JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL

Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers

Carsten Denkert, Gunter von Minckwitz, Jan C Brase, Bruno V Sinn, Stephan Gade, Ralf Kronenwett, Berit M Pfitzner, Christoph Salat, Sherene Loi, Wolfgang D Schmitt, Christian Schem, Karin Fisch, Silvia Darb-Esfahani, Keyur Mehta, Christos Sotiriou, Stephan Wienert, Peter Klare, Fabrice André, Frederick Klauschen, Jens-Uwe Blohmer, Kristin Krappmann, Marcus Schmidt, Hans Tesch, Sherko Kümmel, Peter Sinn, Christian Jackisch, Manfred Dietel, Toralf Reimer, Michael Untch, Sibylle Loibl
Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2015 March 20, 33 (9): 983-91
25534375

PURPOSE: Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) -positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial.

PATIENTS AND METHODS: GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors.

RESULTS: Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pCR rates ≥ 75% were observed in patients with LPBC tumors treated with PMCb, with a significant test for interaction with therapy in the complete (P = .002) and HER2-positive (P = .006), but not the TNBC, cohorts. Hierarchic clustering of mRNA markers revealed three immune subtypes with different pCR rates (P < .001). All 12 immune mRNA markers were predictive for increased pCR. The highest odds ratios (ORs) were observed for PD-L1 (OR, 1.57; 95% CI, 1.34 to 1.86; P < .001) and CCL5 (OR, 1.41; 95% CI, 1.23 to 1.62; P < .001).

CONCLUSION: Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial, particularly in patients treated with Cb. After further standardization, they could be included in histopathologic assessment of BC.

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