Abstract ES3-2: Clinical management of moderate penetrance genes

Abstract

Abstract Genetic epidemiologic studies have found that germline pathogenic mutations in the following 12 genes confer a substantial (two-fold or higher) increase in breast cancer risk: ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53. Mutations in several of these genes, including the notable examples of ATM, CHEK2 and PALB2, are classified as “moderate penetrance”: conferring a relative risk of breast cancer that is between two-times and five-times higher than that of the average woman. Next-generation sequencing technology and lower costs have enabled the widespread use of multiplex germline testing panels that contain both high and moderate penetrance genes. Recent studies have reported a relatively high prevalence of ATM, CHEK2 and PALB2 mutations among unselected breast cancer patients (approximately 0.5-1% per gene), including among women diagnosed at older ages. ATM and CHEK2 mutations are associated with elevated risks of hormone receptor-positive breast cancer, while PALB2 mutations are more associated with triple-negative disease. Important recent developments in the clinical management of patients with moderate penetrance gene mutations include model-based estimates of optimal breast screening protocols; evidence suggesting the safety of adjuvant radiotherapy; emerging data on susceptibility to targeted therapy with poly(ADP-ribose) polymerase inhibitors; and characterization of the risks of developing other, non-breast cancers. Ongoing studies and future research priorities will be discussed. Citation Format: AW Kurian. Clinical management of moderate penetrance 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 ES3-2.