Tumor-Infiltrating Lymphocytes in Patients Receiving Trastuzumab/Pertuzumab-Based Chemotherapy: A TRYPHAENA Substudy

• Published in: JNCI : Journal of the National Cancer Institute 2019-01, Vol.111 (1), p.69-77
• Main Authors: Ignatiadis, Michail, Van den Eynden, Gert, Roberto, Salgado, Fornili, Marco, Bareche, Yacine, Desmedt, Christine, Rothé, Françoise, Maetens, Marion, Venet, David, Holgado, Esther, McNally, Virginia, Kiermaier, Astrid, Savage, Heidi M, Wilson, Timothy R, Cortes, Javier, Schneeweiss, Andreas, Willard-Gallo, Karen, Biganzoli, Elia, Sotiriou, Christos
• Format: Article
• Language: English
• Subjects: Angiogenesis; Anthracycline; Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B7 antigen; Biomarkers; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Chemotherapy; Confidence intervals; Epidermal growth factor; ErbB-2 protein; Female; Follow-Up Studies; Gene expression; Growth factors; Humans; Immunotherapy; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Median (statistics); Mesenchyme; Middle Aged; Monoclonal antibodies; Neoadjuvant Therapy - mortality; Prognosis; Receptor, ErbB-2 - metabolism; Regression analysis; Regression models; Statistical analysis; Statistical tests; Survival Rate; Targeted cancer therapy; Trastuzumab; Trastuzumab - administration & dosage; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djy076

Abstract Background There is an urgent requirement to identify biomarkers to tailor treatment in human epidermal growth factor receptor 2 (HER2)–amplified early breast cancer treated with trastuzumab/pertuzumab-based chemotherapy. Methods Among the 225 patients randomly assigned to trastuzumab/pertuzumab concurrently or sequentially with an anthracycline-containing regimen or concurrently with an anthracycline-free regimen in the Tryphaena trial, we determined the percentage of tumor-infiltrating lymphocytes (TILs) at baseline in 213 patients, of which 126 demonstrated a pathological complete response (pCR; ypT0/is ypN0), with 28 demonstrating event-free survival (EFS) events. We investigated associations between baseline TIL percentage and either pCR or EFS after adjusting for clinicopathological characteristics using logistic and Cox regression models, respectively. To understand TIL biology, we evaluated associations between baseline TILs and baseline tumor gene expression data (800 gene set by NanoString) in a subset of 173 patients. All statistical tests were two-sided. Results Among the patients with measurable TILs at baseline, the median level was 14.1% (interquartile range = 7.1%–32.4%). After adjusting for clinicopathological characteristics, baseline percentage TIL was not associated with pCR (adjusted odds ratio [aOR] for every 10-percentage unit increase in TILs = 1.12, 95% confidence interval [CI] = 0.95 to 1.31, P = .17). At a median follow-up of 4.7 years, for every increase in baseline TILs of 10%, there was a 25% reduction in the hazard for an EFS event (aOR = 0.75, 95% CI = 0.56 to 1.00, P = .05) after adjusting for baseline clinicopathological characteristics and pCR. Additionally, genes associated with epithelial-mesenchymal transition, angiogenesis, and T-cell inhibition such as SNAIL1, ZEB1, NOTCH3, and B7-H3 were statistically significantly inversely correlated with percentage TIL. Conclusions Baseline TIL percentage provides independent prognostic information in patients treated with trastuzumab/pertuzumab-based neoadjuvant chemotherapy. However, further validation is required.