Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing

Melissa C Southey ,Maryam Mahmoodi ,Robert Sebra ,Catherine Speechly ,Katherine Tucker ,James G Dowty ,G B D Scott ,Eric E Schadt ,Paul James ,Judy Kirk ,John J Mcneil ,Bernard J Pope ,Paul Lacaze ,Amanda Willis ,Roger L Milne ,John L Hopper ,Nicola Poplawski ,Derrick Theys ,Nicholas Pachter ,Graham G Giles ,Ingrid Winship ,Helen Tsimiklis ,Amanda Rewse ,Daniel J Park ,Fleur Hammet ,Moeen Riaz ,April Morrow ,Khalid Mahmood ,Rebecca Harris ,Anne-Laure Renault ,Jason A Steen ,Tú Nguyen-Dumont

doi:10.1038/s41523-021-00360-3

Abstract

Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1–16.2] for BRCA1, 4.0 [1.9–9.1] for BRCA2, 3.4 [1.4–8.4] for ATM and 4.3 [1.0–17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.

Highlights

Data from breast cancer predisposition gene panel testing are accumulating rapidly as it becomes more affordable and more accessible in different settings, including clinical care
The value of population-based case-control studies and gene panel testing have recently been illustrated by Hu et al.[9] who reported the outcome of a US-based study (CARRIERS consortium), involving over 32,000 affected and 32,000 unaffected women and Dorling et al.[10] who reported the outcome of an international study (BRIDGES) involving 60,000 women affected and over 53,000 women unaffected by breast cancer
Regarding the six potential confounders that we used as adjustment variables in our main analyses, the Australian Breast Cancer Family Study (ABCFS) cases and controls were very similar to each other, and both were similar to the ASPirin in Reducing Events in the Elderly (ASPREE) controls except that the ASPREE controls were older, as expected due to study design differences

Summary

Introduction

Data from breast cancer predisposition gene panel testing are accumulating rapidly as it becomes more affordable and more accessible in different settings, including clinical care. The value of population-based case-control studies and gene panel testing have recently been illustrated by Hu et al.[9] who reported the outcome of a US-based study (CARRIERS consortium), involving over 32,000 affected and 32,000 unaffected women and Dorling et al.[10] who reported the outcome of an international study (BRIDGES) involving 60,000 women affected and over 53,000 women unaffected by breast cancer. These studies provided improved estimates of the prevalence and the magnitude of breast cancer risk associated with pathogenic variants in known breast cancer predisposition genes to guide genetic counselling

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