Systematic Review: Anti–Epidermal Growth Factor Receptor Treatment Effect Modification by KRAS Mutations in Advanced Colorectal Cancer

Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts 02111, USA.
Annals of internal medicine (Impact Factor: 17.81). 01/2011; 154(1):37-49. DOI: 10.1059/0003-4819-154-1-201101040-00006
Source: PubMed


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.

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    • "In conclusion, because extended RAS mutation status is a powerful predictive biomarker of anti-EGFR treatment for metastatic CRC [4] [5] [6] [7] [8] [9], it is necessary to determine the mutation status before initiation of treatment. Thus, our PCR-HRM screening assay will enable rapid identification of extended RAS mutation status in the clinical setting at a lower cost. "
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    ABSTRACT: Objectives: Recent studies have demonstrated that, in advanced colorectal carcinoma (CRC) patients, extended RAS (in KRAS exons 2-4 and NRAS exons 2-4) and BRAF mutations are negative predictors for anti-EGFR treatment efficacy and negative prognostic factor, respectively. Thus, high-throughput and cost-effective methods for identification of the mutation status are required. Design and methods: We developed a PCR-high-resolution melting (HRM)-based method for screening extended RAS and BRAF mutations, and relative frequency of mutations in formalin-fixed paraffin-embedded samples of CRC was analyzed. Results: Among 93 CRC samples, 29 harbored mutations in KRAS exon 2, and 9 harbored mutations in BRAF exon 15. Analysis of 55 KRAS exon 2 and BRAF exon 15 wild-type CRC samples identified the following mutations: 1/55 in exon 3 and 2/55 in exon 4 of KRAS; 1/55 in exon 2, 3/55 in exon 3, and 0/55 in exon 4 of NRAS. Conclusions: Our PCR-HRM method will enable rapid determination of the extended RAS and BRAF mutation status prior to anti-EGFR treatment in the clinical setting.
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    • "Predictive biomarkers can be selected from a wide array of prognostic biomarkers (which are useful for projecting the natural history of a disease independent of therapy) to define a specific subgroup of patients for which treatment will be beneficial. An example of a predictive marker is the presence or absence of K-Ras mutations in colorectal cancers; patients without K-Ras mutations benefit from antiepidermal growth factor receptor therapy, whilst patients with such mutations derive little, if any, benefit [83]. Where a single biomarker has been identified, several trial designs can be employed [84], including (i) biomarker-enrichment design, which involves only patients testing positive for the biomarker. "
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    • "However, among colorectal tumors carrying wild-type K-ras, mutation of B-raf or PIK3CA or loss of PTEN expression may be associated with resistance to EGFR-targeted monoclonal antibody treatment [16]. The monoclonal antibodies cetuximab and panitumumab have been developed to target EGFR [17]. Improved response rates and prolonged time to metastasis/survival have been demonstrated with the currently registered EGFR blocking antibodies [18]. "
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    ABSTRACT: The monoclonal antibodies (mAbs) that target the epidermal growth factor receptor (EGFR) had expanded the range of treatment options for metastatic colorectal cancer. However, such type of treatment was shown to be ineffective if there is K-ras mutation. In most previous studies K-ras gene mutation was mainly assessed by PCR. Our work is designed to detect K-ras protein expression by immunohistochemistry (IHC) aiming to reach a preliminary method that could be confirmed by PCR and considered an alternative way for the detection of K-ras aberration. We are also aiming to find a relation between K-ras protein expression and K-ras gene mutation. Paraffin embedded tissue samples from 26 metastatic colorectal cancer (mCRC) patients were analyzed for K-ras protein expression by IHC using Rap1A polyclonal antibody. Staining patterns were subjectively assessed and correlated with clinicopathological features. The results were statistically evaluated using the Chi-square test. K-ras cytoplasmic positivity was observed in 42.3% of cases. The positivity was either strong in 26.9% or moderate in 15.4%. With respect to adenocarcinoma variants, 50% of cases were positive for K-ras protein expression while all mucinous and signet ring types were negative. The positivity was noted in 50% of moderately differentiated GII colorectal carcinomas as compared with 38.9% in poorly differentiated GIII. Positive staining was observed in 40% of cases with positive lymph node metastasis while in the absence of nodal metastasis the positivity was 45.5%. No significant correlation was found between clinicopathological parameters and K-ras staining results. IHC may compliment PCR in the detection of K-ras mutation.
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