Ahmet Kürşad Dişli

Background and Objectives: Neoadjuvant dual HER2 blockade combined with chemotherapy is the standard treatment approach for patients with high-risk early-stage or locally advanced HER2-positive breast cancer. However, the optimal chemotherapy backbone and the predictive value of systemic inflammatory biomarkers remain subjects of ongoing investigation. This study aimed to compare pathologic complete response (pCR) rates between neoadjuvant dose-dense doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab and pertuzumab (ddAC+THP) and docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP), and to evaluate the predictive performance of pretreatment inflammatory biomarkers. Materials and Methods: In this multicenter retrospective study, patients with HER2-positive breast cancer treated with neoadjuvant ddAC+THP or TCHP between 2019 and 2025 at three tertiary centers were evaluated. Pretreatment inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and hemoglobin, albumin, lymphocyte, and platelet (HALP) score, were calculated from baseline laboratory parameters. Receiver operating characteristic analyses were performed to determine optimal cutoff values, and logistic regression analyses were used to identify predictors of pCR. Results: A total of 197 patients were included, of whom 138 received ddAC+THP and 59 received TCHP. Overall, 125 patients (63.5%) achieved pCR. The pCR rate was numerically higher in the ddAC+THP group than in the TCHP group (65.2% vs. 59.3%), although the difference was not statistically significant (p = 0.431). Among the evaluated biomarkers, SIRI demonstrated the highest discriminatory performance for predicting pCR (AUC: 0.725, 95% CI: 0.652–0.797), followed by NLR (AUC: 0.673, 95% CI: 0.595–0.750). In multivariable analysis, hormone receptor positivity (OR: 0.291, 95% CI: 0.131–0.645; p = 0.002) and elevated SIRI (>0.845) (OR: 0.088, 95% CI: 0.036–0.216; p < 0.001) were independently associated with lower odds of achieving pCR. No significant difference in pCR was observed between treatment regimens across predefined subgroup analyses. Conclusions: Neoadjuvant ddAC+THP and TCHP achieved comparable pCR outcomes in patients with HER2-positive breast cancer. SIRI was independently associated with a lower likelihood of achieving pCR and showed acceptable discriminatory performance. These findings suggest that SIRI may represent an exploratory, readily available inflammatory biomarker for pCR risk stratification; however, prospective validation is required before clinical application.

Germline BRCA1/2-mutated (gBRCAm) hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) is a biologically distinct subset in which the efficacy of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors remains incompletely characterized. We evaluated real-world outcomes and prognostic factors in a multicenter retrospective Turkish cohort treated with a CDK4/6 inhibitor plus endocrine therapy (June 2020–September 2025). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier and Cox methods. Among 121 patients, 30 (24.8%) had BRCA1, 88 (72.7%) had BRCA2, and three (2.5%) had dual mutations; 66.9% received first-line therapy, with ribociclib in 69.4% and palbociclib in 29.8%. Objective response rate was 69.4% and the clinical benefit rate was 82.6%. Median PFS was 17.0 months and OS 47.0 months. PFS was numerically longer in BRCA1 than in BRCA2 carriers (25.0 vs. 14.0 months), although the difference was not statistically significant in the pairwise comparison (HR 1.50, 95% CI 0.88–2.56; log-rank p = 0.135); the dual BRCA1/2 subgroup (n = 3) had the poorest outcomes and was assessed descriptively. OS did not differ significantly between BRCA1 and BRCA2 carriers (57.0 vs. 49.0 months; log-rank p = 0.520). PFS did not differ between ribociclib and palbociclib (p = 0.192); OS favored ribociclib at borderline significance (p = 0.050), but this was not confirmed in Cox regression. In multivariable analysis, ECOG ≥ 1 (HR 1.85; p = 0.010) and fulvestrant-based therapy (HR 1.74; p = 0.041) predicted shorter PFS; fulvestrant also predicted worse OS (HR 2.39; p = 0.008). CDK4/6 inhibitor-based therapy shows meaningful activity in gBRCAm HR+/HER2- MBC; the numerically poorer outcomes observed in BRCA2 carriers are hypothesis-generating and warrant validation in larger cohorts.