Panitumumab (Vectibix)
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Latest Research Publications

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Latest Research Publications

Price TJ, Peeters M, Kim TW, et al.
Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study.
Lancet Oncol. 2014; 15(6):569-79 [PubMed] Related Publications
BACKGROUND: The anti-EGFR monoclonal antibodies panitumumab and cetuximab are effective in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer. We assessed the efficacy and toxicity of panitumumab versus cetuximab in these patients.
METHODS: For this randomised, open-label, phase 3 head-to-head study, we enrolled patients (from centres in North America, South America, Europe, Asia, Africa, and Australia) aged 18 years or older with chemotherapy-refractory metastatic colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and wild-type KRAS exon 2 status. Using a computer-generated randomisation sequence, we assigned patients (1:1; stratified by geographical region and ECOG performance status, with a permuted block method) to receive panitumumab (6 mg/kg once every 2 weeks) or cetuximab (initial dose 400 mg/m(2); 250 mg/m(2) once a week thereafter). The primary endpoint was overall survival assessed for non-inferiority (retention of ≥ 50% of the cetuximab treatment effect; historical hazard ratio [HR] for cetuximab plus best supportive care vs best supportive care alone of 0.55). The primary analysis included patients who received one or more dose of panitumumab or cetuximab, analysed per allocated treatment. Recruitment for this trial is closed. The trial is registered with, number NCT01001377.
FINDINGS: Between Feb 2, 2010, and July 19, 2012, we enrolled and randomly allocated 1010 patients, 999 of whom began study treatment: 499 received panitumumab and 500 received cetuximab. For the primary analysis of overall survival, panitumumab was non-inferior to cetuximab (Z score -3.19; p=0.0007). Median overall survival was 10.4 months (95% CI 9.4-11.6) with panitumumab and 10.0 months (9.3-11.0) with cetuximab (HR 0.97; 95% CI 0.84-1.11). Panitumumab retained 105.7% (81.9-129.5) of the effect of cetuximab on overall survival seen in this study. The incidence of adverse events of any grade and grade 3-4 was similar across treatment groups. Grade 3-4 skin toxicity occurred in 62 (13%) patients given panitumumab and 48 (10%) patients given cetuximab. The occurrence of grade 3-4 infusion reactions was lower with panitumumab than with cetuximab (one [<0.5%] patient vs nine [2%] patients), and the occurrence of grade 3-4 hypomagnesaemia was higher in the panitumumab group (35 [7%] vs 13 [3%]). We recorded one treatment-related fatal adverse event: a lung infection in a patient given cetuximab.
INTERPRETATION: Our findings show that panitumumab is non-inferior to cetuximab and that these agents provide similar overall survival benefit in this population of patients. Both agents had toxicity profiles that were to be expected. In view of the consistency in efficacy and toxicity seen, small but meaningful differences in the rate of grade 3-4 infusion reactions and differences in dose scheduling can guide physician choice of anti-EGFR treatment.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer KRAS gene Panitumumab (Vectibix) Cetuximab (Erbitux)

Boku N, Sugihara K, Kitagawa Y, et al.
Panitumumab in Japanese patients with unresectable colorectal cancer: a post-marketing surveillance study of 3085 patients.
Jpn J Clin Oncol. 2014; 44(3):214-23 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Panitumumab was approved in Japan in April 2010 for the treatment of Kirsten rat sarcoma-2 virus oncogene wild-type unresectable and recurrent colorectal cancer. We conducted a post-marketing surveillance study to evaluate the safety and effectiveness of panitumumab.
METHODS: After panitumumab was commercially available in Japan, all patients to be treated with panitumumab were enrolled. Data on baseline characteristics, treatment outcome, and incidence and severity of adverse drug reactions were collected.
RESULTS: In total, 3091 patients were registered. In the safety analysis set (n = 3085), panitumumab was administered as monotherapy (40.7%) or combination therapy (59.4%). The median treatment duration was 113 days (range: 1-559 days), and 451 (14.6%) patients received panitumumab for ≥10 months. The overall incidence rate of adverse drug reactions was 84.1%, and the most common adverse drug reaction was skin disorders (78.4%). The incidence rates (all grades) of interstitial lung disease, infusion reaction, electrolyte abnormalities and cardiac disorders were 1.3% (mortality rate: 0.6%), 1.5, 19.3 and 0.2%, respectively. The median survival time of patients treated with panitumumab monotherapy as the third-line, or later, therapy was 10.3 months.
CONCLUSION: This post-marketing survey in clinical practice confirmed the safety and effectiveness of panitumumab. The benefit/risk balance for panitumumab in Japanese patients with unresectable colorectal cancer remains favorable.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Panitumumab (Vectibix) Cetuximab (Erbitux)

Abrams TA, Meyer G, Schrag D, et al.
Chemotherapy usage patterns in a US-wide cohort of patients with metastatic colorectal cancer.
J Natl Cancer Inst. 2014; 106(2):djt371 [PubMed] Related Publications
BACKGROUND: Since the introduction of biologic therapies for the treatment of metastatic colorectal cancer (mCRC), few studies have examined patterns of care or predictors of specific treatment approaches.
METHODS: We assessed 4877 mCRC patients who received chemotherapy between January 2004 and March 2011 at academic, private, and community-based oncology practices subscribing to a US-wide chemotherapy order entry (system capturing disease, patient, provider, and treatment data. Multivariable analyses of these prospectively recorded characteristics were used to identify independent predictors of specific therapeutic choices. All statistical tests were two-sided.
RESULTS: Throughout the study period, fluoropyrimidine/oxaliplatin combination was the most commonly used first-line chemotherapy regimen, representing 71% of first-line therapy by 2007. First-line bevacizumab use averaged 51%, peaking at 55% in 2006. Of those who received first-line bevacizumab, 34% continued to receive bevacizumab in the second-line. Only 26% of patients in our cohort ever received an anti-EGFR monoclonal antibody (cetuximab = 22%; panitumumab = 6%) at some point in their treatment course. Patients treated at academic centers, with longer duration of first-line therapy, and at sites in the western United States were statistically more likely to receive an anti-EGFR antibody. Anti-EGFR antibody use fell by 18% after the US Food and Drug Administration limited its use to patients with KRAS wild-type tumors in June 2009.
CONCLUSIONS: Analysis of this US-wide mCRC cohort demonstrates that bevacizumab has been more consistently integrated into treatment regimens than anti-EGFR antibody therapies, particularly in first-line therapy. However, treatment choices vary substantially according to specific patient, practice, and provider characteristics.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Fluorouracil USA KRAS gene Panitumumab (Vectibix) Bevacizumab (Avastin) Oxaliplatin Irinotecan EGFR Cetuximab (Erbitux)

Bonetti A, Giuliani J, Muggia F
Targeted agents and oxaliplatin-containing regimens for the treatment of colon cancer.
Anticancer Res. 2014; 34(1):423-34 [PubMed] Related Publications
Oxaliplatin and fluoropyrimidines are synergic combinations very active for the treatment of advanced colorectal cancer and for the adjuvant treatment of stage III colon cancer. Oxaliplatin-based regimens can be further strengthened by the addition of a third component, either a traditional drug such as irinotecan or targeted agents such as anti-vascular endothelial growth factor (VEGF) drugs, bevacizumab and aflibercept, or the anti-epidermal growth factor receptor (EGFR), cetuximab and panitumumab. The availabilty of all these active agents prompted several clinical trials on different lines of treatment of advanced colorectal cancer patients and in the adjuvant setting. Clinical studies involving the administration of anti-EGFR drugs also helped identify mutations in KRAS as a negative marker for the activity of these agents. However, positive selection criteria for targeted agents have not been identified. The results of oxaliplatin-containing regimens are critically presented and discussed in this review.

Related: Monoclonal Antibodies Panitumumab (Vectibix) Bevacizumab (Avastin) Oxaliplatin Cetuximab (Erbitux)

Korb ML, Hartman YE, Kovar J, et al.
Use of monoclonal antibody-IRDye800CW bioconjugates in the resection of breast cancer.
J Surg Res. 2014; 188(1):119-28 [PubMed] Related Publications
BACKGROUND: Complete surgical resection of breast cancer is a powerful determinant of patient outcome, and failure to achieve negative margins results in reoperation in between 30% and 60% of patients. We hypothesize that repurposing Food and Drug Administration-approved antibodies as tumor-targeting diagnostic molecules can function as optical contrast agents to identify the boundaries of malignant tissue intraoperatively.
MATERIALS AND METHODS: The monoclonal antibodies bevacizumab, cetuximab, panitumumab, trastuzumab, and tocilizumab were covalently linked to a near-infrared fluorescence probe (IRDye800CW) and in vitro binding assays were performed to confirm ligand-specific binding. Nude mice bearing human breast cancer flank tumors were intravenously injected with the antibody-IRDye800 bioconjugates and imaged over time. Tumor resections were performed using the SPY and Pearl Impulse systems, and the presence or absence of tumor was confirmed by conventional and fluorescence histology.
RESULTS: Tumor was distinguishable from normal tissue using both SPY and Pearl systems, with both platforms being able to detect tumor as small as 0.5 mg. Serial surgical resections demonstrated that real-time fluorescence can differentiate subclinical segments of disease. Pathologic examination of samples by conventional and optical histology using the Odyssey scanner confirmed that the bioconjugates were specific for tumor cells and allowed accurate differentiation of malignant areas from normal tissue.
CONCLUSIONS: Human breast cancer tumors can be imaged in vivo with multiple optical imaging platforms using near-infrared fluorescently labeled antibodies. These data support additional preclinical investigations for improving the surgical resection of malignancies with the goal of eventual clinical translation.

Related: Breast Cancer

Krens LL, Baas JM, de Jong FA, et al.
Pharmacokinetics of panitumumab in a patient with liver dysfunction: a case report.
Cancer Chemother Pharmacol. 2014; 73(2):429-33 [PubMed] Related Publications
PURPOSE: Panitumumab is used for the treatment for metastatic RAS wild-type colorectal cancer (mCRC). It is likely that many of these patients will present with liver metastases and some with liver dysfunction. The pharmacokinetics in patients with hepatic impairment has not been investigated, and dosage adjustments are undetermined. Here, we present a case of a patient with progressive mCRC and liver dysfunction.
METHODS: A heavily pretreated KRAS wild-type mCRC patient with liver disease Child-Pugh class B was treated with 2-weekly intravenous panitumumab (6 mg/kg). The patient received 2 doses of 490 mg i.v. panitumumab after which progressive disease was documented. Toxicities were graded using CTCAEv4.0. Serum samples were collected, and panitumumab concentrations were determined using a validated immunoassay. Pharmacokinetic parameters after the first dose, including dose-normalized AUC from time zero-day 14, clearance (CL), and elimination half-life (T1/2), were estimated via trapezoidal noncompartmental methods. Data were compared to historical data from a population with adequate liver function, as reported by Stephenson (Clin Colorectal Cancer, 8:29-37, 2009). Values within the range of the mean ±1 standard deviation (SD) were considered not deviant.
RESULTS: Calculated AUC after the first dose of 6 mg/kg panitumumab in this patient with hepatic dysfunction was 877 μg day/mL (Stephenson's cohort 1: 744 ± 195 μg day/mL). Estimated T1/2 was 3.58 days (5.28 ± 1.90 days), and CL was 6.9 mL/day/kg (8.21 ± 3.79 mL/day/kg). Estimated PK parameters during the first cycle were inside reported mean ±1 SD of historical controls without liver dysfunction. No toxicity was reported during treatment; particularly, no diarrhea and skin toxicity were noticed.
CONCLUSIONS: The pharmacokinetics of panitumumab in this patient suffering from metastatic colorectal cancer with liver dysfunction Child-Pugh class B was similar compared to patients with adequate liver function. Moreover, no substantial toxicity was detected. The here-presented data may help clinical decision making in real-life practice. Two-weekly panitumumab monotherapy seems to be safely applicable in patients with KRAS wild-type mCRC and hepatic dysfunction, without the need for any dose adjustments.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Panitumumab (Vectibix)

Brown A, Ma Y, Danenberg K, et al.
Epidermal growth factor receptor-targeted therapy in squamous cell carcinoma of the penis: a report of 3 cases.
Urology. 2014; 83(1):159-65 [PubMed] Related Publications
OBJECTIVE: To describe 3 cases of advanced refractory penile cancer treated with targeted therapy against the epidermal growth factor receptor (EGFR).
MATERIALS AND METHODS: We identified 3 patients with advanced penile cancer who had disease progression after platinum chemotherapy refractory and who subsequently received EGFR-targeted therapy. Their tumor tissue was evaluated for expression of EGFR by immunohistochemistry and messenger ribonucleic acid quantitation and was also tested for the presence of human papillomavirus deoxyribonucleic acid by line hybridization. K-ras mutation was evaluated by polymerase chain reaction for 6 mutations in codon 12 and 1 mutation in codon 13.
RESULTS: One patient responded to cetuximab and remains disease-free 42 months after presentation. One patient responded to panitumumab, then suffered relapse. One other progressed through EGFR-targeted therapy. EGFR expression by immunohistochemistry was 1-2+ in all cases, and messenger ribonucleic acid expression ranged from 4.08 to 7.33. No K-ras mutations or human papillomavirus deoxyribonucleic acid was detected.
CONCLUSION: We report 3 cases in which EGFR-targeted therapy was used to treat platinum-refractory penile cancer patients. Because 2 of the 3 had clinical benefit, future prospective trials of EGFR-targeted therapy in penile cancer are warranted.

Related: Monoclonal Antibodies Penile (Penis) Cancer Panitumumab (Vectibix) Cetuximab (Erbitux)

Misiukiewicz K, Posner M
The SPECTRUM of findings in treatment options for recurrent/metastatic head and neck cancer.
J Comp Eff Res. 2013; 2(6):533-5 [PubMed] Related Publications
Evaluation of: Vermorken JB, Stohlmacher-Williams J, Davidenko I et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label Phase 3 randomised trial. Lancet Oncol. 14(8), 697-710 (2013). In recent decades, significant progress has been achieved in the biological understanding of squamous cell carcinoma of the head and neck (SCCHN) and the role of human papillomavirus (HPV) has become more evident. The EGF receptor (EGFR) signaling pathway represents the main target of the new therapeutic agents currently in development and has proven to be efficacious in locally advanced SCCHN. The role of HPV in recurrent and metastatic disease for predicting response to EGFR monoclonal antibodies is still unknown. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of SCCHN in patients with recurrent or metastatic disease, in association with platinum-based chemotherapy. The identification of novel tumor targets has stimulated the search for other anti-EGFR agents with a more favorable side-effect profile, such as aspanitumumab, but the SPECTRUM study failed to meet its primary end point, stipulating the need to test these agents in clinical trials with a more appropriate choice of study end point. Overall survival, considered a gold standard, may be difficult to interpret if treatment only takes place in a small subinterval of overall survival, therefore, progression-free survival should be used as a surrogate end point for regulatory approval.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology

Cohen RB
Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC).
Cancer Treat Rev. 2014; 40(4):567-77 [PubMed] Related Publications
Overexpression of the epidermal growth factor receptor (EGFR) is a common characteristic of head and neck squamous cell carcinomas (HNSCC). Cetuximab is a chimeric anti-EGFR monoclonal antibody (mAb) with multiple approved indications in HNSCC, including with radiation therapy (RT) for locoregionally advanced disease, as monotherapy after platinum progression, and with platinum/5-fluorouracil for recurrent or metastatic disease. There remain, however, numerous unanswered questions regarding the optimal use of cetuximab in HNSCC, including patient selection, its mechanisms of action and resistance, the effect of human papillomavirus status on outcomes, its role when combined with induction chemotherapy or adjuvant radiation, and optimal management of skin toxicity and hypersensitivity reactions. In addition, a variety of other anti-EGFR agents (the multitargeted small molecule tyrosine kinase inhibitors [TKIs] lapatinib, dacomitinib, and afatinib and the anti-EGFR mAbs zalutumumab, nimotuzumab, and panitumumab) are currently under investigation in phase II and III clinical trials in different HNSCC therapeutic settings. The anti-EGFR TKI erlotinib is currently in phase III development for oral cancer prevention. Numerous other drugs are in earlier stages of development for HNSCC treatment, including novel anti-EGFR mAbs (MEHD7945A, necitumumab, and RO5083945), small-molecule TKIs (vandetanib, icotinib, and CUDC-101), EGFR antisense, various add-on therapies to radiation and chemotherapy (bevacizumab, interleukin-12, lenalidomide, alisertib, and VTX-2337), and drugs (temsirolimus, everolimus, OSI-906, dasatinib, and PX-866) intended to overcome resistance to anti-EGFR agents. Overall, a wealth of clinical trial data is expected in the coming years, with the potential to modify significantly the approach to anti-EGFR therapy for HNSCC.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology

Cheng YD, Yang H, Chen GQ, Zhang ZC
Molecularly targeted drugs for metastatic colorectal cancer.
Drug Des Devel Ther. 2013; 7:1315-22 [PubMed] Free Access to Full Article Related Publications
The survival rate of patients with metastatic colorectal cancer (mCRC) has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin)-fluorouracil-irinotecan (FOLFIRI) chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS, the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin)-fluorouracil-oxaliplatin (FOLFOX) or FOLFIRI. Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs.

Related: Colorectal (Bowel) Cancer USA

Selzer E, Kornek G
Targeted drugs in combination with radiotherapy for the treatment of solid tumors: current state and future developments.
Expert Rev Clin Pharmacol. 2013; 6(6):663-76 [PubMed] Related Publications
The continuously rising use of novel drugs, especially of molecules belonging to the group of targeted drugs is now shaping the therapeutic landscape. However, treatment combinations of targeted drugs with radiotherapy are still rare. Only the monoclonal antibody cetuximab (Erbitux®) has been approved for the treatment of locally advanced squamous cell cancer of the head and neck in combination with radiotherapy. Several targeted compounds are in advanced stages of clinical development for combination treatments with radiotherapy, of which substances with either anti-EGFR or anti-angiogenic mechanisms, such as trastuzumab, panitumumab, erlotinib, cilengitide and bevacizumab are the most promising. Aim of this article is to provide, mainly from a radio-oncological point of view, an overview about the current state as well as to give an outlook on the near future of the most advanced targeted combined treatment concepts for solid tumors.

Related: Monoclonal Antibodies Cancer Prevention and Risk Reduction

Ciombor KK, Bekaii-Saab T
Emerging treatments in recurrent and metastatic colorectal cancer.
J Natl Compr Canc Netw. 2013; 11 Suppl 4:S18-27 [PubMed] Related Publications
Metastatic colorectal cancer (mCRC) is a prevalent disease for which many new therapies have been developed over the past decade. Currently, standard of care chemotherapeutic regimens for mCRC include doublet cytotoxic chemotherapy with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab with or without chemotherapy, and single-agent cytotoxic chemotherapy or targeted therapy for patients intolerant of combination regimens. Recent studies have investigated the efficacy of triplet cytotoxic chemotherapeutic regimens, bevacizumab in combination with chemotherapy beyond first-line therapy disease progression, dual anti-VEGF and anti-EGFR antibody therapy, and the more novel agents ziv-aflibercept and regorafenib for treatment of mCRC. Furthermore, molecular profiling of CRC has identified several genetic alterations for which targeted therapies are currently being developed. Optimal drug combinations and treatment sequences have yet to be defined, but an expanding armamentarium of therapies with which to treat CRC offers a promising future.

Related: Angiogenesis Inhibitors Colorectal (Bowel) Cancer

de Mello RA, Marques AM, Araújo A
Epidermal growth factor receptor and metastatic colorectal cancer: insights into target therapies.
World J Gastroenterol. 2013; 19(38):6315-8 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) has high incidence and mortality worldwide. In 2012, CRC was the second most prevalent cancer among males (9%) and the third among females (8%). In recent decades, standard chemotherapies protocols combining 5-fluorouracil, leucovorin, irinotecan and oxaliplatin were important for improve survival in this set of patients. Further, biological drugs throughout epidermal growth factor receptor (EGFR) pathways showed interesting results in metastatic disease (mCRC) control when in association to standard chemotherapy regimens. Cetuximab and panitumumab are two cornerstones for mCRC treatment and are both approved in Europe and United States based on previous results phase III trials. This paper will briefly summarize those anti-EGFR therapies framework in mCRC and discusses some issues in this regard.

Related: Signal Transduction EGFR

Sohal DP, Mykulowycz K, Uehara T, et al.
A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma.
Ann Oncol. 2013; 24(12):3061-5 [PubMed] Related Publications
BACKGROUND: Current data suggest that chemotherapy combinations may be superior to single agents in biliary tract cancer. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan.
PATIENTS AND METHODS: Patients with advanced (unresectable or metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate organ function were treated with panitumumab (9 mg/kg) on day 1, and gemcitabine (1000 mg/m(2)) and irinotecan (100 mg/m(2)) on days 1 and 8 of a 21-day cycle. The primary objective was to evaluate the 5-month progression-free survival (PFS). Secondary objectives included overall response rate (ORR) and overall survival (OS). Mutational analyses of EGFR, KRAS and BRAF were carried out when feasible.
RESULTS: Thirty-five patients received a median of 7 (0-30) cycles. The most common grade 3/4 toxic effects were neutropenia (10 patients, 29%), thrombocytopenia (10 patients, 29%), skin rash (13 patients, 37%) and dehydration (9 patients, 26%). Two patients had CR, 9 had partial response (PR), and 15 had SD for a disease-control rate of 74% (by RECIST) in 28 assessable patients. Two patients went on to have surgical resection. The 5-month PFS was 69%. The median PFS was 9.7 months and the median OS was 12.9 months. In 17 testable samples, no EGFR or BRAF mutations were identified; there were 7 KRAS mutations, with no difference in OS by KRAS status.
CONCLUSIONS: This study showed encouraging efficacy of this regimen with good tolerability. Further study in this area is warranted. Clinical Trials Number: The trial was registered with the National Cancer Institute ( identifier NCT00948935).

Related: Monoclonal Antibodies Extra-Hepatic Bile duct cancer (cholangiocarcinoma) KRAS gene Panitumumab (Vectibix) Irinotecan Gemcitabine

Ratti M, Tomasello G
Emerging combination therapies to overcome resistance in EGFR-driven tumors.
Anticancer Drugs. 2014; 25(2):127-39 [PubMed] Related Publications
The epidermal growth factor receptor (EGFR) is responsible for the growth and progression of tumor cells; its overexpression and deregulation of its downstream signaling pathway have been found in many different neoplasms. These characteristics make it an ideal target for cancer treatment. Two classes of EGFR inhibitors, which bind to different parts of this molecule, have been developed and studied: monoclonal antibodies, such as cetuximab and panitumumab and tyrosine kinase inhibitors, including erlotinib and gefitinib. The effectiveness of these new drugs is considerably reduced by a number of mechanisms of resistance developed by tumor cells. Hence, there is a clear need for better characterization of these processes and finding new therapeutic strategies to make the action of these drugs more incisive. Here, we describe some of the mechanisms of resistance to EGFR inhibitors and review the main innovations attempting to overcome these drawbacks.

Related: Monoclonal Antibodies Cancer Prevention and Risk Reduction VEGFA

Pichler M, Winter E, Ress AL, et al.
miR-181a is associated with poor clinical outcome in patients with colorectal cancer treated with EGFR inhibitor.
J Clin Pathol. 2014; 67(3):198-203 [PubMed] Related Publications
AIMS: miR-181a expression is frequently altered in different types of cancer. Members of the Wnt/β-catenin signalling pathway, which is commonly altered in colorectal cancer (CRC), have been reported as molecular interaction partners of miR-181. However, the role of miR-181a expression in CRC and its ability to predict survival and response to agents targeting the epidermal growth factor receptor (EGFR) have not been explored yet.
METHODS: In this study, we analysed 80 patients with wild type KRAS CRC undergoing treatment with the EGFR-targeting monoclonal antibodies cetuximab and panitumumab for metastatic CRC. The KRAS mutational status was determined by pyrosequencing and miR-181a expression was measured by quantitative RT-PCR in CRC tumour tissue and corresponding non-neoplastic colon tissue. The microRNA expression levels were correlated with clinicopathological characteristics. Cancer-specific survival was calculated by univariate and multivariate analyses, and progression-free survival (PFS) during treatment with EGFR-targeting agents was also evaluated.
RESULTS: A low miR-181a expression level was associated with poor differentiation of CRC (p=0.04). A Kaplan-Meier curve showed a decreased survival time for patients with low miR-181a expression (p=0.019). Low miR-181a expression was furthermore associated with poor PFS (p=0.015).
CONCLUSIONS: In conclusion, our data suggest that the miR-181a expression level is associated with poor survival in patients with CRC. Furthermore, miR-181a expression might predict PFS in EGFR-targeted therapy.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer KRAS gene Panitumumab (Vectibix) EGFR Cetuximab (Erbitux)

Er TK, Chen CC, Bujanda L, Herreros-Villanueva M
Clinical relevance of KRAS mutations in codon 13: Where are we?
Cancer Lett. 2014; 343(1):1-5 [PubMed] Related Publications
Recent advances in molecular diagnosis and the trend towards personalized medicine have made colorectal cancer one of the tumors where therapies have significantly improved patient survival after metastasis development. KRAS mutations in codon 12 and 13 are recognized biomarkers that are analyzed in clinic previously for anti-EGFR therapies administration. Since originally mutations in both codons were considered as a predictor of lack of response to cetuximab or panitumumab, the European Medicines Agency and the US Food and Drug Administration suggested that patients harboring any of those mutations should be excluded from the treatment. However, subsequent retrospective analysis has shown that mutations in codon 12 and codon 13 of KRAS gene could be different in their biological characteristics and as a result could confer variable effects in patients. In addition and increasing and sometimes contradictory number of solutions have been published demonstrating that patients with mutations in codon 13 could have worse outcome but could obtain a significant clinical benefit from anti-EGFR therapies. Here, we review and update the latest data on the biological role leading to a predictive outcome and benefit from anti-EGFR antibodies in patients with specific KRAS mutations in codon 13.

Related: Colorectal (Bowel) Cancer KRAS gene Cetuximab (Erbitux)

Douillard JY, Oliner KS, Siena S, et al.
Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.
N Engl J Med. 2013; 369(11):1023-34 [PubMed] Related Publications
BACKGROUND: Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.
METHODS: In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.
RESULTS: Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.
CONCLUSIONS: Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME number, NCT00364013.).

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Fluorouracil Leucovorin BRAF gene KRAS gene Panitumumab (Vectibix) NRAS gene

Watanabe K, Kawahara H, Enomoto H, et al.
Impact of chemotherapy with S-1 and oxaliplatin (SOX) in combination with molecular-targeting agents on colorectal liver metastases.
Anticancer Res. 2013; 33(9):3941-6 [PubMed] Related Publications
AIM: The aim of this study was to evaluate the impact of chemotherapy with molecular-targeting agents on liver metastases from colorectal cancer.
PATIENTS AND METHODS: Six patients with synchronous colorectal liver metastases who underwent hepatectomy after chemotherapy with S-1 and oxaliplatin (SOX) between January 2010 and December 2011 at the Department of Surgery, Kashiwa Hospital, the Jikei University School of Medicine were enrolled. Two patients received only SOX as chemotherapy, while the others received SOX in combination with one of the three molecular-targeting agents, bevacizumab, cetuximab, and panitumumab.
RESULTS: In the two patients who received SOX alone, liver metastases completely disappeared at more than six months after starting chemotherapy as shown by computed tomographic (CT) scan. However, malignant cells were diffusely detected by pathological examination at the site of liver metastases, as detected by CT scan before chemotherapy. In the other four patients who received SOX in combination with molecular targets, the size of liver metastases appeared unchanged at three months after limited chemotherapy by CT scan. Pathologically, few malignant cells were detected, only at the borderline of the tumor, while most tumor cells inside the tumor were necrotized and been replaced by fibroconnective tissue.
CONCLUSION: Molecular-targeting agents may induce tumor necrosis rapidly from inside the tumor, which might not be detected by CT scan before surgery.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Tegafur-uracil Panitumumab (Vectibix) Oxaliplatin Cetuximab (Erbitux)

Lange A, Prenzler A, Frank M, et al.
A systematic review of cost-effectiveness of monoclonal antibodies for metastatic colorectal cancer.
Eur J Cancer. 2014; 50(1):40-9 [PubMed] Related Publications
UNLABELLED: Metastatic colorectal cancer (mCRC) imposes a substantial health burden on patients and society. In recent years, advances in the treatment of mCRC have mainly resulted from the introduction of monoclonal antibodies (MoAbs). However, the application of these MoAbs considerably increases treatment costs. The objective of this article is to review and assess the economic evidence of MoAB treatment in mCRC. A systematic literature review was conducted and cost-effectiveness (CE) as well as cost-utility-studies were identified. For this, Medline, Embase, SciSearch, Cochrane, and nine other databases were searched from 2000 through February 2013 for full-text publications. The quality of the studies was assessed via a validated assessment tool (Quality of Health Economic Studies (QHES)). A total of 843 publications were screened. Of those, 15 studies involving the MoAbs bevacizumab, cetuximab and panitumumab met all inclusion criteria. Four studies analysed the CE of first-line treatment with bevacizumab and nine the CE of cetuximab in subsequent treatment lines. Two studies dealt with the CE of panitumumab. The analysis of sequential regimes and the direct comparison of two MoABs were analysed by only one study each. The quality of the included studies was high with the exception of one study.
CONCLUSIONS: The treatment with bevacizumab, cetuximab and panitumumab is mainly considered to be not cost-effective in patients with mCRC. However, testing for Kirsten ras oncogene (KRAS) mutation prior to the treatment with cetuximab or panitumumab is found to be clearly cost-effective compared to no testing. Future research should focus on the CE of first-line treatment with cetuximab or panitumumab and studies on upcoming agents like regorafenib and aflibercept.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer

Belum VR, Cercek A, Sanz-Motilva V, Lacouture ME
Dermatologic adverse events to targeted therapies in lower GI cancers: clinical presentation and management.
Curr Treat Options Oncol. 2013; 14(3):389-404 [PubMed] Related Publications
OPINION STATEMENT: Rapid advances in drug discovery and the regulatory approval of a number of novel anticancer agents during the past decade pose unique challenges to the oncology community. While the benefits of such therapies receive most attention, adverse events (AEs), especially those pertaining to subspecialties (e.g., dermatology), often are underemphasized. To ensure best clinical outcomes, it would be important to bridge the gap between approval of a new drug and devising effective management strategies for the AEs. With the incorporation of targeted therapies to the treatment paradigm of gastrointestinal malignancies, there has been a significant rise in dermatologic AEs among those treated. In addition to significantly affecting patients' quality of life, these AEs represent a growing problem and are relatively unfamiliar to many oncologists. The issue is further complicated by the lack of evidence-based management guidelines for such AEs in the oncology setting, the "generalizing" of terminology (e.g., rash) for some AEs, as well as an insufficient number of oncodermatologists for assistance with their management. It is important for the oncologist to gain familiarity with the most common, manageable and predictable AEs. Their identification is usually based on medical history, clinical features, and full-body skin examination (FBSE) and at times by obtaining a skin biopsy to aid in diagnosis. Although efforts are underway, presently, there is a paucity of biomarkers (e.g., serologic, genetic) to predict dermatologic AEs. Management often requires a multifaceted approach and includes topical, systemic, surgical, and physical (e.g., cryotherapy) modalities of treatment. Unfortunately, very few clinical trials have focused on this aspect of supportive care; therefore, most data on management derives from anecdotal data. Patients should be encouraged to actively report skin problems, while oncologists should play a vital role in addressing these AEs in their patients. Lastly, further research at the molecular and cellular level may assist in the elucidation of the mechanisms underlying these AEs and their clinical correlates, paving way for the design of effective therapies in this subset of patients.

Related: Monoclonal Antibodies Gastrointestinal System Cancers Panitumumab (Vectibix) Bevacizumab (Avastin) Cetuximab (Erbitux)

Ensslin CJ, Rosen AC, Wu S, Lacouture ME
Pruritus in patients treated with targeted cancer therapies: systematic review and meta-analysis.
J Am Acad Dermatol. 2013; 69(5):708-20 [PubMed] Related Publications
BACKGROUND: Pruritus has been anecdotally described in association with targeted cancer therapies. The risk of pruritus has not been systematically ascertained.
OBJECTIVE: A systematic review and meta-analysis of the literature was conducted for axitinib, cetuximab, dasatinib, erlotinib, everolimus, gefitinib, imatinib, ipilimumab, lapatinib, nilotinib, panitumumab, pazopanib, rituximab, sorafenib, temsirolimus, tositumomab, vandetanib, and vemurafenib.
METHODS: Databases from PubMed, Web of Science (January 1998 through July 2012), and American Society of Clinical Oncology abstracts (2004 through 2012) were searched. Incidence and relative risk of pruritus were calculated using random- or fixed-effects model.
RESULTS: The incidences of all-grade and high-grade pruritus were 17.4% (95% confidence interval 16.0%-19.0%) and 1.4% (95% confidence interval 1.2%-1.6%), respectively. There was an increased risk of all-grade pruritus (relative risk 2.90 [95% confidence interval 1.76-4.77, P < .001]) and variation among different drugs (P < .001).
LIMITATIONS: The reporting of pruritus may vary, resulting from concomitant medications, comorbidities, and underlying malignancies. We found a higher incidence of pruritus in patients with solid tumors, concordant with those targeted therapies with the highest pruritus incidences.
CONCLUSION: There is a significant risk of developing pruritus in patients receiving targeted therapies. To prevent suboptimal dosing and decreased quality of life, patients should be counseled and treated against this untoward symptom.

Related: Cancer Prevention and Risk Reduction

Yewale C, Baradia D, Vhora I, et al.
Epidermal growth factor receptor targeting in cancer: a review of trends and strategies.
Biomaterials. 2013; 34(34):8690-707 [PubMed] Related Publications
The epidermal growth factor receptor (EGFR) is a cell-surface receptor belonging to ErbB family of tyrosine kinase and it plays a vital role in the regulation of cell proliferation, survival and differentiation. However; EGFR is aberrantly activated by various mechanisms like receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation and is associated with development of variety of tumors. Therefore, specific EGFR inhibition is one of the key targets for cancer therapy. Two major approaches have been developed and demonstrated benefits in clinical trials for targeting EGFR; monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). EGFR inhibitors like, cetuximab, panitumumab, etc. (mAbs) and gefitinib, erlotinib, lapatinib, etc. (TKIs) are now commercially available for treatment of variety of cancers. Recently, many other agents like peptides, nanobodies, affibodies and antisense oligonucleotide have also shown better efficacy in targeting and inhibiting EGFR. Now a days, efforts are being focused to identify molecular markers that can predict patients more likely to respond to anti-EGFR therapy; to find out combinatorial approaches with EGFR inhibitors and to bring new therapeutic agents with clinical efficacy. In this review we have outlined the role of EGFR in cancer, different types of EGFR inhibitors, preclinical and clinical status of EGFR inhibitors as well as summarized the recent efforts made in the field of molecular EGFR targeting.

Related: Monoclonal Antibodies Cancer Prevention and Risk Reduction Panitumumab (Vectibix) Lapatinib (Tyverb) Erlotinib (Tarceva) Cetuximab (Erbitux) Gefitinib (Iressa)

Middleton G, Brown S, Lowe C, et al.
A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO).
Eur J Cancer. 2013; 49(16):3507-16 [PubMed] Related Publications
BACKGROUND: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan.
METHODS: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation.
RESULTS: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference.
INTERPRETATION: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC.
FUNDING: The trial was funded by Cancer Research UK and supported by Amgen Pharma.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Irinotecan

Zaorsky NG, Sun Y, Wang Z, et al.
Identification of a KRAS mutation in a patient with non-small cell lung cancer treated with chemoradiotherapy and panitumumab.
Cancer Biol Ther. 2013; 14(10):883-7 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
RTOG 0839 is a Phase II study of pre-operative chemoradiotherapy with or without panitumumab in potentially operable locally advanced non-small cell lung cancer (NSCLC). The investigational agent, panitumumab, is an anti-epithelial growth factor receptor (EGFR) antibody that improves progression-free survival in chemorefractory metastatic colorectal cancer (mCRC). Recently, both KRAS mutational status (i.e., mutated or not) and subtype (i.e., activating or inactivating) have been shown to be predictive of response to anti-EGFR therapy in mCRC. However, in NSCLC, it is unknown if KRAS mutational status or subtype predict benefit to anti-EGFR therapies because of unique genetic and epigenetic factors unique to each cancer. We present a patient with stage III NSCLC containing a KRAS G12D activating mutation who had a partial pathologic response, with disappearance of a minor KRAS mutant clone. This case suggests possible eradication of the G12D KRAS lung cancer clones by concurrent chemoradiation with panitumumab.

Related: Monoclonal Antibodies Carboplatin Non-Small Cell Lung Cancer Lung Cancer Paclitaxel KRAS gene Panitumumab (Vectibix)

Leone F, Artale S, Marino D, et al.
Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy in patients with colon cancer and advanced liver metastases. The MetaPan study.
Cancer. 2013; 119(19):3429-35 [PubMed] Related Publications
BACKGROUND: Preoperative chemotherapy improves the outcome in patients with colorectal cancer with liver metastases. In the current study, the authors evaluated the activity of a conversion treatment with the combination of capecitabine plus oxaliplatin (XELOX) used in association with panitumumab in patients with unresectable, liver-only, metastatic colon cancer.
METHODS: Chemotherapy-naive patients with unresectable liver metastases from colon cancer with no other metastatic disease sites were enrolled. All patients received upfront therapy with XELOX plus panitumumab (P-XELOX) and were reevaluated for resectability every 4 cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival, the percentage of patients whose disease became radically resectable, and the safety of the P-XELOX combination.
RESULTS: A total of 49 patients were recruited, 35 of whom had wild-type KRAS (wtKRAS) and 14 of whom (who were enrolled before study amendment) had unknown (9 patients) or mutated (5 patients) KRAS mutational status. Forty-six patients were evaluable for response. After conversion P-XELOX therapy, the ORR in the general population was 54%, with 2 complete responses, 23 partial responses, and 14 cases of stable disease. In patients with wtKRAS, the ORR of the patients reached 65% (2 CRs and 19 PRs), which allowed 15 patients with initial unresectable liver metastasis to be reclassified as having resectable disease. Survival analysis demonstrated a median progression-free survival of 8.5 months and a median OS of 21.9 months. Patients who underwent surgery were found to have a significantly better OS when compared with those who did not undergo surgery (P < .001). Overall, toxicities were found to be predictable and manageable, with the most common being cutaneous, gastrointestinal, and neurologic toxicities.
CONCLUSIONS: Conversion P-XELOX therapy yields high response and resectability rates for patients with metastatic colon cancer with extensive liver involvement.

Related: Monoclonal Antibodies Fluorouracil Panitumumab (Vectibix) Oxaliplatin Capecitabine

Wen F, Tang R, Sang Y, et al.
Which is false: oxaliplatin or fluoropyrimidine? An analysis of patients with KRAS wild-type metastatic colorectal cancer treated with first-line epidermal growth factor receptor monoclonal antibody.
Cancer Sci. 2013; 104(10):1330-8 [PubMed] Related Publications
This meta-analysis was performed to determine whether the addition of monoclonal antibodies (mAbs) of epidermal growth factor receptor (EGFR) to oxaliplatin-based chemotherapy treatment improves efficacy in KRAS wild-type metastatic colorectal cancer (mCRC), and whether infusional 5-fluorouracil (5-FU) and oxaliplatin is a preferred combination for EGFR mAbs. Oxaliplatin (including treatment), EGFR mAbs, first-line treatment, KRAS wild-type, and mCRC were used as key words. The PRIME, OPUS, COIN, and NORDIC VII trials were identified by two independent authors. Time-to-event outcomes of overall survival (OS) and progression-free survival (PFS) were analyzed using HRs (hazard ratios) with fixed effect, and response rate (RR) using odd ratios (OR) with fixed effect. A total of 1767 patients who were KRAS wild-type were included in this meta-analysis, with 866 patients in the mAbs and chemotherapy combination group and 901 patients in the chemotherapy alone group. The addition of mAbs to oxaliplatin-based chemotherapy in patients with KRAS wild-type mCRC as first-line treatment resulted in significant improvements in PFS (HR = 0.88; 95% confidence interval (CI), 0.79-0.99; P = 0.03) and response rate (RR) (OR = 1.38; 95% CI, 1.14-1.66; P = 0.009) compared with chemotherapy alone, but the difference in OS was not significant (HR = 0.96; 95% CI, 0.85-1.08; P = 0.48). However, the differences in OS and PFS were not significant when mAbs were added to bolus 5-FU or capecitabine-based regimens compared with chemotherapy alone, whereas PFS improved with an infusional 5-FU and oxaliplatin combination (P = 0.06; PFS, HR = 0.76; 95% CI, 0.65-0.86; P = 0.0002), and even OS was marginally significant, which was consistent with the subgroup analysis of cetuximab and panitumumab. EGFR mAbs combined with oxaliplatin and an infusional 5-FU regimen was associated with significantly improved RR, PFS and OS as first-line treatment in KRAS wild-type mCRC.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Fluorouracil Leucovorin Panitumumab (Vectibix) Oxaliplatin EGFR Cetuximab (Erbitux)

Danitumumab adjunctive therapy. No place in either first- or second-line treatment of metastatic colorectal cancer.
Prescrire Int. 2013; 22(138):120 [PubMed] Related Publications
Adding panitumumab to standard protocols does not prolong survival but provokes additional adverse effects.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Panitumumab (Vectibix)

Mlcochova J, Faltejskova P, Nemecek R, et al.
MicroRNAs targeting EGFR signalling pathway in colorectal cancer.
J Cancer Res Clin Oncol. 2013; 139(10):1615-24 [PubMed] Related Publications
MicroRNAs (miRNAs) are short, 18-25-nucleotide long, non-coding single-stranded RNAs, which are capable to regulate gene expression on post-transcriptional level through binding to their target protein-encoding mRNAs. miRNAs regulate individual components of multiple oncogenic pathways. One of them is epidermal growth factor receptor (EGFR) signalling pathway that regulates cell proliferation, differentiation, migration, angiogenesis and apoptosis. All these processes are deregulated in colorectal cancer (CRC). Moreover, EGFR has been validated as the therapeutic target in CRC, and monoclonal antibodies cetuximab and panitumumab are used in the therapy of patients with metastatic CRC. Because of the extensive involvement of miRNAs in the regulation of EGFR signalling, it seems they could also serve as promising predictive biomarkers to anti-EGFR therapy. In this review, we summarize current knowledge about miRNAs targeting EGFR signalling pathway, their functioning in CRC pathogenesis and potential usage as biomarkers.

Related: Colorectal (Bowel) Cancer Signal Transduction EGFR

Giampieri R, Scartozzi M, Del Prete M, et al.
Molecular biomarkers of resistance to anti-EGFR treatment in metastatic colorectal cancer, from classical to innovation.
Crit Rev Oncol Hematol. 2013; 88(2):272-83 [PubMed] Related Publications
BACKGROUND: Systematic dissection of the EGFR pathway was considered as the best way to identify putative markers of resistance to anti-EGFR therapies. This kind of approach leaves other, less known but by no means less important, putative mechanisms of resistance. We tried to shed some light on these mechanisms of resistance.
MATERIALS AND METHODS: We performed a research through Pubmed database of all published articles highlighting mechanisms of resistance to Cetuximab and Panitumumab based therapies, published in 2000-2012 period.
CONCLUSIONS: We reviewed the "classical" molecular factors, extensively analyzed as predictive factors for efficacy to anti-EGFR therapy, such as K-ras, B-raf, and PI3K-mTOR-Akt, focusing on their predictive or prognostic value and on the controversial aspects of the biomarker analysis for clinical practice. On the second part we will then move on to other less known molecular markers, for the future understanding of biological mechanisms underlying anti-EGFR therapy resistance, such as non-canonical heterodimer candidates, microRNA, IGF1-IGF1R, HGF-cMET and secondary mutations of EGFR.

Related: Angiogenesis Inhibitors Colorectal (Bowel) Cancer Signal Transduction

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