Immune Signatures Following Single Dose Trastuzumab Predict Pathologic Response to PreoperativeTrastuzumab and Chemotherapy in HER2-Positive Early Breast Cancer

Abstract

Purpose Recent data suggest that intrinsic subtype and immune cell infiltration may predict response to trastuzumab-based therapy. We studied the interaction between these factors, changes in immune signatures following brief exposure to trastuzumab, and achievement of pathologic complete response (pCR) to subsequent preoperative trastuzumab and chemotherapy in HER2-positive breast cancer. Experimental Design In patients enrolled on two multicenter trials (03-311 and 211B), tumor core biopsies were obtained at baseline and after brief exposure to single-agent trastuzumab or nab-paclitaxel. Gene expression profiles were assessed to assign PAM50 subtypes, measure immune cell activation, and were correlated with response. Results The pCR rate was significantly higher in HER2-enriched tumors in the Discovery, 03-311 (36%, P = 0.043) dataset, as compared with other subtypes, which validated in 211B (50%, P = 0.048). Significant increases in a signature of immune cell admixture (Immune Index) were observed only following brief exposure to trastuzumab in HER2-enriched tumors (Discovery/03-311, P = 0.05; Validation/211B, P = 0.02). Increased Immune Index was predictive of response after brief exposure (03-311, P = 0.03; 211B, P = 0.04), but not at baseline, in addition to increased expression of a CD4+ follicular helper T-cell signature (03-311, P = 0.05; 211B, P = 0.04). Brief exposure to trastuzumab significantly increased gene expression of the T-cell marker PD-1 in HER2-enriched tumors (Discovery/03-311, P = 0.045) and PD-1 positivity by IHC (Validation/211B, P = 0.035). Conclusions Correlations between pCR rates, increases in Immune Index and markers of T-cell activity following brief exposure to trastuzumab in HER2-enriched tumors provide novel insights into the interaction between tumor biology, antitumor immunity, and response to treatment, and suggest potential clinically useful biomarkers in HER2+ breast cancers.

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

“…44 ERS score was calculated as described. 11 CCL2 expression was analyzed in silico in the GSE70360 public dataset 14 with processed data retrieved from the GEO repository.…”

A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229)

“…Higher TILs were prognostic for longer overall survival but no differential benefit with the addition of pertuzumab to docetaxel chemotherapy and trastuzumab in the first‐line CLEOPATRA trial for patients with HER2‐positive advanced disease . Increased expression of immune activation gene‐expression signatures has also been shown to be predictive of benefit from trastuzumab in the adjuvant setting .…”

Therapeutic strategies to reverse immunosuppressive breast cancer microenvironment

“…Ongoing investigations continue to evaluate components of immune infiltrates as predictors for trastuzumab efficacy in HER2+BC. A recent study reported that the HER2 enriched subtype showed a significant increase in immune index after treatment with trastuzumab but not after treatment with chemotherapy [27]. An increase of immune index after trastuzumab exposure but not at baseline was associated with higher complete pathological response rate.…”

“…TAMs in a M2 macrophage state have a poor antigen presenting capability and suppress the immune response of T cells. It has been shown that CSF-1 can polarize macrophages from an antigen-presenting M1 phenotype towards an immunosuppressive M2 state [27]. The potential of repolarization TAMs towards tumor cell killing phenotype by CSF-1 receptor (CSF-1R) targeting is an attractive strategy.…”