Showing papers by "J. D. Palmer published in 2022"

Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.

Abstract: BACKGROUND Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. METHODS Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. RESULTS For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. CONCLUSIONS Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. IMPACT The study identifies multifaceted evidence of a possible functional effect for rs1318920.

Maximum and Time-Dependent Body Mass Index and Breast Cancer Incidence Among Postmenopausal Women in the Black Women's Health Study.

Abstract: While excess weight is an established risk factor for postmenopausal breast cancer, consideration of maximum body mass index (maxBMI) or BMI at a point in time relevant for breast carcinogenesis may offer new insights. We prospectively evaluated maxBMI and time-dependent BMI in relation to breast cancer incidence among 31,028 postmenopausal women in the Black Women's Health Study. During 1995-2015, 1,384 diagnoses occurred, including 787 estrogen receptor (ER) positive and 310 ER- cases. BMI was assessed at baseline and 2, 4, 6, and 8 years before diagnosis. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and confidence intervals (CIs). Compared to women with BMI <25 kg/m2, those with BMI ≥35 had increased risk of ER+, but not ER-, breast cancer. For BMI assessed 2 years before diagnosis, the HRs for ER+ breast cancer associated with maxBMI ≥35 and time-dependent BMI ≥35 were 1.42 (95% CI 1.10, 1.83) and 1.63 (95% CI: 1.25, 2.13), respectively. The corresponding HR for time-dependent BMI assessed 6 years before diagnosis was 1.95 (95% CI: 1.45, 2.62). These findings suggest strong associations of BMI with risk of ER+ breast cancer in postmenopausal women regardless of timing of BMI assessment.

Research on health disparities: Strategies and findings from the Black Women's Health Study.

Abstract: The American Journal of Epidemiology has been a platform for findings from the Black Women's Health Study relevant to health disparities. Topics addressed have included methods of follow-up of a large cohort of Black women, disparities in health care delivery, modifiable risk factors for health conditions that disproportionately affect Black women, associations with exposures that are highly prevalent in Black women, and methods for genetics research. Black Women's Health Study papers have also highlighted the importance of considering social context, including perceived experiences of racism, in understanding health disparities. In the future, Black Women's Health Study investigators will contribute to documentation of the role that structural racism plays in health disparities.

Results and lessons from dual extraction of DNA and RNA from formalin-fixed paraffin-embedded breast tumor tissues for a large Cancer epidemiologic study

Abstract: The use of archived formalin-fixed paraffin-embedded (FFPE) tumor tissues has become a common practice in clinical and epidemiologic genetic research. Simultaneous extraction of DNA and RNA from FFPE tissues is appealing but can be practically challenging. Here we report our results and lessons learned from processing FFPE breast tumor tissues for a large epidemiologic study.Qiagen AllPrep DNA/RNA FFPE kit was adapted for dual extraction using tissue punches or sections from breast tumor tissues. The yield was quantified using Qubit and fragmentation analysis by Agilent Bioanalyzer. A subset of the DNA samples were used for genome-wide DNA methylation assays and RNA samples for sequencing. The QC metrices and performance of the assays were analyzed with pre-analytical variables.A total of 1859 FFPE breast tumor tissues were processed. We found it critical to adjust proteinase K digestion time based on tissue volume to achieve balanced yields of DNA and RNA. Tissue punches taken from tumor-enriched regions provided the most reliable output. A median of 1475 ng DNA and 1786 ng RNA per sample was generated. The median DNA integrity number (DIN) was 3.8 and median DV200 for RNA was 33.2. Of 1294 DNA samples used in DNA methylation assays, 97% passed quality check by qPCR and 92% generated data deemed high quality. Of the 130 RNA samples with DV200 ≥ 20% used in RNA-sequencing, all but 5 generated usable transcriptomic data with a mapping rate ≥ 60%.Dual DNA/RNA purification using Qiagen AllPrep FFPE extraction protocol is feasible for clinical and epidemiologic studies. We recommend tissue punches as a reliable source material and fine tuning of proteinase K digestion time based on tissue volume.Our protocol and recommendations may be adapted by future studies for successful extraction of archived tumor tissues.

Results and lessons from dual extraction of DNA and RNA from formalin-fixed paraffin-embedded breast tumor tissues for a large Cancer epidemiologic study

Abstract: The use of archived formalin-fixed paraffin-embedded (FFPE) tumor tissues has become a common practice in clinical and epidemiologic genetic research. Simultaneous extraction of DNA and RNA from FFPE tissues is appealing but can be practically challenging. Here we report our results and lessons learned from processing FFPE breast tumor tissues for a large epidemiologic study.Qiagen AllPrep DNA/RNA FFPE kit was adapted for dual extraction using tissue punches or sections from breast tumor tissues. The yield was quantified using Qubit and fragmentation analysis by Agilent Bioanalyzer. A subset of the DNA samples were used for genome-wide DNA methylation assays and RNA samples for sequencing. The QC metrices and performance of the assays were analyzed with pre-analytical variables.A total of 1859 FFPE breast tumor tissues were processed. We found it critical to adjust proteinase K digestion time based on tissue volume to achieve balanced yields of DNA and RNA. Tissue punches taken from tumor-enriched regions provided the most reliable output. A median of 1475 ng DNA and 1786 ng RNA per sample was generated. The median DNA integrity number (DIN) was 3.8 and median DV200 for RNA was 33.2. Of 1294 DNA samples used in DNA methylation assays, 97% passed quality check by qPCR and 92% generated data deemed high quality. Of the 130 RNA samples with DV200 ≥ 20% used in RNA-sequencing, all but 5 generated usable transcriptomic data with a mapping rate ≥ 60%.Dual DNA/RNA purification using Qiagen AllPrep FFPE extraction protocol is feasible for clinical and epidemiologic studies. We recommend tissue punches as a reliable source material and fine tuning of proteinase K digestion time based on tissue volume.Our protocol and recommendations may be adapted by future studies for successful extraction of archived tumor tissues.

Neighborhood disadvantage and lung cancer risk in a national cohort of never smoking Black women.

Abstract: BACKGROUND Compared to women of other races who have never smoked, Black women have a higher risk of lung cancer. Whether neighborhood disadvantage, which Black women experience at higher rates than other women, is linked to never-smoking lung cancer risk remains unclear. This study investigates the association of neighborhood disadvantage and lung cancer risk in Black never-smoking women. METHODS AND MATERIALS This research utilized data from the Black Women's Health Study, a prospective cohort of 59,000 Black women recruited from across the US in 1995 and followed by biennial questionnaires. Associations of lung cancer incidence with neighborhood-level factors (including two composite variables derived from Census Bureau data: neighborhood socioeconomic status and neighborhood concentrated disadvantage), secondhand smoke exposure, and PM2.5 were estimated using Fine-Gray subdistribution hazard models. RESULTS Among 37,650 never-smokers, 77 were diagnosed with lung cancer during follow-up from 1995 to 2018. The adjusted subdistribution hazard ratio (sHR) of lung cancer incidence with ten unit increase in neighborhood concentrated disadvantage index was 1.30 (95 % CI: 1.04, 1.63, p = 0.023). Exposure to secondhand smoke at work was associated with increased risk (sHR = 1.93, 95 % CI: 1.21, 3.10, p = 0.006), but exposure to secondhand smoke at home and PM2.5 was not. CONCLUSION Worse neighborhood concentrated disadvantage was associated with increased lung cancer risk in Black women who never smoked. These findings suggest that non-tobacco-related factors in disadvantaged neighborhoods may be linked to lung cancer risk in Black women and that these factors must be understood and targeted to achieve health equity.

Probing the diabetes and colorectal cancer relationship using gene-environment interaction analyses

Abstract: Diabetes is an established risk factor for colorectal cancer; however, the mechanisms underlying this relationship are not fully understood and the role of genetic variation is unclear. We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes and joint testing of Gxdiabetes, G-colorectal cancer association and/or G-diabetes correlation (2,3-degrees of freedom joint tests; d.f.). Based on the joint tests, variant rs3802177 in SLC30A8 (p-value3-d.f.:5.46x10-11; regulates phosphorylation of the insulin receptor and phosphatidylinositol-3 kinase activity) and rs9526201 in LRCH1 (p-value2-d.f.:7.84x10-09; regulates T cell migration and Natural Killer Cell cytotoxicity) were associated with colorectal cancer. These results suggest that variation in genes related to insulin signalling and immune function may modify the association of diabetes with colorectal cancer and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

Abstract A003: Risks of ductal carcinoma in situ of the breast associated with pathogenic variants in cancer predisposition genes

Abstract: Introduction: The relationship between germline pathogenic variants (PVs) in cancer predisposition genes and ductal carcinoma in situ (DCIS) is not well established. The objective of this study is to determine the risks of DCIS and contralateral breast cancer among women with DCIS associated with germline PVs in cancer predisposition genes. Methods: Associations between pathogenic variants in 11 cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, RAD51C, and RAD51D) and DCIS were determined in case control analyses of a population-based cohort of 3876 women with DCIS and age-matched unaffected women, and in a clinical cohort of 9887 DCIS cases undergoing clinical genetic testing at Ambry Genetics and unaffected reference controls. The incidence of contralateral breast cancer risk in BRCA1, BRCA2, and PALB2 PV carriers with DCIS was also evaluated in a time-to-event analysis. Results: The mean age at diagnosis of DCIS was 50 years in the clinical testing cohort and 59 years in the population-based cohort. The frequency of PVs in 11 predisposition genes among DCIS cases was 6.9% in the clinical testing cohort and 4.9% in the population-based cohort. PVs in ATM, BRCA1, BRCA2, CHEK2, MSH6, PALB2, and RAD51D were associated with significantly increased risks (Odds Ratio (OR) >2) of DCIS in the clinical testing cohort whereas only PVs in BRCA1, CHEK2, PALB2, and ATM were associated with significantly increased risks of DCIS in the population-based cohort. The cumulative incidence of contralateral breast cancer among BRCA1, BRCA2, and PALB2 PV carriers with DCIS was 11% in 5-years and 20% in 15-years. Conclusions: This study provides new insights into PVs that predispose to DCIS. In addition, it establishes an increased risk of contralateral breast cancer risk among women with DCIS who are carriers of PVs in BRCA1, BRCA2, or PALB2. These findings will guide surveillance and risk reducing strategies in germline PV carriers with DCIS. Citation Format: Huaizhi Huang, Ronan E. Couch, Holly LaDuca, Siddhartha Yadav, Eric C. Polley, Nicholas J. Boddicker, Jie Na, Rohan D. Gnanaolivu, David E. Goldgar, Tina Pesaran, Steven N. Hart, Jill S. Dolinsky, Julie R. Palmer, Lauren Teras, Alpa V. Patel, Kathryn J. Ruddy, Janet E. Olson, Celine M. Vachon, Peter Kraft, Song Yao, Amy Trentham-Dietz, Katherine L. Nathanson, Jeffrey N. Weitzel, Susan M. Domchek, Fergus J. Couch, Chunling Hu. Risks of ductal carcinoma in situ of the breast associated with pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr A003.

Circadian disruption and colorectal cancer incidence in Black women.

Abstract: BACKGROUND Animal and experimental studies suggest circadian disruption increases colorectal cancer risk, but evidence in humans is limited. We examined night shift work, chronotype, and residential position within a time zone, proxies for circadian disruption, in relation to colorectal cancer risk. METHODS Participants in the Black Women's Health Study, a prospective cohort of 59,000 Black American women established in 1995, reported history of night shift work and chronotype on follow-up questionnaires. Residential position within a time zone was estimated using participant addresses at each questionnaire cycle. Number of colorectal cancer cases and follow-up duration varied by analysis depending on timing of exposure assessment, ranging from 204 over the 2005-2018 night shift work study period to 452 over the 1995-2018 residential position study period. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). RESULTS Compared to never having worked a night shift, working a night shift for ≥10 years was associated with increased colorectal cancer risk (HR=1.64, 95% CI 1.01-2.66). However, shorter duration was not. The HR for evening vs. morning chronotype was 0.96 (95% CI 0.73-1.27). Westward position of residence within a time zone was not associated with colorectal cancer risk (HR per 5-degree longitude increase: 0.92, 95% CI 0.82-1.03). CONCLUSIONS Our findings suggest a possible increased risk of colorectal cancer associated with long duration night shift work; however, results require confirmation in larger studies. IMPACT Circadian disruption from long-term night shift work may contribute to colorectal cancer development in Black women.

Risk factors for endometrial cancer in Black women

Abstract: The incidence of endometrial cancer (EC) has been increasing faster among Black women than among other racial/ethnic groups in the United States. Although the mortality rate is nearly twice as high among Black than White women, there is a paucity of literature on risk factors for EC among Black women, particularly regarding menopausal hormone use and severe obesity. We pooled questionnaire data on 811 EC cases and 3,124 controls from eight studies with data on self-identified Black women (4 case–control and 4 cohort studies). We analyzed cohort studies as nested case–control studies with up to 4 controls selected per case. We used logistic regression to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). We observed a positive association between BMI and EC incidence (Ptrend < 0.0001) The OR comparing BMI ≥ 40 vs. < 25 kg/m2 was 3.92 (95% CI 2.91, 5.27). Abdominal obesity among those with BMI < 30 kg/m2 was not appreciably associated with EC risk (OR 1.21, 95% CI 0.74, 1.99). Associations of reproductive history with EC were similar to those observed in studies of White women. Long-term use of estrogen-only menopausal hormones was associated with an increased risk of EC (≥ 5 years vs. never use: OR 2.08, 95% CI: 1.06, 4.06). Our results suggest that the associations of established risk factors with EC are similar between Black and White women. Other explanations, such as differences in the prevalence of known risk factors or previously unidentified risk factors likely underlie the recent increases in EC incidence among Black women.

Prevalence of monoclonal gammopathy of undetermined significance in US black women

Abstract: To the Editor: Compared to non-Hispanic whites (NHWs), Black Americans have over a 2-fold higher incidence of multiple myeloma (MM). Based on data from the US Surveillance, Epidemiology, and End Results Program, the age-adjusted incidence rate of MM in Black individuals increased from 11 per 100 000 in 2000 to 14.6 per 100 000 in 2018, an average annual percent change (APC) of 1.7 [95% confidence interval (CI), 1.4 to 2.1]. Over the same time period, the corresponding rate in NHWs increased from 5.5 to 6.6 (average APC, 1.0; 95% CI: 0.4, 1.6). It is well established that virtually all cases of MM are preceded by the asymptomatic precursor state, monoclonal gammopathy of undetermined significance (MGUS), and individuals with MGUS have overall shorter survival than ageand sex-matched controls. Rates of progression from MGUS to MM – about 1% per year –do not appear to vary by race. Thus, the disparity in incidence of MM appears to be determined by a disparity in incidence of MGUS. Indeed, MGUS prevalence is higher in Black individuals than NHWs. Landgren et al. estimated the age-adjusted prevalence of MGUS in Black individuals ages 50 and older to be 3.7% (vs. 2.3% in NHWs) using data from the National Health and Nutritional Examination Survey (NHANES). These estimates, however, were based on blood samples collected between 1988–1994 and 1999–2004. More recent nationwide prevalence estimates of MGUS are not available. The Black Women's Health Study (BWHS) is a prospective cohort study that enrolled 59 000 self-identified Black women ages 21–69 in 1995 from across the US. The BWHS has followed participants for cancer and other outcomes through biennial questionnaires and linkage to 24 cancer registries in states in which 95% of participants live. Between 2014 and 2018, blood samples from 13 030 BWHS participants (approximately 25% of the surviving cohort) were collected and processed by Patient Service Centers at Quest Diagnostics (Madison, NJ). Participants who provided samples were 39 to 89 years old (median 58 years) at the time of blood draw. The samples are stored as serum, plasma, buffy coats, and red blood cells at the Boston University Molecular Genetics Core Laboratory in 80°C freezers. For the present analysis, 1707 participants ages 50–79 with available serum samples and no personal history of cancer were randomly selected for laboratory screening, with approximately equal number of individuals within 10-year age groups. Samples were de-identified and all assays were performed and interpreted by individuals blinded to health, demographic, and other individual data. Total serum protein quantitation, serum protein electrophoresis (SPEP) by agarose gel, and immunofixation electrophoresis (IFE) were performed on all samples according to standard protocols at the Clinical Chemistry Laboratory at Boston Medical Center, a CLIA-certified laboratory. All samples were interpreted by one pathologist (YK). We also measured serum free light chains (sFLCs) by nephelometry using the Freelite assay from Binding Site (Birmingham, UK); sFLCs were not measured for one individual. We used diagnostic criteria from the International Myeloma Working Group to classify individuals as having MGUS, characterized by presence of a M protein <3 g/dl in the serum, consistent with the definition used in other cohorts. A sFLC κ/λ ratio <0.26 or >1.65 is also an indication of MGUS and present in about 30–45% of MGUS patients; however, in the absence of data regarding renal function, light-chain MGUS diagnosis was determined based on SPEP/IFE only. We excluded one individual with a restricted band in the lambda region without heavy chain immunoglobulin expression whose sFLC λ was >100 mg/L and involved/uninvolved sFLC ratio was >100 – suggestive of myeloma – leaving an analytic cohort of 1706. We used year 2000 US Census data to directly standardize crude prevalence estimates to the population distribution for women in 10-year age groups (50–59, 60–69, and 70–79) for comparison to previous literature. We tabulated immunoglobulin isotype and abnormal sFLC κ/λ ratio and calculated the median M protein concentration among cases, using half the limit of detection (LOD) when concentrations were below the LOD (<0.10 g/dl). We identified 162 cases of MGUS (crude prevalence, 9.5%), 125 of which were identified by SPEP and confirmed by IFE and 37 of which were identified on IFE only. The overall age-adjusted prevalence was 9.0% (95% confidence interval: 7.6%, 10.4%). Prevalence of MGUS increased with increasing age, with a prevalence of 12.3% (9.3, 15.4) in women age > 70 (Table 1). Observed prevalence estimates in the BWHS were markedly higher than previously reported estimates in Black populations. In a community-based sample of 976 Black residents of North Carolina >70 years of age (1992–1993), MGUS prevalence was 8.4%. In the Southern Community Cohort Study (SCCS), 39 cases were detected among 1000 Black women ages 40–79 screened (3.9%). The only nationwide estimates are from the NHANES study mentioned previously; the prevalence of MGUS among Black women ages 50 and older was 3.4% (95% CI: 2.4, 4.7). Non-IgG isotype, abnormal sFLC ratio, and M protein ≥1.5 g/dl are predictors associated with increased risk of progression to MM or lymphoplasmacytic lymphoma. IgG MGUS was observed in 114 cases (70%), IgA MGUS in 34 cases (21%) and IgM MGUS in 9 cases (5.6%). Three individuals presented with biclonal MGUS. Interestingly, we Received: 26 April 2022 Revised: 15 June 2022 Accepted: 17 June 2022

Abstract 3225: Time since last birth in relation to breast cancer mortality

Abstract: Women who develop breast cancer less than 10 years after giving birth have been shown to have a poorer prognosis than women with a longer time since their last birth. Only a few studies have examined this relation separately by molecular features of the tumor; two observed poorer outcomes for women with hormone receptor positive tumors. A better understanding of the relation between time since last birth and risk of recurrence and death could lead to targeted treatments and/or surveillance of young women who develop breast cancer within 10 years of giving birth. There has been little research on this topic among Black women, who have a higher incidence of breast cancer at young ages compared to White women. We assessed the relation of time since last birth to breast cancer mortality according to estrogen receptor (ER) status of the primary tumor among breast cancer patients who are participants in the prospective Black Women’s Health Study (BWHS). The BWHS includes 59,000 U.S. Black women who enrolled in the study in 1995 and have been followed by biennial questionnaire since then. The present analysis was restricted to parous women diagnosed before age 50 (N=658) because older patients would have been unlikely to have given birth within the past 10 years. ER status was positive for 348 cases, negative for 199, and unknown for 111. Follow-up time was from time of diagnosis to death or the end of 2018, whichever came first. Cox regression analysis, adjusted for age and stage at diagnosis, was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer specific death for women diagnosed <10 years since last birth relative to women diagnosed ≥10 years since last birth. The median age at diagnosis was 44, with 41% of cancers diagnosed at stage I, 43% at stage II, and 16% at stage III. About a third (31%) had given birth <10 years before diagnosis. During follow-up, there were 159 total deaths, 132 of which were due to breast cancer. Among women diagnosed with ER-positive breast cancer, the HR for breast cancer death for women who gave birth <10 years prior to diagnosis relative to women who had not had a recent birth was 2.45 (95% 1.07-5.58). The association was even stronger among women who survived the first five years, with an HR of 3.38 (95% CI 1.34-8.51). Time since last birth was not associated with ER-negative breast cancer mortality (HR 1.06, 95% CI 0.46-2.46). Late recurrences are a particular problem with ER-positive breast cancer. The present findings suggest a relatively short interval (e.g., <10 years) between childbirth and a breast cancer diagnosis may increase risk of a late recurrence and death from ER-positive breast cancer. Greater awareness of this association may lead to improved surveillance of survivors of early-onset breast cancer. Citation Format: Gary R. Zirpoli, Nelsy Castro-Webb, Kimberly A. Bertrand, Julie R. Palmer. Time since last birth in relation to breast cancer mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3225.

Associations between quantitative measures of TDLU involution and breast tumor molecular subtypes among breast cancer cases in the Black Women’s Health Study: a case–case analysis

Abstract: Terminal duct lobular units (TDLUs) are the structures in the breast that give rise to most breast cancers. Previous work has shown that TDLU involution is inversely associated with TDLU metrics, such as TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU, and that these metrics may be elevated in the normal breast tissue of women diagnosed with triple-negative (TN) compared with luminal A breast tumors. It is unknown whether this relationship exists in Black women, who have the highest incidence of TN breast cancer and the highest overall breast cancer mortality rate. We examined relationships between TDLU metrics and breast cancer molecular subtype among breast cancer cases in the Black Women's Health Study (BWHS).We assessed quantitative TDLU metrics (TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU) in digitized 247 hematoxylin and eosin-stained adjacent normal tissue sections from 223 BWHS breast cancer cases, including 65 triple negative (TN) cancers (estrogen receptor (ER) negative, progesterone receptor (PR) negative, human epidermal growth factor-2 (HER2) negative) and 158 luminal A cancers (ER positive, HER2 negative). We evaluated associations of least square mean TDLU metrics adjusted for age and body mass index (BMI) with patient and clinical characteristics. In logistic regression models, we evaluated associations between TDLU metrics and breast cancer subtype, adjusting for age, BMI, and tumor size.Older age and higher BMI were associated with lower TDLU metrics and larger tumor size and lymph node invasion with higher TDLU metrics. The odds of TN compared with luminal A breast cancer increased with increasing tertiles of TDLU metrics, with odds ratios (95% confidence intervals) for tertile 3 versus tertile 1 of 2.18 (0.99, 4.79), 2.77 (1.07, 7.16), and 1.77 (0.79, 3.98) for TDLU count, TDLU span, and acini count/TDLU, respectively.Associations of TDLU metrics with breast cancer subtypes in the BWHS are consistent with previous studies of White and Asian women, demonstrating reduced TDLU involution in TN compared with luminal A breast cancers. Further investigation is needed to understand the factors that influence TDLU involution and the mechanisms that mediate TDLU involution and breast cancer subtype.

Abstract P2-09-01: Population-based risk estimates of clinical subtypes of breast cancer among carriers of germline pathogenic variants in cancer predisposition genes

Abstract: Introduction: The risk of specific clinical subtype of breast cancer (defined by ER and HER2 status) among women in the general population who are carriers of germline pathogenic variants (PVs) in cancer predisposition genes is not well-defined. Methods: A total of 13,153 women with breast cancer (ER+/HER2-: 9381; ER+/HER2+: 1462; ER-/HER2+: 690; and ER-/HER2-: 1620) and 25,005 unaffected women (controls) from nine studies within the CAnceR RIsk Estimates Related to Susceptibility (CARRIERS) consortium that were not enriched for family history or early onset disease were included in the present analysis. A multiplex amplicon-based panel was used to perform germline sequencing for cancer predisposition genes. Case-control associations for each of the four clinical subtype of breast cancer was performed for PVs in 5 common breast cancer predisposition genes (ATM, BRCA1, BRCA2, CHEK2 and PALB2) utilizing a logistic regression model adjusting for study, age at diagnosis, race/ethnicity and family history of breast cancer. Results: The frequency of PVs in 5 genes was 3.8% for ER+/HER2-, 6.2% for ER+/HER2+, 4.2% for ER-/HER2+ and 9.3% for ER-/HER2- subtypes. PVs in BRCA1 and BRCA2 were associated with high risk (Odds Ratio (OR) >4) for all clinical subtypes of breast cancer, but the risk was highest (OR>8) for ER-/HER2- breast cancer. PVs in PALB2 were associated with high risk (OR>4) of ER-/HER2- and ER+/HER2+ subtypes and moderate risk (OR: 2-4) of ER+/HER2- breast cancer. Irrespective of the HER2 status, PVs in ATM were associated with a moderately increased risk (OR: 2-4) of ER+ breast cancer but the risk of ER- breast cancer was not elevated. In contrast, PVs in CHEK2 were associated with high risk (OR>4) of ER+/HER2+ breast cancer and moderate risk (OR: 2-4) of ER+/HER2- and ER-/HER2+ breast cancer, but the risk of ER-/HER2- breast cancer was not elevated. Conclusions: This study provides population-based estimates of risk of specific clinical subtypes of breast cancer which will be useful for genetic counseling and targeting appropriate screening strategies in PV carriers based on subtype specific risks of breast cancer. Citation Format: Siddhartha Yadav, Chunling Hu, Nicholas J. Boddicker, Eric Polley, Steven Hart, Rohan Gnanaolivu, Jie Na, Hongyan Huang, Song Yao, Celine M. Vachon, Lauren Teras, Jack A. Taylor, Dale P. Sandler, Julie R. Palmer, Janet E. Olson, Susan Neuhausen, Elena Martinez, Sara Lindstroem, Loic Le Marchand, Charles Kooperberg, Christopher Haiman, Mia M. Gaudet, James V. Lacey, Kimberly A. Bertrand, Leslie Bernstein, Paul W. Auer, Christine Ambrosone, Jeffrey N. Weitzel, Peter Kraft, David E. Goldgar, Katherine L. Nathanson, Susan M. Domchek, Fergus J. Couch, CARRIERS Consortium. Population-based risk estimates of clinical subtypes of breast cancer among carriers of germline pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-01.