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

被引：883

作者：

Denkert, Carsten ^{[1
,2
]}

von Minckwitz, Gunter ^{[6
,7
]}

Brase, Jan C. ^{[9
]}

Sinn, Bruno V. ^{[1
]}

Gade, Stephan ^{[6
]}

Kronenwett, Ralf ^{[9
,10
]}

Pfitzner, Berit M. ^{[1
]}

Salat, Christoph ^{[12
]}

Loi, Sherene ^{[18
,19
]}

Schmitt, Wolfgang D. ^{[1
]}

Schem, Christian ^{[11
]}

Fisch, Karin ^{[9
]}

Darb-Esfahani, Silvia ^{[1
]}

Mehta, Keyur ^{[6
]}

Sotiriou, Christos ^{[19
]}

Wienert, Stephan ^{[1
]}

Klare, Peter ^{[3
]}

Andre, Fabrice ^{[20
]}

Klauschen, Frederick ^{[1
]}

Blohmer, Jens-Uwe ^{[1
,4
]}

Krappmann, Kristin ^{[9
]}

Schmidt, Marcus ^{[13
]}

Tesch, Hans ^{[8
]}

Kuemmel, Sherko ^{[14
]}

Sinn, Peter ^{[15
]}

Jackisch, Christian ^{[16
]}

Dietel, Manfred ^{[1
]}

Reimer, Toralf ^{[17
]}

Untch, Michael ^{[5
]}

Loibl, Sibylle ^{[6
,16
]}

机构：

[1] Charite, D-10117 Berlin, Germany

[2] German Canc Consortium DKTK, Berlin, Germany

[3] Praxisklin & Breast Ctr, Berlin, Germany

[4] St Gertrauden Hosp, Berlin, Germany

[5] Helios Klinikum Berlin Buch, Berlin, Germany

[6] Neu Isenburg, German Breast Grp, Frankfurt, Germany

[7] Goethe Univ Frankfurt, Womens Hosp, D-60054 Frankfurt, Germany

[8] Bethanien Hosp, Frankfurt, Germany

[9] Sividon Diagnost, Cologne, Germany

[10] Univ Dusseldorf, Dusseldorf, Germany

[11] Univ Kiel, Kiel, Germany

[12] Onkol Schwerpunktpraxis, Munich, Germany

[13] Johannes Gutenberg Univ Mainz, D-55122 Mainz, Germany

[14] Kliniken Essen Mitte, Essen, Germany

[15] Heidelberg Univ, Heidelberg, Germany

[16] Sana Klinikum Offenbach, Offenbach, Germany

[17] Klinikum Sudstadt, Rostock, Germany

[18] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[19] Inst Jules Bordet, B-1000 Brussels, Belgium

[20] Inst Gustave Roussy, Villejuif, France

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2015年 / 33卷 / 09期

关键词：

PHASE-2; TRIAL; OPEN-LABEL; TRASTUZUMAB; MULTICENTER; EXPRESSION; SURVIVAL; MARKER; SAFETY;

D O I：

10.1200/JCO.2014.58.1967

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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. (C) 2014 by American Society of Clinical Oncology

引用

页码：983 / 991

页数：9

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