The immune microenvironment and relation to outcome in patients with advanced breast cancer treated with docetaxel with or without gemcitabine

Abstract

Preclinical studies suggest that some effects of conventional chemotherapy, and in particular, gemcitabine, are mediated through enhanced antitumor immune responses. The objective of this study was to use material from a randomized clinical trial to evaluate whether patients with preexisting immune infiltrates responded better to treatment with gemcitabine + docetaxel (GD) compared to docetaxel alone. Formalin fixed, paraffin-embedded breast cancer tissues from SBG0102 phase 3 trial patients randomly assigned to treatment with GD or docetaxel were used. Immunohistochemical staining for CD8, FOXP3, LAG3, PD-1, PD-L1 and CD163 was performed. Tumor infiltrating lymphocytes (TILs) and tumor associated macrophages were evaluated. Prespecified statistical analyses were performed in a formal prospective-retrospective design. Time to progression was primary endpoint and overall survival secondary endpoint. Correlations between biomarker status and endpoints were evaluated using the Kaplan-Meier method and Cox proportional hazards models. Biomarker data was obtained for 237 patients. There was no difference in treatment effect according to biomarker status for the whole cohort. In planned subgroup analysis by PAM50 subtype, in non-luminal (basal-like and HER2E) breast cancers FOXP3 was a significant predictor of treatment effect with GD compared to docetaxel, with a HR of 0.22 (0.09-0.52) for tumors with low FOXP3 compared to HR 0.92 (0.47-1.80) for high FOXP3 TILs (P interaction = 0.01). Immune biomarkers were not predictive of added benefit of gemcitabine in a cohort of mixed breast cancer subtypes. However, in non-luminal breast cancers, patients with low FOXP3+ TILs may have significant benefit from added gemcitabine.

Topical application of gemcitabine generates microvesicle particles in human and murine skin

“…[26][27][28] Of significance, multiple studies have reported the abilities of PAFR antagonists to control the growth of cancer cells or augment the responses of therapeutic agents. 26,29,30 Given that gemcitabine chemotherapy used against multiple human malignancies either alone or in combination with other agents, exhibits adverse effects, including skin rash/necrosis, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] our current studies sought to determine the potential role of MVP release in the pathologic effects of topical gemcitabine application. To that end, pharmacologic approaches using human skin explants and genetic approaches using murine skin were used as relevant models.…”

“…However, often these drugs are associated with adverse side effects, including localized skin eruptions and necrosis as well as systemic pathologies, including ototoxicity and neutropenia 6–11 . Gemcitabine is one of the commonly used chemotherapy drugs, which has been used either alone, or in combination with other antineoplastic agents for the treatment of malignancies, including pancreatic cancer, non‐small cell lung cancer, intrahepatic cholangiocarcinoma, colorectal cancer, ovarian cancer, breast cancer, and melanoma 12–18 . Nevertheless, the development of tumor resistance mechanisms to gemcitabine therapy remained one of the ongoing challenges in its limited therapeutic efficacy 19–21 .…”

The Impact of Tumor Infiltrating Lymphocytes Densities and Ki67 Index on Residual Breast Cancer Burden following Neoadjuvant Chemotherapy

“…Neither of these studies have been able to explain why pre-NACT TILs were exclusively linked to pCR in TNBC [ 33 , 34 ]. A prominent inflammatory infiltrate is a well-known feature of TNBC [ 36 , 37 ]. To confirm whether the observed significance was due to the molecular subtype itself or it is linked to the density of TILs, we used logistic regression and a significant association between pCR, and TNBC subtype was confirmed irrelevant to TILs.…”

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

“…Each case was represented by 2–3 cores, measuring 2 mm in diameter, with the full trial cohort spread over 24 tissue microarray blocks. Tissue microarray slides were created by sectioning at 4 µm and staining with hematoxylin and eosin (H&E) or by immunohistochemistry (IHC) for CD8 (1:50, mouse monoclonal, clone C8/144B, Agilent Technologies, Santa Clara, CA, USA), FOXP3 (1:20, mouse monoclonal, clone 236A/E7, Abcam, Cambridge, UK), LAG-3 (1:100, mouse monoclonal, clone 17B4, Abcam, Cambridge, UK), PD-1 (mouse monoclonal, clone NAT105, Cell Marque, Rocklin, CA, USA), and PD-L1 (1:100, rabbit monoclonal, clone SP142, Roche Diagnostics, Laval, QC, Canada) as previously described [ 36 ].…”

“…All biomarkers except for PD-L1 were stained at the Genetic Pathology Evaluation Centre (Vancouver, BC, Canada) on the Ventana Discovery Ultra autostainer. PD-L1 was stained at the Deeley Research Centre (Victoria, BC, Canada) [ 36 ]. Stained slides were scanned using a Leica Aperio AT2 scanner (Leica Biosystems, Concord, Canada).…”