Breast Cancer Association Consortium Studies Research Articles

Abstract P2-10-05: A breast cancer multi-racial/ethnic polygenic risk score for improved personalized breast cancer screening

Abstract Background: Polygenic risk scores (PRS) integrate risk information from breast cancer associated SNPs (single nucleotide polymorphism). The risk scores have mostly been developed in populations of European ancestry, and have been shown to improve risk prediction over standard breast cancer risk models in these populations. The ability of the PRS to personalize screening is currently being studied. We included PRS as a component of breast cancer risk assessment in the WISDOM Study, a trial of personalized vs. annual breast cancer screening. In order to account for race/ethnicity in PRS risk assessment, we developed a race/ethnicity calibrated and inclusive PRS risk score that we incorporated here into the Gail model to determine impact on risk stratification. Methods: We constructed two different PRS for each race/ethnicity: For Caucasian populations, we constructed two PRS based on SNPs discovered in European-ancestry populations. One PRS was based on 167 SNPs (PRS-167) and the other based on 313 SNPs (PRS-313) from the Breast Cancer Association Consortium studies as previously published. For each of the Asian-, Hispanic- and African-ancestry populations we added additional ancestry specific SNPs to the PRS-167 or the PRS-313, that were literature curated or our own identified race/ethnicity SNPs that we validated to provide independent risk prediction for their ancestry group: Asian added 10 or 4 additional SNPs, Hispanic 2 SNPs, and African 8 and 12 SNPs, respectively to each model. We tested this approach using datasets from several case-control studies of multiple racial/ethnic populations and compared discrimination of the models using area under the receiver operating characteristic curve (AUROC). Furthermore, we applied our multi-racial/ethnic PRS-313 in a sample of ~3000 multi-racial/ethnic women from the Athena Breast Screening Registry, case-control sampled by Gail score to be at elevated (Gail >1.67) or average (Gail≤1.67) risk, to evaluate the impact of our multi-ethnic adjustment on risk stratification. Results: A multi-race/ethnicity adjusted PRS-313 and PRS-167 plus ethnicity specific SNPs has moderate-high discriminatory power with AUROCs of 0.65 and 0.64, respectively. The specificity of our PRS-167 in the different race/ethnicity ancestries performs relatively well in Asian (AUROC 0.59) and Hispanic (AUROC 0.63) populations, but less so in African-ancestry (AUROC 0.56). Incorporating multi-race/ethnicity PRS into Gail model selected women, resulted in 20% of average-risk women transitioning to risk above 1.67%, and conversely, 38% of elevated risk patients were reclassified to average risk. Conclusion: We constructed a PRS risk score that can be applied to multi-ethnic populations and found moderate-high discrimination. Additional work is needed for the African-ancestry population. The addition of a multi-race/ethnicity SNP model to risk classification based on the Gail model significantly changes risk stratification and clinical care recommendations due to down- or up-reclassification of women at average versus elevated risk. Citation Format: Sarah Theiner, Donglei Hu, Scott Huntsman, Yiwey Shieh, Laura Fejerman, Irene Acerbi, Sarah D Sawyer, Paige Kendall, Wei Zheng, Dezheng Huo, Olufunmilayo I Olopade, Christopher Haiman, Karla Kerlikowske, Steven Cummings, Ester John, Gabriela Torres-Mejia, Lawrence H Kushi, Denise Wolf, Jeffery A Tice, David A Pearce, Laura Esserman, Athena Breast Health Network Investigators and Advocate Partners, Laura J van ‘t Veer, Elad Ziv. A breast cancer multi-racial/ethnic polygenic risk score for improved personalized breast cancer screening [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-05.

Abstract 3286: Breast cancer risk factors and survival by tumor subtypes: A pooled analysis from the breast cancer association consortium studies

Abstract Background: Breast cancer (BC) is a heterogeneous disease with differing risk factors, prognosis and response to treatment strategies. Lifestyle and personal factors have been shown to influence BC prognosis. It is unknown whether lifestyle factors are differentially associated with prognosis according to BC subtypes. Methods: Analyses were based on 102,823 BC patients from 58 studies participating in the Breast Cancer Association Consortium. Cox regression models were used to assess associations between prediagnosis lifestyle and reproductive BC risk factors—including age at menarche, age at first full-term pregnancy, parity, breastfeeding, time since last full-term birth, BMI, oral contraceptive (OC) use, use of estrogen and progesterone therapy (EPT) and cigarette smoking- and 10-year overall survival (OS) and BC survival in all patients and by tumor subtypes. We used two tumor classifications: by estrogen receptor (ER) status; and by invasive subtypes based on ER, progesterone receptor, the human epidermal growth factor receptor 2 (HER2), and grade. Multiple imputation of risk factors and clinico-pathological variables was performed simultaneously. All analyses were stratified by study and adjusted for age at diagnosis, tumor size, nodal status, tumor grade (except for the luminal B HER2- subgroup), and systemic treatment. Multiple testing was accounted for using Bonferroni correction. Results: There were a total of 13,953 total deaths and 6,893 BC deaths over 10 years. The most significant associations were observed between OS and the following risk factors: parous vs nulliparous (HR (95%CI): 0.84 (0.78,0.89), P=1.4E-07); OC use vs never use (0.82 (0.78,0.87), P=1.2E-11); EPT use vs never use (0.64 (0.58,0.70), P=1.5E-19); BMI > 30 kg/m2 vs 18.5-25.0 kg/m2 in postmenopausal women (1.25 (1.17,1.34), P=1.9E-10 and 1.34 (1.18, 1.53), P=4.6E-06 in premenopausal women); cigarette smoking vs nonsmokers (1.37 (1.28,1.47), P=2.1E-19); time since last full-term birth < 5 years vs ≥ 10 years (2.09 (1.78, 2.44), P=1.3E-19). Associations with BC survival were similar to those for OS but weaker. We observed no differential associations by tumor subtype. The strongest evidence of subtype differential effects was for time since last full-term birth < 5 years vs ≥ 10 years for luminal A (3.00 (2.25,3.98)) vs luminal B-HER2- (1.69 (1.27,2.24)), HER2+ enriched (1.40 (0.96,2.05)), and triple negative (1.49 (1.15,1.93)), respectively. Multivariable models are being constructed to account for the interplay between risk factors. Conclusion: Our results suggest that BC risk factors influence survival after diagnosis. The effect appears to be stronger when OS is considered as endpoint, which may be due to power or associations of BC risk factors with other diseases. The data did not support a strong differential effect of BC risk factors on prognosis by tumor subtype. Citation Format: Anna Morra, Audrey Y. Jung, Sabine Behrens, Rose Yang, Heather Eliassen, Michelle Holmes, Montserrat Garcia-Closas, Marjanka K. Schmidt, Jenny Chang-Claude, on behalf of the Breast Cancer Association Consortium. Breast cancer risk factors and survival by tumor subtypes: A pooled analysis from the breast cancer association consortium studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3286.

Abstract 3451: Breast cancer risk factor associations by loss of E-cadherin tumor tissue expression: A pooled analysis of 5,896 cases in 12 studies from the Breast Cancer Association Consortium (BCAC)

Abstract Purpose: Expression of the tumor suppressor gene E-cadherin is diminished in lobular breast cancers and has been implicated in epithelial mesenchymal transition. We assessed risk factor associations for breast cancer stratified by low vs. high E-cadherin protein expression in a pooled analysis within the Breast Cancer Association Consortium (BCAC) studies. Methods: E-cadherin tumor tissue staining was performed centrally at the NCI on formalin-fixed paraffin-embedded tissue microarray (TMA) sections representing 6,010 breast cancer patients from 12 US and European BCAC studies. TMAs were digitally scanned and scored using the SlidePath Digital Image Hub (Leica Biosystems, Wetzlar, Germany). For 5,896 cancers with evaluable tumors, E-cadherin was visually scored as estimated percent of positive cells times stain intensity (0, 1+, 2+, 3+) (score range 0-300). E-cadherin low was defined as tumors with a score < 100. Risk factor associations for low vs. high E-cadherin expressing tumors were evaluated by logistic regression, adjusted for age and study site, and stratified by ER status and histologic subtype. To assess the consistency in results by study, meta-analyses were performed using the random-effects model. All statistical tests were two-sided. Results: E-cadherin low cancers comprised 20% of tumors and were associated with lobular histology, well/moderately differentiated cancers, > 2cm in size, and HER2-negative status (χ2, P < 0.003 for all factors). E-cadherin low status was associated with family history of breast cancer (FH) (OR = 1.32, 95% CI = 1.09-1.60, P-het = 0.005) and ever use of menopausal hormones (OR = 1.26, 95% CI = 1.02-1.56, P-het = 0.03). Study specific meta-plots showed consistent effects across studies for menopausal hormone therapy (I2 = 0.0%, p = 0.64); however, E-cadherin loss by FH did show evidence of heterogeneity by study (I2 = 54%, P = 0.03). Differences in E-cadherin expression remained significant for FH, and menopausal hormone use when further adjusted for ER (P < 0.05). We also found relationships with E-cadherin loss to vary by BMI, number of live births, age at first birth, and oral contraceptive use in stratified analysis by ER status and histologic subtype. Conclusion: This large pooled analysis shows that breast cancer risk factor associations may differ by E-cadherin expression independent of ER status, suggesting that it may represent a marker of etiologic heterogeneity. Citation Format: Hisani N. Horne, Hannah Oh, Mark E. Sherman, Maya Palakal, Stephen H. Hewitt, Marjanka Schmidt, Javier Benitez, Roger Milne, Hermann Brenner, Heli Nevanlinna, Arto Mannermaa, Georgia Chenevix-Trench, Fergus Couch, Peter Devilee, Diana Eccles, Maartje Hooning, Anthony J. Swerdlow, Nick Orr, Melissa A. Troester, Renata Cora, Paul D. Pharoah, Montserrat Garcia-Closas, Jonine D. Figueroa. Breast cancer risk factor associations by loss of E-cadherin tumor tissue expression: A pooled analysis of 5,896 cases in 12 studies from the Breast Cancer Association Consortium (BCAC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3451.

A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients.

BackgroundPersonalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment.MethodsWe assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p < 0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed.Resultsrs878156 in PARP2 showed a differential effect by chemotherapy (p = 0.093) and was replicated in BCAC studies (p = 0.009; combined analysis p = 0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency = 0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR) = 0.75, 95 % 0.53–1.07) and poorer survival when not treated with chemotherapy (HR = 1.42, 95 % 1.08–1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR = 0.73, 95 % CI 0.40–1.32). None of the SNPs showed significant differential effects by radiotherapy.ConclusionsOur data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1957-7) contains supplementary material, which is available to authorized users.

A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6×10(-6) for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P=3×10(-7)) on chromosome 2 but was not replicated in the BCAC studies (P=0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP×MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.

Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies

Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies

Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.

Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.