Tumor-Specific Major Histocompatibility-II Expression Predicts Benefit to Anti–PD-1/L1 Therapy in Patients With HER2-Negative Primary Breast Cancer

Abstract

Purpose: Immunotherapies targeting PD-1/L1 enhance pathologic complete response (pCR) rates when added to standard neoadjuvant chemotherapy (NAC) regimens in early-stage triple-negative, and possibly high-risk estrogen receptor–positive breast cancer. However, immunotherapy has been associated with significant toxicity, and most patients treated with NAC do not require immunotherapy to achieve pCR. Biomarkers discerning patients benefitting from the addition of immunotherapy from those who would achieve pCR to NAC alone are clearly needed. In this study, we tested the ability of MHC-II expression on tumor cells, to predict immunotherapy-specific benefit in the neoadjuvant breast cancer setting. Patients and Methods: This was a retrospective tissue-based analysis of 3 cohorts of patients with breast cancer: (i) primary nonimmunotherapy-treated breast cancers (n = 381), (ii) triple-negative breast cancers (TNBC) treated with durvalumab and standard NAC (n = 48), and (iii) HER2-negative patients treated with standard NAC (n = 87) or NAC and pembrolizumab (n = 66). Results: HLA-DR positivity on ≥5% of tumor cells, defined a priori, was observed in 10% and 15% of primary non-immunotherapy–treated hormone receptor–positive and triple-negative breast cancers, respectively. Quantitative assessment of MHC-II on tumor cells was predictive of durvalumab + NAC and pembrolizumab + NAC (ROC AUC, 0.71; P = 0.01 and AUC, 0.73; P = 0.001, respectively), but not NAC alone (AUC, 0.5; P = 0.99). Conclusions: Tumor-specific MHC-II has a strong candidacy as a specific biomarker of anti–PD-1/L1 immunotherapy benefit when added to standard NAC in HER2-negative breast cancer. Combined with previous studies in melanoma, MHC-II has the potential to be a pan-cancer biomarker. Validation is warranted in existing and future phase II/III clinical trials in this setting.

Immunotherapy for early triple negative breast cancer: research agenda for the next decade

“…Gains in CD274 gene (which encodes for PD-L1) were recently found to be common in TNBC, and associated with benefit to maintenance durvalumab in the advanced setting, warranting the study of this biomarker in the early setting for its promising predictive value 27 . The expression of Major Histocompatibility (MHC)-II complex on tumor cells was also retrospectively found to identify TNBC patients deriving benefit from the addition of immunotherapy to neoadjuvant chemotherapy in the I-SPY2 trial 28 . Lastly, evidence regarding the role of MHC I loss in immune-evasion is emerging for multiple tumor types 29 , warranting additional study in the field of breast cancer.…”

MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression

“… 31 , 32 The PD-1/PD-L1 signaling pathway leads to exhaustion and functional inhibition of T cells, which is currently the main immunotherapy target. 14 , 33 , 34 Therefore, after efferocytosis, the PD-L1 expression on tumor-associated macrophages is worthy of attention. However, it is unclear how efferocytosis impacts the expression of PD-L1, as well as the tumor growth and immune landscape of osteosarcoma.…”

Identification of Five Cytotoxicity-Related Genes Involved in the Progression of Triple-Negative Breast Cancer

“…This study has several contributions to breast cancer research. First of all, the previously identified key biomarkers of breast cancer are either related to the pathogenesis or related to progression ( Wang et al, 2021b ; Dameri et al, 2021 ; Gonzalez-Ericsson et al, 2021 ; Xing et al, 2021 ), and few biomarkers have been identified that are related to both occurrence and progression of TNBC. Here, we identified five key genes that played a role in the pathogenesis and progression of TNBC, suggesting their potential to be candidate therapeutic targets that benefit more patients.…”