KRAS Early Testing: Consensus Initiative and Cost-Effectiveness Evaluation for Metastatic Colorectal Patients in an Italian Setting

Carlo Barone,Carmine Pinto,Lorenzo Mantovani,Lorenzo Capussotti,Francesco Cognetti,Alfredo Falcone,Nicola Normanno,Valli De Re

doi:10.1371/journal.pone.0085897

Carlo Barone, Carmine Pinto + Show 6 more

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https://doi.org/10.1371/journal.pone.0085897

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Abstract

KRAS testing is relevant for the choice of the most appropriate first-line therapy of metastatic colorectal cancer (CRC). Strategies for preventing unequal access to the test should be implemented, but their relevance in the practice is related to economic sustainability. The study adopted the Delphi technique to reach a consensus on several topics. Issues related to execution of KRAS testing were identified by an expert’s board and proposed to 108 Italian oncologists and pathologists through two subsequent questionnaires. The emerging proposal was evaluated by decision analyses models employed by technology assessment agencies in order to assess cost-effectiveness. Alternative therapeutic strategies included most commonly used chemotherapy regimens alone or in combination with cetuximab or bevacizumab. The survey indicated that time interval for obtaining KRAS test should not exceed 15 days, 10 days being an optimal interval. To assure the access to proper treatment, a useful strategy should be to anticipate the test after radical resection in patients at high risk of relapse. Early KRAS testing in high risk CRC patients generates incremental cost-effectiveness ratios between 6,000 and 13,000 Euro per quality adjusted life year (QALY) gained. In extensive sensitivity analyses ICER’s were always below 15,000 Euro per QALY gained, far within the threshold of 60,000 Euro/QALY gained accepted by regulatory institutions in Italy. In metastatic CRC a time interval higher than 15 days for result of KRAS testing limits access to therapeutic choices. Anticipating KRAS testing before the onset of metastatic disease in patients at high risk does not affect the sustainability and cost-effectiveness profile of cetuximab in first-line mCRC. Early KRAS testing may prevent this inequality in high-risk patients, whether they develop metastases, and is a cost-effective strategy. Based on these results, present joined recommendations of Italian societies of Oncology and Pathology should be updated including early KRAS testing.

Highlights

Since 2008 KRAS mutational status has become the main tissue biomarker of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (CRC)
Large phase III and randomized phase II studies have demonstrated that mutation of KRAS gene predicts resistance to treatment with an anti-EGFR antibody either alone or in combination with chemotherapy [1,2]
Q1 was sent to 160 specialists involved in diagnosis and treatment process in the oncology field: 17 molecular biologists (10.7%), 21 surgeons (13.1%), 85 oncologists (53.1%), 37 pathologists (23.1%)

Summary

Introduction

Since 2008 KRAS mutational status has become the main tissue biomarker of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (CRC). The most accepted guidelines consider KRAS mutation status a central step of decision-making process in the therapy of metastatic CRC, both in potentially resectable and palliative treatment settings. Mutational analysis, needs technical and expertise resources that may be not everywhere available [8] Both complexity of the test and different access to molecular biology laboratory may cause delays, which often conflict with the urgency of clinical decision. This means that an unknown, but not irrelevant, percentage of patients is excluded from a potential therapeutic advantage with negative consequences either on symptom control or resection rate and survival

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