The Influence of Variants in ER-Positive Breast Cancer Predisposition Genes on Breast Cancer Risk and Response to Therapy

Germline pathogenic variants in the BRCA1, BRCA2 and PALB2 cancer predisposition genes are associated with high risks of breast cancer. Pathogenic variants in ATM and CHEK2 are associated with moderate lifetime risks.

Of these, pathogenic variants in ATM, BRCA2, CHEK2 and PALB2 are associated mainly with estrogen receptor (ER) positive breast cancer, also called ER positive (ER+) breast cancer. While much is known about ER positive breast cancer, little is known about the contribution of pathogenic variants in these predisposition genes to ER+ breast cancer risks and to the influence of these pathogenic variants on prognosis.

In this research project, we address some of the important clinical questions that remain unanswered for these ER+ breast cancer predisposition genes.

Overall risks of breast cancer are well established. But 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 pathogenic variants are of limited clinical value.

We're using information from large population-based studies, including targeted studies of African Americans and West Africans, to estimate these cancer risks.

It's not currently known if breast cancer driven by ER positive-predisposition genes, other than BRCA2, display specific responses to standard therapy, such as chemotherapy and endocrine therapy.

We're screening germline DNA from participants in large breast cancer adjuvant clinical trials for pathogenic variants in the ER positive breast cancer predisposition genes. We're also assessing the influence of pathogenic variants on disease-free survival and overall survival in response to adjuvant therapy. In addition, we're determining whether the pathogenic variants are correlated with the Oncotype Dx Breast Recurrence Score, which is a prognostic and predictive biomarker for ER+ breast cancer. People with germline variants of uncertain significance, which are mainly missense variants, can't benefit from enhanced risk assessment and cancer screening or make informed decisions about surgical prevention or screening.

We're conducting individual and high-throughput functional assay studies. We're also applying rules-based U.S. Food and Drug Administration-approved ClinGen methods to determine the clinical relevance of many variants of uncertain significance in these genes.

Project aims

This project has three aims:

  • Aim 1: Assess age-related risks of cancers associated with ER positive breast cancer predisposition gene pathogenic variants.
  • Aim 2: Establish the influence of pathogenic variants in ER positive breast cancer predisposition genes on prognosis.
  • Aim 3: Determine the clinical relevance of variants of uncertain significance in ER positive breast cancer predisposition genes.

Project co-leaders

  • Susan M. Domchek, M.D.
  • University of Pennsylvania
  • Co-Leader