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

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

New developments in the management of non-small-cell lung cancer, focus on rociletinib: what went wrong?

Recently, the development of the third-generation epidermal growth factor receptor-small molecule inhibitor (EGFR-TKI) rociletinib had failed. In this review, the wide-ranging aspects of the evolution of EGFR-TKIs were collected, with a special focus on rociletinib. The influence of different oncogenic mutations on EGFR activity was also discussed. Resistance to the first (erlotinib, gefitinib)- and second (afatinib)-generation EGFR-TKIs provided the rationale behind the development of the third-generation inhibitors (rociletinib, osimertinib). On the basis of these data, a comparison of their efficacy on the different mutated EGFRs and the respective resistance mechanisms is further reported. Moreover, the evolution and results of the clinical trials of rociletinib (TIGER trials) are compared with the trials on osimertinib, another third-generation EGFR-TKI that now has been granted US Food and Drug Administration approval. The reasons behind the arrest in the further development of rociletinib are put in the perspective of future drug development