RAS mutation prevalence among patients with metastatic colorectal cancer: A meta-analysis of real-world data.

Abstract

513 Background: Guidelines for prescribing anti-EGFR therapy for metastatic colorectal cancer (mCRC) require prior testing to confirm RAS (exons 2, 3, 4 of KRAS and NRAS) wild-type status in Europe and the USA. There is limited published evidence reporting the prevalence of RAS mutations in patients with mCRC in a real-world setting. The aim of this study was to use data from a range of real-world sources to obtain RAS mutation prevalence estimates for different geographic regions. Methods: Aggregated RAS mutation prevalence data were collected from 13 sources, including individual pathology centers (n = 7), mCRC registries (n = 3), and Amgen-sponsored studies (n = 3). Data sources included in this study originated in Europe (n = 10), the Middle East (n = 2), and South America (n = 1). A meta-analysis of all collected data was carried out to investigate the effect of heterogeneity amongst the data sources and obtain pooled RAS prevalence estimates for each, using a mixed regression model. Results: Aggregate data from 4322 patients with mCRC were included in the pooled meta-analysis. The overall RAS mutation prevalence across all data sources was estimated to be 43.5% (95% CI: 41.5–45.5%). RAS mutation prevalence varied between data sources, ranging from low estimates of 33.7% (95% CI: 28.4–39.3%) for a Middle Eastern pathology dataset, and 34.6% (95% CI: 27.7–42.1%) for a Middle Eastern mCRC registry, to the highest estimates of 53.6% (95% CI: 43.2–63.8%) and 54.1% (95% CI: 51.7–56.5%) in two European pathology centers, in the Czech Republic and Poland, respectively. Conclusions: This is one of the first studies to carry out a large pooled analysis of RAS mutation prevalence, based on real-world data. There was a high degree of heterogeneity between the sources included, possibly due to the types of data source, patient selection criteria, geographic location, or differences in laboratory testing methods. The estimated RAS mutation prevalence reported here is lower than that in a recent pooled analysis of past clinical trials, which reported an overall prevalence of 55.5% (95% CI: 53.9–57.9%) (Peeters M, et al. Eur J Cancer 2015;51:1704–13). Further investigations are required to explain the disparity in these findings.

Evolution of RAS Testing Over Time: Factors Influencing Mutation Rates in Metastatic Colorectal Cancer Patients

“…This study aimed to provide an overview of RAS biomarker testing in Europe, in relation to mutation rates and testing practices, based on data from the ESP Colon EQA program and a European-wide survey. The results demonstrated an overall RAS mutation rate in the tested samples of 45.2% (12,341/27,325, 95% CI: [44.6-45.8%]), which is in line with other observational studies of RAS mutations in Europe [24,31]. Although this is substantially lower than the 55.9% (95% CI: [53.9-57.9%]) reported in some clinical trials [32].…”

“…Therefore, in July 2013, the therapeutic indication for panitumumab was restricted by the European Medicines Agency (EMA) to patients with RAS (exons 2, 3 and 4 of KRAS and NRAS) wild-type mCRC tumors only (codons 12,13,59,61,117,146). In November 2013, the EMA also determined that cetuximab could only be given to mCRC patients without a RAS mutation Mutations in the BRAF gene occur in 6-15% of all CRC patients [24,25]. Testing for this gene is often combined with RAS testing for its prognostic value, rather than for predicting response to anti-EGFR mAbs, as there is no clear evidence of its predictive role at the moment [17,26].…”

Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer

“…Because patients with mCRC can sometimes be cured with combinations of systemic treatment and surgery, added efficacy could make a major difference in outcomes. Unfortunately, although the RAS pathway is dominant in approximately 40% to 50% of patients with mCRC, 10 there are numerous specific mutations within the RAS family that may drive cancer progression in a given patient. Therefore, even if, for example, the excitement recently engendered by new agents with an inhibitory effect on a K-RAS-12C-mutated preclinical mCRC model 11 is affirmed in clinical trials, the impact will likely be limited to the 4% or so of patients whose tumors harbor that precise mutation.…”

Microsatellite Instability and KRAS Mutation in Stage IV Colorectal Cancer: Prevalence, Geographic Discrepancies, and Outcomes From the National Cancer Database

“…Furthermore, the KRAS mutation prevalence of 42.4% in our cohort is also similar to that reported elsewhere. For instance, Lowe et al 19 reported 35.9% KRAS mutation prevalence in a meta-analysis of patients with metastatic CRC, whereas Kafatos et al 20 showed RAS mutations (combined KRAS and NRAS) in 43.6% of patients with metastatic CRC pooled from 12 primary data sources.…”