Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer

Pancreatic cancer (PDAC) is still lacking of reliable markers to monitor tumor response. CA 19-9 is the only biomarker approved, despite it has several limitations in sensitivity and specificity. Since mutations of KRAS occur in more than 90% of tumors, its detection in circulating free tumor DNA (cftDNA) could represent a biomarker to monitor chemotherapy response. Twenty-seven advanced PDAC patients given first-line 5-fluorouracil, irinotecan and oxaliplatin or gemcitabine and nab-paclitaxel were enrolled. Three ml of plasma were collected: 1) before starting chemotherapy (baseline); 2) at day 15 of treatment; and 3) at each clinical follow-up. cftDNA was extracted and analysed for KRAS mutations (mutKRAS) by digital droplet PCR. Nineteen patients displayed a mutKRAS in baseline plasma samples. There was a statistically significant difference in progression-free survival (PFS) and overall survival (OS) in patients with increase vs. stability/reduction of cftDNA in the sample collected at day 15 (median PFS 2.5 vs 7.5 months, p = 0.03; median OS 6.5 vs 11.5 months, p = 0.009). The results of this study demonstrate that cftDNA mutKRAS changes are associated with tumor response to chemotherapy and support the evidence that mutKRAS in plasma may be used as a new marker for monitoring treatment outcome and disease progression in PDAC

Trattamento di prima linea con FOLFOXIRI nel carcinoma del pancreas avanzato. Fattori clinici prognostici e valutazione di miRNA.

Il carcinoma del pancreas è la quarta causa di morte per neoplasia con una mortalità che è pressochè sovrapponibile alla sua incidenza. Il trattamento con FOLFIRINOX, nonostante i buoni risultati in termini di tasso di risposte, è gravato da importati eventi avversi ematologici e non. FOLFOXIRI, una schedula già sviluppata per il carcinoma del colon-retto, evitando il bolo di 5-fluorouracile sembrerebbe avere un profilo di tossicità vantaggioso. In questo lavoro sono illustrati i dati relativi a una coorte di pazienti con malattia in stadio III e IV trattati con regime FOLFOXIRI nella pratica clinica, l’outcome dei pazienti, il profilo di tossicità, i fattori prognostici.Ad oggi non abbiamo inoltre alcun fattore predittivo di risposta al trattamento con FOLFIRINOX;i micro-RNA (miRNA), piccole molecole di RNA non codificanti a doppio filamento, rappresentano dei biomarcatori potenzialmente ideali. E' stata eseguita una valutazione, raccogliendo a vari timepoints campioni di sangue di pazienti in trattamento con FOLFOXIRI, dell’espressione di miRNA nel plasma, prima del trattamento e dopo il trattamento

Oxaliplatin in pre-treated patients: Maybe not the match point?

Pancreatic cancer is an aggressive disease and is projected to become one of the major causes of cancer-related death in western countries. Intensification of first-line treatment with the use of polychemotherapeutic regimens (FOLFIRINOX, gemcitabine plus nab-paclitaxel) has significantly improved the overall survival and progression-free survival; as a consequence, the number of patients alive and fit for second-line treatment is increasing. However, the selection of the best second-line treatment is difficult and large phase III trials are urgently needed. After the positive results of oxaliplatin and fluorouracil combination in the CONKO-003 trial, two recent phase III studies, PANCREOX and NAPOLI-1, investigating the use of second-line chemotherapy after gemcitabine-based first-line, showed controversial results. Giving the practice-changing advances rapidly growing in last years and the multiple therapeutic strategies that are becoming available for the treatment of pancreatic cancer, the real issue seems to be the optimal sequence of treatment much more than second-line treatment

Oxaliplatin in pre-treated patients: Maybe not the match point?

Pancreatic cancer is an aggressive disease and is projected to become one of the major causes of cancer-related death in western countries. Intensification of first-line treatment with the use of polychemotherapeutic regimens (FOLFIRINOX, gemcitabine plus nab-paclitaxel) has significantly improved the overall survival and progression-free survival; as a consequence, the number of patients alive and fit for second-line treatment is increasing. However, the selection of the best second-line treatment is difficult and large phase III trials are urgently needed. After the positive results of oxaliplatin and fluorouracil combination in the CONKO-003 trial, two recent phase III studies, PANCREOX and NAPOLI-1, investigating the use of second-line chemotherapy after gemcitabine-based first-line, showed controversial results. Giving the practice-changing advances rapidly growing in last years and the multiple therapeutic strategies that are becoming available for the treatment of pancreatic cancer, the real issue seems to be the optimal sequence of treatment much more than second-line treatment

Chemotherapy for Metastatic Invasive Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas

Context IPMNs are intraductal mucin-producing cystic neoplasms of the pancreas. The incidence of these neoplasms is rising and it has been reported in recent works that IPMNs account for approximately 25% of resected pancreatic neoplasms. It has been described that recurrence of disease is observed in 26-65% of patients resected for invasive IPMN (also named papillary mucinous carcinoma), usually within 3 years from surgery and often in form of distant disease. The natural history of metastatic invasive IPMNs is not clear and few data regarding the role of palliative treatments are available. Objective To evaluate the clinical outcome of this disease and the response to medical treatment. Methods We retrospectively collected data about patients with diagnosis of metastatic invasive IPMN who were treated with palliative chemotherapy at our institution from 2008 to 2012. Results Thirteen patients (M/F 8/5) affected by metastatic invasive IPMN were identified. Median age was 69 years (range 64-81). Most patients (12, 92%) had a recurrence after radical resection while one patient had synchronous metastases. All patients were treated with first line gemcitabine-based chemotherapy: seven (54%) patients received gemcitabine mono­therapy; six (46%) received the combination of gemcitabine and oxaliplatin. All patients except one experienced disease progression and 6 died. Two (15%) patients experienced partial response with first-line chemotherapy; 6 (46%) had stable disease while 5 (38%) showed disease progression. The estimated median progression-free survival was 9.6 months. Eight patient received also further lines of chemotherapy. Median overall survival was 15.4 months. Conclusion Our results confirm that metastatic invasive IPMNs have a dismal prognosis. The outcome of these patients is similar to patients affected by pancreatic ductal adenocarcinoma. In the absence of prospective clinical trials conducted in patients with this histology, the choice of chemotherapy should be based on data about pancreatic ductal adenocarcinoma

Lung Progression After Resection for Invasive Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas

Context IPMNs are intraductal mucin-producing cystic neoplasms of the pancreas. The incidence of these neoplasms is rising and it has been recently reported that IPMNs account for approximately 25% of resected pancreatic neoplasms. It has been described that recurrence of disease is observed in 26-65% of patients resected for invasive IPMN (also named papillary mucinous carcinoma), usually within 3 years from surgery and often in form of distant disease. However, in clinical trials of adjuvant chemotherapy for pancreatic cancer patients with disease free survival as primary end-point, the postoperative work-up included only abdominal evaluation. Objective The main aim of our study was to evaluate the pattern of recurrence for patients resected for invasive IPMNs in order to better understand the natural history of disease and to optimize the follow up procedures. Methods We retrospectively reviewed clinical data of patients who underwent radical surgical resection for invasive IPMN at University Hospital of Pisa, Italy, and who were adequately followed up at our institution; for these patients, total body computer tomography (CT) was repeated every 3 to 6 months for the first three years after surgical resection. Results Twenty-nine patients (M/F 16/13) progressed after resection for invasive IPMN were identified. Median age was 70 years (range 61-86 years). Disease progression occurred in form of liver metastases for 12 (41%) of them (with liver-only disease in 5 patients), lymph node involvement in 8 (28%), peritoneal carcinosis in 4 (14%), local recurrence in 5 (17%) and finally lung metastases in 14 (48%) patients; for 7 (24%) of these patients lung was the only site of progression. Median overall survival from evidence of metastases was 13.0 months. Conclusion We observed a high percentage of lung metastases as first and unique site of progression in patients resected for invasive IPMN. These data suggest the importance to perform chest CT as pre-operative and follow up exam in order to obtain an optimal staging and to early detect lung metastases

Pharmacoepigenetics in gastrointestinal tumors: MGMT methylation and beyond

Epigenetic mechanisms are involved in gastrointestinal (GI) cancer pathogenesis. Insights into the molecular basis of GI carcinogenesis led to the identification of different epigenetic pathways and signatures that may play a role as therapeutic targets in metastatic colorectal cancer (mCRC) and non-colorectal GI tumors. Among these alterations, O6-methylguanine DNA methyltransferase (MGMT) gene promoter methylation is the most investigated biomarker and seems to be an early and frequent event, at least in CRC. Loss of expression of MGMT as a result of gene promoter methylation has been associated with interesting activity of alkylating agents in mCRC. However, the optimal methods for the definition of the MGMT status and additional predictive factors beyond MGMT in GI malignancies are lacking. Here we review the current role of MGMT methylation and other epigenetic alterations as potential treatment targets in GI tumors