Issa J. Dahabreh, MD; Teruhiko Terasawa, MD, PhD; Peter J. Castaldi, MD, MS; Thomas A. Trikalinos, MD
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.
KRAS mutations may mark resistance to anti–epider-mal growth factor receptor (EGFR) antibody treatments for patients with advanced colorectal cancer.
This systematic review of trials and cohort studies found that KRAS mutations were consistently associated with increased rates of treatment failure and reduced survival in adults with advanced colorectal cancer treated with anti-EGFR antibodies.
Patient-level data about pathologic features of tumors and other potential prognostic factors were not available.
Benefits of anti-EGFR monoclonal antibody treatment of colorectal cancer may be limited to patients without KRAS mutations.
RCT = randomized, controlled trial.
Each publication is represented by an ellipse, and ellipses of publications with at least partial overlap are linked. The graph indicates that a substantial amount of overlap is present: Of a total of 45 studies, only 24 reported on independent patient populations.
Forest plots on the left present results for the treatment effect (anti-EGFR antibody group vs. comparator), stratified by KRAS mutation status, for each clinical trial. These estimates are indicative of the treatment effect (anti-EGFR treatment group vs. control) within the subgroups of patients defined by KRAS mutation status. Circles represent the point estimate of the treatment effect among KRAS wild-type patients, and squares represent the point estimate of the treatment effect among KRAS-mutated patients. Forest plots on the right summarize the relative treatment effect within each of the 4 studies (KRAS mutant vs. wild-type). These estimates are comparing the treatment effects (anti-EGFR treatment group vs. control) between the groups defined by KRAS mutation status. For each estimate, horizontal lines indicate the 95% CI. Diamonds indicate the summary relative estimates (hazard ratios or odds ratios, as appropriate) by random-effects calculations; the width of the diamond represents the 95% CI of the summary estimates. EGFR = epidermal growth factor receptor. Top. Results for overall survival. Middle. Results for progression-free survival. Bottom. Results for treatment failure.
Forest plots on the left present results for the treatment effect (anti-EGFR antibody group vs. comparator), stratified by KRAS mutation status, for each clinical trial. Circles represent the point estimate of the treatment effect among KRAS wild-type patients, and squares represent the point estimate of the treatment effect among KRAS-mutated patients. Forest plots on the right summarize the relative treatment effect within each of the 4 studies (KRAS mutant vs. wild-type). Reference 46 is represented by 2 strata because survival information was presented separately on the basis of cytotoxic chemotherapy regimens used. For each estimate, horizontal lines indicate the 95% CI. Diamonds indicate the summary relative estimates (hazard ratios or odds ratios, as appropriate) by random-effects calculations; the width of the diamond represents the 95% CI of the summary estimates. EGFR = epidermal growth factor receptor. Top. Results for overall survival. Middle. Results for progression-free survival. Bottom. Results for treatment failure.
Each study is shown by the point estimate of the HR (size of square is proportional to the weight of each study) and 95% CI; the summary HR and its 95% CI by random-effects calculations are depicted by the diamond. Values greater than 1 indicate that patients with the KRAS mutation have reduced survival compared with wild-type patients. HR = hazard ratio.
Study results are plotted in the receiver-operating characteristic curve space. Each study is represented by a circle, whose size is proportional to the study size. EGFR = epidermal growth factor receptor.
Ezzeldin M. Ibrahim
International Medical Center
October 24, 2011
Systematic Review: Anti-Epidermal Growth Factor Receptor Treatment Effect Modification by KRAS Mutations in Advanced Colorectal Cancer
We read with interest the systematic review by Dahabreh et al that was recently published in the Annals (1). The authors investigated whether KRAS mutation status modifies effects of anti-EGFR-based treatments for patients with advanced colorectal cancer (CRC) and whether KRAS status predicts clinical outcomes. Unfortunately, the authors did not refer to our meta-analysis - the largest published so far - that addressed similar questions (2). The article was published online on March 2010, perhaps after Dahabreh et al have locked their literature search database. In our meta-analysis there were four randomized studies (RS) that compared cetuximab-based therapy (CBT) versus non-cetuximab control (NCC) in 2,292 patients, and six non-randomized studies (NRS) included patients received cetuximab after failure of prior chemotherapy (411 patients). Patients in RS with wild K-ras tumor gained more benefit from CBT vs. NCC. For objective response rate (ORR), the odds ratio (OR) was 2.10 (p=0.0002), while the hazard ratio (HR) for progression-free survival (PFS) was 0.64 (p=0.04). On the other hand, CBT was associated with an adverse effect on RR and no effect on PFS in mutated K-ras. In all patients who received CBT in RS and NRS, those with wild vs. mutated K-ras demonstrated higher RR (odds ratio 3.72; p<0.0001). Compared with NCC in three RS, CBT showed significant overall survival (OS) advantage in patients with wild K-ras (HR=0.68; p=0.01). Subsequent to that meta-analysis, we performed a more recent meta-analysis intended to examine the clinical outcome of panitumumab for metastatic CRC (3). In the later meta-analysis, we identified four RS that included 1,010 and 1,105 patients who received panitumumab-based therapy (PBT) PBT and the control intervention, respectively. Used in subsequent-line setting and among those with wild k-ras, PBT was associated with 42% improvement in PFS (HR = 0.58; P = 0.02), a non-significant overall survival (OS) benefit (HR = 0.90; P = 0.18), and a significant increase in ORR (OR = 0.67; P = 0.04). PBT showed no benefit in the first-line setting. Restricted analysis to two studies (first- and second-line setting), where the treatment effect of PBT was prospectively analyzed according to tumor KRAS status, showed significant PFS (HR = 0.77), OS (HR = 0.84), and ORR (OR = 2.06) advantage. Our two published meta-analyses support and certainly complement the conclusions derived by Dahabreh et al (1).
1. Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA. Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 2011;154(1):37-49.
2. Ibrahim EM, Zekri JM, Bin Sadiq BM. Cetuximab-based therapy for metastatic colorectal cancer: a meta-analysis of the effect of K-ras mutations. Int J Colorectal Dis. 2010;25(6):713-21.
3. Ibrahim EM, Abouelkhair KM. Clinical outcome of panitumumab for metastatic colorectal cancer with wild-type KRAS status: a meta-analysis of randomized clinical trials. Med Oncol. 2011. Jan 9. [Epub ahead of print].
Dahabreh IJ, Terasawa T, Castaldi PJ, et al. Systematic Review: Anti–Epidermal Growth Factor Receptor Treatment Effect Modification by KRAS Mutations in Advanced Colorectal Cancer. Ann Intern Med. 2011;154:37–49. doi: https://doi.org/10.7326/0003-4819-154-1-201101040-00006
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Published: Ann Intern Med. 2011;154(1):37-49.
Colorectal Cancer, Gastroenterology/Hepatology, Gastrointestinal Cancer, Hematology/Oncology.
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