KRAS mutational status assessment in patients with metastatic colorectal cancer: Are the clinical implications so clear?

ArticleinEuropean Journal of Cancer Care 19(2):167-71 · August 2009with5 Reads
DOI: 10.1111/j.1365-2354.2009.01134.x · Source: PubMed
HEBBAR M., FOURNIER P. & ROMANO O. (2010) European Journal of Cancer Care19, 145–166 KRAS mutational status assessment in patients with metastatic colorectal cancer: are the clinical implications so clear? The CRYSTAL study demonstrated an advantage in terms of objective response and progression-free survival for the FOLFIRI–cetuximab combination compared with first-line FOLFIRI for patients with metastatic colorectal cancer. The results of an ancillary biological study with screening for a KRAS gene mutation in 540 patients were reported at the 2008 American Society of Clinical Oncology congress. The analysis confirmed the value of adding cetuximab only in the absence of KRAS mutation. These results led to recommend restriction of the use of cetuximab in Europe to patients with a tumour bearing wild-type KRAS. How should this apparent simplification be integrated into clinical practice? The FOLFIRI–cetuximab combination is certainly a useful supplementary first-line option although its place in relation to other high-dose regimens (high-dose FOLFIRI, FOLFOXIRI or FOLFOX-7), conventional chemotherapy plus bevacizumab, or even a fluoropyrimidine alone in the case of unresectable metastases, has yet to be specified. For subsequent lines, no study has prospectively assessed the value of the chemotherapy–anti-epidermal growth factor receptor combination as a function of KRAS status. Should the absence of objective response constantly observed in retrospective analyses in patients with a tumour presenting a KRAS mutation definitively exclude these patients while stable disease (and potentially a slight gain in survival) may be obtained?
  • [Show abstract] [Hide abstract] ABSTRACT: This work aimed to explore the induction of cetuximab-resistant human nasopharyngeal carcinoma (hNPC) 5-8F/Erbitux cells and the mechanisms of drug resistance. The 5-8F cells with high EGFR expression and cetuximab sensitivity were screened and then induced by stepwise exposure to increasing doses of cetuximab. Western blot was conducted to detect protein levels. Our results are as follows: we successfully induced the cetuximab-resistant 5-8F/Erbitux hNPC cells. After treatment with cetuximab for 3 and 5 days, the RI was 1.2 and 1.1, respectively. The 5-8F/Erbitux cells showed cross-resistance to 5-FU (P<0.01) and some resistance to Taxol (P>0.05) as well as enhanced sensitivity to DDP (P>0.05). The cells had increased levels of P-gP, IGF-1R, P-IGF-1R, K-ras, H-ras, and PTEN protein expression (P<0.001), while survivin decreased (P<0.001). Through sequence alignments, gene mutations in the PTEN gene at exons 5, 7, and 8, as well as the H-ras and K-ras genes in codons 12, 13, 59, and 61, were not observed. After transfection with H-ras-shRNA plasmid, the 5-8F/Erbitux cells showed reduced levels of gene and protein expression of H-ras and elevated sensitivity to cetuximab. In conclusion, gene amplification and overexpression of H-ras was the major mechanism that caused resistance of 5-8F/Erbitux cells to cetuximab, while the overexpression of the H-ras gene was probably associated with the over-activity of the IGF-1R signaling pathway. Gene deletion or mutation of PTEN was not associated with resistance of 5-8F/Erbitux cells to cetuximab.
    Article · Oct 2010
  • [Show abstract] [Hide abstract] ABSTRACT: KRAS mutations have been extensively investigated as predictive biomarkers for treatment of advanced colorectal cancer with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab. To summarize whether KRAS mutation status modifies effects of anti-EGFR-based treatments for patients with advanced colorectal cancer and whether KRAS status predicts clinical outcomes among such patients. MEDLINE and 2 curated genetics databases (through 24 March 2010) were searched for observational studies. MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects (through 1 September 2010) were searched for randomized, controlled trials. No search was restricted by language. Three reviewers screened titles and abstracts to identify published studies assessing KRAS mutations as predictors of overall and progression-free survival or treatment failure for patients who received anti-EGFR-based therapy for metastatic colorectal cancer. Three investigators extracted data on population and study-design characteristics, including quality items, and on outcomes of interest. Random-effects meta-analyses were done on nonoverlapping studies. In 4 reanalyses of randomized trials of anti-EGFR-based therapy versus best supportive care or cytotoxic chemotherapy, no significant benefit was found for overall or progression-free survival from anti-EGFR-based treatment among KRAS-positive patients (hazard ratio [HR], 1.0). However, evidence favors anti-EGFR therapy among KRAS wild-type patients; the relative HR across KRAS-positive and wild-type patients was 1.30 (95% CI, 0.95 to 1.78) for overall survival and 2.22 (CI, 1.74 to 2.84) for progression-free survival by random-effects meta-analysis. In 13 cohorts of patients who received anti-EGFR antibodies, the summary HR for overall survival was 1.79 (CI, 1.48 to 2.17), with better survival in wild-type patients. The corresponding HR for progression-free survival was 2.11 (CI, 1.74 to 2.55 [16 cohorts]). In random-effects bivariate meta-analysis of 22 studies, the summary sensitivity of KRAS mutations for predicting lack of response was 0.49 (CI, 0.43 to 0.55), and summary specificity was 0.93 (CI, 0.87 to 0.97). Limited evidence from randomized studies exists. Patient-level data are needed to assess modifiers of the mutation-by-treatment interaction. Publication bias could be a concern. KRAS mutations are consistently associated with reduced overall and progression-free survival and increased treatment failure rates among patients with advanced colorectal cancer treated with anti-EGFR antibodies. Agency for Healthcare Research and Quality.
    Article · Jan 2011
  • [Show abstract] [Hide abstract] ABSTRACT: The KRAS oncogene has been extensively studied for more than three decades, however, it is only recently that it attained a central role in the clinical decision-making process for the practicing oncologist. Recently, based on retrospective analyses of large randomized clinical trials, the use of anti-epidermal growth factor (EGFR) monoclonal antibodies, cetuximab and panitumumab, was restricted to patients with metastatic colorectal cancer that carry the "wild-type"KRAS genotype. Challenges remain in the laboratory implementation of KRAS mutational testing and the clinical application of the test for treatment planning. This review attempts to offer a global view of KRAS biology, its functional role in cell signaling, mechanisms of resistance to anti-EGFR agents and its predictive potential in metastatic colorectal cancer. We also survey the growing list of candidate biomarkers that may shortly supplement KRAS in routine clinical patient stratification. Finally, we discuss practical aspects of KRAS testing that may be useful for those involved in mutational screening in their centers. This general overview of KRAS for clinical oncology practice aims to assist in data interpretation and offer insight into potential pitfalls of mutational testing. KRAS is a prime example of how translational research can fulfill the promises of personalized medicine for tailoring treatment to match the underlying tumor biology.
    Article · May 2011
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