Genomic profiling of young-onset g BRCA1/2 breast cancer reveals distinct genomic landscapes and therapeutic implications for PARP and CDK4/6 inhibitor selection

  1. Mwangala P. Akamandisa
  2. Mingyi Xia
  3. Wilson Cheah
  4. Bradley Wubbenhorst
  5. Kurt D’Andrea
  6. Mengyao Fan
  7. Jake Shilan
  8. Dana Pueschl
  9. Anupma Nayak
  10. Hayley McKenzie
  11. William Tapper
  12. Ellen R. Copson
  13. Ramsey I. Cutress
  14. Susan M. Domchek
  15. Diana M. Eccles
  16. Katherine L. Nathanson
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Abstract

Purpose

g BRCA1/2 pathogenic variant (PV) carriers have elevated young-onset breast cancer risk. Understanding the distinct genomic landscapes of g BRCA1- and g BRCA2 -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): g BRCA1 86(63.2%), g BRCA2 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.

Results

Both g BRCA1 (93%) and g BRCA2 (96%) breast cancers had high rates of asLOH. We found significant differences between g BRCA1 and g BRCA2 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 g BRCA2 tumors, g BRCA1 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 g BRCA1/2 carriers compared to noncarriers from the TCGA, we found significant enrichment of RB1 (OR:6.3, 95%CI:2.8-15.4, p adj =0.001), TP53 (OR:4.6, 95%CI:1.9-12.1, p adj =0.017), FAT1 (OR:3.9, 95%CI:1.84-8.7, p adj =0.013), and MYC (OR:4.0, 95%CI:1.8-9.1, p adj =0.017) SNV/indels/CNVs, which are associated with CDK4/6i resistance.

Conclusion

Our data suggest that PARPi may be preferable over CDK4/6i to treat ER-positive, HER2-negative breast cancer in young-onset g BRCA1/2 -associated breast cancer when both therapies are considered in adjuvant and metastatic settings. Additionally, we identified significant differences between g BRCA1- and g BRCA2 -associated tumors, which may inform therapeutic development.

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  1. Version published to 10.1101/2025.09.19.25336150 on medRxiv