Riccardo Giampieri

Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab

BACKGROUND Arterial hypertension occurring during antiangiogenic therapy has been correlated with the biological inhibition of the vascular endothelial growth factor-related pathway and may represent a possible clinical marker for treatment efficacy. The aim of our study was to retrospectively assess if grades 2-3 hypertension were associated with response to bevacizumab, progression-free survival (PFS) and survival in metastatic colorectal cancer patients treated with first-line bevacizumab. PATIENTS AND METHODS Patients with histologically proven, metastatic colorectal cancer receiving bevacizumab as first-line therapy in combination with irinotecan and 5-fluorouracil were eligible for our analysis. RESULTS Thirty-nine metastatic colorectal cancer patients were eligible. Eight patients (20%) developed grades 2-3 hypertension. A partial remission was observed in six of eight cases with bevacizumab-related hypertension (75%) and in 10 of 31 (32%) patients with no hypertension (P = 0.04). Median PFS was 14.5 months for patients showing bevacizumab-related hypertension, while it was 3.1 months in those without hypertension (P = 0.04). Median overall survival was not reached in patients with hypertension while it was 15.1 months in the remaining cases (P = 0.11). CONCLUSIONS Our data indicate that bevacizumab-induced hypertension may represent an interesting prognostic factor for clinical outcome in advanced colorectal cancer patients receiving first-line bevacizumab.

Pre-treatment lactate dehydrogenase levels as predictor of efficacy of first-line bevacizumab-based therapy in metastatic colorectal cancer patients

Background:Lactate dehydrogenase (LDH) represents a predictive factor in colorectal cancer patients treated with the angiogenesis inhibitor PTK/ZK. We explored the role of pre-treatment LDH serum levels in colorectal cancer patients receiving first-line bevacizumab.Methods:Metastatic colorectal cancer treated with first-line bevacizumab was eligible. A control group including all consecutive patients treated with chemotherapy alone was also considered. Pre-treatment LDH serum levels were collected for all cases.Results:Median progression-free survival (PFS) in the control group for patients with high and low LDH levels was 4.2 and 8 months, respectively (P=0.0003). Median overall survival (OS) was 19.6 and 34.9 months for patients with high and low LDH levels, respectively (P=0.0014). In the bevacizumab group, partial responses were seen in 14 (58%) high-LDH and 8 (14%) low-LDH patients (P=0.0243), respectively, median PFS was 7.3 and 8.5 months, respectively (P=0.2), and median OS was 22 and 26.6 months, respectively (P=0.7).Conclusion:High LDH levels correlated with worse prognosis. Bevacizumab seemed capable of improving clinical outcome in this specific group of patients who usually present with an adverse natural history. The improved response rate also suggests a role for LDH as a predictive marker.

Clinical Evidence for Three Distinct Gastric Cancer Subtypes: Time for a New Approach

Background Recently, a new classification for gastric cancer (GC) has been proposed, based on Laurens histology and on anatomic tumour location, identifying three subtypes of disease: type 1 (proximal non diffuse GC), type 2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to compare clinical outcome according to different GC subtypes (1,2,3) in metastatic GC patients receiving first-line chemotherapy. Patients and Methods Advanced GC pts treated with a first-line combination chemotherapy were included in our analysis. Pts were divided in three subgroups (type 1, type 2 and type 3) as previously defined. Results A total of 248 advanced GC pts were included: 45.2% belonged to type 2, 43.6% to type 3 and 11.2% to type 1. Patients received a fluoropyrimidine-based chemotherapy doublet or three drugs regimens including a platinum derivate and a fluoropyrimidine with the addition of an anthracycline, a taxane or mytomicin C. RR was higher in type 1 pts (RR = 46.1%) and type 3 (34,3%) compared to type 2 (20,4%), (p = 0.015). Type 2 presented a shorter PFS, median PFS = 4.2 months, compared to type 1, mPFS = 7.2 months, and type 3, mPFS = 5.9 months (p = 0.011) and also a shorter OS (p = 0.022). Conclusions Our analysis suggests that GC subtypes may be important predictors of benefit from chemotherapy in advanced GC patients. Future clinical trials should take in account these differences for a better stratification of 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 sunitinib.

Epidermal growth factor receptor (EGFR) gene promoter methylation and cetuximab treatment in colorectal cancer patients

Background:Epidermal growth factor receptor (EGFR) promoter methylation may be responsible for the loss of EGFR expression in neoplastic cells. The primary aim of our study was to verify a possible correlation between EGFR gene promoter methylation and clinical outcome in metastatic colorectal cancer patients receiving chemotherapy with irinotecan and cetuximab.Methods:Colorectal samples from patients treated with irinotecan–cetuximab were analysed for EGFR promoter methylation and EGFR immunohistochemistry.Results:Fifty-two patients were analysed. Thirty patients (58%) showed EGFR promoter hypermethylation. In EGFR promoter methylated and EGFR promoter unmethylated patients, we observed a partial response in 3 (10%) and 13 (59%) patients, respectively (P=0.03), progressive disease was obtained in 19 (63%) and 2 (9%) patients, respectively, with EGFR promoter methylated and EGFR promoter unmethylated tumours (P=0.0001). Median progression-free survival was 2.4 months in patients showing EGFR promoter methylated tumours and 7.4 months for those who had EGFR promoter unmethylated tumours (P<0.0001; Figure 1). Median overall survival was 6.1 months in patients showing EGFR promoter methylated tumours and 17.8 months for those who had EGFR promoter unmethylated tumours (P<0.0001; Figure 2). CONCLUSION: EGFR promoter hypermethylation, after confirmation in larger data set, may represent a valuable asset in further studies investigating EGFR as a therapeutic target in colorectal cancer.

Insulin-like growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan.

Seventy to 40% of K‐RAS wild type colorectal tumors does not seem to benefit from treatment with antiepidermal growth factor receptor (anti‐EGFR) monoclonal antibodies. Recent data suggested that in presence of IGF‐1 system, altered activation colorectal cancer cells may escape anti‐EGFR mediated cell death. The interaction between IGF‐1 expression and K‐RAS mutational analysis was tested to verify the ability of IGF‐1 to identify a subgroup of patients more likely to benefit from EGFR‐targeted antibodies treatment. IGF‐1 expression and K‐RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. One hundred twelve patients were analyzed. IGF‐1 was negative in 30 patients (27%) and overexpressed in the remaining 82 cases (73%). In IGF‐1 negative and IGF‐1 positive tumors, we observed progressive disease in 9 (30%) and 55 (67%) patients, respectively (p = 0.001). Median progression‐free survival was 7.5 mo in patients showing IGF‐1 negative tumors and 3 mo for IGF‐1 expressing tumors (p = 0.002). Among K‐RAS wild type patients, IGF‐1 negative and positive tumors showed a partial response to cetuximab‐irinotecan in 13 (65%) and 11 (22%) cases, respectively (p = 0.002). Median progression‐free survival in IGF‐1 negative tumors was 10 mo and 3.2 mo in IGF‐1 positive colorectal cancers (p = 0.02). IGF‐1 proved to be a possible predictive factor for resistance to anti‐EGFR monoclonal antibodies in K‐RAS wild type colorectal cancer. Combined IGF‐1 and K‐RAS analysis may represent an effective strategy for a better selection of responding colorectal cancer patients.

The Role of HER-3 Expression in the Prediction of Clinical Outcome for Advanced Colorectal Cancer Patients Receiving Irinotecan and Cetuximab

Preclinical data suggested that, in the presence of human epidermal growth factor receptor (HER)-3-altered activation, colorectal cancer cells may escape anti-epidermal growth factor receptor (EGFR)-mediated cell death. HER-3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER-3 expression and clinical outcome in wild-type K-RAS advanced colorectal cancer patients receiving cetuximab and irinotecan. We retrospectively analyzed immunoreactivity for HER-3 in wild-type K-RAS advanced colorectal cancer patients receiving irinotecan and cetuximab. Eighty-four advanced wild-type K-RAS colorectal cancer patients were available for HER-3 analysis. Forty patients (48%) had a HER-3(-) colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER-3(+). In patients with HER-3(-) and HER-3(+) tumors, we observed a partial response in 17 (42%) and eight (18%) patients respectively; progressive disease occurred in 11 (35%) and 26 (53%) patients with HER-3(-) and HER-3(+) tumors, respectively (p = .003). The median progression-free survival time was 6.3 months in patients with HER-3(-) tumors and 2.8 months for those who had HER-3-overexpressing tumors (p < .0001). The median overall survival time was 13.6 months in patients showing HER-3(-) tumors and 10.5 months for those who had HER-3-expressing tumors (p = .01). HER-3 proved to be a predictive factor for clinical outcome in wild-type K-RAS colorectal cancer patients treated with cetuximab. Combined HER-3 and K-RAS analysis may represent an effective strategy for better selection of responding colorectal cancer patients.

The role of Micro-RNAs in Hepatocellular Carcinoma: From Molecular Biology to Treatment

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer deaths. microRNAs (miRNAs) are evolutionary conserved small non-coding RNA that negatively regulate gene expression and protein translation. Recent evidences have shown that they are involved in many biological processes, from development and cell-cycle regulation to apoptosis. miRNAs can behave as tumor suppressor or promoter of oncogenesis depending on the cellular function of their targets. Moreover, they are frequently dysregulated in HCC. In this review we summarize the latest findings of miRNAs regulation in HCC and their role as potentially diagnostic and prognostic biomarkers for HCC. We highlight development of miRNAs as potential therapeutic targets for HCC.

5-fluorouracil pharmacogenomics: still rocking after all these years?

The 5-fluorouracil (5-FU) metabolic pathway is mainly dependent on the activity of several intracellular enzymes. Among them, four in particular; thymidylate synthase, methylenetetrahydrofolate reductase, dihydropyrimidine dehydrogenase and thymidine phosphorylase are considered the key points in determining sensitivity or resistance to this drug. These enzymes are needed to metabolize the drug in its active form (thymidylate phosphorylase) or to drop the concentration of the active drug in the cell (dihydropyrimidine dehydrogenase) or both (thymidylate synthase and methylenetetrahydrofolate reductase). Several different studies have tried to investigate the relationship between the presence of mutations in these enzymes and a reduced/improved activity of treatment based on 5-FU or its derivatives. In this article, we will focus on the often contradictory results of these studies.

The Role of LDH Serum Levels in Predicting Global Outcome in HCC Patients Undergoing TACE: Implications for Clinical Management

In many tumor types serum lactate dehydrogenase (LDH) levels is an indirect marker of tumor hypoxia, neo-angiogenesis and worse prognosis. However data about hepatocellular carcinoma (HCC) are lacking in the clinical setting of patients undergoing transarterial-chemoembolization (TACE) in whom hypoxia and neo-angiogenesis may represent a molecular key to treatment failure. Aim of our analysis was to evaluate the role of LDH pre-treatment levels in determining clinical outcome for patients with HCC receiving TACE. One hundred and fourteen patients were available for our analysis. For all patients LDH values were collected within one month before the procedure. We divided our patients into two groups, according to LDH serum concentration registered before TACE (first: LDH≤450 U/l 84 patients; second: LDH>450 U/l 30 patients). Patients were classified according to the variation in LDH serum levels pre- and post-treatment (increased: 62 patients vs. decreased 52 patients). No statistically significant differences were found between the groups for all clinical characteristics analyzed (gender, median age, performance status ECOG, staging systems). In patients with LDH values below 450 U/l median time to progression (TTP) was 16.3 months, whereas it was of 10.1 months in patients above the cut-off (p = 0.0085). Accordingly median overall survival (OS) was 22.4 months and 11.7 months (p = 0.0049). In patients with decreased LDH values after treatment median TTP was 12.4 months, and median OS was 22.1 months, whereas TTP was 9.1 months and OS was 9.5 in patients with increased LDH levels (TTP: p = 0.0087; OS: p<0.0001). In our experience, LDH seemed able to predict clinical outcome for HCC patients undergoing TACE. Given the correlation between LDH levels and tumor angiogenesis we can speculate that patients with high LDH pretreatment levels may be optimal candidates for clinical trial exploring a multimodality treatment approach with TACE and anti-VEGF inhibitors in order to improve TTP and OS.