cellular metabolism. In a randomized controlled trial, we investigated effects of diet and/or exercise on biomarkers of oxidative stress. A total of 439 overweight/obese [body mass index (BMI) > 25 kg/m2] postmenopausal women, ages 50 of 75 years, were randomized to 12 months of (i) reduced-calorie weight loss diet (“diet”; n = 118); (ii) moderate-to-vigorous intensity aerobic exercise (“exercise”; n = 117); (iii) combined diet and exercise intervention (“diet + exercise”; n = 117); or (iv) control (n = 87). Outcomes were circulating markers of oxidative stress, including fluorescent oxidation products (FOP), F2-isoprostanes, and oxidized low-density lipoprotein (LDL). On average, participants were 57.9 years, with a BMI of 30.9 kg/m2. F2-isprostanes were significantly reduced in the diet (−22.7%, P = 0.0002) and diet + exercise (−23.5%, P < 0.0001) arms versus controls (−2.99%) and nonsignificantly reduced in the exercise arm (−14.5%, P = 0.01). Participants randomized to the diet and diet + exercise arms had significant increases in levels of FOP [control −5.81%; diet +14.77% (P = 0.0001); diet + exercise +17.45%, (P = 0.0001)]. In secondary analyses, increasing weight loss was statistically significantly associated with linear trends of greater reductions in oxidized LDL and in F2-isoprostanes and increases in FOP. Compared with controls, exercise participants whose maximal oxygen consumption increased had significant decreases in levels of F2-isoprostanes and in oxidized LDL and increases in FOP. Dietary weight loss, with or without exercise, significantly reduced some markers of oxidative stress in postmenopausal women. Cancer Prev Res; 9(11); 835–43. ©2016 AACR.
Data from Effects of Supplemental Calcium and Vitamin D on Circulating Biomarkers of Gut Barrier Function in Patients with Colon Adenoma: A Randomized Clinical Trial
Authors: Vermandere Kelly , Bostick Roberd M. , Tran Hao Q. , Gewirtz Andrew T. , Barry Elizabeth L. , Rutherford Robin E. , Seabrook March E. , Fedirko Veronika
Published: March 2024

Abstract
Gut barrier dysfunction promotes chronic inflammation, contributing to several gastrointestinal diseases, including colorectal cancer. Preliminary evidence suggests that vitamin D and calcium could prevent colorectal carcinogenesis, in part, by influencing gut barrier function. However, relevant human data are scarce. We tested the effects of supplemental calcium (1,200 mg/day) and/or vitamin D3 (1,000 IU/day) on circulating concentrations of biomarkers of gut permeability (anti-flagellin and anti-lipopolysaccharide IgA and IgG, measured via ELISA) from baseline to 1 and 3 or 5 years postbaseline among 175 patients with colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial. We also assessed factors associated with baseline concentrations of these biomarkers. We found no appreciable effects of supplemental vitamin D3 and/or calcium on individual or aggregate biomarkers of gut permeability. At baseline, a combined permeability score (the summed concentrations of all four biomarkers) was 14% lower among women (P = 0.01) and 10% higher among those who consumed >1 serving per day of red or processed meats relative to those who consumed none (Ptrend = 0.03). The permeability score was estimated to be 49% higher among participants with a body mass index (BMI) > 35 kg/m2 relative to those with a BMI < 22.5 kg/m2 (Ptrend = 0.17). Our results suggest that daily supplemental vitamin D3 and/or calcium may not modify circulating concentrations of gut permeability biomarkers within 1 or 3–5 years, but support continued investigation of modifiable factors, such as diet and excess adiposity, that could affect gut permeability.
Prevention Relevance:
Calcium and vitamin D may be involved in regulating and maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which results in exposure of the host to luminal bacteria, endotoxins, and antigens leading to potentially cancer-promoting endotoxemia and chronic colon inflammation. While our results suggest that daily supplementation with these chemopreventive agents does not modify circulating concentrations of gut permeability biomarkers, they support continued investigation of other potential modifiable factors, such as diet and excess adiposity, that could alter gut barrier function, to inform the development of treatable biomarkers of risk for colorectal neoplasms and effective colon cancer preventive strategies.
Data from Cancer-related Beliefs and Preventive Health Practices among Residents of Rural versus Urban Counties in Alabama
Authors: Aly Salma , Daniel Casey L. , Bae Sejong , Scarinci Isabel C. , Hardy Claudia M. , Fouad Mona N. , Baskin Monica L. , Hoenemeyer Teri , Acemgil Aras , Demark-Wahnefried Wendy
Published: March 2024

Abstract
Higher prevalence of cancer-related risk factors, for example, tobacco use, obesity, poor diet, and physical inactivity, is observed in the U.S. Deep South and likely contributes to its increased cancer burden. While this region is largely rural, it is unknown whether cancer-related beliefs and lifestyle practices differ by rural–urban status or are more influenced by other factors. We contacted 5,633 Alabamians to complete a cross-sectional survey to discern cancer-related beliefs and lifestyle practices, and compared data from respondents residing in rural- versus urban-designated counties. Findings were summarized using descriptive statistics; rural–urban subgroups were compared using two-tailed, χ2 and t tests. Multivariable logistic regression models were used to explore associations by rural–urban status and other sociodemographic factors. Surveys were completed by 671 rural- and 183 urban-county respondents (15.2% response rate). Overall, the prevalence for overweight and obesity (77.8%) and sugar-sweetened beverage intake (273–364 calories/day) was higher than national levels. Most respondents (58%) endorsed raising the state tobacco tax. Respondents from rural- versus urban-designated counties were significantly more likely to be racial/ethnic minority, have lower education, employment, income, food security, and internet access, and endorse fatalistic cancer-related beliefs (<0.05; although regression models suggested that cancer belief differences are more strongly associated with education than counties of residence). Lifestyle practices were similar among rural–urban subgroups. Few rural–urban differences in cancer-related beliefs and lifestyle practices were found among survey respondents, although the high overall prevalence of fatalistic health beliefs and suboptimal lifestyle behaviors suggests a need for statewide cancer prevention campaigns and policies, including increased tobacco taxation.

Prevention Relevance: Cancer incidence and mortality are higher in the U.S. Deep South, likely due to increased tobacco-use, obesity, poor diet, and physical inactivity. This study explores whether cancer-related beliefs and lifestyle practices differ by rural-urban status or other sociodemographic factors in a random sample of 855 residents across Alabama.
Data from The Quality of Pap Smears from the Brazilian Cervical Cancer Screening Program According to the Human Development Index
Authors: Costa Ricardo Filipe Alves , Longatto-Filho Adhemar , de Lima Vazquez Fabiana , Pinheiro Céline , Zeferino Luiz Carlos , Fregnani José Humberto Tavares Guerreiro
Published: March 2024

Abstract
Brazil is a country with strong socioeconomic disparities, which may explain the different rates of cervical cancer incidence and mortality and influence the quality of cervical cancer screening tests. The aim of this study was to perform a trend analysis of some quality indicators of Pap smears according to the Municipal Human Development Index (MHDI). Information about cytopathological exams (approximately 65,000,000) performed from 2006 to 2014 in women ages 25 to 64 years was obtained from the Cervical Cancer Information System (SISCOLO). The average annual percentage change (AAPC) for each indicator was calculated using the Joinpoint Regression Program, according to MHDI levels. Very low frequencies of unsatisfactory cases (<5%) were observed at different MHDI levels. Although the positivity index in the low- and medium-MHDI groups has increased, the values remained below international recommendations (3%–10%). The HSIL (high-grade squamous intraepithelial lesion) percentage remained stationary at all levels of the MHDI. In the low- and medium-MHDI groups, most quality indicators were below the recommendations by Brazilian National Cancer Institute INCA, with no improvement trend; in the high-MHDI group, the majority of the indicators also presented no improvement, although they show slightly better quality indicators. The MHDI should be considered in the definition of the policies of the screening program for cervical cancer in Brazil, and the current program may require adjustments to achieve improved efficiency.
Data from Amplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer
Authors: Bardelli Alberto , Corso Simona , Bertotti Andrea , Hobor Sebastijan , Valtorta Emanuele , Siravegna Giulia , Sartore-Bianchi Andrea , Scala Elisa , Cassingena Andrea , Zecchin Davide , Apicella Maria , Migliardi Giorgia , Galimi Francesco , Lauricella Calogero , Zanon Carlo , Perera Timothy , Veronese Silvio , Corti Giorgio , Amatu Alessio , Gambacorta Marcello , Diaz Luis A. , Sausen Mark , Velculescu Victor E. , Comoglio Paolo , Trusolino Livio , Di Nicolantonio Federica , Giordano Silvia , Siena Salvatore
Published: March 2024

Abstract
EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification.

Significance: Amplification of the MET proto-oncogene is responsible for de novo and acquired resistance to anti-EGFR therapy in a subset of colorectal cancers. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies. Cancer Discov; 3(6); 658–73. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 591