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NAB-PACLITAXEL AND GEMCITABINE DECREASE CANCER-ASSOCIATED FIBROBLASTS THROUGH PANCREATIC STROMAL DEPLETION
Tomoharu Miyashita*1, Hidehiro Tajima1, Hirohisa Kitagawa1, Isamu Makino1, Ali K. Ahmed2, John W. Harmon2, Tetsuo Ohta1
1Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan; 2Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
Background: Treatment with Nab-paclitaxel (n-PTX) and gemcitabine (GEM) causes decreased cancer-associated fibroblasts (CAFs), inducing a marked alteration in the cancer stroma. This may result in potentially improved survival outcomes. We investigated the immunohistochemical effects of a combination n-PTX plus GEM regimen in patients with pancreatic ductal adenocarcinoma (PDAC).
Methods: Patients with resected PDAC received two cycles of n-PTX plus GEM, prior to surgical resection. FDG-PET and CA19-9 tumor marker levels were used to measure clinical activity before and after chemotherapy. The effect on the tumor stroma was examined by α-smooth muscle actin (αSMA) expression using immunohistochemistry. The αSMA+ fibroblasts density was determined by Hybrid Cell Count in the resected surgical specimens. These were compared to a group of untreated specimens, and to specimens treated with conventional GEM plus S-1.
Results: A total of 42 patients were enrolled in this study. Analysis of αSMA expression revealed markedly disorganized collagen with a very low density of αSMA+ fibroblasts in the n-PTX plus GEM treated group (Figure 1c). This was not observed in the untreated (Figure 1a) or conventionally treated GEM plus S-1 control group (Figure 1b). The total number of αSMA+ fibroblasts in n-PTX plus GEM was significantly lower than that of the untreated (p<0.05) or conventional GEM plus S-1 group (p<0.05) (Figure 1d). Moreover, there was no significant difference between the untreated and the GEM plus S-1 group. FDG-PET reflected a decrease in αSMA+ density but not CA19-9 levels.
Conclusion: This data suggests that the n-PTX plus GEM regimen may induce stromal depletion, resulting in decreased CAF content.
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