BACKGROUND: We have previously shown that TILs are predictive of benefit to trastuzumab and chemotherapy in HER2+ BC in the FinHER study, an adjuvant, phase III study in early-stage BC, where HER2+ patients were randomized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy (Loi et al, ASCO 2012). We sought to further confirm this positive association as well as to understand the composition of TILs.
METHODS: The association between TILs and response to trastuzumab with chemotherapy (epirubicin/cyclophosphamide with docetaxel with or without capecitabine) was evaluated in 156 HER2+ patients from the neoadjuvant GeparQuattro trial. The primary correlative endpoint was the association between TILs (quantified using the same method as previously published) with pathological complete response rates (pCR), adjusted for clinicopathological characteristics.
To understand the composition of TILs, correlations between TILs and gene expression levels of 13 pre-defined immune markers were evaluated from 202 HER2+ samples from the FinHER study. These represented T and B cell infiltration (CD3D, IGKC), Th1 (IFNG, CD8A), chemoattractants (CXCL9, CXCL13), immunosuppression (VEGFA, FOXP3, IDO1) and T-cell checkpoint receptors and ligands (PD-1, PD-L1, CTLA-4, CD80). Prognostic associations and interactions with trastuzumab were studied in Cox regression models for distant-disease free survival (DDFS). Preclinical mice models of HER2 mammary cancer were used to investigate combination therapies.
RESULTS: In the GeparQuattro trial data, each 10% increment in TILs was associated with higher rates of pCR (adjusted OR:1.14 95%CI:1.01-1.29;P = 0.037) after neoadjuvant trastuzumab and chemotherapy supporting the findings from the FinHER study.
Gene expression analyses using the FinHER samples revealed IDO1 and CXCL13 were most highly correlated with TILs (R = 0.58 and 0.51;p<0.001 respectively). Whilst no immune genes were significantly associated with prognosis in HER2+ BC, high expression of PD-1 and IDO1 were significantly associated with greater trastuzumab benefit for DDFS (Interaction p values: PD-1 = 0.029; IDO1 = 0.039) suggesting that trastuzumab modulates the immune microenvironment.
We next postulated that enhancing T-cell responses would be synergistic with trastuzumab. Trastuzumab in combination with several inhibitors of T-cell negative regulation (anti-CTLA4, anti-PD-1, anti-PD-L1) resulted in higher tumor regressions compared with monotherapy in a mouse transplant model of HER2+ mammary cancer. In particular, anti-PD1 (P = 0.02) and anti-PD-L1 (P = 0.008) were most effective. In a BALB/c-MMTV-neu transgenic mice mouse model (i.e. immune tolerant to HER2 antigen), the combination of trastuzumab and anti-PD1 antibody could significantly delay mammary gland tumor formation (p<0.001).
CONCLUSIONS: We confirm that TILs are associated with higher responses to trastuzumab and chemotherapy. Furthermore, tumor-mediated immunosuppression is evident in the lymphocytic infiltrate with PD-1 and IDO1 significantly predictive of trastuzumab benefit. The addition of a T-cell checkpoint inhibitor in a preclinical model significantly enhanced trastuzumab responses. These combinations warrant evaluation in the clinical setting.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-05.