Background: Molecular alterations described in Pancreatic Ductal AdenoCarcinoma (PDAC) include MicroSatellite Instability (MSI), phenotype related to a damage of DNA Mismatch Repair (MMR) system, in which protein expression is alterated in 30% of genes (MLH1, MSH2, MSH6 and PMS2). In PDAC, Humphris et al. recently identified MMR/MSI in 1% of tumors. The MSI-driven cancer pathway leads to the synthesis of aberrant and potentially immunogenic neo-antigens by tumor cells. The emergence of immunotherapy with ICK inhibitors has recently constituted a source of personalized treatment for MSI cancer patients and support the evaluation of MSI phenotype in PDAC. The aim of this study is to evaluate MSI in metastatic PDAC patients after pancreatic resection featuring first line of chemotherapy in order to evaluate a possible immunotherapy treatment. Methods: Ten patients with metastatic PDAC after surgical resection and adjuvant chemotherapy with curative intent were selected for MSI analyses. Immunohistochemistry (IHC) evaluations 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 consulting VIII edition of TNM and the dimension of tumor 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 19.02 months and the living patients were 70% (7/10). The median PFS and OS were 7.51 months and 23.02 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 immunotherapy. However, looking at the PFS survival, we identified two different groups (5 patients each), based on their early (E) or late (L) metastatic pathology (less or more six months after surgery), respectively. Furthermore we found a significant difference in terms of PFS between these two groups (E vs L; 2.20 vs14.63; HR=4.644; CI95% 3.982-103.200; p=0.0018). Nevertheless, we found significant differences comparing E vs L group in terms 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: Our results confirmed that MMR/MSI alterations are very rare or absent in PDAC patients. This represents a limit in order to submit the PDAC patients to immunotherapy clinical trials. However, the 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 pathology. The molecular sub-types of PDAC and their validation and application in early metastatic patients may increase the know-how around the PFS in PDAC patients in order to up-grade their quality of life.

TUMOR VOLUME AND MICROSATELLITE INSTABILITY INVERSELY AFFECT EARLY PROGRESSION FREE SURVIVAL IN ADJUVANT SETTING OF PATIENTS WITH PANCREATIC DUCTAL ADENOCARCINOMA: LIGHTS AND SHADOWS OF MOLECULAR PATHOLOGY AND IMMUNOTHERAPY

PALMERI M;FUNEL N;DI FRANCO G;GUADAGNI S;FURBETTA N;GIANARDI D;BIANCHINI M;GENTILUOMO M;CAMPA D;CATANESE S;DI CANDIO G;FALCONE A;MOSCA F;MORELLI L
2018

Abstract

Background: Molecular alterations described in Pancreatic Ductal AdenoCarcinoma (PDAC) include MicroSatellite Instability (MSI), phenotype related to a damage of DNA Mismatch Repair (MMR) system, in which protein expression is alterated in 30% of genes (MLH1, MSH2, MSH6 and PMS2). In PDAC, Humphris et al. recently identified MMR/MSI in 1% of tumors. The MSI-driven cancer pathway leads to the synthesis of aberrant and potentially immunogenic neo-antigens by tumor cells. The emergence of immunotherapy with ICK inhibitors has recently constituted a source of personalized treatment for MSI cancer patients and support the evaluation of MSI phenotype in PDAC. The aim of this study is to evaluate MSI in metastatic PDAC patients after pancreatic resection featuring first line of chemotherapy in order to evaluate a possible immunotherapy treatment. Methods: Ten patients with metastatic PDAC after surgical resection and adjuvant chemotherapy with curative intent were selected for MSI analyses. Immunohistochemistry (IHC) evaluations 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 consulting VIII edition of TNM and the dimension of tumor 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 19.02 months and the living patients were 70% (7/10). The median PFS and OS were 7.51 months and 23.02 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 immunotherapy. However, looking at the PFS survival, we identified two different groups (5 patients each), based on their early (E) or late (L) metastatic pathology (less or more six months after surgery), respectively. Furthermore we found a significant difference in terms of PFS between these two groups (E vs L; 2.20 vs14.63; HR=4.644; CI95% 3.982-103.200; p=0.0018). Nevertheless, we found significant differences comparing E vs L group in terms 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: Our results confirmed that MMR/MSI alterations are very rare or absent in PDAC patients. This represents a limit in order to submit the PDAC patients to immunotherapy clinical trials. However, the 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 pathology. The molecular sub-types of PDAC and their validation and application in early metastatic patients may increase the know-how around the PFS in PDAC patients in order to up-grade their quality of life.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/935014
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