Objectives: Pancreatic Ductal AdenoCarcinoma (PDAC) presents in about 1% of cases MicroSatellite Instability (MSI), a phenotype correlated to damage of DNA Mismatch Repair (MMR) system. Tumor cells with MSI express aberrant protein and potentially immunogenic antigens: since, Immunotherapy (IT) with ICK inhibitors represents a kind of personalized treatment for patients with MSI-related cancer and supports the evaluation of MSI phenotype in PDAC. The aim of this study is to evaluate MSI in metastatic PDAC patients after surgery featuring first line of chemotherapy (CT) in order to evaluate a possible role of immunotherapy treatment. Materials and Methods: Ten patients with metastatic PDAC after pancreatic resection and adjuvant CT were for MSI analyses. Immunohistochemistry evaluations for genes MLH1, MSH2, MSH6 and PMS2 were performed. We considered 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 size 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 out of 10). The median PFS and OS were 7.5 months and 23 months, respectively. All of these patients presented a microsatellite stability, in which no alterations of protein expression in MMR system were found. Indeed, nobody underwent IT. However, regarding PFS, we identified two different groups (each one composed by 5 patients), 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; CI 95% 3.982-103.200; p=0.0018). Furthermore, we found significant differences between E and 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 differences in OS were observed, until now. Conclusion: Our study confirmed that MMR/MSI alterations are extremely rare in patients with PDAC and this represents a limit in order to include these patients in IT clinical trials. However, whether MSI pathways might be involved in early metastatic process of PDAC still remains unclear. Nevertheless we demonstrated that both tumor scoring and tumor volume play a pivotal role in early recurrence of PDAC. The molecular analysis of PDAC should be performed to define a correlation with early metastatis that may increase the know-how around PFS in PDAC patients.

THE ROLE OF MOLECULAR PATHOLOGY AND IMMUNOTHERAPY IN ADJUVANT SETTING OF PANCREATIC DUCTAL ADENOCARCINOMA: TUMOR VOLUME AND MICROSATELLITE INSTABILITY INVERSELY AFFECT EARLY PROGRESSION FREE SURVIVAL

Funel N;Palmeri M;Di Franco G;Guadagni S;Furbetta N;Gianardi D;Bianchini M;Rossi L;Stefanini G;Gentiluomo M.;Campa D;Catanese S;Di Candio G;Falcone A;Mosca F;Morelli L
2018

Abstract

Objectives: Pancreatic Ductal AdenoCarcinoma (PDAC) presents in about 1% of cases MicroSatellite Instability (MSI), a phenotype correlated to damage of DNA Mismatch Repair (MMR) system. Tumor cells with MSI express aberrant protein and potentially immunogenic antigens: since, Immunotherapy (IT) with ICK inhibitors represents a kind of personalized treatment for patients with MSI-related cancer and supports the evaluation of MSI phenotype in PDAC. The aim of this study is to evaluate MSI in metastatic PDAC patients after surgery featuring first line of chemotherapy (CT) in order to evaluate a possible role of immunotherapy treatment. Materials and Methods: Ten patients with metastatic PDAC after pancreatic resection and adjuvant CT were for MSI analyses. Immunohistochemistry evaluations for genes MLH1, MSH2, MSH6 and PMS2 were performed. We considered 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 size 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 out of 10). The median PFS and OS were 7.5 months and 23 months, respectively. All of these patients presented a microsatellite stability, in which no alterations of protein expression in MMR system were found. Indeed, nobody underwent IT. However, regarding PFS, we identified two different groups (each one composed by 5 patients), 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; CI 95% 3.982-103.200; p=0.0018). Furthermore, we found significant differences between E and 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 differences in OS were observed, until now. Conclusion: Our study confirmed that MMR/MSI alterations are extremely rare in patients with PDAC and this represents a limit in order to include these patients in IT clinical trials. However, whether MSI pathways might be involved in early metastatic process of PDAC still remains unclear. Nevertheless we demonstrated that both tumor scoring and tumor volume play a pivotal role in early recurrence of PDAC. The molecular analysis of PDAC should be performed to define a correlation with early metastatis that may increase the know-how around PFS in PDAC patients.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/936877
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact