Neither Tumor-Infiltrating Lymphocytes nor Cytotoxic T Cells Predict Enhanced Benefit from Chemotherapy in the DBCG77B Phase III Clinical Trial

Abstract

Recent studies have shown that immune infiltrates in the tumor microenvironment play a role in response to therapy, with some suggesting that patients with immunogenic tumors may receive increased benefit from chemotherapies. We evaluated this hypothesis in early breast cancer by testing the interaction between immune biomarkers and chemotherapy using materials from DBCG77B, a phase III clinical trial where high-risk premenopausal women were randomized to receive chemotherapy or no chemotherapy. Tissue microarrays were evaluated for tumor-infiltrating lymphocytes (TILs) assessed morphologically on hematoxylin and eosin-stained slides, and by immunohistochemistry for CD8, FOXP3, LAG-3, PD-1 and PD-L1. Following REMARK reporting guidelines, data analyses were performed according to a prespecified statistical plan, using 10-year invasive disease-free survival as the endpoint. Differences in survival probabilities between biomarker groups were evaluated by Kaplan–Meier and Cox proportional hazard ratio analyses and prediction for treatment benefit by an interaction test. Our results showed that stromal TILs were associated with an improved prognosis (HR = 0.93; p-value = 0.03), consistent with previous studies. However, none of the immune biomarkers predicted benefit from chemotherapy in the full study set nor within major breast cancer subtypes. Our study indicates that primary tumors with higher immune infiltration do not derive extra benefit from cyclophosphamide-based cytotoxic chemotherapy.

Expression of Programmed Death Ligand-1 and Correlation with Clinicopathological Features and CD8 Infiltration in Breast Cancer

“…And according to Shenasa et al who concluded that TILs has no unusual predictability for gaining substantial benefits from chemotherapy but still can tell that the primary molecular subgroups, the non-luminal, and basal BC subtypes are frequently willing to immunotherapy [30]. In general terms, TILs like CD8, CD4, B cells, and macrophages were found to be associated with favorable outcomes of the disease [28] (27).…”

Relationship between Aldehyde Dehydrogenase, PD-L1 and Tumor-Infiltrating Lymphocytes with Pathologic Response and Survival in Breast Cancer

“…In this line, Shenasa et al assessed the interaction of chemotherapy with different biomarkers such as TILs in BC. These authors reported the association of stromal TILs with improved invasive DFS but failed to predict the benefit from cyclophosphamide-based adjuvant chemotherapy in the full study set [ 29 ]. Moreover, the specific role of different lymphocyte subtypes in tumor immune response remains unclear.…”

Recent Advances in Optimizing Radiation Therapy Decisions in Early Invasive Breast Cancer

“…Furthermore, stromal TILs have also shown potential for identifying such intrinsically low-risk TNBCs that chemotherapy de-escalation could be considered as a potentially safe choice [129,130]. The clinical relevance of TILs for predicting response to adjuvant [131,132] or neoadjuvant systemic therapies [133][134][135] alone or in combination with immune checkpoint inhibitors is gaining momentum [136,137]. However, the value of immune biomarkers in relation to radiation responses and clinical outcomes in early breast cancer is much less well explored.…”