Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

Tumor-infiltrating lymphocytes and breast cancer mortality in racially and ethnically diverse participants of the Northern California Breast Cancer Family Registry.

Stromal tumor-infiltrating lymphocyte (sTIL) enrichment in pretreatment breast tumors has been associated with superior response to neoadjuvant treatment and survival. In a population-based cohort, we studied sTIL-survival associations by race and ethnicity. We assessed associations of continuous sTIL scores and sTIL-enriched breast cancers (defined as percent lymphocytic infiltration of tumor stroma or cell nests at cutoffs of 30%, 50%, and 70%) with clinical and epidemiologic characteristics and conducted multivariable survival analyses. Although we identified no difference in sTIL score by race and ethnicity, higher continuous sTIL score was associated with lower breast cancer-specific mortality only among non-Hispanic White and Asian American but not African American and Hispanic women. This finding suggests that complex factors influence treatment response and survival, given that sTIL enrichment was not associated with a survival advantage among women from minoritized groups, who more often experience health disparities. Further study of patient selection for sTIL-guided treatment strategies is warranted.

Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.

Childhood physical activity and pubertal timing: findings from the LEGACY girls study.

BACKGROUND: There is limited research on whether physical activity (PA) in early childhood is associated with the timing of pubertal events in girls. METHODS: We used data collected over 2011-16 from the LEGACY Girls Study (n = 984; primarily aged 6-13 years at study enrolment), a multicentre North American cohort enriched for girls with a breast cancer family history (BCFH), to evaluate if PA is associated with age at thelarche, pubarche and menarche. Maternal-reported questionnaire data measured puberty outcomes, PA in early childhood (ages 3-5 years) and total metabolic equivalents of organized PA in middle childhood (ages 7-9 years). We used interval-censored Weibull parametric survival regression models with age as the time scale and adjusted for sociodemographic factors, and we tested for effect modification by BCFH. We used inverse odds weighting to test for mediation by body mass index-for-age z-score (BMIZ) measured at study enrolment. RESULTS: Being highly active vs inactive in early childhood was associated with later thelarche in girls with a BCFH [adjusted hazard ratio (aHR) = 0.39, 95% CI = 0.26-0.59), but not in girls without a BCFH. In all girls, irrespective of BCFH, being in the highest vs lowest quartile of organized PA in middle childhood was associated with later menarche (aHR = 0.70, 95% CI = 0.50-0.97). These associations remained after accounting for potential mediation by BMIZ. CONCLUSION: This study provides new data that PA in early childhood may be associated with later thelarche in girls with a BCFH, also further supporting an overall association between PA in middle childhood and later menarche.

A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study.

BACKGROUND: Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. FINDINGS: We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. CONCLUSIONS: The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

Risk of Multiple Primary Cancers in Patients With Merkel Cell Carcinoma: A SEER-Based Analysis.

Importance: The risk of subsequent primary cancers after a diagnosis of cutaneous Merkel cell carcinoma (MCC) is not well established. Objective: To evaluate the risk of subsequent primary cancers after the diagnosis of a first primary cutaneous MCC. Design, Setting, and Participants: This cohort study analyzed data from 17 registries of the Surveillance, Epidemiology, and End Results (SEER) Program from January 1, 2000, to December 31, 2019. In all, 6146 patients diagnosed with a first primary cutaneous MCC were identified. Main Outcomes and Measures: The primary outcome was the relative and absolute risks of subsequent primary cancers after the diagnosis of a first primary MCC, which were calculated using the standardized incidence ratio (SIR; ratio of observed to expected cases of subsequent cancer) and the excess risk (difference between observed and expected cases of subsequent cancer divided by the person-years at risk), respectively. Data were analyzed between January 1, 2000, and December 31, 2019. Results: Of 6146 patients with a first primary MCC diagnosed at a median (IQR) age of 76 (66-83) years, 3713 (60.4%) were men, and the predominant race and ethnicity was non-Hispanic White (5491 individuals [89.3%]). Of these patients, 725 (11.8%) developed subsequent primary cancers, with an SIR of 1.28 (95% CI, 1.19-1.38) and excess risk of 57.25 per 10 000 person-years. For solid tumors after MCC, risk was elevated for cutaneous melanoma (SIR, 2.36 [95% CI, 1.85-2.97]; excess risk, 15.27 per 10 000 person-years) and papillary thyroid carcinoma (SIR, 5.26 [95% CI, 3.25-8.04]; excess risk, 6.16 per 10 000 person-years). For hematologic cancers after MCC, risk was increased for non-Hodgkin lymphoma (SIR, 2.62 [95% CI, 2.04-3.32]; excess risk, 15.48 per 10 000 person-years). Conclusions and Relevance: This cohort study found that patients with MCC had an increased risk of subsequently developing solid and hematologic cancers. This increased risk may be associated with increased surveillance, treatment-related factors, or shared etiologies of the other cancers with MCC. Further studies exploring possible common etiological factors shared between MCC and other primary cancers are warranted.

Elevated Risk of Visceral Malignant Neoplasms in Extramammary Paget Disease.

This cross-sectional study evaluates the incidence and types of cancers that develop years after an extramammary Paget disease (EMPD) diagnosis.

Trends in Radiation Dose to the Contralateral Breast During Breast Cancer Radiation Therapy.

Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in the contralateral breast for long-term survivors of breast cancer. Individually estimated radiation absorbed doses to the four quadrants and areola central area of the contralateral breast were estimated for 2,132 women treated with radiation therapy for local/regional breast cancers at age <55 years diagnosed between 1985 and 2008. The two inner quadrant doses and two outer quadrant doses were averaged. Trends in dose to each of the three areas of the contralateral breast were evaluated in multivariable models. The population impact of reducing contralateral breast dose on the incidence of radiation-associated CBC was assessed by estimating population attributable risk fraction (PAR) in a multivariable model. The median dose to the inner quadrants of the contralateral breast was 1.70 Gy; to the areola, 1.20 Gy; and to the outer quadrants, 0.72 Gy. Ninety-two percent of patients received ≥1 Gy to the inner quadrants. For each calendar year of diagnosis, dose declined significantly for each location, most rapidly for the inner quadrants (0.04 Gy/year). Declines in dose were similar across subgroups defined by age at diagnosis and body mass index. The PAR for CBC due to radiation exposure >1 Gy for women <40 years of age was 17%. Radiation dose-reduction measures have reduced dose to the contralateral breast during breast radiation therapy. Reducing the dose to the contralateral breast to <1 Gy could prevent an estimated 17% of subsequent radiation-associated CBCs for women treated under 40 years of age. These dose estimates inform CBC surveillance for the growing number of breast cancer survivors who received radiation therapy as young women in recent decades. Continued reductions in dose to the contralateral breast could further reduce the incidence of radiation-associated CBC.

Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium.

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2.

BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

Antimicrobial exposure is associated with decreased survival in triple-negative breast cancer.

Antimicrobial exposure during curative-intent treatment of triple-negative breast cancer (TNBC) may lead to gut microbiome dysbiosis, decreased circulating and tumor-infiltrating lymphocytes, and inferior outcomes. Here, we investigate the association of antimicrobial exposure and peripheral lymphocyte count during TNBC treatment with survival, using integrated electronic medical record and California Cancer Registry data in the Oncoshare database. Of 772 women with stage I-III TNBC treated with and without standard cytotoxic chemotherapy - prior to the immune checkpoint inhibitor era - most (654, 85%) used antimicrobials. Applying multivariate analyses, we show that each additional total or unique monthly antimicrobial prescription is associated with inferior overall and breast cancer-specific survival. This antimicrobial-mortality association is independent of changes in neutrophil count, is unrelated to disease severity, and is sustained through year three following diagnosis, suggesting antimicrobial exposure negatively impacts TNBC survival. These results may inform mechanistic studies and antimicrobial prescribing decisions in TNBC and other hormone receptor-independent cancers.

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.

BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility. OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. RESULTS AND LIMITATIONS: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4). CONCLUSIONS: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. PATIENT SUMMARY: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Diet Quality and All-Cause Mortality in Women with Breast Cancer from the Breast Cancer Family Registry.

BACKGROUND: The impact of diet on breast cancer survival remains inconclusive. We assessed associations of all-cause mortality with adherence to the four diet quality indices: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index (AHEI), Alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH). METHODS: Dietary intake data were evaluated for 6,157 North American women enrolled in the Breast Cancer Family Registry who had been diagnosed with invasive breast cancer from 1993 to 2011 and were followed through 2018. Pre-diagnosis (n = 4,557) or post-diagnosis (n = 1,600) dietary intake was estimated through a food frequency questionnaire. During a median follow-up time of 11.3 years, 1,265 deaths occurred. Cox proportional hazards models were used to estimate multivariable-adjusted HR and 95% confidence intervals (CI). RESULTS: Women in the highest versus lowest quartile of adherence to the HEI-2015, AHEI, aMED, and DASH indices had a lower risk of all-cause mortality. HR (95% CI) were 0.88 (0.74-1.04; Ptrend = 0.12) for HEI-2015; 0.82 (0.69-0.97; Ptrend = 0.02) for AHEI; 0.73 (0.59-0.92; Ptrend = 0.02) for aMED; and 0.78 (0.65-0.94; Ptrend = 0.006) for DASH. In subgroup analyses, the associations with higher adherence to the four indices were similar for pre- or post-diagnosis dietary intake and were confined to women with a body mass index <25 kg/m2 and women with hormone receptor positive tumors. CONCLUSIONS: Higher adherence to the HEI-2015, AHEI, aMED, and DASH indices was associated with lower mortality among women with breast cancer. IMPACT: Adherence to a healthy diet may improve survival of women with breast cancer.

Breast Cancer Diagnosis, Treatment, and Outcomes of Patients From Sex and Gender Minority Groups.

Importance: Sexual orientation and gender identity data are not collected by most hospitals or cancer registries; thus, little is known about the quality of breast cancer treatment for patients from sex and gender minority (SGM) groups. Objective: To evaluate the quality of breast cancer treatment and recurrence outcomes for patients from SGM groups compared with cisgender heterosexual patients. Design, Setting, and Participants: Exposure-matched retrospective case-control study of 92 patients from SGM groups treated at an academic medical center from January 1, 2008, to January 1, 2022, matched to cisgender heterosexual patients with breast cancer by year of diagnosis, age, tumor stage, estrogen receptor status, and ERBB2 (HER2) status. Main Outcomes and Measures: Patient demographic and clinical characteristics, as well as treatment quality, as measured by missed guideline-based breast cancer screening, appropriate referral for genetic counseling and testing, mastectomy vs lumpectomy, receipt of chest reconstruction, adjuvant radiation therapy after lumpectomy, neoadjuvant chemotherapy for stage III disease, antiestrogen therapy for at least 5 years for estrogen receptor-positive disease, ERBB2-directed therapy for ERBB2-positive disease, patient refusal of an oncologist-recommended treatment, time from symptom onset to tissue diagnosis, time from diagnosis to first treatment, and time from breast cancer diagnosis to first recurrence. Results were adjusted for multiple hypothesis testing. Compared with cisgender heterosexual patients, those from SGM groups were hypothesized to have disparities in 1 or more of these quality metrics. Results: Ninety-two patients from SGM groups were matched to 92 cisgender heterosexual patients (n = 184). The median age at diagnosis for all patients was 49 years (IQR, 43-56 years); 74 were lesbian (80%), 12 were bisexual (13%), and 6 were transgender (6%). Compared with cisgender heterosexual patients, those from SGM groups experienced a delay in time from symptom onset to diagnosis (median time to diagnosis, 34 vs 64 days; multivariable adjusted hazard ratio, 0.65; 95% CI, 0.42-0.99; P = .04), were more likely to decline an oncologist-recommended treatment modality (35 [38%] vs 18 [20%]; multivariable adjusted odds ratio, 2.27; 95% CI, 1.09-4.74; P = .03), and were more likely to experience a breast cancer recurrence (multivariable adjusted hazard ratio, 3.07; 95% CI, 1.56-6.03; P = .001). Conclusions and Relevance: This study found that among patients with breast cancer, those from SGM groups experienced delayed diagnosis, with faster recurrence at a 3-fold higher rate compared with cisgender heterosexual patients. These results suggest disparities in the care of patients from SGM groups and warrant further study to inform interventions.

Changes in Breast Cancer Risk and Risk Factor Profiles among U.S.-Born and Immigrant Asian American Women Residing in the San Francisco Bay Area.

BACKGROUND: Breast cancer incidence rates in women of Asian descent have been increasing in the United States and Asia. METHODS: In a case-control study of Asian American women from the San Francisco Bay Area, we assessed associations with birthplace and migration-related characteristics and compared risk factors between Asian American and non-Hispanic White women by birthplace and birth cohort. RESULTS: Birthplace and migration-related characteristics were associated with breast cancer risk only among women in the younger birth cohort (1951-1984) that comprised 355 cases diagnosed at age ≤55 years and 276 sister and population controls. Breast cancer risk was marginally increased among foreign-born women [OR = 1.40; 95% confidence interval (CI), 0.97-2.03] and two-fold among foreign-born Chinese women (OR = 2.16; 95% CI, 1.21-3.88). Two-fold increased risks were associated with migration at age ≥40 years and longer U.S. residence (≥30 years or ≥75% of life). The education level was high among both cases and controls. Differences in the prevalence of risk factors by birthplace and birth cohort suggest temporal changes in reproductive and lifestyle-related factors. The prevalence in risk factors was similar between foreign-born and U.S.-born women in the younger birth cohort, and did not fully explain the observed associations with birthplace and other migration characteristics. CONCLUSIONS: In contrast to studies from earlier decades, younger foreign-born Asian American women had a higher risk of breast cancer than U.S.-born Asian American women. IMPACT: It is important and urgent to understand what factors drive the increasing burden of breast cancer in women of Asian descent and implement effective prevention programs.

Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifies FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer.

Introduction: Breast cancer (BC) is one of the most common cancers globally. Genetic testing can facilitate screening and risk-reducing recommendations, and inform use of targeted treatments. However, genes included in testing panels are from studies of European-ancestry participants. We sequenced Hispanic/Latina (H/L) women to identify BC susceptibility genes. Methods: We conducted a pooled BC case-control analysis in H/L women from the San Francisco Bay area, Los Angeles County, and Mexico (4,178 cases and 4,344 controls). Whole exome sequencing was conducted on 1,043 cases and 1,188 controls and a targeted 857-gene panel on the remaining samples. Using ancestry-adjusted SKAT-O analyses, we tested the association of loss of function (LoF) variants with overall, estrogen receptor (ER)-positive, and ER-negative BC risk. We calculated odds ratios (OR) for BC using ancestry-adjusted logistic regression models. We also tested the association of single variants with BC risk. Results: We saw a strong association of LoF variants in FANCM with ER-negative BC (p=4.1×10-7, OR [CI]: 6.7 [2.9-15.6]) and a nominal association with overall BC risk. Among known susceptibility genes, BRCA1 (p=2.3×10-10, OR [CI]: 24.9 [6.1-102.5]), BRCA2 (p=8.4×10-10, OR [CI]: 7.0 [3.5-14.0]), and PALB2 (p=1.8×10-8, OR [CI]: 6.5 [3.2-13.1]) were strongly associated with BC. There were nominally significant associations with CHEK2, RAD51D, and TP53. Conclusion: In H/L women, LoF variants in FANCM were strongly associated with ER-negative breast cancer risk. It previously was proposed as a possible susceptibility gene for ER-negative BC, but is not routinely tested in clinical practice. Our results demonstrate that FANCM should be added to BC gene panels.

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

PURPOSE: To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS: The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS: Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION: Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Maternal and prenatal factors and age at thelarche in the LEGACY Girls Study cohort: implications for breast cancer risk.

BACKGROUND: Earlier onset of breast development (thelarche) is associated with increased breast cancer risk. Identifying modifiable factors associated with earlier thelarche may provide an opportunity for breast cancer risk reduction starting early in life, which could especially benefit girls with a greater absolute risk of breast cancer due to family history. METHODS: We assessed associations of maternal pre-pregnancy body mass index (BMI), physical activity during pregnancy, gestational weight gain and daughters' weight and length at birth with age at thelarche using longitudinal Weibull models in 1031 girls in the Lessons in Epidemiology and Genetics of Adult Cancer from Youth (LEGACY) Girls Study-a prospective cohort of girls, half of whom have a breast cancer family history (BCFH). RESULTS: Girls whose mothers had a pre-pregnancy BMI of ≥25 and gained ≥30 lbs were 57% more likely to experience earlier thelarche than girls whose mothers had a pre-pregnancy BMI of <25 and gained <30 lbs [hazard ratio (HR) = 1.57, 95% CI: 1.16, 2.12]. This association was not mediated by childhood BMI and was similar in girls with and without a BCFH (BCFH: HR = 1.41, 95% CI: 0.87, 2.27; No BCFH: HR = 1.62, 95% CI: 1.10, 2.40). Daughters of women who reported no recreational physical activity during pregnancy were more likely to experience earlier thelarche compared with daughters of physically active women. Birthweight and birth length were not associated with thelarche. CONCLUSION: Earlier thelarche, a breast cancer risk factor, was associated with three potentially modifiable maternal risk factors-pre-pregnancy BMI, gestational weight gain and physical inactivity-in a cohort of girls enriched for BCFH.

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.