Association of T-Cell Receptor Repertoire Use With Response to Combined Trastuzumab-Lapatinib Treatment of HER2-Positive Breast Cancer: Secondary Analysis of the NeoALTTO Randomized Clinical Trial

Abstract

Importance: Dual anti-HER2 blockade increased the rate of pathologic complete response (pCR) in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) trial, and high immune gene expression was associated with pCR in all treatment arms. So far, no marker has been identified that is specifically associated with the benefit from dual HER2 blockade.

Objective: To examine if use of the T-cell β chain variable genes adds to the potential association of immune gene signatures with response to dual HER2 blockade.

Design, setting, and participants: In the NeoALTTO trial, HER2-positive patients recruited between January 5, 2008, and May 27, 2010, were treated with paclitaxel plus either lapatinib or trastuzumab or both as neoadjuvant therapy. In this study, RNA sequencing data from baseline tumor specimens of 245 patients in the NeoALTTO trial were analyzed and reads were aligned to TRBV gene reference sequences using a previously published Basic Local Alignment Search Tool T-cell receptor mapping pipeline. Total TRBV gene use, Shannon entropy, and gene richness were calculated for each tumor, and nonnegative matrix factorization was used to define TRBV co-use metagenes (TMGs). The association between TRBV metrics, tumor genomic metrics, and response was assessed with multivariable logistic regression. Statistical analysis was performed from January 23 to December 2, 2017.

Main outcomes and measures: The association between TRBV use metrics and pCR.

Results: Among the 245 women with available data (mean [SD] age, 49 [11] years), total TRBV use correlated positively with a gene expression signature for immune activity (Spearman ρ = 0.93; P < .001). High use of TRBV11-3 and TMG2, characterized by high use of TRBV4.3, TRBV6.3, and TRBV7.2, was associated with a higher rate of pCR to dual HER2-targeted therapy (TRBV11-3 interaction: odds ratio, 2.63 [95% CI, 1.22-6.47]; P = .02; TMG2 interaction: odds ratio, 3.39 [95% CI, 1.57-8.27]; P = .004). Immune-rich cancers with high TMG2 levels (n = 92) had significantly better response to dual HER2-targeted treatment compared with the single therapy arms (rate of pCR, 68% [95% CI, 52%-83%] vs 21% [95% CI, 10%-31%]; P < .001), whereas those with low TMG2 levels did not benefit from dual therapy. High TMG2 levels were also associated with a higher rate of pCR to the combined therapy in immune-poor tumors (n = 30; pCR, 50% [95% CI, 22%-78%] vs 6% [95% CI, 0%-16%]; P = .009).

Conclusions and relevance: Use patterns of TRBV genes potentially provide information about the association with response to dual HER2 blockade beyond immune gene signatures. High use of TRBV11.3 or TRBV4.3, TRBV6.3, and TRBV7.2 identifies patients who have a better response to dual HER2 targeted therapy.

Trial registration: ClinicalTrials.gov Identifier: NCT00553358.

Conflict of interest statement

Conflict of Interest Disclosures: Dr de Azambuja reported receiving travel grants from GlaxoSmithKline and Roche and honoraria from Roche, outside this work. Dr Sarp reported being an employee of Novartis. Dr Baselga reported receiving personal fees from Roche. Dr Piccart-Gebhart reported receiving personal fees from Roche. Drs Sotiriou and Piccart-Gebhart reported being co-inventors of the Genomic Grade Index. No other disclosures were reported.

Figures

Figure 1.. T-Cell Receptor (TCR) Structure and T-Cell β Chain Variable (TRBV) Gene Use

A, Structure of the TCR. The TCR recognizes peptide antigens presented by the major histocompatibility complex (MHC) class 1. The TCR is a heterodimer of 2 subunits, TCRα and TCRβ, with each subunit consisting of a constant region that functions to anchor the receptor to the cell membrane and a hypervariable region that functions in antigen recognition. In this study, the hypervariable regions of the TCRβ subunit were characterized. B, Heatmap of TRBV gene use. Heatmap of log counts per million (CPM) of 245 patients across 65 TRBV genes. Significantly stable clusters (top row) are identified through bootstrap resampling of hierarchical clustering. Pathologic complete response (pCR; middle row) indicates patients who had a pCR in light blue and those with residual disease (RD) in dark blue. Estrogen receptor (ER) status (bottom row) indicates patients who are ER positive in dark red and patients who are ER negative in light red.

Figure 2.. Rates of Pathologic Complete Response (pCR) Compared Between Treatments Dichotomized (Median Split) by Immune Enrichment Signature and TRBV Metagene 2 (TMG2) Level

Significant differences between groups determined by use of the Fisher exact test. Error bars indicate 95% CI.