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Using Genomic Heterogeneity to Inform Therapeutic Decisions for Metastatic Colorectal Cancer: An Application of the
Reka E Pataky1,2, Stuart Peacock3,4, Stirling Bryan5,6
1Canadian Centre for Applied Research in Cancer Control, BC Cancer, Vancouver, BC, Canada. rpataky@bccrc.ca.
Background And Objective:
Mutations in KRAS and NRAS are predictive of poor response to cetuximab and panitumumab, two anti-epidermal growth factor receptor (EGFR) monoclonal antibodies used in metastatic colorectal cancer (mCRC). Our objective was to explore the value of using KRAS and NRAS mutation status to inform third-line anti-EGFR therapy for mCRC using the value of heterogeneity (VOH) framework.
Methods:
We used administrative data to identify mCRC patients who were potentially eligible for third-line therapy in 2006-2019 in British Columbia (BC), Canada. We compared three alternative stratification policies in place during the study period: the unstratified policy where anti-EGFR therapy was not offered (2006-2009), stratification by KRAS mutation (2009-2016), and stratification by KRAS+NRAS mutation (2016-2019). We used inverse-probability-of-treatment weighting to balance covariates across the three groups. Cost and survival time were calculated using a 3-year time horizon and adjusted for censoring, with bootstrapping to characterize uncertainty. Mean net monetary benefit (NMB) was calculated at a range of threshold values. The VOH of using KRAS and NRAS mutation status to inform treatment selection was calculated as the change in NMB with increasing stratification, under current (static VOH) or perfect (dynamic VOH) information.
Results:
We included 2664 patients in the analysis. At a willingness-to-pay of CA$100,000/ life-year gained (LYG), stratification on KRAS mutation status provided a static VOH of CA$1565 per patient; further stratification on KRAS+NRAS provided additional static VOH of CA$594. The static VOH exceeded the marginal cost of genomic testing under both policies.
Conclusions:
Stratification of anti-EGFR therapy by KRAS and NRAS mutation status can provide additional value at a threshold of CA$100,000/LYG. There is diminishing marginal value and increasing marginal costs as the policy becomes more stratified. The VOH framework can illustrate the value of subgroup-specific decisions in a comprehensive way, to better inform targeted treatment policies.
Insights
Testing KRAS and NRAS mutations improves anti-EGFR therapy for metastatic colorectal cancer (mCRC). Stratifying treatment by these mutations offers significant value, exceeding genomic testing costs.
Area of Science:
- Oncology
- Pharmacoeconomics
- Genomics
Background:
- Mutations in KRAS and NRAS predict poor response to anti-EGFR therapies like cetuximab and panitumumab in metastatic colorectal cancer (mCRC).
- Current treatment guidelines often do not fully leverage genomic information for third-line therapy selection.
Purpose of the Study:
- To evaluate the value of heterogeneity (VOH) framework in assessing the economic benefit of using KRAS and NRAS mutation status for third-line anti-EGFR therapy in mCRC.
- To compare the cost-effectiveness of different anti-EGFR therapy stratification policies based on KRAS and NRAS mutation status.
Main Methods:
- Retrospective analysis of administrative data for mCRC patients in British Columbia (2006-2019).
- Comparison of three policies: unstratified, KRAS-stratified, and KRAS+NRAS-stratified anti-EGFR therapy.
- Inverse-probability-of-treatment weighting, bootstrapping, and net monetary benefit (NMB) calculation at a willingness-to-pay threshold of CA$100,000/life-year gained (LYG).
Main Results:
- Stratification by KRAS mutation status yielded a static VOH of CA$1565 per patient.
- Further stratification by KRAS+NRAS mutations provided an additional static VOH of CA$594 per patient.
- The value of genomic testing (VOH) exceeded its marginal cost under both stratification policies.
Conclusions:
- Stratifying anti-EGFR therapy by KRAS and NRAS mutation status demonstrates significant added value in mCRC treatment.
- The VOH framework effectively illustrates the economic benefits of subgroup-specific treatment decisions.
- While stratification increases value, diminishing marginal returns and increasing costs necessitate careful policy design.
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