Lights and shadows of molecular pathology and immunotherapy in adjuvant setting of patients with pancreatic ductal adenocarcinoma: Tumor volume and microsatellite instability inversely affect early progression free survival

Objectives: Molecular alterations inaboit 1%of Pancreatic Ductal AdenoCarcinoma(PDAC) includes MicroSatellite Instability (MSI) anddamage of DNA Mismatch Repair (MMR) system. Immunotherapy (IT) with ICK inhibitorsconstitutes a source of personalized treatment for MSI cancer patients andsupport the evaluation of MSI phenotype in PDAC. The aim of thisstudy is to evaluate MSI in metastatic PDAC patients after surgery featuring first line of chemotherapy(CT) in order to evaluate a possible immunotherapy treatment. Method:Ten patients with metastatic PDAC after pancreatic resection and adjuvant CT were selected for MSI analyses. Immunohistochemistryevaluations for genes MLH1, MSH2, MSH6 and PMS2 were performed. We assessed MSI when at the least 30% of selected markers lost their protein expression. Pathological data of primary tumor were assessed according to VIII edition of TNM and tumor dimension was evaluated as volume (cm3). Clinical data, Progression Free Survival(PFS) and Overall Survival(OS) were obtained by Long-Rank tests. Results:The mean follow-up was 19 months,living patients were 70% (7/10). The median PFS and OS were 7.5 months and 23 months, respectively. All patients showed a microsatellite stability, in which no alteration of protein expression in MMR system was found. Indeed nobody was treated with IT. However, looking at PFS survival, we identified two different groups (5 patients each), based on their early (E) or late (L) metastatic pathology (less or more than 6 months after surgery), respectively. We found a significant difference of PFS between these two groups(E 2.20 vs L 14.63; HR=4.644; CI95% 3.982-103.200; p=0.0018). We also found significant differences comparing E vs L group interms of mean tumor score (2.780 vs 1.870; p=0.0067) and mean tumor volume (88.68 vs 8.30; p=0.0068). No significant difference in term of OS were observed, until now. Conclusion: MMR/MSI alterations are very rare or absent in PDAC patients and thisrepresents a limit in order to submit PDAC patients to IT clinical trials. However, MSI analyses leave the open question whether MSI pathways might be involved in early metastatic process of PDAC. Nevertheless we demonstrated that both tumor scoring and tumor volume play a pivotal role in early recurrence of PDAC.The molecular sub-types of PDAC and their validation and application in early metastatic patients may increase the know-how around PFS in PDAC patients in order to upgrade their quality of life.