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.
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.
Among the 245 women with available data (mean [SD] age, 49 
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
ClinicalTrials.gov Identifier: NCT00553358.
Powles R L, Redmond D, Sotiriou C, Loi S, Fumagalli D, Nuciforo P,
Harbeck N, de Azambuja E, Sarp S, Di Cosimo S, Huober J, Baselga J,
Piccart-Gebhart M, Elemento O, Pusztai L, Hatzis C. 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. JAMA
Oncol 2018; 4:e181564.