Early immune modulation by single-agent trastuzumab as a marker of trastuzumab benefit

Tiziana Triulzi,Loris De Cecco,Viola Regondi,Pier Luigi Lollini,Elda Tagliabue,Martina Di Modica,Daniele Generali,Maria Rosa Cappelletti,Biagio Paolini,Lucia Sfondrini,Serena Di Cosimo

doi:10.1038/s41416-018-0318-0

Abstract

BackgroundOptimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging. We analysed BC samples before and after treatment with 1 cycle of trastuzumab according to the response to trastuzumab.MethodsGene expression profiles of pre- and post-treatment tumour samples from 17 HER2-positive BC patients were analysed on the Illumina platform. Tumour-associated immune pathways and blood counts were analysed with regard to the response to trastuzumab. HER2-positive murine models with differential responses to trastuzumab were used to reproduce and better characterise these data.ResultsPatients who responded to single-agent trastuzumab had basal tumour biopsies that were enriched in immune pathways, particularly the MHC-II metagene. One cycle of trastuzumab modulated the expression levels of MHC-II genes, which increased in patients who had a complete response on treatment with trastuzumab and chemotherapy. Trastuzumab increased the MHC-II-positive cell population, primarily macrophages, only in the tumour microenvironment of responsive mice. In patients who benefited from complete trastuzumab therapy and in mice that harboured responsive tumours circulating neutrophil levels declined, but this cell subset rose in nonresponsive tumours.ConclusionsShort treatment with trastuzumab induces local and systemic immunomodulation that is associated with clinical outcomes.

Highlights

Optimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging
Molecular features associated with trastuzumab antitumour activity To identify the molecular features that are associated with trastuzumab activity in the clinical setting, we analysed tumour biopsies from patients with locally advanced primary HER2+ BC at diagnosis who underwent brief exposure to trastuzumab monotherapy.[10]
Circulating biomarkers reflect the immunomodulatory activity of trastuzumab Based on the ability of trastuzumab to recruit immune cells in the tumour microenvironment, in patients who respond to trastuzumab-based therapy, we examined whether such immune modulation occurred in the blood, analysing immune cell blood counts at baseline and at the time of Tru-cut biopsy

Summary

Introduction

Optimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging. One cycle of trastuzumab modulated the expression levels of MHC-II genes, which increased in patients who had a complete response on treatment with trastuzumab and chemotherapy. As more potential therapies appear over the horizon, advancements in biomarker discovery will be critical in optimising treatment selection and providing personalised therapy for patients. It remains unknown which patients benefit from single-agent trastuzumab and those who require instead the dual blockade upfront. Many efforts have been made toward identifying biomarkers that predict a benefit from trastuzumab: HER2 addiction and immune features have demonstrated the best predictive ability in several trials (reviewed in ref. 2), but HER2 expression in the primary tumour remains the only marker that is used in clinical practice

Methods

Results

Conclusion