Citations

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to 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 status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p< 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In 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 15-year cumulative incidence of CBC was >20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was < 20% for PV carriers in any of the 5 genes. Conclusions 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. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.

Abstract Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09–1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words)

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.

Abstract Women who have had breast cancer in the past are at increased risk of developing a second primary cancer (SPC), including second primary breast cancer (SPBC) or a second primary non-breast cancer (SPNBC). In the Multiethnic Cohort (MEC) Study, we conducted a prospective cohort analysis in 3,223 female breast cancer survivors from five racial/ethnic populations (White, African American, Japanese American, Latino, and Native Hawaiian) to assess the association of rare pathogenic variants (PV) in 37 known cancer predisposition genes with risk of SPC. A total of 719 (22.3%) women developed SPC, of which, 323 (10.0%) were SPBC. Germline PVs in BRCA1 (HR, 2.28; 95% CI, 1.11–4.65) and ERCC2 (HR, 3.51; 95% CI, 1.29–9.54) were significantly enriched in women with SPC. In the subtype analysis for SPBC, a significant association of ERCC2 PVs (HR, 5.09; 95% CI, 1.58–16.4) and a suggestive association of BRCA2 PVs (HR, 2.24; 95% CI, 0.91–5.55) were observed. There was also a higher risk of SPNBC in carriers of BRCA1 PVs (HR, 2.98; 95% CI, 1.21–7.36). These results provide evidence that germline PVs in BRCA1, BRCA2, and ERCC2 contribute to the development of SPC in breast cancer survivors. These findings also suggest that compromised DNA repair mechanisms could be a predisposition factor for SPC in patients with breast cancer, supporting the need for closer monitoring of SPC in women carrying PVs in these genes. Significance: This multiethnic study links germline pathogenic variants in BRCA1, BRCA2, and ERCC2 to the development of second primary cancer in breast cancer survivors, providing biological insights and biomarkers to guide patient monitoring.

AbstractBackgroundReproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.MethodsAnalyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2–like, HER2-enriched–like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.ResultsCompared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2–like, and HER2-enriched–like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.ConclusionsThis large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P < 0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE = 4.44 × 10−6). In this transcriptome-informed genome-wide gene–environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Our study suggests a limited role of gene–environment interactions in breast cancer risk.

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.

Abstract Introduction: Prostate Cancer (PCa) risk is influenced by both rare germline pathogenic variants (GPVs) in DNA damage repair genes and common variants as measured by polygenic risk scores (PRS) however, the combined effect of GPVs and PRS on PCa risk in men of African ancestry has not been investigated. Methods: We examined the combined effect of rare GPVs and PRS on PCa risk in 1,795 PCa cases and 1,424 controls of African ancestry men from the Multiethnic Cohort, the Los Angeles Study of Aggressive Prostate Cancer, and the Uganda Prostate Cancer Study. GPVs in 19 DNA genes were defined as clinically validated missense variants and variants that alter the protein sequence. The PRS was constructed as a weighted sum of 267 established PCa risk variants. The combined effect of the PRS and GPV status on PCa risk was evaluated using logistic regression models adjusting for age, study, and the first 10 principal components of ancestry to account for population stratification. Results: We identified 91 GPVs carried by 31 controls and 68 cases. Among GPV non-carriers, compared to those with average PRS (33.3-66.7%), odds ratios for PCa ranged from 0.56 (95% CI=0.45-0.70; P=1.2E-7) in low PRS men (0-33.3%) to 3.04 (95% CI=2.54-3.63; P=5.6E-35) in high PRS men (66.7-100%). Among GPV carriers, odds ratios for PCa ranged from 2.09 (95% CI=0.85-5.12; P=0.11) in low PRS men to 5.03 (95% CI=2.37-10.66; P=2.5E-5) in high PRS men, compared to GPV non-carriers with average PRS. Next, we restricted GPVs to ATM, BRCA2, PALB2, and NBN[BD2] (n=51 variants carried by 8 controls and 44 cases), which we previously reported as being the genes most strongly associated with advanced PCa in this population and study sample. Among GPV non-carriers, odds ratios for PCa ranged from 0.56 (95% CI=0.46-0.71; P=2.7E-7) in low PRS men to 5.03 (95% CI=0.85-5.12; P=0.11) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.08 (95% CI=0.58-7.49; P=0.26) in low PRS men to 18.06 (95% CI=4.24-76.84; P=9.0E-5) in high PRS men, compared to average PRS GPV non-carriers. When comparing aggressive cases to controls, considering the top four genes, GPV non-carrier odds ratios for PCa ranged from 0.52 (95% CI=0.40-0.70; P=6.2E-6) in low PRS men to 3.16 (95% CI=2.56-3.91; P=1.6E-26) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.97 (95% CI=073-12.16; P=0.13) in low PRS men to 23.58 (95% CI=5.39-103.20; P=2.7E-5) in high PRS men, compared to average PRS GPV non-carriers. Conclusion: We found that PCa risk in African ancestry men carrying GPVs in DNA damage repair and cancer predisposition genes, particularly ATM, BRCA2, PALB2, and NBN, varied depending on an individual's PRS. This implies that to comprehensively assess genetic risk of PCa, it is important to consider both rare and common variants. These findings could have implications for risk stratification in this high-risk population and emphasize the need for larger genetic studies of PCa in African ancestry men to identify and characterize genetic risk factors in this population. Citation Format: Raymond W. Hughley, Burcu F. Darst, Marco Matejcic, Yesha Patel, Jenna Lilyquist, Steven N. Hart, Eric C. Polley, Lucy Xia, Xin Sheng, Alexander Lubmawa, Sue A. Ingles, Lynne Wilkens, Loïc L. Marchand, Stephen Watya, Fergus J. Couch, David V. Conti, Christopher A. Haiman. Combined effect of a prostate cancer polygenic risk score and germline pathogenic variants in DNA damage repair genes on prostate cancer risk in men of African ancestry [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-197.

PURPOSETo determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.MATERIALS AND METHODSThe study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).RESULTSThe frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.CONCLUSIONThe study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.