Heather Spencer Feigelson1, Chan Zeng1, Pamala A Pawloski2, Adedayo A Onitilo3, C Sue Richards4, Monique A Johnson4, Tia L Kauffman5, Jennifer Webster5, Carsie Nyirenda1, Gwen L Alexander6, Clara Hwang7, Deanna Cross8, Catherine A McCarty9, Robert L Davis10, Denise Schwarzkopf5, Andrew E Williams11, Stacey Honda11, Yihe Daida11, Lawrence H Kushi12, Thomas Delate13, Katrina A B Goddard5. 1. Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado, United States of America. 2. HealthPartners Institute for Education and Research, Bloomington, Minnesota, United States of America. 3. Department of Hematology/Oncology, Marshfield Clinic Weston Center, Weston, Wisconsin, and Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States of America; Clinical Epidemiology Unit, School of Population Health, University of Queensland, Brisbane, Queensland, Australia. 4. Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, United States of America. 5. The Center for Health Research Kaiser Permanente Northwest, Portland, Oregon, United States of America. 6. Henry Ford Health System, Department of Public Health Sciences, Detroit, Michigan, United States of America. 7. Henry Ford Health System, Department of Internal Medicine, Division of Hematology/Oncology, Detroit, Michigan, United States of America. 8. Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States of America. 9. Essentia Institute of Rural Health, Duluth, Minnesota, United States of America. 10. Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, Tennessee, United States of America. 11. Center for Health Research, Kaiser Permanente Hawai'i, Honolulu, Hawaii, United States of America. 12. Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America. 13. Kaiser Permanente Colorado, Pharmacy Department, Denver, Colorado, United States of America.
Abstract
PURPOSE: Epidermal growth factor receptor (EGFR) inhibitors are approved for treating metastatic colorectal cancer (CRC); KRAS mutation testing is recommended prior to treatment. We conducted a non-inferiority analysis to examine whether KRAS testing has impacted survival in CRC patients. PATIENTS AND METHODS: We included 1186 metastatic CRC cases from seven health plans. A cutpoint of July, 2008, was used to define two KRAS testing time period groups: "pre-testing" (n = 760 cases) and "post-testing" (n = 426 cases). Overall survival (OS) was estimated, and the difference in median OS between the groups was calculated. The lower bound of the one-sided 95% confidence interval (CI) for the difference in survival was used to test the null hypothesis of post-testing inferiority. Multivariable Cox regression models were constructed to adjust for covariates. RESULTS: The median unadjusted OS was 15.4 months (95% CI: 14.0-17.5) and 12.8 months (95% CI: 10.0-15.2) in the pre- and post-testing groups, respectively. The OS difference was -2.6 months with one-sided 95% lower confidence bound of -5.13 months, which was less than the non-inferiority margin (-5.0 months, unadjusted p = 0.06), leading to a failure to reject inferiority of OS in the post-testing period. In contrast, in the adjusted analysis, OS non-inferiority was identified in the post-testing period (p = 0.001). Sensitivity analyses using cutpoints before and after July, 2008, also met the criteria for non-inferiority. CONCLUSION: Implementation of KRAS testing did not influence CRC OS. Our data support the use of KRAS testing to guide administration of EGFR inhibitors for treatment of metastatic CRC without diminished OS.
PURPOSE:Epidermal growth factor receptor (EGFR) inhibitors are approved for treating metastatic colorectal cancer (CRC); KRAS mutation testing is recommended prior to treatment. We conducted a non-inferiority analysis to examine whether KRAS testing has impacted survival in CRC patients. PATIENTS AND METHODS: We included 1186 metastatic CRC cases from seven health plans. A cutpoint of July, 2008, was used to define two KRAS testing time period groups: "pre-testing" (n = 760 cases) and "post-testing" (n = 426 cases). Overall survival (OS) was estimated, and the difference in median OS between the groups was calculated. The lower bound of the one-sided 95% confidence interval (CI) for the difference in survival was used to test the null hypothesis of post-testing inferiority. Multivariable Cox regression models were constructed to adjust for covariates. RESULTS: The median unadjusted OS was 15.4 months (95% CI: 14.0-17.5) and 12.8 months (95% CI: 10.0-15.2) in the pre- and post-testing groups, respectively. The OS difference was -2.6 months with one-sided 95% lower confidence bound of -5.13 months, which was less than the non-inferiority margin (-5.0 months, unadjusted p = 0.06), leading to a failure to reject inferiority of OS in the post-testing period. In contrast, in the adjusted analysis, OS non-inferiority was identified in the post-testing period (p = 0.001). Sensitivity analyses using cutpoints before and after July, 2008, also met the criteria for non-inferiority. CONCLUSION: Implementation of KRAS testing did not influence CRC OS. Our data support the use of KRAS testing to guide administration of EGFR inhibitors for treatment of metastatic CRC without diminished OS.
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