Cost-effectiveness analysis of screening for KRAS and BRAF mutations in metastatic colorectal cancer.

Overall survival of patients with metastatic colorectal cancer (mCRC) has considerably improved in the last decade (1). Improvements in the treatment of mCRC have reportedly led to six to eight months of survival with best supportive care alone, and more than twenty months with different lines of treatments (2). About 20% of patients with CRC present with synchronous colorectal liver metastases at diagnosis, and 80% to 90% of them are unresectable (3–6). Roughly, 14% to 16% of unresectable colorectal liver metastasis could become resectable with chemotherapy (7,8). Of those whose cancer metastasizes later, nearly 60% have metastases of the liver (3,9,10). Developments in surgery and chemobiologic therapies have allowed more patients to undergo hepatic resection, the potential cure for mCRC (11–13). Patients who have hepatic resections have a nearly 20% probability that they will be alive after 10 years (3,14). Cetuximab, a monoclonal antibody acting against epidermal growth factor receptor (EGFR), was approved by the US Food and Drug Administration (FDA) in 2004 for use with irinotecan for the treatment for EGFR-expressing mCRC in patients refractory to irinotecan-based chemotherapy. Cetuximab is also approved for use as a single agent in patients with recurrent EGFR-expressing mCRC who do not tolerate irinotecan-based therapy. Approval was based on objective response rates. No data demonstrated an improvement in survival (15). In 2007, cetuximab received regular approval after findings from a multinational open-label trial by NCI-Canada in patients with EGFR-expressing mCRC following both oxaliplatin- and irinotecan-containing treatments. The trial found statistically significant differences in overall survival (6.1 months vs. 4.6 months) between patients randomly assigned to receive best supportive care only and those receiving both best supportive care and cetuximab (15). In 2009, retrospective subset analyses of trials with patients with mCRC whose tumors have codon 12 and 13 V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations noted a lack of benefit from cetuximab (and panitumumab, which is also a monoclonal antibody acting against EGFR that was approved in 2006) (16). Bevacizumab, a monoclonal antibody that inhibits the function of vascular endothelial growth factor (VEGF), was approved by the FDA in 2004, for first-line treatment in patients with mCRC. In 2006, following a trial (E3200) demonstrating a statistically significant difference in overall survival (13.0 months vs. 10.8 months) between patients on 5-FU + folinic acid + oxaliplatin (FOLFOX4) and bevacizumab and those on FOLFOX4 only, the FDA extended approval for its use as second-line therapy with 5-fluoroucil-based chemotherapy (17). On the other hand, the effect on overall survival of genetic mutations in the serine/threonine-protein kinase B-Raf (BRAF-V600, or BRAF) is unclear (4,18,19). Patients with BRAF mutations appear to have a poorer prognosis. Retrospective subset analyses suggest that, regardless of BRAF status, patients might benefit from anti-EGFR therapies in the first-line setting. There appears to be no benefit after the patient has progressed after first-line therapy (4). KRAS and BRAF mutations are mutually exclusive in individuals. Both carry additional potential harms (16,20). In 2009, the American Society of Clinical Oncology issued a provisional clinical opinion recommending that all patients with mCRC who are candidates for anti-EGFR treatments have their tumors tested for KRAS mutations (21). Screening for and then limiting anti-EGFR therapy to those without KRAS mutations is aimed at providing the treatment to those who are likely to benefit from it while avoiding unnecessary costs and harm to those who are not likely to benefit. Anti-EGFR treatments are provided to patients with both curative and palliative intent. In the case of treatments administered with a curative intent, the only potential cure is resection of the metastases. Such a successful cure carries additional costs. The monoclonal antibody treatments, especially anti-EGFR therapy, are considerably more expensive than other existing treatments (22,23). In addition, for many patients without a KRAS mutation who do receive anti-EGFR treatment, there may be no meaningful gain in terms of length of survival and only harmful side effects and expenses. In the case of BRAF screening, an economic analysis is warranted to understand the effect of poorer prognosis and lack of effect following progression after first-line treatment. Blank et al. (24) reports cost-effectiveness analyses of screening for KRAS and BRAF mutations in mCRC in the Swiss health systems. They estimated anti-EGFR therapy combined with screening costs at $83 147 (€62 653) per quality-adjusted life year (QALY) saved. For the United States, it has been estimated that KRAS testing would save more than $700 million compared with providing anti-EGFR screening to all mCRC patients, excluding the costs of additional resections (25). Another study has also advocated the use of screening for KRAS mutations, with very accommodating breakeven pricing of $3500 per screening (26). These studies lack transparency regarding how they analyze the treatments, resection of metastases, and survival for the different types of metastases. These aspects have major effects on the costs and effects in the analysis. This paper aims to evaluate the costs and effects of screening for KRAS and BRAF mutations in mCRC in the context of targeting the use of cetuximab to those without these mutations. The analysis uses the available evidence base, including the use of treatments, resection probabilities, and length of survival to create and calibrate a comprehensive analytical framework. Reported overall survival rates from different trials are used to develop best estimates to analyze the base case and conduct subsequent sensitivity analyses. The paper provides insight into the major costs in the treatment of mCRC, including resection costs, and clarifies the economic case for anti-EGFR therapy and associated screening in the United States.