Current Approaches for Predicting a Lack of Response to Anti-EGFR Therapy in<i>KRAS</i>Wild-Type Patients

Er, Tze‐Kiong; Chen, Chih-Chieh; Bujanda, Luís; Herreros-Villanueva, Marta

doi:10.1155/2014/591867

Cited by 12 publications

(13 citation statements)

References 68 publications

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“…58,59 Genotype is an important determinant of both the response to treatment and the susceptibility to adverse reactions for a wide range of drugs, 60,61 for example response to EGFR inhibitors has been shown to be dependent on gene expression in colon cancer, with studies demonstrating a treatment interaction between RAS status and the effectiveness of EGFR inhibitors. [62][63][64] In line with research evaluating the negative impact of RAS mutations on the effectiveness of EGFR inhibitors, approval for the use of anti-EGFR antibodies has now been limited to people with mCRC with RAS WT tumours. 44,65 Tumour samples from trial populations supporting the original licensed indications were evaluated retrospectively for RAS status.…”

Section: Methods For Reviewing Effectivenessmentioning

confidence: 99%

“…60,61 In CRC response to EGFR inhibitors has been shown to be dependent on gene expression; studies have demonstrated a treatment interaction between RAS status and the effectiveness of EGFR inhibitors. [62][63][64] It was in line with these research developments evaluating the negative impact of RAS mutations on the effectiveness of EGFR inhibitors that tumour samples from trial populations supporting the original licensed indications were evaluated retrospectively for RAS status. Therefore, data are not from the ITT population for any of the included studies, but are from a subgroup of people contained within the original RCTs.…”

Section: Applicability To the Nhs In Englandmentioning

confidence: 99%

“…[62][63][64] In line with research developments evaluating the negative impact of RAS mutations on the effectiveness of EGFR inhibitors, approval for the use of anti-EGFR antibodies has now been limited to people with mCRC with RAS WT tumours. Tumour samples from trial populations supporting the original licensed indications were evaluated retrospectively for RAS status.…”

Section: Clinical Effectiveness Systematic Reviewmentioning

confidence: 99%

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The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation

Huxley

Crathorne

Varley-Campbell

et al. 2017

Health Technol Assess

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BackgroundColorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Targeted agents are available, including the antiepidermal growth factor receptor (EGFR) agents cetuximab (Erbitux®, Merck Serono UK Ltd, Feltham, UK) and panitumumab (Vecitibix®, Amgen UK Ltd, Cambridge, UK).ObjectiveTo investigate the clinical effectiveness and cost-effectiveness of panitumumab in combination with chemotherapy and cetuximab in combination with chemotherapy for rat sarcoma (RAS) wild-type (WT) patients for the first-line treatment of metastatic colorectal cancer.Data sourcesThe assessment included a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions, and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted up to 27 April 2015 in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library.Review methodsStudies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab or panitumumab in participants with previously untreated metastatic colorectal cancer withRASWT status. All steps in the review were performed by one reviewer and checked independently by a second. Narrative synthesis and network meta-analyses (NMAs) were conducted for outcomes of interest. An economic model was developed focusing on first-line treatment and using a 30-year time horizon to capture costs and benefits. Costs and benefits were discounted at 3.5% per annum. Scenario analyses and probabilistic and univariate deterministic sensitivity analyses were performed.ResultsThe searches identified 2811 titles and abstracts, of which five clinical trials were included. Additional data from these trials were provided by the manufacturers. No data were available for panitumumab plus irinotecan-based chemotherapy (folinic acid + 5-fluorouracil + irinotecan) (FOLFIRI) in previously untreated patients. Studies reported results forRASWT subgroups. First-line treatment with anti-EGFR therapies in combination with chemotherapy appeared to have statistically significant benefits for patients who areRASWT. For the independent economic evaluation, the base-case incremental cost-effectiveness ratio (ICER) forRASWT patients for cetuximab plus oxaliplatin-based chemotherapy (folinic acid + 5-fluorouracil + oxaliplatin) (FOLFOX) compared with FOLFOX was £104,205 per quality-adjusted life-year (QALY) gained; for panitumumab plus FOLFOX compared with FOLFOX was £204,103 per QALY gained; and for cetuximab plus FOLFIRI compared with FOLFIRI was £122,554 per QALY gained. The ICERs were sensitive to treatment duration, progression-free survival, overall survival (resected patients only) and resection rates.LimitationsThe trials includedRASWT populations only as subgroups. No evidence was available for panitumumab plus FOLFIRI. Two networks were used for the NMA and model, based on the different chemotherapies (FOLFOX and FOLFIRI), as insufficient evidence was available to the assessment group to connect these networks.ConclusionsAlthough cetuximab and panitumumab in combination with chemotherapy appear to be clinically beneficial forRASWT patients compared with chemotherapy alone, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT in patients withRASWT.Study registrationThis study is registered as PROSPERO CRD42015016111.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Section: Methods For Reviewing Effectivenessmentioning

confidence: 99%

Section: Applicability To the Nhs In Englandmentioning

confidence: 99%

Section: Clinical Effectiveness Systematic Reviewmentioning

confidence: 99%

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The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation

Huxley

Crathorne

Varley-Campbell

et al. 2017

Health Technol Assess

View full text Add to dashboard Cite

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“…The recent identification of molecular genetics has enabled considerable advancements in the management of patients with advanced CRC. The development of targeted therapies directed against specific mutations such as those in the epidermal growth factor receptor (EGFR) tyrosine kinase gene has improved treatment efficacy and clinical outcome in advanced CRC patients [ 1 – 4 ]. However, CRCs are molecularly heterogeneous tumors that harbor various gene alterations including mutations in KRAS , BRAF , and PIK3CA , as well as HER2 amplification; many patients with these mutations therefore experience resistance against anti-EGFR drugs and exhibit poor prognosis [ 2 , 3 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

BRAF, PIK3CA, and HER2 Oncogenic Alterations According to KRAS Mutation Status in Advanced Colorectal Cancers with Distant Metastasis

et al. 2016

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BackgroundAnti-EGFR antibody–based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC); despite this, several mutations—including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification—are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC.MethodsKRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR) in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI) status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases.ResultsMutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%), 6 (3.1%), and 25 (13.1%) cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6%) and 16 (8.4%) cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3%) than KRAS wild type (6.9%) (P = 0.020). In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively). In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004). When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7%) CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%).ConclusionsKRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients.

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“…Interestingly Kras is a biomarker associated with decreased responses to anti-EGFR therapies and is theorised that Kras mutations independently activate the downstream pathways of EGFR including RAS/MAPK signalling (213). Kras mutation status and not EGFR expression dictates cetuximab use in metastatic colorectal cancer (213,214).…”

Section: Cscchn Overexpress Egfr Highlighting Its Potential Role In Pmentioning

confidence: 99%

Investigating therapeutic possibilities for treatment of perineural invasion

Huang¹

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Perineural invasion (PNI) is a pathological diagnosis whereby tumour cells infiltrate the perineural space of a peripheral nerve. This can lead to perineural spread (PNS) with dissemination of tumour cells away from the original tumour mass eventuating in a sensory or motor deficit. PNI is an accepted risk factor for poorer prognosis in cutaneous squamous cell carcinoma of the head and neck (cSCCHN) with increased locoregional recurrence, more aggressive disease and metastasis. Not exclusive to cutaneous malignancies, it also portends poorer prognosis in colorectal, cervical, gastric and prostate cancers. Despite its prognostic ramifications, PNI and PNS are poorly understood forms of I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School.

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Current Approaches for Predicting a Lack of Response to Anti-EGFR Therapy inKRASWild-Type Patients

Cited by 12 publications

References 68 publications

The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation

The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation

BRAF, PIK3CA, and HER2 Oncogenic Alterations According to KRAS Mutation Status in Advanced Colorectal Cancers with Distant Metastasis

Investigating therapeutic possibilities for treatment of perineural invasion

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