Grant Number:	1R01CA289804-01A1 Interpret this number
Primary Investigator:	Bernstein, Jonine
Organization:	Sloan-Kettering Inst Can Research
Project Title:	The Genetic Epidemiology of Radiation-Associated Contralateral Breast Cancer
Fiscal Year:	2025

ABSTRACT The risk of contralateral breast cancer (CBC) after a first breast cancer diagnosis is well-documented and substantial. Radiation therapy (RT) is an important component of treatment for over half of all women with primary breast cancer yet it is a potent carcinogen and an established risk factor for future CBC. Despite major advances in defining the genetic basis of breast cancer susceptibility, and the identification of multiple risk genes with key roles in the DNA damage response (DDR), the influence of inherited genetics in modifying risk of CBC in the setting of RT, a potent carcinogen, remains poorly understood. This critical knowledge gap has hindered the ability of providers and patients to select tailored treatment plans guided by the rapidly expanding germline and tumor DNA sequencing data available in the clinic. In this proposal, we seek to identify the genetic determinants of radiation-associated breast cancer and develop detailed CBC risk estimation, with the long-term goal of enabling informed therapeutic decisions that balance benefits and risks to optimize outcomes. We leverage the extensive resources of the WECARE Study, a multi-site population-based case-control study of 1233 CBC cases and 1746 individually-matched controls with unilateral breast cancer (UBC) all of whom provided a biospecimen and were interviewed using the same questionnaire; for those who received radiation therapy (RT) individual absorbed radiation dose was estimated. Specifically, we will screen for variants in all WECARE Study CBC cases and UBC controls using whole exome sequencing (WES), apply functional screening in the presence or absence of radiation to classify variants, and utilize these data to develop a comprehensive integrated model of CBC risk. Our goals are to provide detailed CBC risk estimation and define the genetic basis of radiation-associated breast cancer. In AIM 1 we will identify variants that confer risk for radiation associated CBC. In AIM 2 we will develop, and validate, a comprehensive integrative model of genetic predisposition to radiation-associated CBC. Research focused on genetic predisposition to radiation-associated CBC has been sparse. The proposed study in our large well characterized study population offers a unique opportunity to clarify the underlying genetics of radiation sensitivity, identify genetic variants that act jointly with RT to increase risk of CBC, and inform clinical decision-making related to RT and other treatment options. The potential impact of this novel study should be considered in the context of the over 3 million breast cancer survivors in the US alone, the high lifelong risk of CBC they incur, and the indications that women with genetic predisposition may be more susceptible to radiation- associated CBC.





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