Anthracycline-free neoadjuvant therapy induces pathological complete responses by exploiting immune proficiency in HER2+ breast cancer patients

Gianmaria Miolo, Elena Muraro, Debora Martorelli, Davide Lombardi, Simona Scalone, Simon Spazzapan, Samuele Massarut, Tiziana Perin, Elda Viel, Elisa Comaro, Renato Talamini, Ettore Bidoli, Elisa Turchet, Diana Crivellari, Riccardo Dolcetti

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Abstract

Background: Neoadjuvant Chemotherapy (NC) including trastuzumab induces a high rate of pathological Complete Responses (pCR) in patients with locally advanced HER2-overexpressing Breast Cancer (BC), but is penalized by a severe cardiotoxicity when combined with anthracyclines. A phase II study was designed to assess whether an anthracycline-free NC regimen based on the early addition of trastuzumab to paclitaxel may increase the pCR rate without inducing severe cardiotoxicity in patients with locally advanced HER2-overexpressing BC. Immunomonitoring was performed to assess the contribution of patients' immunological background to the induction of clinical responses. Methods: Stage II-III HER2-positive BC patients received 24 weeks paclitaxel and trastuzumab NC, followed by 1 year adjuvant trastuzumab ± hormonal and/or radio-therapy. Assessment of pCR rate was the primary endpoint. A group of HER2-negative BC patients treated with neoadjuvant taxanes and anthracyclines was included. Serum levels of 10 cytokines and the efficiency of trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC) were monitored in vitro every 3 months. Results: From July 2006 to February 2013, we enrolled 109 patients including 46 evaluable HER2-positive cases. A pCR rate of 50% was reached and no severe cardiotoxicity occurred. Serum cytokine profiling revealed only an IL-10 decrease (P = 0.02) in patients achieving a partial response, while HER2-negative patients disclosed marked cytokines changes. Compared to the unfavourable F/F genotype, patients carrying the V allele in the FcγRIIIa-158 polymorphism showed a higher efficacy of trastuzumab-ADCC throughout treatment (P ≤0.05). Conclusions: In the absence of anthracyclines, trastuzumab and paclitaxel induced a high rate of pCR, exploiting the synergy between the immunomodulating properties of these drugs and the retained immunological proficiency of patients with HER2-overexpressing BC.

Original languageEnglish
Article number954
JournalBMC Cancer
Volume14
Issue number1
DOIs
Publication statusPublished - Dec 15 2014

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Keywords

  • Breast cancer
  • HER2
  • Immune response
  • Neoadjuvant chemotherapy
  • Trastuzumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

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