Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline CHEK2or ATMPV have not previously been described. This is of particular relevance as CHEK2 BC have been associated with a worse prognosis. Methods: Prospective Registry of MultiPlex Testing (PROMPT) is an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. We retrospectively evaluated Oncotype DX recurrence scores from PROMPT participants (pts) with PV or likely PV in CHEK2 or ATM. Mood’s median tests were used to compare median RS, and Yates corrected Chi-square tests were used to compare RS distributions between carriers and a genetically unselected reference population. Results: Oncotype DX reports were reviewed for 75 pts with 77 BC (n = 50 pts with CHEK2 PV with 51 BC; n = 24 with ATM PV; n = 1 with CHEK2 and ATM PV with 2 BC). Among CHEK2 carriers, median RS was 17 (range 2-43) overall, 17 (2-36) for pts < age 50, and 18.5 (8-43) for pts ≥age 50 (p-value 0.47), with distributions not significantly different than reference ( < 50, p = 0.70; ≥50, p = 0.93). Ten pts had low penetrance CHEK2 alleles (p.S428F or p.I157T) with median RS 16 (9-28) compared to 18 (2-43) in those with other CHEK2 alleles (p = 0.35). Among ATM carriers, median RS was 17 (1-35) overall, 17 (1-35) for pts < age 50, and 16 (11-32) for pts ≥age 50 (p = 0.51), with distributions also not significantly different ( < 50, p = 0.78; ≥50, p = 0.79). Conclusions: Unlike data seen in BC associated with BRCA1 and BRCA2, Oncotype DX RS in individuals with CHEK2 and ATM-associated BC are similar to the published genetically unselected commercial database median RS of 16, with no clear difference based on penetrance of CHEK2 allele. Proportions of patients < 50 and ≥50 with CHEK2 and ATM PV with RS within the range for chemoendocrine therapy consideration are also similar to the historical reference. The inferior prognosis that has been suggested in CHEK2 BC is not reflected in Oncotype DX RS.

*Jakubowski et al., J Surg Oncol 2020. PMID 3249731.