Cost Estimates and Economic Implications of Expanded RAS Testing in Metastatic Colorectal Cancer

This analysis found that the increased cost of expanded RAS testing for metastatic colorectal cancer was small when compared with the amount saved by not treating the additional 18% of patients who harbor additional RAS mutations (beyond exon 2) with anti-EGFR therapy. Increased use of expanded biomarkers to predict efficacy of targeted agents will provide more precise therapies for patients and reduce the use of potentially ineffective high-cost therapy.

Abstract

Background.

In colorectal cancer (CRC), evidence shows that expanding RAS testing to analyze more mutations may better predict benefit from anti-EGFR therapy. The economic implications of expanding RAS testing for metastatic CRC were analyzed.

Materials and Methods.

Estimates of standard KRAS exon 2 testing were based on the Centers for Medicare and Medicaid Services (CMS) 2014 Diagnostic Laboratory Fee Schedule, and expanded RAS testing was estimated using a sensitivity analysis done with various potential cost scenarios (1, 2, 10, and 30 times the cost of the standard KRAS test). The cost estimates for cetuximab and panitumumab were based on the CMS payment allowance limits for Medicare Part B.

Results.

A total of 28,692 patients with metastatic CRC were estimated to be eligible annually for RAS testing. For cetuximab, the societal cost of standard KRAS testing plus the drug versus expanded testing plus the drug would be $1.16 billion versus $816 million if the cost of the tests were the same. If the cost of the expanded RAS test were 30 times the cost of the standard test, then the societal cost of standard KRAS testing plus the drug versus expanded testing plus the drug would be $1.16 billion versus $980 million, a continued savings of more than $184 million annually. Similar savings were seen with panitumumab.

Conclusion.

The increased societal cost of expanded RAS testing versus standard approved KRAS exon 2 testing was inconsequential when compared with the amount of money saved by not treating the additional 18% of patients who harbor additional RAS mutations (beyond exon 2) with anti-EGFR therapy.

Implications for Practice:

Predictive biomarkers and targeted therapies in metastatic colorectal cancer are evolving. This analysis found that the increased cost of expanded RAS testing was small when compared with the amount saved by not treating the additional 18% of patients who harbor additional RAS mutations (beyond exon 2) with anti-EGFR therapy. Increased use of expanded biomarkers to predict efficacy of targeted agents will provide more precise therapies for patients and reduce the use of potentially ineffective high-cost therapy.

Introduction

The development of predictive biomarkers and targeted therapies has been one of the most significant advances in understanding the biology and treatment of cancers, but the high costs of both laboratory-based biomarker testing and drug therapies present challenges to our evolving health care system.

In metastatic colorectal cancer (mCRC), it is well established that activating mutations in the oncogene KRAS, which results in constitutive activation of the downstream RAS-RAF-ERK pathway, predict resistance to the anti-EGFR inhibitors cetuximab and panitumumab [1–16]. Approximately 40% of patients with mCRC have a mutation in KRAS exon 2, and 60% will have wild-type (WT) KRAS [17, 18]. KRAS mutations are mainly identified in exon 2 (codons 12 and 13) [19]. The U.S. Food and Drug Administration (FDA) has approved a polymerase chain reaction (PCR) assay, the Therascreen KRAS RCQ PCR kit (Qiagen, Hilden, Germany, http://www.qiagen.com), that detects mutation of the KRAS gene only within exon 2 at either codon 12 or 13. Tumors that are KRAS-mutation negative using these standardized assay platforms are commonly referred to as WT tumors. Identifying exon 2 mutations of KRAS has become standard of care, and insurance coverage of cetuximab and panitumumab anti-EGFR therapies are exclusively permitted for wild-type tumors.

WT KRAS in exon 2 does not ensure benefit from EGFR inhibitors. The response rate (RR) is only ∼40%, even when restricted to highly selected patient cohorts [7, 20, 21]. Data suggest that resistance to anti-EGFR therapy can be mediated by lower frequency mutations outside of KRAS exon 2, including RAS mutations [22, 23], and downstream of EGFR, including mutations in PI3K and PTEN [10, 22, 24].

The most recent compelling data suggesting the benefit of expanded mutational RAS testing in metastatic colorectal cancer was reported by the Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) trial [22]. This study included 639 mCRC patients with KRAS exon 2 WT. Analysis was performed for at least one of the following additional mutations: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. A total of 108 patients (18%) with WT KRAS exon 2 harbored other RAS mutations, for which tests are not performed routinely in current clinical practice. These additional RAS mutations predicted lack of response to panitumumab. In addition, a recent report from the 2014 Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology updated data analysis of progression-free survival (PFS) from PRIME that took into account all identified RAS mutations. These reanalyzed retrospective data showed an improvement in PFS from a hazard ratio of 0.73 (original report) to 0.695 in the WT population [25]. This finding highlights the importance of precise biomarker testing to better select patients that are likely to benefit the most from specific targeted therapies.

An updated retrospective analysis of an expanded KRAS and NRAS mutational status was performed on all archival tissue from patients with mCRC enrolled in the Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer (OPUS) randomized phase III trial that investigated the first-line addition of cetuximab to the FOLFOX4 regimen. Patients previously identified in OPUS as KRAS WT exon 2 codon 12/13 were tested for additional mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4, and 31% of patients in OPUS who were identified as WT were found to have mutations in other loci. When all mutations were considered, those with mutant RAS at any loci (including expanded testing) had no benefit in RR, median PFS, or overall survival (OS) with the addition to cetuximab to FOLFOX4 (RR: 47.1% vs. 36.8%, p = .57; PFS: 7.3 vs. 7.4 months, p = .96; OS: 14.8 vs. 17.8 months, p = .41). This analysis echoed the results from the PRIME trial showing that additional RAS mutant tumors, outside of standard exon 2 testing, can identify patients who are unlikely to benefit from anti-EGFR cetuximab therapy [26]. Raising concerns even further were trends toward inferior outcomes with use of anti-EGFR therapy in RAS-mutant colorectal tumors, as elucidated by the Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and PRIME trials [25, 27].

Testing for standard KRAS mutations before administering EGFR-directed therapy has been evaluated in the past and proven to be cost-effective [28]. In this brief report, we did an economic analysis of the impact of additional expanded RAS testing versus standard of care in mCRC.

Materials and Methods

Population and Assumptions

We used the 2012 American Cancer Society [29] estimated new incidence of mCRC. We assumed that all mCRC patients diagnosed would be tested for standard KRAS exon 2 and for additional RAS mutations. We assumed all patients with KRAS/RAS/NRAS WT mCRC would be treated with anti-EGFR therapy (cetuximab or panitumumab) at one time point.

Testing

Standard testing was defined as KRAS exon 2, and expanded RAS testing was defined as KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4.

Cost Estimates

We estimated the cost of single standard KRAS exon 2 testing as $197 based on the 2014 Centers for Medicare and Medicaid Services (CMS) Clinical Diagnostic Laboratory Fee Schedule [30]. The expanded RAS testing is not standard and is not offered in most laboratories, so sensitivity analysis was done with various potential cost scenarios (1, 2, 10, and 30 times the cost of the standard KRAS test). The cost estimates for cetuximab and panitumumab were based on the payment allowance limits for Medicare Part B drugs that are published quarterly (as of December 2013) [31].

Results

In 2012, the total incidence of colorectal cancer in the U.S. was 142,460 cases [29]. Because 20% of patients are initially diagnosed with metastatic disease [29, 32], we used 28,692 patients as our estimate of patients eligible for RAS testing. This number is likely an underestimation of total patients eligible for RAS testing because it does not include those patients with recurrent metastatic disease. Using the Medicare payment allowance limits for cetuximab ($4,205 per loading dose and $2,628 per weekly dose for a patient of average height and weight with a body surface area of 2.0 m²), the drug cost estimate was $67,277 per patient, assuming an average of 25 weeks per patient, as seen in the CRYSTAL trial analysis [2]. For panitumumab, each dose for an average 70-kg patient costs $3,838. Based on data from the PRIME study, in which patients received panitumumab for a median duration of 22 weeks, the total cost estimate was $42,218 per patient [15].

In both scenarios, we made the assumption that all patients with mCRC would receive RAS testing (Fig. 1). In scenario 1, patients received only standard KRAS exon 2 testing. Based on the total incidence of mCRC of 28,692 patients and the supporting literature showing that ∼60% will have a WT KRAS exon 2 [22], 17,215 patients would be eligible for anti-EGRF therapy. Based on the CMS laboratory schedule of $197 for KRAS exon 2 testing, the total annual cost of all patients receiving standard KRAS testing is $5,652,324.

Figure 1.

Patients with metastatic colorectal cancer with either standard KRAS testing (exon 2) versus expanded testing (KRAS exon 2, 3, 4; NRAS exon 2, 3, 4). Figure shows the different distribution of mutated versus wild type tumors based on type of testing with associated cost of the test and the EGFR inhibitor. The scenario in this figure is that the standard testing cost was $197 and the expanded testing cost was 30 times that amount, or $5,910. The total costs of getting cetuximab or panitumumab include the cost of the drug and the test.

Abbreviations: C, cetuximab; mCRC, metastatic colorectal cancer; P, panitumumab; WT, wild type.

In scenario 2, all patients received expanded RAS testing including KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4. Using the estimates from Doulliard et al. [22], with this expanded testing, 40% would be found to have mutated KRAS exon 2, 42% would have WT KRAS with no other mutations in RAS, and 18% would have WT KRAS exon 2 and another RAS mutation gene. Consequently, only 42%—an estimate of 12,051 patients—would be eligible for anti-EGFR therapy in scenario 2. Table 1 and Table 2 show the differences in cost between standard testing plus EGFR inhibitor versus expanded testing plus EGFR inhibitor if the expanded test were the same cost or 2, 10, and 30 times the cost. In each cost situation, even when expanded testing cost 30 times the cost of standard testing, there is overall cost savings with expanded RAS testing. Economic benefit was lost if expanded RAS testing cost >30 times standard KRAS testing, making 30 times the cost the upper limit for our sensitivity analysis. Cost estimates were done for both cetuximab and panitumumab (Tables 1 and 2)

Table 1.

Cost scenarios for cetuximab if the cost of expanded RAS testing is the same or 2, 10, or 30 times the cost of standard KRAS testing

Table 2.

Cost scenarios for panitumumab if the cost of expanded RAS testing is the same or 2, 10, or 30 times the cost of standard KRAS testing

Discussion

In today’s health care environment, the cost of cancer treatment is increasingly relevant for all stakeholders including payers, hospitals, physicians, and patients. Cancer is the second-most expensive disease in the U.S. after heart disease, with an annual estimated cost of $124 billion in 2010 and a projected rise to $157 billion in 2020, which reflects a 27% increase [33]. In the case of metastatic colorectal cancer, there is a high price tag on both expanded RAS testing and the contingently recommended specific targeted therapies. It is of the utmost importance to understand how to balance the high costs of biomarker testing and expensive drugs with the true clinical benefit for patients with incurable mCRC.

In this analysis, we found that the increased societal cost of expanded RAS testing versus standard FDA-approved KRAS exon 2 testing was inconsequential when compared with the amount of money saved by not treating the additional 18% of patients who harbor additional RAS mutations (beyond exon 2) with anti-EGFR therapy. More than $184 million of annual absolute savings was seen, even with a higher cost for the expanded RAS test and with a test cost that was 30 times the cost of the standard exon 2 test. The savings increased to more than $297 million annually if the cost of the expanded testing was 10 times the cost of standard KRAS testing.

The cost estimates in these analyses were exclusively for drugs alone and did not include the cost of drug preparation, administration, or supportive medication. If all of these costs were taken into consideration, an even larger cost-savings benefit would be found. These findings highlight the striking benefit of a biomarker-driven targeted treatment approach and its impact on our health economy.

In addition to cost, the fear of potential harm and inferior outcome in OS and PFS in patients receiving anti-EGFR-based therapy in this selected cohort, which carries other RAS mutations, may push the bar further toward a more precise biomarker-driven treatment approach. Mounting evidence highlights the clinical impact of expanded RAS testing with anti-EGFR agents, and the National Comprehensive Cancer Network (NCCN) now recommends that all patients with metastatic colorectal cancer have their tumors genotyped for KRAS and NRAS before consideration of these agents [34, 35]. Several NCCN institutions have begun implementing expanded RAS analysis through institutionally developed genomic platforms; however, widespread implementation remains challenging because of a lack of commercially available testing at this time. Given the supportive clinical evidence mentioned above, it is likely that an FDA-approved expanded RAS test will be widely available for clinical use in the near future.

It will be imperative to understand the downstream clinical and cost implications as the number of potential targets and biomarker identifications increase. The development of novel diagnostic tools that allow molecular profiling will need to evolve in reliability and efficiency to provide this important information in a timely way. In our analysis, we found that biomarker testing was economically advantageous if the cost of testing all patients newly diagnosed metastatic colorectal cancer remained lower than the cost of treating the patients who were identified as not likely to benefit from the proposed treatment. This report obviously simplifies the complex cost and economic implications of both biomarker testing and contingent biologic therapies; there is significant variation in our health care system. In addition, these cost estimates are from a societal perspective and do not reflect the out-of-pocket costs for patients. The intention of this analysis is to emphasize that as we move toward precision medicine, a cost-effectiveness balance will need to be understood and embraced in today’s health care environment.

Conclusion

Our brief analysis demonstrates that even if the cost of specific biomarker testing is high, substantial downstream savings could be realized for our health care system. RAS testing is one aspect of a larger effort within oncology to use large-scale molecular testing. Consequently, certified laboratories will need to develop new and efficient assays to handle large-volume biomarker testing. At the same time, hospital systems and payers need to develop innovative pricing and reimbursement strategies to contain the high cost of biomarker testing. The promise of precision medicine may allow us to maximize benefit and improve clinical outcomes for our patients, yet the cost of doing so must remain sustainable in an evolving health care environment.

Author Contributions

Conception/Design: Sheetal M. Kircher, Halla Nimeiri

Provision of study material or patients: Sheetal M. Kircher, Nisha Mohindra, Halla Nimeiri

Collection and/or assembly of data: Sheetal M. Kircher, Nisha Mohindra, Halla Nimeiri

Data analysis and interpretation: Sheetal M. Kircher, Nisha Mohindra, Halla Nimeiri

Manuscript writing: Sheetal M. Kircher, Nisha Mohindra, Halla Nimeiri

Final approval of manuscript: Sheetal M. Kircher, Nisha Mohindra, Halla Nimeiri

Disclosures

The authors indicated no financial relationships.