Immunologic Factors Predict Pathologic Complete Response to Neoadjuvant Therapy With or Without Carboplatin in Breast Cancer
In a study reported in the Journal of Clinical Oncology, Denkert et al found that increased tumor-infiltrating lymphocytes and the presence of lymphocyte-predominant breast cancer were associated with increased rates of pathologic complete response in patients receiving neoadjuvant anthracycline-taxane treatment with or without carboplatin. Higher rates were observed with carboplatin, with treatment interactions being significant among all patients and among those with HER2-positive disease but not among those with triple-negative disease. mRNA profiles for immune-related genes also distinguished pathologic complete response rates.
Study Details
The study involved 580 tumors from patients in the GeparSixto trial, which assessed the effects on pathologic complete response rates of adding carboplatin to neoadjuvant anthracycline plus taxane treatment. The current analysis assessed the effects on pathologic complete response of tumor-infiltrating lymphocyte levels, the presence of lymphocyte–predominant disease, and levels of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) and immunosuppressive genes (IDO1, PD-1, PD-L1, CTLA4, FOXP3).
Tumor-Infiltrating Lymphocytes
Increased levels of stromal tumor-infiltrating lymphocytes predicted pathologic complete response in univariate (P < .001) and multivariate analyses (odds ratio [OR] = 1.20 per 10% increase, P < .001), with a significant interaction by treatment among all 580 patients (P = .006; ORs = 1.35 with carboplatin and 1.11 without carboplatin) and among 266 patients with HER2-positive disease (P = .007; ORs = 1.53 and 1.13) but not among 314 patients with triple-negative disease (P = .27; ORs = 1.22 and 1.09).
Lymphocyte-Predominant Disease
The pathologic complete response rate was 59.9% in patients with lymphocyte-predominant disease vs 33.8% in those with nonlymphocyte-predominant disease (P < .001), with pathologic complete response rates ≥ 75% in patients with lymphocyte-predominant tumors who received carboplatin. Significant interaction by treatment was observed among all patients (P = .002; ORs = 5.96 with carboplatin and 1.63 without carboplatin) and among patients with HER2-positive disease (P = .006; ORs = 13.21 and 2.00) but not among those with triple-negative disease (P = .12; ORs = 3.35 and 1.44).
Immune-Related Genes
All 12 immune mRNA markers were predictive of increased pathologic complete response, with the highest ORs observed for PD-L1 (1.57, P < .001) and CCL5 (1.41, P < .001). Hierarchic clustering of mRNA markers distinguished three immune subtypes with significantly different pathologic complete response rates (P < .001): low gene expression levels = 24%, intermediate = 37.4%, and high = 56.2%. All immune markers had highly significant (P < .001) positive correlations with each other and with stromal tumor-infiltrating lymphocyte levels.
The investigators concluded: “Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial, particularly in patients treated with [carboplatin]. After further standardization, they could be included in histopathologic assessment of [breast cancer].”
Carsten Denkert, MD, of Charité Universitätsmedizin Berlin, is the corresponding author of the Journal of Clinical Oncology article.
The study was supported by a European Commission grant. For full disclosures of the study authors, visit jco.ascopubs.org.
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