We recently published a study which included information from over 200 BRCA1, BRCA2, PALB2, CHEK2 and ATM carriers in ICARE who had breast cancer (mostly early-stage) combined with data from over 200 carriers (predominantly with metastatic breast cancer) who had clinical tumor testing. We pursued this research because we believe that distinct genomic changes in tumors from these carriers can uncover distinct pathways by which these tumors develop. This in turn can give us information about best treatments, and may also refine prognostic and predictive markers, as well as inform treatment targets. Of note, women with early-stage breast cancer are not generally offered sequencing of their tumors, as it is not clinically indicated. This means that current information about tumor sequencing is from mostly tumors of women with metastatic breast cancer. Consequently, recruitment through ICARE was instrumental in being able to include early-stage cases, which is essential to see what changes occur at early versus later stages in these tumors. This information is important in figuring out how tumors develop and how best to treat them.
For ICARE participants, we collected their breast tumor specimens and conducted both DNA and RNA sequencing studies through Tempus labs. Our findings showed that even in BRCA1 carriers with HR+/HER2- disease, almost half still had basal subtypes (which may not respond to hormone receptor blockers). Other interesting findings included that TP53 somatic mutations are enriched in BRCA1 carriers, regardless of subtype, yet not observed in BRCA2 carriers. This suggests that despite playing similar roles in DNA repair, the evolution of BRCA1 versus BRCA2-associated breast tumors are distinct. PIK3CA mutations are increased in ATM and CHEK2 carriers across locoregional and metastatic HR+ cases.
Finally, ESR1 mutations are increased in ATM carriers, but only in metastatic cases. These findings suggest that GPVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2 are associated with distinct intrinsic breast cancer subtypes and somatic genomic alterations, which could enhance precision in risk stratification and eventually be used to guide treatment.
Yadav, et al. J Natl Cancer Inst. 2026:djag070. PMID: 41832987.
Article available at: https://pubmed.ncbi.nlm.nih.gov/41832987/
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