Abstract PD3-02: Polygenic risk scores provide clinically meaningful risk stratification among women carrying moderate penetrance pathogenic variants in breast cancer predisposition genes: Results from the CARRIERS study

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The 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). RESULTS The 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. CONCLUSION The 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.

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Germline pathogenic variants in cancer predisposition genes among women with invasive lobular cancer of breast.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10581 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10581-10581

Author(s):

Siddhartha Yadav ◽

Chunling Hu ◽

Susan M. Domchek ◽

Jeffrey N. Weitzel ◽

David Goldgar ◽

...

Keyword(s):

Breast Cancer ◽

Population Based ◽

Cancer Predisposition ◽

Clinical Cohort ◽

Breast Cancer Predisposition ◽

Panel Testing ◽

Pathogenic Variants ◽

Predisposition Genes ◽

Multigene Panel Testing ◽

Multigene Panel

10581 Background: The prevalence of germline pathogenic variants (PVs) in cancer predisposition genes among women with invasive lobular breast cancer (ILC) and the risk of ILC in PV carriers is not well-defined. Methods: The study included 2,999 women with ILC and 32,544 unaffected controls from a population-based cohort; 3,796 women with ILC and 20,323 women with invasive ductal carcinoma (IDC) undergoing clinical multigene panel testing (clinical cohort); and 125,748 exome sequences from unrelated women without a cancer diagnosis in the gnomAD 3.0 dataset. 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 controls in both cohorts and between women with ILC and IDC in the clinical cohort. Results: The 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 analyses, 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. PV frequencies in these genes in ILC and IDC were similar except for PV frequencies in BRCA1 and CDH1. Conclusions: The 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. While, multigene panel testing may be appropriate for women with ILC, CDH1 should be specifically discussed in the context of low prevalence and attendant gastric cancer risk.

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Abstract PD10-02: The influence of pathogenic variants in breast cancer predisposition genes on secondary breast cancer events in a prospectively collected cohort of breast cancer patients

10.1158/1538-7445.sabcs20-pd10-02 ◽

2021 ◽

Author(s):

Judy C. Boughey ◽

Tanya L. Hoskin ◽

Siddhartha Yadav ◽

Fergus J. Couch

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Cancer Predisposition ◽

Breast Cancer Patients ◽

Breast Cancer Predisposition ◽

Pathogenic Variants ◽

Predisposition Genes ◽

Secondary Breast Cancer

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Meta-analysis of breast cancer risk associated with established germline pathogenic variants in breast cancer-predisposition genes in population-based studies

10.37766/inplasy2021.2.0017 ◽

2021 ◽

Author(s):

Ziqi Jia ◽

Jiang Wu ◽

Jiaxin Li ◽

Jiaqi Liu ◽

Xiang Wang

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Meta Analysis ◽

Population Based ◽

Cancer Predisposition ◽

Breast Cancer Predisposition ◽

Pathogenic Variants ◽

Predisposition Genes

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Discovery of structural deletions in breast cancer predisposition genes using whole genome sequencing data from > 2000 women of African-ancestry

Human Genetics ◽

10.1007/s00439-021-02342-8 ◽

2021 ◽

Author(s):

Zhishan Chen ◽

Xingyi Guo ◽

Jirong Long ◽

Jie Ping ◽

Bingshan Li ◽

...

Keyword(s):

Breast Cancer ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

African Ancestry ◽

Cancer Predisposition ◽

Whole Genome Sequencing Data ◽

Whole Genome ◽

Sequencing Data ◽

Breast Cancer Predisposition ◽

Predisposition Genes

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Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score

Journal of Clinical Oncology ◽

10.1200/jco.20.01992 ◽

2021 ◽

pp. JCO.20.01992

Author(s):

Chi Gao ◽

Eric C. Polley ◽

Steven N. Hart ◽

Hongyan Huang ◽

Chunling Hu ◽

...

Keyword(s):

Breast Cancer ◽

General Population ◽

Association Studies ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

First Degree Relatives ◽

Pathogenic Variants ◽

Predisposition Genes ◽

Brca1 Brca2

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

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