The presence of germline pathogenic variants (gPVs) in DNA repair-related genes is independently associated with worse survival outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors, according to a real-world study published in JCO Precision Oncology.
Researchers analyzed 217 patients with hormone receptor-positive, HER2-negative advanced breast cancer who were treated with CDK4/6 inhibitors in combination with endocrine therapy. Treatments included palbociclib, ribociclib, or abemaciclib as well as letrozole or fulvestrant.
The study population was stratified into 3 cohorts: patients harboring gPVs in DNA repair-related genes (gBRCA1/2–ATM–CHEK2 mutated), those without these mutations (wild-type), and those who were not tested for these mutations.
There were 15 patients with gPVs, including BRCA1 (4 patients), BRCA2 (6 patients), ATM (4 patients), and CHEK2 (1 patient). The remaining patients were wild-type (45 patients) or were not tested (157 patients).
The median follow-up was 41.7 months overall. The median progression-free survival (PFS) was shorter in patients with gPVs than in wild-type or non-tested patients — 10.2 months, 15.6 months, and 17.6 months, respectively (P =.002).
Similarly, the median overall survival (OS) was shorter in patients with gPVs than in wild-type patients — 31.4 months and 49.3 months, respectively (P =.006).
On multivariate analysis, mutation status was an independent predictor of PFS and OS. After adjusting for age, performance status, disease site, and prior therapy, wild-type patients had significantly better outcomes than gPV patients. The hazard ratio was 0.463 for PFS (95% CI, 0.241-0.887; P =.020) and 0.314 (95% CI, 0.127-0.777; P =.012) for OS.
“Our results support the necessity of addressing heterogeneity in patients with hormone receptor-positive aBC [advanced breast cancer], given the prevalence of germline homologous recombination-related mutations in this subgroup,” the researchers wrote. “Understanding of clinical outcomes in specific breast cancer populations is urgently needed for a better selection of the treatment strategies.”
Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Bruno L, Ostinelli A, Waisberg F, et al. Cyclin-dependent kinase 4/6 inhibitor outcomes in patients with advanced breast cancer carrying germline pathogenic variants in DNA repair-related genes. JCO Precis Oncol. Published online March 2, 2022. doi:10.1200/PO.21.00140