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Prevalence of tumor genomic alternations in homologous recombination genes among Taiwanese breast cancers


 Purpose 
Deleterious BRCA1 / 2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. PARP (poly ADP ribose polymerase) inhibitors selectively cause failure of single-strand but does not affect double-strand DNA break repair, and ant-tumor activity is observed in BRCA mutant breast cancers. Recently genes implicated into the homologous recombination repair (HRR) pathways are investigated extensively, as defective HRR genes may indicate potential clinical benefits from PARP inhibitors beyond BRCA1 / 2 mutations.
 
Materials and Methods 
We evaluated the prevalence of BRCA1 / 2 mutations as well as alternations in HRR genes for Taiwanese breast cancers with targeted sequencing. Consecutive 648 breast cancer samples were assayed, and HRR genes by Heeke et al. and those interrogated in Talazoparib Beyond BRCA (TBB) trial were evaluated for prevalence from breast cancer tissues.
 
Results 
Among 648 breast cancer samples, there were 18 truncating and 2 missense mutations in BRCA1 and 48 truncating and 2 missense mutations in BRCA2 , impacting 3% and 5% of study population (collectively altered in 6%) with co-occurrence of BRCA1 / 2 in 7 breast cancers. On the other hand, HRR genes defined by Heeke et al. were altered in 122 (19%) breast cancers while TBB interrogated genes (excluding BRCA1 / 2 ) were mutated in 107 (17%) patients. Beyond BRCA1/2 , the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%) and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples were impacted by at least one HRR gene.
 
Conclusion 
The prevalence of high-penetrant BRCA1 / 2 mutations was far below one tenth of assayed samples while the prevalence of tumor DNA mutations in HRR pathways was much higher and approached one fifth among Taiwanese breast cancers. Further studies to evaluate the efficacy of PARP inhibitors in patients with defective HRR gene(s) are warranted to broaden the targeted population of synthetic lethality.