Anthracycline-free neoadjuvant therapy induces pathological complete responses by exploiting immune proficiency in HER2 breast cancer patientsReport as inadecuate




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BMC Cancer

, 14:954

Clinical oncology

Abstract

BackgroundNeoadjuvant 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.

MethodsStage 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.

ResultsFrom 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.

ConclusionsIn 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 registrationTrial registration number: NCT02307227, registered on ClinicalTrials.gov http:-www.clinicaltrials.gov, November 26, 2014.

KeywordsBreast cancer Neoadjuvant chemotherapy HER2 Immune response Trastuzumab AbbreviationsADCCAntibody-Dependent Cell Cytotoxicity

BCBreast Cancer

BCTBreast Conservation Therapy

DFSDisease-Free Survival

EDEpirubicin Docetaxel

FBSFetal Bovine Serum

GM-CSFGranulocyte Macrophage Colony-Stimulating Factor

HER2Human Epidermal growth factor Receptor 2

IHCImmunohistochemistry

ILInterleukin

LVEFLeft Ventricular Ejection Fraction

MHCMajor Histocompatibility Complex

NCNeoadjuvant Chemotherapy

NKNatural Killer

ORRObjective Response Rate

OSOverall Survival

PBMCsPeripheral Blood Mononuclear Cells

pCRpathological Complete Response

PCRPolymerase Chain Reaction

RECISTResponse Evaluation Criteria In Solid Tumors

TGFTransforming Growth Factor

TNFTumor Necrosis Factor

TPTrastuzumab Paclitaxel

UNLUpper Normal Limit.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-954 contains supplementary material, which is available to authorized users.

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Author: Gianmaria Miolo - Elena Muraro - Debora Martorelli - Davide Lombardi - Simona Scalone - Simon Spazzapan - Samuele Massarut

Source: https://link.springer.com/







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