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J Clin Oncol. 2015 Mar 20;33(9):983-91. doi: 10.1200/JCO.2014.58.1967. Epub 2014 Dec 22.

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.

Author information

1
Carsten Denkert, Bruno V. Sinn, Berit M. Pfitzner, Wolfgang D. Schmitt, Silvia Darb-Esfahan, Stephan Wienert, Frederick Klauschen, and Manfred Dietel, Charité Universitätsmedizin Berlin; Carsten Denkert, German Cancer Consortium (DKTK); Peter Klare, Praxisklinik and Breast Center; Jens-Uwe Blohmer, St Gertrauden Krankenhaus and Charité Universitätsmedizin; Micheal Untch, Helios Klinikum Berlin-Buch, Berlin; Gunter von Minckwitz, Stephan Gade, Keyur Mehta, and Sibylle Loibl, German Breast Group, Neu-Isenburg; Gunter von Minckwitz, Women's Hospital, University of Frankfurt; Hans Tesch, Bethanien Hospital, Frankfurt; Jan C. Brase, Ralf Kronenwett, Karin Fisch, and Kristin Krappmann, Sividon Diagnostics, Cologne; Ralf Kronenwett, Heinrich-Heine University Düsseldorf, Düsseldorf; Christian Schem, Christian-Albrechts Universität zu Kiel, Kiel; Christoph Salat, Onkologische Schwerpunktpraxis, Munich; Marcus Schmidt, Johannes-Gutenberg Universität Mainz, Mainz; Sherko Kümmel, Kliniken Essen-Mitte, Essen; Peter Sinn, University of Heidelberg, Heidelberg; Christian Jakisch and Sibylle Loibl, Sana Klinikum Offenbach, Offenbach; Toralf Reimer, Klinikum Südstadt, Rostock, Germany; Sherene Loi, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; Sherene Loi and Christos Sotiriou, Institute Jules Bordet, Brussels, Belgium; and Fabrice André, Institute Gustave Roussy, Villejuif, France. carsten.denkert@charite.de.
2
Carsten Denkert, Bruno V. Sinn, Berit M. Pfitzner, Wolfgang D. Schmitt, Silvia Darb-Esfahan, Stephan Wienert, Frederick Klauschen, and Manfred Dietel, Charité Universitätsmedizin Berlin; Carsten Denkert, German Cancer Consortium (DKTK); Peter Klare, Praxisklinik and Breast Center; Jens-Uwe Blohmer, St Gertrauden Krankenhaus and Charité Universitätsmedizin; Micheal Untch, Helios Klinikum Berlin-Buch, Berlin; Gunter von Minckwitz, Stephan Gade, Keyur Mehta, and Sibylle Loibl, German Breast Group, Neu-Isenburg; Gunter von Minckwitz, Women's Hospital, University of Frankfurt; Hans Tesch, Bethanien Hospital, Frankfurt; Jan C. Brase, Ralf Kronenwett, Karin Fisch, and Kristin Krappmann, Sividon Diagnostics, Cologne; Ralf Kronenwett, Heinrich-Heine University Düsseldorf, Düsseldorf; Christian Schem, Christian-Albrechts Universität zu Kiel, Kiel; Christoph Salat, Onkologische Schwerpunktpraxis, Munich; Marcus Schmidt, Johannes-Gutenberg Universität Mainz, Mainz; Sherko Kümmel, Kliniken Essen-Mitte, Essen; Peter Sinn, University of Heidelberg, Heidelberg; Christian Jakisch and Sibylle Loibl, Sana Klinikum Offenbach, Offenbach; Toralf Reimer, Klinikum Südstadt, Rostock, Germany; Sherene Loi, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; Sherene Loi and Christos Sotiriou, Institute Jules Bordet, Brussels, Belgium; and Fabrice André, Institute Gustave Roussy, Villejuif, France.

Abstract

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.

PMID:
25534375
DOI:
10.1200/JCO.2014.58.1967
[Indexed for MEDLINE]

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