Prospective study of a molecular selection profile for RAS wild type colorectal cancer patients receiving irinotecan-cetuximab

Background: The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed might be able to predict patients' clinical outcome more accurately than RAS status alone. Methods: K-RAS (exons 2, 3, 4) wild type colorectal cancer patients, candidates to second/third-line cetuximab with chemotherapy were prospectively allocated into 2 groups on the basis of their profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ≥ 2.6, HER-3 Rajkumar score ≤ 8, IGF-1 immunostaining < 2) or unfavourable (any of the previous markers altered or mutated). After the introduction of N-RAS status (exons 2, 3, 4) only RAS wild type patients were considered eligible. Results: Forty-six patients were enrolled. Seventeen patients (37%) were allocated to the favourable and 29 patients (63%) to the unfavourable profile. RR in the favourable and unfavourable group was 11/17 (65%) and 2/29 (7%) (p = 0.007) respectively. The favourable group also showed an improved PFS (8months vs. 3months, p < 0.0001) and OS (15months vs. 6months, p < 0.0001). Conclusions: Our results suggest that prospective selection of optimal candidates for cetuximab treatment is feasible and may be able to improve clinical outcom

Prognostic value for incidental antihypertensive therapy with β-blockers in metastatic colorectal cancer

Previous studies suggested that the incidental use of β-blockers might influence clinical outcome in solid tumors. We assessed the correlation between the incidental use of β-blockers and clinical outcome in colorectal cancer patients treated with first-line chemotherapy alone or in combination with bevacizumab in metastatic colorectal cancer patients. We collected data from 235 metastatic colorectal cancer patients treated with first-line chemotherapy alone (128 patients) or with bevacizumab (107 patients). Patients were stratified for clinical factors such as β-blockers use, age, sex, and site of metastases, previous adjuvant chemotherapy and ECOG performance status. In the chemotherapy alone group patients receiving β-blockers showed an improved overall survival (median OS 41.3 vs 25.7 months, P = 0.03, HR: 2.26, 95% CI: 1.05-3.24). A significant relationship with improved response rate was also evident for B-blocker users (P = 0.044). On the contrary in the β-blockers users group treated with chemotherapy in combination with bevacizumab we observed a trend toward a worse overall survival although nonstatistically significant (median OS 18.5 vs 23.6 months, HR: 0. 89, 95% CI: 0.38-2.03, P = 0.77). Our analysis confirmed a potential prognostic role for the use of β-blockers in colorectal cancer patients treated with chemotherapy. Our findings also suggest a potential worse outcome for patients on β-blockers receiving bevacizumab. Future prospective studies should include the incidental use of β-blockers as stratification factor for clinical outcome

Lactate dehydrogenase in hepatocellular carcinoma: something old, something new

Hepatocellular carcinoma (HCC) is the most common primary liver tumour (80-90%) and represents more than 5.7% of all cancers. Although in recent years the therapeutic options for these patients have increased, clinical results are yet unsatisfactory and the prognosis remains dismal. Clinical or molecular criteria allowing a more accurate selection of patients are in fact largely lacking. Lactic dehydrogenase (LDH) is a glycolytic key enzyme in the conversion of pyruvate to lactate under anaerobic conditions. In preclinical models, upregulation of LDH has been suggested to ensure both an efficient anaerobic/glycolytic metabolism and a reduced dependence on oxygen under hypoxic conditions in tumour cells. Data from several analyses on different tumour types seem to suggest that LDH levels may be a significant prognostic factor. The role of LDH in HCC has been investigated by different authors in heterogeneous populations of patients. It has been tested as a potential biomarker in retrospective, small, and nonfocused studies in patients undergoing surgery, transarterial chemoembolization (TACE), and systemic therapy. In the major part of these studies, high LDH serum levels seem to predict a poorer outcome. We have reviewed literature in this setting trying to resume basis for future studies validating the role of LDH in this diseas

Angiogenesis genotyping in the selection of first-line treatment with either sunitinib or pazopanib for advanced renal cell carcinoma

Recent data from the COMPARZ study seem to suggest a noninferiority of pazopanib confronted with sunitinib in PFS and OS. We previously reported how VEGF and VEGFR polymorphisms might have a predictive role in patients treated with first-line sunitinib. Aim of our study was to investigate whether tumour angiogenesis genotyping could influence clinical outcome in RCC patients treated with either sunitinib or pazopanib, in order to help clinicians select the appropriate treatment for each patient. Results: 19 patients were treated with pazopanib while 78 received sunitinib. VEGF A rs833061 resulted significant in PFS in sunitinib vs pazopanib patients (CC+CT > TT in sunitinib, TT > CC+CT in pazopanib; p CC in sunitinib, CC > GG+CG in pazopanib; p CC in sunitinib, CC > AA+AC in pazopanib; p < 0,0001). OS showed no statistically significant difference. Conclusions: In our analysis patients with opposite polymorphisms of rs833061, rs2010963, rs699947 of VEGF A seems to have a better PFS if treated with either sunitinib or pazopanib. Our data seem to suggest that biology could have a role choosing first line treatment for mRCC patients. Methods: A retrospective analysis on 97 histologic samples of mRCC patients was conducted for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs

Prognostic clinical factors in pretreated colorectal cancer patients receiving regorafenib: implications for clinical management

We assessed the impact on survival of angiogenesis and inflammation-related factors, particularly LDH serum levels, platelet, neutrophil and lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR), in metastatic colorectal cancer patients receiving regorafenib monotherapy

Cancer stem cell gene profile as predictor of relapse in high risk stage II and stage III, radically resected colon cancer patients.

Clinical data indicate that prognostic stratification of radically resected colorectal cancer based on disease stage only may not be always be adequate. Preclinical findings suggest that cancer stem cells may influence the biological behaviour of colorectal cancer independently from stage: objective of the study was to assess whether a panel of stemness markers were correlated with clinical outcome in resected stage II and III colon cancer patients. A panel of 66 markers of stemness were analysed and thus patients were divided into two groups (A and B) with most patients clustering in a manner consistent with different time to relapse by using a statistical algorithm. A total of 62 patients were analysed. Thirty-six (58%) relapsed during the follow-up period (range 1.63-86.5 months). Twelve (19%) and 50 (81%) patients were allocated into group A and B, respectively. A significantly different median relapse-free survival was observed between the 2 groups (22.18 vs 42.85 months, p=0.0296). Among of all genes tested, those with the higher "weight" in determining different prognosis were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and ABCG2. This analysis supports the idea that, other than stage, biological variables, such as expression levels of colon cancer stem cell genes, may be relevant in determining an increased risk of relapse in resected colorectal cancer patient

Role of vascular endothelial growth factor (VEGF) and VEGF-R genotyping in guiding the metastatic process in pT4a resected gastric cancer patients.

In radically resected gastric cancer the possibility to predict the site of relapse could be clinically relevant for the selection of post-surgical management. We previously showed that specific tumour integrins genotypes are independently associated with either peritoneal or hematogenous metastases (ITGA and ITGV). Recently VEGF and VEGF-R polymorphisms have been demonstrated to potentially affect tumour angiogenesis and the metastatic process in gastric cancer. We then investigated the role of VEGFs and VEGF-R genotyping in determining either peritoneal carcinosis or hematogenous metastases in radically resected gastric cancer patients. Tumour genotyping for integrins (ITGA and ITGV) was also performed according to our previous findings. Genotyping for VEGF-A, VEGF-C, VEGFR-1,2,3 and ITGA and ITGV was carried out on pT4a radically resected gastric tumours recurring with either peritoneal-only carcinosis or hematogenous metastases. 101 patients fulfilled the inclusion criteria: 57 with peritoneal carcinomatosis only and 44 with hematogenous spread only. At multivariate analysis, intestinal histology and the AC genotype of rs699947 (VEGFA) showed to independently correlate with hematogenous metastases (p = 0.0008 and 0.008 respectively), whereas diffuse histology and the AA genotype of rs2269772 (ITGA) independently correlated with peritoneal-only diffusion (p = &lt;0.0001 and 0.03 respectively). Our results seem to indicate that combining information from genotyping of rs699947 (VEGFA, AC), rs2269772 (ITGA, AA) and tumour histology could allow clinicians to individuate gastric cancer at high risk for recurrence either with peritoneal or hematogenous metastases. The selection tool deriving from this analysis may allow an optimal use of the available treatment strategies in these patients

VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib

Background: Currently, sunitinib represents one of the therapeutic strongholds for renal cell carcinoma, but the criteria for treatment selection are lacking. We assessed the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms in the prediction of the clinical outcome in metastatic renal cell carcinoma (mRCC) patients.Methods:A total of 84 tumour samples from mRCC patients receiving first-line sunitinib were tested for VEGF and VEGFR single-nucleotide polymorphisms (SNPs). The SNP results were correlated with progression-free survival (PFS) and overall survival (OS).Results:Median PFS was 8.22 months, although whereas median OS was 32.13 months. The VEGF A rs833061 resulted significant in PFS (17 vs 4 months; P<0.0001) and OS (38 vs 10 months; P<0.0001). The VEGF A rs699947 was significant for PFS (18 vs 4 months; P=0.0001) and OS (37 vs 16 months; P<0.0001). The VEGF A rs2010963 was significant in PFS (18 vs 8 vs 2 months; P=0.0001) and OS (31 vs 36 vs 9 months; P=0.0045). The VEGR3 rs6877011 was significant in PFS (12 vs 4 months; P=0.0075) and OS (36 vs 17 months; P=0.0001). At multivariate analysis, rs833061, rs2010963 and rs68877011 were significant in PFS, and rs833061 and rs68877011 were independent factors in OS.Conclusions:In our analysis, patients with TT polymorphism of rs833061, CC polymorphism of rs699947, CC polymorphism of rs2010963 and CG polymorphism of rs6877011 seem to have a worse PFS and OS when receiving first-line sunitini

Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced hcc patients treated with sorafenib: results from a retrospective analysis of the HCC-AVR group

Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (-0.30, p=0.0008) in the responder group (-0.58, p=0.003) than in those with progressive disease (-0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatmen

p 53 abnormal expression might influence global outcome through egfr modulation in ras braf wild type metastatic colorectal cancer patients receiving later line irinotecan cetuximab

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