Comparison of the response to neoadjuvant therapy between immunohistochemistry HER2 (3+) and HER2 (2+)/ISH-positive early- stage breast cancer: A retrospective multicenter cohort study

Abstract Background According to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria, both immunohistochemical HER2(3+) and HER2(2+)/in situ hybridization (ISH) amplified [HER2(2+)/ISH+] breast cancer(BC)s fall under the HER2-positive BC category.However,there is a lack of studies exploring the difference of neoadjuvant therapeutic response between patients with HER2(3+) and HER2(2+)/ISH+ early BC.We aimed to evaluate the neoadjuvant therapeutic response, long-term outcome, and intrinsic subtype heterogeneity between HER2(3+) and HER2(2+)/ISH+ BC. Methods We examined two distinct cohorts. Cohort one (C1) encompassed 2648 patients with HER2-positive early BC diagnoses, and they received neoadjuvant therapy(NT) and surgery between January 1, 2009 and December 31, 2022, from the Shanghai Jiao Tong University Breast Cancer Data Base (SJTU-BCDB). Cohort 2 (C2) comprised 135 patients with early-stage HER2-positive BC who underwent NT and surgery at Henan Cancer Hospital from January 1, 2021, to December 31, 2022. These patients had available genomic and transcriptomic data at their disposal. C1 and C2 were further categorized into 2 patient cohorts as follows: (1) patients with IHC HER2(3+) early BC [HER2(3+) group], (2) patients with HER2(2+)/ISH+ early BC [HER2(2+)/ISH+ group]. Among those excluded from analysis were patients 80 years of age. Clinicopathological parameters,long-term outcomes and intrinsic subtypes were analyzed. Results In the C1 population, 83.7% had HER2(3+) BC, while 16.3% had HER2(2+)/ISH+ BC. HER2(3+) patients had a significantly higher PCR rate (38.9%) than HER2(2+)/ISH+ patients (18.1%) (P<0.001) ,but the DFS was comparable after a median follow-up of 29 months(P=0.556). The addition of trastuzumab or trastuzumab plus pertuzumab to neoadjuvant chemotherapy (NAC) improved PCR rates and DFS in HER2(3+) BC but not in HER2(2+)/ISH+ BC. In the C2 population, 97.75% HER2(3+) and 52.17% HER2(2+)/ISH+ were HER2 enriched(HER2E) subtype (P<0.001). HER2E showed increased PCR rates compared to non-HER2E (P=0.004). Conclusions Compared to HER2(3+) BC, the limited effectiveness of neoadjuvant trastuzumab and pertuzumab therapy for HER2(2+)/ISH+ BC is due to subtype heterogeneity. Reassessment of targeted therapy efficacy in HER2 (2+)/ISH+ BC patients is essential.