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RESEARCH PRODUCT

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

Ralf KronenwettManfred DietelSilvia Darb-esfahaniChristoph SalatKeyur MehtaPeter SinnKristin KrappmannToralf ReimerKarin FischMarcus SchmidtSherko KümmelStephan GadeSherene LoiSherene LoiStephan WienertGunter Von MinckwitzChristian SchemBruno Valentin SinnJan C. BraseChristian JackischMichael UntchHans TeschFabrice AndreWolfgang D. SchmittChristos SotiriouSibylle LoiblPeter KlareCarsten DenkertBerit M. PfitznerJens-uwe BlohmerFrederick Klauschen

subject

AdultOncologyCancer Researchmedicine.medical_specialtyStromal cellReceptor ErbB-2medicine.medical_treatmentAntineoplastic AgentsTriple Negative Breast NeoplasmsCarboplatinchemistry.chemical_compoundLymphocytes Tumor-InfiltratingPredictive Value of TestsInternal medicineBiomarkers TumormedicineHumansAgedRandomized Controlled Trials as TopicChemotherapybusiness.industryTumor-infiltrating lymphocytesCancerFOXP3Middle AgedPrognosismedicine.diseaseNeoadjuvant TherapyCarboplatin3. Good healthCD8AGene Expression Regulation NeoplasticOncologychemistryChemotherapy AdjuvantCXCL9Femalebusiness

description

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.

yearjournalcountryeditionlanguage
2015-03-20Journal of Clinical Oncology
https://doi.org/10.1200/jco.2014.58.1967