[Show abstract][Hide abstract] ABSTRACT: Gastric cancer remains one of the most common malignancies worldwide. Despite the significant advances in surgical treatment and multimodality strategies, prognosis has modestly improved over the last two decades. Locoregional relapse remains one of the main issues and the combined chemoradiation treatment seems to be one of the preferred approaches. However, more than ten years after the hallmark INT-0116 trial, minimal progress has been made both in terms of effectiveness and toxicity. Moreover, new regimens added to combined therapy failed to prove favourable results. Herein, we attempt a thorough literature review comparing pros and cons of all relative studies and potential bias, targeting well-designed future approaches.
Gastroenterology Research and Practice 01/2015; 2015(4):1-9. DOI:10.1155/2015/650846 · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lynch syndrome is the most common form of hereditary colorectal cancer and is caused by germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Mutation carriers have an increased lifetime risk of developing colorectal cancer as well as other extracolonic tumours. The aim of the current study was to evaluate the frequency and distribution of mutations in the MLH1, MSH2 and MSH6 genes within a cohort of Cypriot families that fulfilled the revised Bethesda guidelines. The study cohort included 77 patients who fulfilled at least one of the revised Bethesda guidelines. Mutational analysis revealed the presence of 4 pathogenic mutations, 3 in the MLH1 gene and 1 in the MSH2 gene, in 5 unrelated individuals. It is noted that out of the 4 pathogenic mutations detected, one is novel (c.1610delG in exon 14 of the MLH1) and has been detected for the first time in the Cypriot population. Overall, the pathogenic mutation detection rate in our patient cohort was 7%. This percentage is relatively low but could be explained by the fact that the sole criterion for genetic screening was compliance to the revised Bethesda guidelines. Larger numbers of Lynch syndrome families and screening of the two additional predisposition genes, PMS2 and EPCAM, are needed in order to decipher the full spectrum of mutations associated with Lynch syndrome predisposition in Cyprus.
PLoS ONE 08/2014; 9(8):e105501. DOI:10.1371/journal.pone.0105501 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.
Design To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.
Results Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.
Conclusions No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.
Gut 07/2014; 64(6). DOI:10.1136/gutjnl-2014-307234 · 13.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a continuously aging population, the burden of colorectal cancer (CRC) is rising among older patients. Despite the fact that almost half of the cases occur in patients over 75 years, this age group is subjected to disparities regarding diagnostic and therapeutic options. So far, exclusion of older patients from randomized clinical trials has resulted in a lack of evidence-based guidelines. Nevertheless, newer data from studies specifically targeting older patients and subgroup analyses indicate that proper treatment planning and specific medical and geriatric assessment can achieve a safe and beneficial treatment result in older patients, often with similar outcomes to their younger counterparts. Resection of the primary tumour, if feasible, should be the primary goal of surgery aiming for cure, although it should be avoided under emergency conditions. Chronological age per se should not be an exclusion criterion for adjuvant or palliative chemotherapy, or targeted therapies. Careful patient selection, dose adjustments, close monitoring and early intervention in the event of side effects are essential. The benefits of treatment must be balanced with potential effects of treatment and patients' wishes.
[Show abstract][Hide abstract] ABSTRACT: Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking.
We profiled expession of 24526 genes by means of whole genome 24 K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab + chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS).
Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1 + TFF2 + MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p = 0.007), but not in the Control set (ORR 36.4%, p = 0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1 + TFF2 + MCM5) profile versus any other ALDH6A1 + TFF2 + MCM5 profile was 15 (p = 0.018) in the Bevacizumab qPCR set but only 0.72 (p = 0.63) in the Control set. The tumor expression profile of (KLF12-high + TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12 + TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p = 0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12 + TFF2 expression profile was 2.92 (p = 0.03) in the Validation and 1.29 (p = 0.39) in the Control set.
Our «three-stage» hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer.
BMC Cancer 02/2014; 14(1):111. DOI:10.1186/1471-2407-14-111 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with colorectal cancer (CRC) with wild-type KRAS mutations are often treated with the endothelial growth factor receptor (EGFR) monoclonal antibody cetuximab. Despite the presence of a specific molecular target, most patients still do not derive benefit from this biological treatment. Our study explores the role of ephrin A2 (EphA2) receptor expression and of EGFR pathway mediators as predictors of cetuximab benefit.
Formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 226 cetuximab-treated patients with CRC were studied for mRNA expression of insulin growth factor binding protein 2 (IGFBP2), insulin growth factor receptor 1 (IGF1R), cMET, EphA2, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 by means of TaqMan reverse-transcribed polymerase chain reaction (RT-PCR).
Of the 226 patients evaluable for exploratory analysis, 222 had complete data from follow-up visits. The univariate analysis revealed the following significant adverse prognostic factors for risk of death: high EphA2 mRNA levels (hazard ratio [HR], 1.61; P = .015), high HER2 mRNA levels (HR, 1.51; P = .045), and high IGF1R mRNA levels (HR, 1.56; P = .021). Low EphA2 tumor expression was significantly associated with objective response to cetuximab therapy. In multivariate analysis of a broad biomarker panel, factors with independent prognostic value included EphA2 mRNA levels (HR, 1.67; P = .029), high amphiregulin (AREG) mRNA levels in KRAS wild-type tumors (HR, 0.17; P < .0001), and high epiregulin (EREG) mRNA levels (HR, 0.38; P = .006).
High EphA2 receptor expression in CRC was associated with a worse outcome in patients treated with cetuximab-based therapy. Prospective validation in treated and control patients is required to dissect the predictive from prognostic role in advanced CRC.
Clinical Colorectal Cancer 09/2013; 12. DOI:10.1016/j.clcc.2013.07.001 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer is the commonest malignancy in patients aged 75 years or older. The incidence is likely to rise further over the next two decades as the population ages and survival increases. Robust data on the adherence to guidelines for the elderly and the uptake of treatment in the elderly are limited—particularly with regard to rectal cancer. However, the evidence available suggests that clinical attitudes observed regarding age and cancer treatment are consistent. Older people with colorectal cancer tend to be offered either less intensive treatment or no treatment at all. Population data confirm that treatment rates for surgery, chemotherapy and radiotherapy in patients with colorectal cancer all decline for those over 70 years old, and continue to decline exponentially with increasing age. So should new, more tolerable strategies which may avoid radical surgery be more widely available (short-course preoperative radiotherapy, chemoradiotherapy, transanal excision microsurgery, brachytherapy, contact therapy)? It is not clear if oncologists are always making the most appropriate management decisions. So how do oncologists and surgeons balance chronological age, comorbidity, social isolation and other influences in their clinical decision-making? We need to recognise that this is a difficult issue and will be an increasing issue for multidisciplinary teams.
Current Colorectal Cancer Reports 06/2013; 9(2). DOI:10.1007/s11888-013-0163-8
[Show abstract][Hide abstract] ABSTRACT: Background
More than half of patients with KRAS-wild type advanced colorectal cancer (CRC) fail anti-EGFR monoclonal antibodies. We studied EGFR-axis messenger RNA (mRNA) expression and RAS, RAF, PIK3CA mutations in order to identify additional biomarkers of cetuximab efficacy.
Previously genotyped (KRAS, NRAS, BRAF, PIK3CA mutations) formalin-fixed paraffin-embedded tumour biopsies of 226 cetuximab-treated CRC patients (1st to 3rd line therapy) were assessed for mRNA expression of epidermal growth factor receptor (EGFR) and its ligands EGF, Transofrming Growth Factor-a (TGFA), Amphiregulin (AREG) and Epiregulin (EREG) with real time quantitative PCR. Mutations were detected in 72 (31.9%) tumours for KRAS, in 6 (2.65%) for BRAF, in 7 (3.1%) for NRAS and in 37 (16.4%) for PIK3CA.
Only PIK3CA mutations occasionally coexisted with other gene mutations. In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7). EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1). In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA. Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC. Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20–35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25–35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19 months, 95% CI 15–26).
BRAF and codon 12 KRAS mutations predict for adverse outcome of CRC patients receiving cetuximab. AREG mRNA reflects EGFR signalling in KRAS wild type tumours, predicting for cetuximab efficacy when high and failure when low. EREG may have a prognostic role independent of KRAS mutation.
BMC Cancer 02/2013; 13(1):49. DOI:10.1186/1471-2407-13-49 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) largely affects older individuals; almost half of cases occur in patients >75 years old. The incidence increases with advancing age, doubling every 7 years in patients aged ≥50 years. The medical and societal burdens of CRC will probably worsen over the coming decades as the number of older individuals (>70) continues to grow. No evidence-based guidelines are available for this age group, as older patients with CRC are generally excluded from randomized clinical trials and the fit ones who are recruited are not representative of the general elderly population. When feasible, surgery is the most successful treatment option for eradicating the primary lesion, as well as any metastases. The operative risk under elective conditions is not markedly different in older than in younger patients; however, the acute setting is to be avoided as it is associated with high operative death rates. Well-selected older patients can tolerate chemotherapy, but benefits need to be balanced against potentially limited life expectancy and reduced quality of life. The use of combination chemotherapy is an area of much controversy, but this treatment should not necessarily be withheld because of the age of the patient. Careful monitoring of toxicities and early intervention is essential in older patients undergoing chemotherapy.
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer remains a major cause of cancer mortality in the Western world. With a median age at presentation of 71, patients with metastatic disease are often elderly with significant co-morbidities. In addition, elderly patients are more likely to be undertreated and under-represented in clinical trials. Therefore, as the available data from clinical trials are scarce, the optimal treatment strategy for this group of patients has not been adequately defined. In the setting of metastatic colorectal cancer, the introduction of so called targeted agents has significantly improved outcomes in the context of randomized clinical trials, while at the same time increasing treatment options for such patients. This review focuses on the role of targeted therapies in elderly patients with metastatic colorectal cancer, with specific reference to toxicity and tolerability. It should be noted that studies reviewed herein will have mostly included fit elderly patients fulfilling specific inclusion criteria. The available data so far are limited but suggest that targeted agents have similar efficacy and tolerability in elderly fit patients when compared with younger ones, provided caution is exercised in specific high-risk sub-groups. Clearly, further studies aimed at this specific patient population using well-established geriatric end-points will hopefully identify those patients more likely to benefit and less likely to suffer severe side effects.
[Show abstract][Hide abstract] ABSTRACT: EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib, an oral tyrosine kinase inhibitor (TKI), administered in patients with advanced non-small cell lung cancer (NSCLC), not progressing following standard 1st-line chemotherapy.
Patients with advanced NSCLC, not-progressing after four cycles of platinum-based chemotherapy, were randomised to receive either gefitinib 250mg/d or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival (OS). Secondary end-points were progression-free survival (PFS) and toxicity. The study was powered to detect a 28% increase in OS from a median of 11-14.1months (HR=0.78) and planned to randomise 598 patients to observe 514 deaths.
After inclusion of 173 patients, the trial was prematurely closed due to low accrual. Baseline characteristics for gefitinib (n=86) and placebo (n=87) arms were well balanced. After a median follow up of 41months, the difference in median OS in the gefitinib and placebo arms was not statistically significant (10.9 and 9.4months, HR 0.83 [95% confidence interval (95% CI) 0.60-1.15]; p=0.2). The difference in median PFS significantly favoured gefitinib (4.1 and 2.9months, HR=0.61, [95% CI 0.45, 0.83]), p=0.0015). Adverse events reported in more than 10% of patients were rash (47% with gefitinib versus 13% with placebo) and diarrhoea (34% with gefitinib versus13% with placebo).
Despite its premature closure, this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS. However, no difference in OS was observed in this study (NCT00091156).
European journal of cancer (Oxford, England: 1990) 07/2011; 47(15):2331-40. DOI:10.1016/j.ejca.2011.06.045 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Systemic chemotherapy improves survival in oesophagogastric cancer however no standard second-line regimen exists due to a paucity of randomised data. Docetaxel combined with irinotecan (DI) provides a suitable option due to the lack of cross-reactivity with first-line therapeutics and a tolerable toxicity profile.
We retrospectively reviewed a cohort of patients with advanced oesophagogastric cancer in two institutions treated with the combination of docetaxel 35 mg/m(2) plus irinotecan 60 mg/m(2) day 1 and day 8 every 21 days, following progression with first-line platinum-based therapy.
Between January 2000 and September 2009, 41 eligible patients were identified. Median age was 58 years, male:female 25:16, adenocarcinoma:squamous cell carcinoma 37:4, oesophageal:oesophagogastric junction:gastric 7:10:24. Locally advanced:metastatic disease 6:35. Previous radical surgery:radiotherapy:both 6:4:7. 27/41 had progressed within 90 days of receiving platinum-based therapy. Median number of chemotherapy cycles: 3 (range 1-12). Eight patients required dose reductions due to DI toxicity. 10/28 evaluable patients had a response, median progression-free survival (PFS) was 11 weeks (95% confidence intervals (CI): 9-13 weeks) with median overall survival 24 weeks (95%CI: 12-35 weeks). No significant prognostic factors were identified.
Weekly docetaxel combined with irinotecan has acceptable safety and modest efficacy in the second-line treatment of advanced oesophagogastric cancer. Further prospective evaluation of this regimen is warranted.
European journal of cancer (Oxford, England: 1990) 05/2011; 47(8):1146-51. DOI:10.1016/j.ejca.2010.12.021 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era.
1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy.
40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio [HR] 1.98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0.0% (0/9) versus 36.8% (121/329; OR 0.00, 0.00-0.89; p=0.029), a median PFS of 11.5 weeks versus 24 weeks (HR 2.52, 1.33-4.78; p=0.013), and a median overall survival of 34 weeks versus 51 weeks (3.29, 1.60-6.74; p=0.0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24.4% in the unselected population, 36.3% in the KRAS wild-type selected population, and 41.2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population.
While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population.
Belgian Federation against Cancer (Stichting tegen Kanker).
The Lancet Oncology 08/2010; 11(8):753-62. DOI:10.1016/S1470-2045(10)70130-3 · 24.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC).
Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117).
No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56% vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated.
This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.
World Journal of Gastroenterology 07/2010; 16(25):3133-43. · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Targeted agents have become an integral part of the treatment of a number of malignant diseases and regimens containing agents that disrupt the epidermal growth factor receptor (EGFR) signaling pathway are now considered a standard therapeutic approach for a range of tumor types. Recently, the mutational status of the KRAS gene in tumors was shown to be predictive of outcome to treatment with EGFR-targeted therapies in metastatic colorectal cancer (mCRC). The immoglobulin (Ig) G1 EGFR-targeting monoclonal antibody (mAb), cetuximab, has been shown to provide significant clinical benefits when added to standard irinotecan- and oxaliplatin-containing chemotherapy regimens, first-line, in patients with KRAS wild-type mCRC. Its effects on tumor response and resectability of metastases make cetuximab a particularly useful treatment option for patients with bulky or initially unresectable disease. With an ever-increasing array of management options available, it is important that patients with mCRC receive the treatment that offers them the best chance of prolonged survival. In view of this, testing for tumor KRAS mutation status should be mandatory at diagnosis of mCRC, prior to treatment decision-making.
[Show abstract][Hide abstract] ABSTRACT: Nasopharyngeal carcinoma (NPC) represents a seldom malignancy in most developed countries. Nevertheless, NPC receives an endemic form in concrete racial entities. The aims of this study were to detect the presence of Epstein-Barr virus DNA (EBV-DNA) in peripheral blood of NPC patients, to molecularly define human leukocyte antigens (HLA) DRB1*, DQA1* and DQB1* allele frequencies, and, finally, to determine whether the genetic predisposition of an individual to NPC depends on the liability to EBV infection.
A total of 101 patients of Hellenic origin and nationality, with histologically proven NPC, participated in this study. EBV-DNA detection was also applied in 66 patients with EBV-related malignancies (Hodgkin's [HL] and non-Hodgkin's lymphoma [NHL]) and infectious mononucleosis (IM), as well as in 80 healthy EBV-seropositive controls.
81% of the NPC patients, 77.8% with HL, 72.2% with NHL, and 66.7% with IM were EBV-DNA positive, whereas the EBV genome was detected only in 15% of the healthy controls. These differences were statistically significant in all cases. Analysis of HLA class II antigens showed decreased frequency of the DRB1*07 (p = 0.003), DQA1*0103 (p = 0.002), and DQA1*0201 (p = 0.003) alleles among NPC patients. A significant association between the HLA-DR/DQ alleles and the presence of EBV-DNA in peripheral whole blood was not established.
Circulating EBV-DNA and specific HLA class II alleles may predispose to or protect from NPC. However, the results of this study suggest that the genetic predisposition of an individual to NPC is independent of the liability to EBV infection.
Strahlentherapie und Onkologie 07/2008; 184(6):325-31. DOI:10.1007/s00066-008-1816-4 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Familial adenomatous polyposis (FAP) is one of the two commonest familial syndromes that predispose to colorectal cancer. FAP is caused by mutations in the adenomatous polyposis coli (APC) tumour suppressor gene that has a high penetrance. The disease is characterized by the occurrence of hundreds to thousands of colorectal polyps, which if left untreated give rise to colorectal cancer. In Cyprus, there are no molecular data available as yet on families with FAP. This work presents the results of APC analysis in our population for the first time. The APC gene was analyzed in 33 DNA samples from 20 individuals belonging to four FAP families and 13 patients with sporadic polyposis. We identified three truncating mutations, four missense mutations and 11 polymorphisms. It is of interest that two of the three truncating mutations, 2307delA and Q1242X, are novel, which supports the existence of a unique genetic pool in the Cypriot population. This ethnic molecular study in addition to highlighting population heterogeneity also contributes to phenotype-genotype associations that are essential for the clinical management of FAP families in Cyprus.