Real-world insights: Neoadjuvant KEYNOTE-522 regimen in triple-negative breast cancer patients with germline BRCA mutations.

e12618 Background: Triple-negative breast cancer (TNBC) is the most immunogenic subtype and is highly prevalent among patients (pts) with germline BRCA1/2 mutations (gBRCAm). Regardless of mutation status, the current standard treatment for early-stage TNBC is chemotherapy combined with pembrolizumab, as per the KEYNOTE-522 protocol. Methods: Data were collected from pts diagnosed with early-stage TNBC treated according to the KEYNOTE-522 regimen at ten cancer centers from July 2020 to December 2024. Epidemiological data and treatment outcomes of pts with gBRCAm were compared to those with BRCA wild-type/unknown (BRCAwt). Results: A total of 413 pts were analyzed, of whom 320 (82%) underwent germline testing; 49 (12.7%) had a gBRCAm, including 45 (91%) with BRCA1 and 4 (9%) with BRCA2 mutations. Pts with gBRCAm were younger (median 39 vs. 44 years, P<0.001) and more likely to be premenopausal (80.8% vs. 65.6%, P=0.045) and have grade 3 tumors (91% vs. 80%, P=0.214) than BRCAwt pts. Stage II disease was the most common in both groups (71.4% vs. 70%, P=0.315). Regarding treatment, gBRCAm pts were more frequently treated with dose-dense AC (doxorubicin and cyclophosphamide) (66% vs. 54%, P=0.160) and underwent mastectomy more often (93.9% vs. 35.9%, P=0.001). Only 2% of gBRCAm pts experienced disease progression during neoadjuvant therapy compared to 5% of BRCAwt pts (P=0.491).Pathological complete response (pCR; ypT0-Tis ypN0) rates were 73% in gBRCAm pts compared to 61% in BRCAwt pts (P=0.114). Residual cancer burden (RCB) 0-1 occurred in 83.7% vs. 76.6% (P=0.345). Subgroup analysis by disease stage revealed pCR rates of 74.3% in stage II gBRCAm pts versus 65.2% in BRCAwt pts (P=0.334), and 72.7% in stage III gBRCAm pts compared to 45.3% in BRCAwt pts (P=0.113).Grade 3 or higher adverse events (AEs) occurred in 50% of gBRCAm pts versus 34.9% of BRCAwt pts (P=0.055), with more frequent neutropenia (32.6% vs. 19.5%, P=0.041), diarrhea (6.1% vs. 1.6%, P=0.079), and immune-related AEs (12.2% vs. 7.4%, P=0.259). There were no significant differences in drug discontinuation rates due to toxicity (28% vs. 22%, P=0.327). Conclusions: Pts with gBRCAm exhibited high pCR rates with the KEYNOTE-522 regimen, achieving pCR rates over 70% even in stage III disease. Further research is needed to optimize treatment strategies in this population, including potential de-escalation approaches.