De-escalation of neoadjuvant chemotherapy for HER2-positive breast cancer: A systematic review and meta-analysis.

616 Background: The addition of carboplatin to taxane-based dual HER2 blockade (TCbHP) is a standard neoadjuvant regimen for high-risk, HER2-positive breast cancer. However, this combination incurs significant hematological toxicities. Whether omitting carboplatin (THP) preserves efficacy while enabling de-escalation of toxicity remains a critical unanswered question. Methods: A comprehensive search of PubMed, Embase, Cochrane CENTRAL, and major oncology conference abstracts was conducted through June 15, 2025, for studies comparing THP with TCbHP. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included grade ≥3 hematological toxicities. A non-inferiority margin for pCR was pre-specified at a risk ratio (RR) of 0.85. Data were pooled using a DerSimonian-Laird random-effects model. The study was registered on PROSPERO (CRD420251084035). Results: Seven studies (2 RCTs, 5 observational) comprising 2,061 patients (989 THP; 1,072 TCbHP) were included. The pooled pCR rate was 61.9% for THP versus 63.9% for TCbHP (RR 0.92, 95% CI 0.79–1.07). Statistical non-inferiority was not met, as the lower bound of the 95% CI crossed the pre-specified margin. The absolute pCR difference was a modest -2.0%. Although pCR showed substantial heterogeneity (I² = 69%), this was largely driven by study design differences (RCTs: RR 1.06 vs. observational: RR 0.80). In stark contrast, the THP regimen demonstrated a profound and remarkably consistent safety advantage, with an 82% reduction in grade ≥3 thrombocytopenia (RR 0.18, 95% CI 0.09–0.39), a 69% reduction in anemia (RR 0.31, 95% CI 0.17–0.57), and a 56% reduction in neutropenia (RR 0.44, 95% CI 0.33–0.58). Crucially, all three major hematological toxicity endpoints showed a complete absence of statistical heterogeneity (I² = 0% for all), indicating a robust and generalizable safety benefit. Conclusions: While the carboplatin-free THP regimen did not meet the strict criteria for statistical non-inferiority in pCR, the small absolute efficacy decrement is substantially offset by a large, clinically meaningful, and highly consistent reduction in severe hematological toxicities. These findings provide strong evidence to support THP as a reasonable and safer de-escalation strategy for selected patients with HER2-positive breast cancer, particularly those where toxicity is a major concern.