Best of the Best Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2020

Population-based estimates of breast cancer risk for germline pathogenic variants identified by gene-panel testing: an Australian perspective (#72)

Tu Nguyen-Dumont 1 , James Dowty 2 , Kathy Tucker 3 , Judy Kirk 4 , Paul James 5 , Alison Trainer 5 , Ingrid Winship 6 , Nicholas Pachter 7 , Nicola Poplawski 8 , Scott Grist 9 , Daniel J Park 2 , Anne-Laure Renault 1 , Fleur Hammet 1 , Maryam Mahmoodi 1 , Helen Tsimiklis 1 , Jason A Steen 1 , Derrick Theys 1 , Amanda Rewse 1 , Amanda Willis 3 , April Morrow 3 , Catherine Speechly 3 , Rebecca Harris 4 , Moeen Riaz 1 , Robert Sebra 10 , Eric Schadt 10 , Paul Lacaze 1 , John McNeil 1 , John L Hopper 2 , Melissa C Southey 1
  1. Monash university, Clayton, VIC, Australia
  2. The University of Melbourne, Parkville, VIC, Australia
  3. Prince of Wales Hospital, Randwick, NSW, Australia
  4. Westmead Institute for Cancer Research, Sydney, NSW, Australia
  5. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  6. Royal Melbourne Hospital, Parkville, VIC, Australia
  7. King Edward Memorial Hospital, Perth, WA, Australia
  8. South Australian Clinical Genetics Services, Adelaide, SA, Australia
  9. SA Pathology - Flinders Medical Centre, Adelaide, SA, Australia
  10. Icahn School of Medicine at Mount Sinai, New York, NY, USA

BRA-STRAP is an Australia-wide study of breast cancer (BC) predisposition that brings together gene-panel data from 30,000 adult Australian women of all ages, across the BC risk spectrum, with and without a diagnosis of BC. We aimed to estimate risks for 24 genes* that are commonly included on panel tests for BC predisposition, despite insufficient evidence for clinical translation for most of these genes.

We present findings from the population-based case-control sub-study of BRA-STRAP, involving 1451 women diagnosed with BC and 857 age-matched controls participating in the Australian Breast Cancer Family Registry (ABCFR), and 6101 healthy, elderly Australian women enrolled in the ASPREE study. These analyses focused on rare genetic variants predicted to lead to loss-of-function and/or classified as pathogenic/likely pathogenic (P/LP) in ClinVar. Odds ratios (ORs) for their associations with BC were estimated by aggregating genetic variants for each gene.

We combined both control datasets and, after adjusting for potential confounders, the ORs associated with P/LP variants in BRCA1 and BRCA2 were 5.4 [95% confidence interval (CI): 2.1-17.3; p<0.001] and 4.0 [95% CI: 1.8-10.1; p=0.0035], respectively. We also found statistically significant associations for ATM and PALB2, with ORs of 3.8 [95% CI: 1.5-9.7; p=0.006] and 6.1 [95% CI: 1.4-28.6; p=0.013], respectively.

These results contribute to international efforts to refine the BC risk estimates for genetic variants identified from population-based screening of unselected women using genes that are included on panel tests and thought to be potentially BC predisposition genes. The case-control-family design of the ABCFR will also allow us to estimate the age specific cumulative risk (penetrance) of these genetic variants, which is important for genetic counselling and the clinical management of carrier families.