Powles RL, et al. - In this biomarker study of data from the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) trial, researchers investigated if the use of specific T-cell receptor β variable region (TRBV) genes adds to the potential association of immune gene signatures with response to dual HER2 blockade in HER2-positive breast cancer. According to findings, with regard to the association with response to dual HER2 blockade, use patterns of TRBV genes potentially provide information beyond immune gene signatures. Patients who have a better response to dual HER2 targeted therapy can be identified by high use of TRBV 11.3 or TRBV 4.3, TRBV 6.3, and TRBV 7.2.

Methods

• Paclitaxel plus either lapatinib or trastuzumab or both as neoadjuvant therapy were used to treat HER2-positive patients recruited between January 5, 2008 and May 27, 2010 in the NeoALTTO trial.
• Researchers, in the present study, analyzed RNA sequencing data from baseline tumor specimens of 245 patients in the NeoALTTO trial and used a previously published Basic Local Alignment Search Tool T-cell receptor mapping pipeline to align the reads to TRBV gene reference sequences.
• For each tumor, they calculated total TRBV gene use, Shannon entropy, and gene richness, and using nonnegative matrix factorization, they defined TRBV co-use metagenes (TMGs).
• Using multivariable logistic regression, they evaluated the link between TRBV metrics, tumor genomic metrics, and response.
• From January 23 to December 2, 2017, statistical analysis was carried out.
• Main outcomes included the link between TRBV use metrics and pCR.

Results

• This study included 245 women with available data (mean [SD] age, 49 [11] years).
• In these subjects, a positive correlation of total TRBV use with a gene expression signature for immune activity (Spearman ρ = 0.93; P < .001) was observed.
• Findings revealed that, high use of TRBV 11-3 and TMG2, characterized by high use of TRBV 4.3, TRBV6.3, and TRBV 7.2, was related to a higher rate of pCR to dual HER2-targeted therapy (TRBV 11-3 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).
• Remarkably better response to dual HER2-targeted treatment was seen in immune-rich cancers with high TMG2 levels (n = 92) vs the single therapy arms (rate of pCR, 68% [95% CI, 52%-83%] vs 21% [95% CI, 10%-31%]; P < .001), while those with low TMG2 levels did not benefit from dual therapy.
• Data also showed an association of high TMG2 levels 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).