Rare germline heterozygous pathogenic BLM variants and correlations with co-occurring pathogenic variants and severe treatment-related adverse events in breast cancer.

e12603 Background: The BLM gene encodes a RecQ family DNA helicase. Biallelic pathogenic mutations in BLM cause Bloom syndrome, and carriers are at an increased risk of various malignancies, including breast and colorectal cancer. However, data on the clinical features and prognosis of breast cancer patients harboring germline pathogenic BLM variants remain limited. Methods: From 13,269 breast disease patients who underwent germline genetic testing, we identified 12 cases with germline pathogenic BLM variants (BLM group) and selected 24 matched controls without such variants. We collected data on clinicopathologic features, co-occurring pathogenic variants, grade ≥3 adverse events (AEs, per CTCAE v5.0), and overall survival (OS). Statistical analyses were performed using Fisher's exact test and log-rank test. Results: In the BLM group, 30.0% (3/10) of patients carried concurrent pathogenic variants (BRCA1, BRCA2, or MLH3), a finding not observed in the control group (0/24), with a statistically significant difference (P = 0.020). Furthermore, the incidence of grade ≥3 treatment-related AEs was higher in the BLM group (70.0%, 7/10) compared to the control group (29.2%, 7/24), approaching statistical significance (P = 0.054). No statistically significant difference in median OS was observed between the two groups (log-rank P = 0.134). Conclusions: Despite the absence of biallelic BLM variants in this cohort, germline heterozygous pathogenic BLM variants are associated with a higher burden of co-occurring pathogenic variants and a clinically relevant trend toward elevated grade ≥3 treatment-related AEs, supporting the need for tailored clinical monitoring in this patient subset. Larger prospective studies are warranted to validate these findings and establish optimal clinical monitoring strategies for breast cancer patients with germline pathogenic BLM variants.