Ryan L Powles1,2, David Redmond3, Christos Sotiriou4, Sherene Loi5, Debora Fumagalli4, Paolo Nuciforo6, Nadia Harbeck7, Evandro de Azambuja4, Severine Sarp8, Serena Di Cosimo9, Jens Huober10, Jose Baselga11, Martine Piccart-Gebhart4, Olivier Elemento3,12, Lajos Pusztai1, Christos Hatzis1. 1. Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. 2. Computational Biology and Bioinformatics Program, Yale University, New Haven, Connecticut. 3. Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York. 4. Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. 5. Division of Cancer Medicine and Research, Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia. 6. Molecular Oncology Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain. 7. Department of Obstetrics and Gynecology, University of Munich, Munich, Germany. 8. Novartis AG, Basel, Switzerland. 9. Department of Oncology, Istituto Nazionale Tumori, Milan, Italy. 10. Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany. 11. Breast Medical Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 12. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, New York.
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 withpaclitaxel 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.
RCT Entities:
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.
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