Introduction

Approximately 5-10% of breast cancers (BC) are inherited, primarily due to germline pathogenic/likely pathogenic variants (GPV) in high and moderate penetrance genes. We sought to compare intrinsic BC subtypes from females with GPVs in these genes and conduct subgroup analysis among hormone receptor positive (HR+, estrogen and/or progesterone positive); HER2 negative (HER2-) BC, comparing distribution of intrinsic subtypes compared to sporadic BC.

Methods

A retrospective cohort of female BC patients with GPV in BRCA1, BRCA2, PALB2, ATM or CHEK2 detected incidentally by tumor-normal matched Tempus xT assay or via a validated germline test, and tumor testing including whole transcriptome RNA expression analysis via the xR assay underwent PAM50 subtyping to determine intrinsic subtypes (i.e., Luminal A, Luminal B, Basal, HER2-enriched). Intrinsic subtype distribution was compared across inherited genes, and to sporadic cases. Subgroup analysis was conducted in the HR+/HER2- subgroup, comparing intrinsic subtype distribution for each gene to sporadic BCs.

Results

Among 97 BRCA1, 124 BRCA2, 68 PALB2, 52 ATM, 78 CHEK2, and 4599 sporadic BC patients, the median age was 47, 49, 53, 52, 57 and 57, respectively. Distribution of the 4 intrinsic subtypes showed that basal subtype encompassed a majority in BRCA1 carriers (74.4%) and was less common in ATM (6.7%) and CHEK2 (8.5%) carriers. In contrast, the Luminal A subtype encompassed a higher proportion in ATM (60.0%) and CHEK2 (75%) carriers, compared to PALB2 (52.5%), BRCA2 (48.6%) and BRCA1 (11.0%). Among the HR+ subgroup, basal and Luminal B subtypes were over-represented among 21 BRCA1 (43%; n=9 and 33%; n=7 respectively) compared to sporadic (11%; n=207 and 22%; n=398 respectively). Among HR+ Luminal A subtype, CHEK2 tumors (n=41) were over-represented (80%; n=33) while BRCA1 tumors were under-represented (24%; n=5), compared to sporadic tumors (60.4%; n=1093).

Conclusion

Our findings demonstrate significant differences in the distribution of intrinsic subtypes across inherited BC genes, with the basal subtype seen predominantly in BRCA1, and under-represented in both ATM and CHEK2. Among the HR+ subgroup, basal subtypes remained over-represented in BRCA1 carriers; and Luminal B subtype was also over-represented. Identification of non-Luminal A tumors based on intrinsic subtyping may be of both prognostic and predictive importance, with consideration of more aggressive treatment. Consequently, our findings highlight the importance of intrinsic tumor subtyping to identify aggressive tumors over-represented among females with inherited BC due to BRCA1, BRCA2, and PALB2 GPVs.

VIEW THE PUBLICATION

VIEW THE POSTER