Pathological Response to Herceptin-containing Neoadjuvant Therapy in HER2 IHC2+/ISH+ and IHC3+ Early-Stage Invasive Ductal Carcinoma

ABSTRACTBackground:HER2-positive breast cancers exhibit heterogeneous responses to neoadjuvant therapy. This study compared pathologic response between IHC 3+ and IHC 2+/ISH+ invasive ductal carcinomas (IDCs) treated with trastuzumab (T) and pertuzumab (P)-containing chemotherapy.Methods:We identified 207 patients with HER2-positive early-stage IDC who received neoadjuvant T/P-based chemotherapy followed by surgery between 2017 and 2024. Patients were categorized as IHC 3+ (n = 168) or IHC 2+/ISH+ (n = 39). Clinicopathologic parameters from pretreatment biopsies and post-treatment excisions were reviewed. Pathologic complete response (pCR) was defined as the absence of residual invasive carcinoma in breast and lymph nodes. Residual cancer burden (RCB) score and recurrence-free survival (RFS) at 36 months were analyzed.Results:The pCR rate was 66% (111/168) in IHC 3+ and 28% (11/39) in IHC 2+/ISH+ tumors (p < 0.001). IHC 3+ tumors more frequently exhibited an ER-/PR- profile (55%, 92/168) compared with IHC 2+/ISH+ tumors (18%, 7/39) (p < 0.001). Among 51 cases with complete ISH data (IHC 3+, n = 12; IHC 2+, n = 39), RCB category inversely correlated with both HER2/CEP17 ratio and HER2 copy number. Within 36 months, local or distant recurrence occurred in 8.8% (3/34) of IHC 2+/ISH+ and 1.7% (2/118) of IHC 3+ cases (p = 0.07). Kaplan–Meier analysis showed significantly better RFS in IHC 3+ than in IHC 2+/ISH+ cancers (log-rank p = 0.04).Conclusions:Compared with IHC 3+ IDC, IHC 2+/ISH+ IDC demonstrated lower pCR rates and poorer RFS following neoadjuvant T/P-containing therapy. Pathologic response correlated inversely with HER2/CEP17 ratio and HER2 copy number. Reassessment of HER2 expression with more sensitive quantitative methods, particularly in IHC 2+/ISH+ tumors, may improve therapeutic stratification.