PROJECT SUMMARY Germline pathogenic variants (PV) in the BRCA1, BRCA2 and PALB2 cancer predisposition genes are associated with high risks of breast cancer (lifetime risks to age 80 of >50%), whereas PVs in ATM and CHEK2 are associated with moderate lifetime risks of 20-25%. Of these, PVs in ATM, BRCA2, CHEK2 and PALB2 are predominantly associated with estrogen receptor positive (ER+) breast cancer. While much is known about ER+ breast cancer overall, little is known about the contribution of PVs in these predisposition genes to ER+ breast cancer risks and to the influence of these PVs on prognosis. Here we aim to address some of the important clinical questions that remain unanswered for these ER+ breast cancer predisposition genes. In Aim #1 we propose to assess age-related risks of cancers associated with ER+ breast cancer predisposition gene PVs. Specifically, while overall risks of breast cancer are well established, age-related risks of breast cancer in 5-10 year categories and risks of contralateral breast cancer are not known for the ATM, CHEK2 and PALB2 genes. In the absence of this information the overall risks of cancer associated with PVs are of limited clinical value. We will use information from very large population-based including targeted studies of African Americans and West Africans and from high-risk breast cancer studies to estimate these cancer risks. In Aim #2 we propose to establish the influence of PVs in ER- positive breast cancer predisposition genes on prognosis. It is not currently known whether breast cancers driven by ER+ predisposition genes, other than BRCA2, display specific responses to standard therapy (such as chemotherapy, endocrine therapy or HER2 directed therapy). We propose to screen germline DNA from participants in large breast cancer adjuvant clinical trials for PVs in the ER+ breast cancer predisposition genes and to assess the influence of PVs on disease free survival and overall survival in response to adjuvant therapy. In addition, we will determine whether the PVs are correlated with the Oncotype Dx Breast Recurrence Score, which is an effective prognostic and predictive biomarker for ER+ breast cancer patients. In Aim #3 we propose to determine the clinical relevance of Variants of Uncertain Significance (VUS) in ER-positive breast cancer predisposition genes. Individuals carrying germline VUS, which are predominantly missense variants, cannot benefit from enhanced risk assessment and cancer screening or make informed decisions about surgical prevention or screening. We will conduct individual and high-throughput functional assay studies and apply rules- based FDA-approved ClinGen methods for determination of the clinical relevance of many VUS in these genes.
|Effective start/end date||9/21/22 → 8/31/23|
- National Cancer Institute: $385,456.00
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