Introduction
tumor, breast cancer
TUMOR, CYTOTOXICITY, HER2-POSITIVE BREAST CANCER, BREAST CANCER
Neoadjuvant treatment escalation approaches with dual anti-human epidermal growth factor receptor 2 (HER2) blockade have been proven effective in early-stage HER2-positive breast cancer, leading to an increase in pathological complete response (pCR) ratesHER2-positive breast cancer is considered an immunogenic tumor, and the host immune response in this breast cancer subtype has been extensively explored due to its known role in modulating the activity of anti-HER2 agents [e.g., through antibody-dependent cellular cytotoxicity (ADCC)]Of note, increased diversity and clonal expansion of B cell receptor (BCR) and TCR repertoires, which can be described with different metrics (Supplementary Fig. Moreover, the achievement of pCR after neoadjuvant treatments is a robust prognostic indicatorIn this retrospective study, we further dissect the heterogeneity of HER2-positive breast cancer by evaluating the characteristics of the BCR and TCR repertoires in the context of two phase III clinical trials, namely NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. Moreover, we explore the impact of BCR and TCR repertoires and diversity measures on treatment response and long-term clinical outcomes. We present a prognostic model integrating baseline immunological and clinical features, as well as treatment response, aimed at identifying distinct prognostic groups in HER2-positive breast cancer patients treated with neoadjuvant therapies. The prognostic stratification of patients and the biological characterization of determinants of prognosis can open the avenue for the implementation of optimized neoadjuvant/post-operative treatment strategies.