Genomic profiling of young-onset gBRCA1/2 breast cancer reveals distinct genomic landscapes and therapeutic implications for PARP and CDK4/6 inhibitor selection

Purpose gBRCA1/2 pathogenic variant (PV) carriers have elevated young-onset breast cancer risk. Understanding the distinct genomic landscapes of gBRCA1- and gBRCA2-associated breast cancer, including presence of PARP and CDK4/6 inhibitor (PARPi; CDK4/6i) response-associated alterations, may inform treatment selection for these patients. Patients and methods We evaluated 136 treatment-naïve primary tumors from POSH study participants diagnosed with breast cancer before age 50 years (92.6% diagnosed ≤40): gBRCA1 86(63.2%), gBRCA2 50(36.8%). We evaluated somatic mutational and copy number variations (CNV), allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution signatures (SBS) from whole exome sequencing.

Both gBRCA1 (93%) and gBRCA2 (96%) breast cancers had high rates of asLOH. We found significant differences between gBRCA1 and gBRCA2 tumors in average HRD scores (57.4±1.3 vs 43.7±1.5, p<0.0001) and SBS composition: SBS1 (aging-associated) 12.9 vs 7.3, p=0.013; SBS18 (reactive oxygen species [ROS]-associated) 1.4 vs 0, p=0.007; SBS3 (HRD-associated) 27.3 vs 42.6, p=0.002; and SBS26 (mismatch repair-associated) 5.9 vs 9.4, p=0.049. Compared to gBRCA2 tumors, gBRCA1 tumors with asLOH were significantly enriched for gains of chr6q, and alterations in Hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from POSH gBRCA1/2 carriers compared to noncarriers from the TCGA, we found significant enrichment of RB1 (OR:6.3, 95%CI:2.8-15.4, padj=0.001), TP53 (OR:4.6, 95%CI:1.9-12.1, padj=0.017), FAT1 (OR:3.9, 95%CI:1.84-8.7, padj=0.013), and MYC (OR:4.0, 95%CI:1.8-9.1, padj=0.017) SNV/indels/CNVs, which are associated with CDK4/6i resistance.

Our data suggest that PARPi may be preferable over CDK4/6i to treat ER-positive, HER2-negative breast cancer in young-onset gBRCA1/2-associated breast cancer when both therapies are considered in adjuvant and metastatic settings. Additionally, we identified significant differences between gBRCA1- and gBRCA2-associated tumors, which may inform therapeutic development. Competing Interest Statement ERC reports: Honorarium AstraZeneca, Eli-Lilly, Guardant, Menarini Stemline, Novartis, Pfizer, Roche; Advisory boards/consultation: AstraZeneca, Eli-Lilly, Nanostring, Pfizer, Roche; Conference fees/travel/accommodation: Roche, Novartis; Educational grant: Daiichi-Sankyo; ERC and RIC report research support from SECA. Funding Statement Supported by Breast Cancer Research Foundation (K.L.N., and S.M.D); the Basser Center for BRCA (K.L.N.; S.M.D.); Gray Foundation (KLN); Funding for the POSH study has been provided by the Wessex Cancer Trust, Cancer Research UK, Breast Cancer Now and Prevent Breast Cancer. The long-term follow-up of the POSH study is supported by an Institutional Grant from AstraZeneca (CI: ERC, Co-I: DE, REC& WT). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The South West Multi-center Research Ethics Committee gave ethical approval for this work (MREC 00/6/69) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors