KRAS Mutations Linked to Worse Outcomes From Anti-EGFR Treatment of Colorectal Cancer

Laurie Barclay, MD

January 05, 2011

January 5, 2011 — KRAS mutations are associated with reduced survival time and increased treatment failure in patients with colorectal cancer (CRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies, according to the results of a systematic review reported in the January 4 issue of the Annals of Internal Medicine.

"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," write Issa J. Dahabreh, MD, from the Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, and colleagues.

The goal of the study was to examine the effect of KRAS mutation status on outcomes of anti-EGFR–based treatments of patients with advanced CRC and to determine whether KRAS status would predict clinical outcomes in these patients. Randomized controlled trials published in any language were identified from a search of 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). Observational studies published in any language were identified from a search of MEDLINE and 2 curated genetics databases (through 24 March 2010).

Inclusion criteria were trials that evaluated KRAS mutations as predictors of overall and progression-free survival time or treatment failure for patients who received anti-EGFR–based treatment of metastatic CRC. Three reviewers screened titles and abstracts to identify published trials meeting inclusion criteria, and 3 reviewers extracted data on methodologic characteristics including population and study-design, quality items, and relevant outcomes. Nonoverlapping studies were subjected to random-effects meta-analyses.

Among KRAS-positive patients, anti-EGFR–based therapy offered no significant benefit for overall or progression-free survival time, based on 4 reanalyses of randomized trials of anti-EGFR–based treatment vs best supportive care or cytotoxic chemotherapy (hazard ratio [HR], 1.0). Among patients with the KRAS wild-type mutation, however, evidence favored anti-EGFR treatment. By random-effects meta-analysis, the relative HR across KRAS-positive and wild-type patients was 1.30 (95% confidence interval [CI], 0.95 - 1.78) for overall survival and 2.22 (95% CI, 1.74 - 2.84; P < .001) for progression-free survival.

For overall survival, the summary HR was 1.79 (95% CI, 1.48 - 2.17; P < .001) in 13 cohorts of patients treated with anti-EGFR antibodies, with better survival time in wild-type patients. For progression-free survival, the corresponding HR was 2.11 (95% CI, 1.74 - 2.55) in 16 cohorts of patients treated with anti-EGFR antibodies.

The summary sensitivity of KRAS mutations to predict lack of response was 0.49 (95% CI, 0.43 - 0.55), and summary specificity was 0.93 (95% CI, 0.87 - 0.97), based on random-effects bivariate meta-analysis of 22 studies.

"KRAS mutations are consistently associated with reduced overall and progression-free survival and increased treatment failure rates among patients with advanced ...CRC treated with anti-EGFR antibodies," the review authors write. "...Benefits of anti-EGFR monoclonal antibody treatment of ...CRC may be limited to patients without KRAS mutations."

Limitations of this systematic review include limited evidence from randomized studies, possible publication bias, and lack of patient-level data about pathologic features of tumors and other potential prognostic factors needed to evaluate modifiers of the mutation-by-treatment interaction.

"Evidence indicates that the predictive effect is stronger among patients who have received previous cytotoxic chemotherapy, but more evidence is needed to establish this observation," the review authors conclude. "Further research is warranted to identify subgroups of the disease in which the predictive effect may be stronger and to integrate several molecular biomarkers, such as BRAF, PTEN, or PIK3CA aberrations, along with KRAS mutations in predictive instruments, to further improve predictive accuracy."

The Agency for Healthcare Research and Quality (AHRQ) supported this study. Some of the study authors have disclosed various financial relationships with AHRQ. Disclosures of the study authors can also be viewed at the Annals of Internal Medicine Web site .

Ann Intern Med. 2011;154:37-49. Abstract

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