AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin.

The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin +/- cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.

Molecular signatures of mRNAs and miRNAs as prognostic biomarkers in pancreatobiliary and intestinal types of periampullary adenocarcinomas.

Periampullary adenocarcinomas include four anatomical sites of origin (the pancreatic duct, bile duct, ampulla and duodenum) and most of them fall into two histological subgroups (pancreatobiliary and intestinal). Determining the exact origin of the tumor is sometimes difficult, due to overlapping histopathological characteristics. The prognosis depends on the histological subtype, as well as on the anatomical site of origin, the former being the more important. The molecular basis for these differences in prognosis is poorly understood. Whole-genome analyses were used to investigate the association between molecular tumor profiles, pathogenesis and prognosis. A total of 85 periampullary adenocarcinomas were characterized by mRNA and miRNA expressions profiling. Molecular profiles of the tumors from the different anatomical sites of origin as well as of the different histological subtypes were compared. Differentially expressed mRNAs and miRNAs between the two histopathological subtypes were linked to specific molecular pathways. Six miRNA families were downregulated and four were upregulated in the pancreatobiliary type as compared to the intestinal type (P < 0.05). miRNAs and mRNAs associated with improved overall and recurrence free survival for the two histopathological subtypes were identified. For the pancreatobiliary type the genes ATM, PTEN, RB1 and the miRNAs miR-592 and miR-497, and for the intestinal type the genes PDPK1, PIK3R2, G6PC and the miRNAs miR-127-3p, miR-377* were linked to enriched pathways and identified as prognostic markers. The molecular signatures identified may in the future guide the clinicians in the therapeutic decision making to an individualized treatment, if confirmed in other larger datasets.

Plasma microRNAs predicting clinical outcome in metastatic colorectal cancer patients receiving first-line oxaliplatin-based treatment.

The conventional first-line chemotherapy for metastatic colorectal cancer (mCRC) consists of fluorouracil (5-FU) in combination with either oxaliplatin or irinotecan. We have explored microRNAs (miRNAs) in plasma as potential predictive markers to oxaliplatin-based chemotherapy. The expression of 742 miRNAs was examined in plasma samples from 24 mCRC patients (12 responders and 12 non-responders) before onset and after four cycles of 5-FU/oxaliplatin. The top differentially expressed miRNAs between responders and non-responders were selected for further analysis in a validation cohort of 150 patients. In the validation cohort, there was a significant overrepresentation of miRNAs with higher mean expression in the non-responder group than in the responder group before treatment (p < 0.002). Moreover, we found three miRNAs (miR-106a, miR-484, and miR-130b) to be significantly differentially expressed before treatment (p = 0.008, 0.008, and 0.008, respectively). All three miRNAs were upregulated in non-responders. High expression of miR-27b, miR-148a, and miR-326 were associated with decreased progression-free survival (Hazard ratios (HR) of 1.4 (95% CI 1.1-1.8, p = 0.004), 1.3 (95% CI 1.1-1.6, p = 0.007), and 1.4 (95% CI 1.1-1.8, p = 0.008), respectively). miR-326 was also associated with decreased overall survival (HR 1.5 (95% CI 1.1-2.0, p = 0.003)). There were no significantly differentially expressed miRNAs in association with clinical outcome after four cycles of chemotherapy. The present study demonstrates that plasma miRNAs analyzed before treatment may serve as non-invasive markers predicting outcome in mCRC patients treated with 5-FU and oxaliplatin-based chemotherapy.

Follow-up after curative surgery for pancreatic ductal adenocarcinoma: asymptomatic recurrence is associated with improved survival.

AIM: There is no consensus on the optimal follow-up schedule of patients after surgery for pancreatic cancer. In this retrospective study, recurrence and survival were investigated for patients presenting with either symptomatic or asymptomatic recurrence. Patient, tumor and treatment characteristics that predicted the length of postrecurrence survival were identified. METHODS: Clinical records of 164 patients who underwent a pancreatic resection (R0/R1) for pancreatic ductal adenocarcinoma from January 2000 to December 2010 were retrieved. Patients underwent a systematic follow-up program. Patient, tumor and treatment characteristics were compared between patients with asymptomatic and symptomatic recurrence. RESULTS: Of 164 consecutive patients, 144 patients (88%) had recurrence (29 asymptomatic, 115 symptomatic). The most frequent reported symptoms were abdominal pain, fatigue/weakness, back pain, weight loss, nausea/loss of appetite and jaundice. Median time to recurrence was 12.0 months for asymptomatic and 7.0 months for symptomatic patients (P = 0.036). Median postrecurrence survival was 10.0 months for asymptomatic and 4.0 months for symptomatic patients (P < 0.0001). Median overall survival was 24.5 months for asymptomatic and 11.0 months for symptomatic patients (P < 0.0001). Symptomatic recurrence, disease free survival <12 months, and no adjuvant chemotherapy were the only independent predictors of poor postrecurrence survival. 72% of asymptomatic and 37% of symptomatic patients received oncological treatment. CONCLUSIONS: Patients with asymptomatic pancreatic cancer recurrence have improved recurrence-free, postrecurrence and overall survival. Symptoms when recurrence is diagnosed are a good surrogate marker of biological aggressiveness. Detection of asymptomatic recurrence may facilitate patient eligibility for investigational studies or other forms of treatment.