Myofibroblastic CAF Density, Not Activated Stroma Index, Indicates Prognosis after Neoadjuvant Therapy of Pancreatic Carcinoma

SIMPLE SUMMARY: Pancreatic cancer is increasingly treated with chemotherapy before surgery, but this does not improve prognosis for every patient. On a cellular level, pancreatic cancer tissue is usually mixed with a dense matrix called the stroma which interacts with the tumor and contains fibers, large molecules and cells. The role of this stroma in chemotherapy and subsequent surgical tumor resection is unclear, especially for current first-line chemotherapy regimens. We analyzed two of the main stromal components, activated fibroblasts and collagen, and found that treatment with gemcitabine + nab-paclitaxel reduced collagen content while FOLFIRINOX had no quantitative effect. Meanwhile, a higher number of activated fibroblasts was beneficial for prognosis after chemotherapy. These findings will serve to further elucidate mechanisms of response and chemoresistance in pancreatic cancer and potentially to stratify patients for different treatment pathways. ABSTRACT: Neoadjuvant therapy (NT) for advanced PDAC is an emerging concept, affecting both stroma and tumor. The Activated Stroma Index (ASI; ratio of activated cancer-associated fibroblasts (CAF) to collagen deposition) is a prognostic marker in upfront resected pancreatic adenocarcinoma (PDAC). We assessed ASI and its prognostic relevance after NT. Tissue from resection specimens of n = 48 PDAC patients after neoadjuvant chemotherapy with FOLFIRINOX (FOL; n = 31), gemcitabine + nab-paclitaxel (GEM; 7) or combination treatment (COMB; 10) was compared with upfront resected matched controls (RES; 69). Activated CAFs were assessed by immunohistochemistry for α-SMA, and collagen was stained with aniline blue; the stained area was then determined by computational imaging analysis and ASI was calculated. In GEM, ASI was significantly higher and collagen deposition lower than in controls and FOL. The lowest quartile of ASI values had significantly longer overall survival (OS) in RES, whereas in FOL, the highest quartile had the best prognosis. After NT, OS was significantly improved in the α-SMA-high group; in RES, however, survival was independent of α-SMA. Reversed prognostic association of ASI thus points to the differing significance of stromal composition after FOL, while improved prognosis with high CAF abundance suggests a synergistic effect of myofibroblasts with chemotherapy. These divergences impede usability of ASI after NT.