Visvanathan, Kala

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Abstract Background Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–PA interaction analysis. Methods Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. Results PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81–0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10 − 8 ). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75–0.85), but no significant PA–CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10 − 8 ). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72–0.82). Conclusions In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5 , suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.

Abstract Breast cancer risk assessment tools are widely used in clinical practice to guide decisions regarding screening timing and modality, lifestyle interventions, genetic testing, preventive therapy, and risk-reducing surgery. Although a number of tools designed for the general population are used in practice, they face a series of challenges including: (i) modest discriminatory ability due to lack of a unified model that flexibly incorporates a comprehensive set of risk factors; (ii) inability to produce subtype-specific risk estimates, relevant for tailoring screening and/or preventive strategies (e.g. prophylactic endocrine therapy that is effective only for hormone receptor positive tumors); (iii) lack of data from diverse populations to build models that work well for all women; and, (iv) scarcity of opportunities for comparative validation of different models. The Breast Cancer Risk Prediction Project (BCRPP), a collaboration currently including 20 prospective cohorts from the National Cancer Institute’s Cohort Consortium, is addressing these challenges by harmonizing, sharing, and analyzing data on over 1.8 million women, over 115, 000 of whom have developed breast cancer. The BCRPP is developing a comprehensive tool that will predict breast cancer risk, overall and by subtypes, across major racial and ethnic groups in the United States. This tool incorporates known and emerging risk factors (e.g. reproductive history, anthropometry, smoking, alcohol intake, medication use, mammography, family history, and measured genotypes). In parallel to model building and validation efforts, BCRPP investigators are developing privacy-preserving web and mobile interfaces to deliver the risk tools to patients and clinicians. Here we present descriptive data on participating cohorts (e.g. dates of enrollment, ages at enrollment, length of follow up, numbers of cases by subtype), summarize missing data patterns and our approach to model development and validation that accounts for heterogeneity in missingness patterns across cohorts, and describe data governance procedures and data sharing infrastructure (including pooled and federated analyses, to account for policy limitations on sharing individual data). Descriptive information and procedures for requesting and accessing data are available via the BCRPP data platform (https://epidataplatforms.cancer.gov/bcrpp/). Although originally assembled for risk model development, these data on a large and diverse sample of women with extensive harmonized risk factors and covariates can be a resource to address other outstanding questions in breast cancer epidemiology across time, the lifecourse, and diverse populations. Citation Format: Peter Kraft, Laura Beane-Freeman, Julie Palmer, Ellen O'Meara, Jeanine Genkinger, James Lacey, Thomas Rohan, Lauren Teras, Marian L. Neuhouser, Kala Visvanathan, Celine Vachon, Roger Milne, Christopher Haiman, Yu Chen, Heather Eliassen, Cari Kitahara, Katie O'Brien, Emily White, Garnet Anderson, I-Min Lee, Archie Campbell, Renee Fortner, Ylva Lagerros, Sven Sandin, Mia Gaudet, Montserrat Garcia-Closas, Nilanjan Chatterjee. The Breast Cancer Risk Prediction Project: a resource of 1.8 million women with diverse backgrounds from 20 prospective cohorts to improve breast cancer risk prediction and advance breast cancer epidemiology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3583.

Abstract Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case–control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10−8 in the meta-analysis; Pinteraction = 2.1 × 10−9 in the case–control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.

e23171 Background: A011502 is a phase 3 trial that randomized high-risk nonmetastatic breast cancer (BC) patients (pts) to aspirin 300 mg daily vs. placebo. Obesity and Black race have been shown to be associated with worse clinical outcomes. We studied the association of stress, depression, sleep and pain with each other, and with BMI and race. Methods: At baseline, 2735, 2610, 2720, and 2422 pts completed Perceived Stress Scale (PSS), Center for Epidemiologic Studies Depression Scale Revised (CESD-R), Brief Pain Inventory (BPI), and Pittsburgh Sleep Quality Index (PSQI) respectively. Stress was categorized with PSS scores: low (0-13), moderate (14-26) or high (27-40). Depression was categorized with CESD-R scores: no depression (0-15) or depression (≥16). Pain was categorized with BPI scores: none/mild (0-3) or moderate/severe (≥4). Sleep quality was categorized with PSQI scores: good (0-5) or poor ( > 5). Associations of measures by race and BMI were analyzed using chi-square test. Results: There was a statistically significant association among stress, depression, pain, and sleep quality (p < 0.01 for all). Compared to pts with BMI < 25, overweight and obese women reported higher stress (2.9%, 2.3% vs. 1.7%, p = 0.04), depression (13.4%, 18% vs. 9.6%, p < 0.01), moderate/severe pain (16.5%, 20.3% vs. 12%, p < 0.01), and poor sleep (64.9%, 71.5% vs. 60.4%, p < 0.01). Black women reported more moderate/severe pain compared to White women or other races (32.9% vs. 14.2% vs. 27.8%, p < 0.01). There was no association of other symptoms with race (Table 1). Conclusions: Obesity was associated with higher stress, depression, poor sleep and pain among BC pts from A011502. Black women reported higher pain compared to other races. Future studies are warranted that determine causal associations, how symptoms may relate to outcome disparities, and develop approaches to address them. U10CA180821, U10CA180882, UG1CA233196; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02927249 . [Table: see text]

11016 Background: A011502 is a phase 3 randomized double-blind clinical trial that enrolled high-risk nonmetastatic breast cancer (BC) patients (pts) and randomized pts to aspirin 300 mg daily vs. placebo. There was no significant difference in invasive disease-free survival (iDFS) between the two arms. A secondary objective was to determine the association of inflammation-affiliated factors (stress, depression, poor sleep quality and pain) with iDFS and overall survival (OS). We hypothesized that these baseline factors are associated with worse clinical outcomes. Methods: At baseline, 2735, 2720, 2422 and 2610 pts completed Perceived Stress Scale (PSS), Brief Pain Inventory (BPI), Pittsburgh Sleep Quality Index (PSQI) and Center for Epidemiologic Studies Depression Scale Revised (CESD-R) respectively. Stress was categorized with PSS scores: low (0-13), moderate (14-26) or high stress (27-40). Pain was categorized with BPI scores: none/mild (0-3) or moderate/severe (≥4). Sleep quality was categorized with PSQI scores: good (0-5) or poor ( > 5).Depression was categorized with CESD-R scores: no depression (0-15) or depression (≥16). Associations between the measures of interest and outcomes were performed with multivariable Cox models controlling for age, body mass index, time since diagnosis, race, ethnicity, hormone receptor status and treatment arm. Results: Median follow up was 35 months. The associations from multivariable Cox model are shown in Table 1. Pts who reported high PSS had significantly worse iDFS and (non-significant) worse OS. Moderate/severe average (avg) pain was significantly associated with worse iDFS and OS. Poor sleep quality and depression were associated with worse iDFS and OS but not statistically significant. Conclusions: Pts reporting higher stress and pain at baseline had worse outcomes. We acknowledge that both pain and stress may be related to other non-cancer issues (chronic comorbidities). Our study highlights the need for clinical trials to consider including questionnaires to assess pt-reported outcomes. Future studies are warranted to determine if measures to decrease pain and stress would improve BC outcomes. U10CA180821, U10CA180882, UG1CA233196; https://acknowledgments.alliancefound.org . NCT02927249: Clinical trial information: NCT02927249 . [Table: see text]

Importance Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking. Objective To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer. Design, Setting, and Participants A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023. Interventions Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [≤30 vs &amp;gt;30], stage II vs III, and time since diagnosis [&amp;lt;18 vs ≥18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years. Main Outcomes and Measures The primary outcome was invasive disease–free survival. Overall survival was a key secondary outcome. Results A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease–free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease–free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups. Conclusion and Relevance Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment. Trial Registration ClinicalTrials.gov Identifier: NCT02927249

PURPOSE There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2–enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1 , BRCA2 , CDH1 , PALB2 , PTEN , and TP53 , and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.