Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study.

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10-6 ) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55-2.77, ptrend = 0.7 × 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants.

TRIBE-2: a phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group.

BACKGROUND: Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. METHODS/DESIGN: TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. DISCUSSION: The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. TRIAL REGISTRATION: TRIBE2 is registered at Clinicaltrials.gov: NCT02339116 . January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014.

Metronomic oral vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer: results of a phase II trial (MOVE trial).

BACKGROUND: Metronomic oral vinorelbine could be a safe option for elderly patients with advanced non small cell lung cancer (NSCLC). Metronomic administration of chemotherapy leads to a cytostatic action shifting treatment target from cancer cell to tumor angiogenesis. METHODS: 43 chemotherapy naive elderly (≥ 70 yrs) PS 0-2 patients with stage IIIB-IV NSCLC were prospectively recruited. Median age was 80 yrs (M/F 36/7) with predominantly squamous histology. PS distribution was 0-1(16)/2(27) with a median of 3 serious co-morbid illnesses. Study treatment consisted of oral vinorelbine 50mg three times weekly (Monday-Wednesday-Friday) continuously until disease progression, unacceptable toxicity or patient refusal. Primary endpoints were overall response rate (ORR), clinical benefit (CB--disease response plus disease stabilization >12 weeks) and safety. Health-related QoL (HRQoL) was also assessed with FACT-L V4 scoring questionnaire. We conducted an exploratory time-course analysis of VEGF and thrombospondin-1 (TSP1) serum levels in a subgroup of patients. RESULTS: Patients received a median of 5 (range 1-21) cycles with a total of 272 cycles delivered. ORR was 18.6% with 7 partial and 1 complete responses; 17/43 experienced stable disease lasting more than 12 weeks leading to an overall CB of 58.1%. Median time to progression was 5 (range 2-21) and median overall survival 9 (range 3-29) months. Treatment was well tolerated with rare serious toxicity. Regardless of severity main toxicities observed were anemia in 44%, fatigue in 32.4%, and diarrhoea 10.5%. FACT-L v4 scores did not significantly vary during treatment. Baseline VEGF levels were lower and showed a rapid increase during treatment in non-responders pts only while TSP1 levels did not change. CONCLUSIONS: Metronomic oral vinorelbine is safe in elderly patients with advanced NSCLC with an interesting activity mainly consisting in long-term disease stabilization coupled with an optimal patient compliance (Eudra-CT 2010-018762-23, AIFA OSS on 26 February 2010).

Evaluation of HER2 and p53 expression in predicting response to docetaxel-based first-line chemotherapy in advanced breast cancer.

BACKGROUND: The human epidermal growth factor receptor 2 (HER2) and p53 pathways may be involved in chemotherapy sensitivity and/or resistance. We explore the value of HER2 and p53 status to foretell docetaxel sensitivity in advanced breast cancer. METHODS: HER2 and p53 expression was analysed in 36 (median age 55 yrs; range 37-87) metastatic breast cancer patients receiving docetaxel-based first-line chemotherapy. HER2 was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), p53 was tested by IHC. We correlate the expression of study parameters with pathologic parameters, RECIST response and survival. The standard cut-off value of 2 was used to determine HER2 overexpression while p53 mean expression level was used to divide low/high expressors tumors. RESULTS: Median time to progression and overall survival were 9 (range 2-54) and 20 (range 3-101) months. Overall response rate was 41.6%. Nine cases showed HER2 overexpression. HER2 was more frequently overexpressed in less differentiated (p=0.05) and higher stage (p=0.003) disease. Mean FISH-HER2 values were significantly higher in responder than in non-responder pts (8.53±10.21 vs 2.50±4.12, p=0.027). Moreover, HER2 overexpression correlates with treatment response at cross-tabulation analysis (p=0.046). p53 expression was only associated with higher stage disease (p=0.02) but lack of any significant association with HER status or docetaxel response. No significant relation with survival was observed for any parameter. CONCLUSION: Our data seem to indicate that FISH-determined HER2 status but not p53 is associated with docetaxel sensitivity in metastatic breast cancer.

Sorafenib in a patient with advanced hepatocellular carcinoma and serious impairment of left ventricular function: a case report.

INTRODUCTION: sorafenib, a tyrosine-kinase inhibitor, is widely used in the treatment of advanced hepatocellular carcinoma. Drug-related toxicities are generally mild but sorafenib, as other similar agents, may induce elevation of systemic arterial blood pressure levels in relation to an interaction with cardiovascular system probably mediated by HIF pathway. This side effect may be particularly critical for patients with underlying serious heart disease as it can induce acute heart failure, a life-threatening condition, and usually such patients are excluded from active treatment with tyrosine-kinase inhibitors. We report the case of a patient affected by advanced hepatocellular carcinoma and serious impairment of cardiac function treated with sorafenib without any worsening of heart function. To our knowledge this is the first report of this kind in the literature. CASE PRESENTATION: We report the case of a 74-year-old patient affected by advanced multifocal HCV-cirrhosis related hepatocellular carcinoma and severe post-ischemic fall of left-ventricular function with serious risk of cardiac functional impairment. The patient presented with an ECOG performance status of 0. Blood chemistry tests showed a substantial elevation of alpha-fetoprotein values and slight increases of bilirubin, of gamma-GT and of GOT; the absence of encephalopathy and ascites and the normality of coagulation parameters and of albumin led to classify the patient into the functional class Child-Pugh A. The patients was successfully treated with sorafenib at the reduced daily dose of 400 mg for long-time without any worsening of heart function. CONCLUSION: The presented case can offer to oncologists a clinical support to take into consideration when deciding to treat with sorafenib advanced hepatocellular carcinoma patients presenting with serious impairment of cardiac function that are usually excluded from an active treatment.

Fulvestrant treatment is associated with cholesterol plasma level reduction in hormone-receptor-positive metastatic breast cancer patients.

BACKGROUND: Fulvestrant is a pure anti-estrogen hormoal agent formally lacking any estrogen-agonist activity. We analyze the effect(s) of fulvestrant treatment on estrogen target systems in hormoe-sensitive advanced breast cancer patients. RESULTS: Patients received a median of five fulvestrant injections (range 3-19). We observed a partial response in one patient, disease stability in 21 and disease progression in 29 patients with a clinical benefit of 43.2% and a median time to progression of 5 [range 3-20] mo. Total cholesterol levels significantly decreased during treatment (219.8 +/- 45.3 vs. 201.4 +/- 42.1 mg/dl; p = 0.0054) together with LDL-cholesterol (129.7 +/- 41.39 vs. 112.3 +/- 37.1 mg/dl; p = 0.018). HDL-cholesterol and triglycerides did not show significant changes. Reduction of total and LDL-cholesterol was independent from last hormoal treatment or treatment duration. All coagulation indices and mean endometrial mucosa thickness value did not vary. METHODS: Fifty-one patients [median age 65 (range 48-82) y] were enrolled. All patients received previous hormoal treatments, with 90.2% receiving > or =2 courses. Last hormoal treatment was exemestane, letrozole, anastrozole and other in 30-10-7-4/51 patients respectively. Median withdrawal time was 18 d (range 3-1456). Complete fasting lipid blood profile and coagulation indices were assessed before fulvestrant administration, every 3 mo and at discontinuation time. Endometrial mucosa thickness was evaluated before fulvestrant administration and at end-study time. CONCLUSIONS: We observed a lipid lowering effect of fulvestrant possibly related to an influence on lipid metabolism by a mechanism in which a role could be played by progesterone receptor.

Expression of dystroglycan correlates with tumor grade and predicts survival in renal cell carcinoma.

The dystroglycan (DG) complex is a transmembrane glycoprotein that forms a continuous link from the extracellular matrix to the actin cytoskeleton. Deregulated expression of DG has been reported in a variety of human malignancies and related to tumor aggressiveness. In this study expression of the DG subunit was evaluated by immunostaining in a series of renal epithelial cancers and its relation with traditional prognostic indicators and with the clinical outcome of the patients was evaluated. alphaDG expression was undetectable in a significant fraction of tumors (54%). In renal cell carcinomas (RCC) loss of alpha-DG staining correlated with higher tumor grade (p = 0.02) but not with tumor stage nor tumor size. In clear cell RCC patients loss of alphaDG staining correlated with an increased risk of recurrence (p = 0.002 by log-rank test) and death (p = 0.004) also when patients with lower grade or stage tumors were analyzed separately. In a multivariate analysis loss of DG staining confirmed to be and independent predictor of shorter disease-free (p = 0.001; RR = 4.9) and overall (p = 0.009; RR = 4.9) survival stronger than tumor grade and size. These findings demonstrate that loss of alphaDG expression, which correspond to loss of a functional DG complex, is a frequent event in human renal tumorigenesis and is an independent predictor of early recurrence and death for patients with clear cell RCC.