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

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.

TRIAL REGISTRATION:

Trial registration number: NCT02307227, registered on ClinicalTrials.gov (http://www.clinicaltrials.gov, November 26, 2014).

• Authors: 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
• Journal: BMC cancer (BMC Cancer) Vol. 14 Pg. 954 (Dec 15 2014) ISSN: 1471-2407 [Electronic] England
• PMID: 25512030 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Cytokines
• FCGR3A protein, human
• Receptors, IgG
• Receptor, ErbB-2
• Trastuzumab
• Paclitaxel

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antibody-Dependent Cell Cytotoxicity (immunology)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Breast Neoplasms (drug therapy, genetics, immunology, metabolism, mortality, pathology)
• Cytokines (blood)
• Female
• Humans
• Middle Aged
• Neoadjuvant Therapy
• Neoplasm Staging
• Paclitaxel (administration & dosage)
• Polymorphism, Genetic
• Receptor, ErbB-2 (metabolism)
• Receptors, IgG (genetics)
• Trastuzumab
• Treatment Outcome
• Young Adult