Does KRAS testing in metastatic colorectal cancer impact overall survival? A comparative effectiveness study in a population-based sample

Membership of the CERGEN Study Team is provided in the Acknowledgments. The Comparative Effectiveness Research in Genomics of Colon Cancer (CERGEN) Study Team includes: Gwen Alexander, Henry Ford Health System (HFHS); Chris Anderson, Health Partners Institute for Education and Research (HPIER); Ajay Behl, HPIER; Kris Bennett, Kaiser Permanente Northwest (KPNW); Kathleen Bow, Kaiser Permanente Hawai'i (KPHI); Jennifer Carney, KPHI; Ned Colange, Denver Public Health of Colorado; Christopher Cold, Marshfield Clinic Research Foundation (MCRF); Deanna Cross, MCRF; YeeHwa Daida, KPHI; Padmavati Dandamudi, KPNW; Robert Davis, KPG; Teri Defor, HPIER; Thomas Delate, Kaiser Permanente Colorado (KPCO); Jessica Engel, MCRF; Rene Faryniarz, HFHS; Heather Spencer Feigelson, KPCO (lead author); Thomas Flottemesch, HPIER; Mamie Ford, KPNC; Jared Freml, KPCO; Kellyan Funk, KPCO; Joan Garhy, HFHS; Katrina Goddard, KPNW; Julie Harris, Kaiser Permanente Northern California (KPNC); Mia Hemmes, Kaiser Permanente Georgia (KPG); Paul Hitz, MCRF; Rebecca Holmes, KPNW; Stacey Honda, KPHI; Stephen Houston, KPNW; Karl Huang, KPNC; Clara Hwang, HFHS; Sheng-Fang Jiang, KPNC; Monique Johnson, Oregon Health and Sciences University (OHSU); Tia Kauffman, KPNW; Terrie Kitchner, MCRF; Richard Krajenta HFHS; Tatjana Kolevska, KPNC; Lawrence Kushi, KPNC; Smyth Lai, KPNW; Anh Q Le, KPCO; Loic LeMarchand, University of Hawaii; Petra Liljestrand, KPNC;Jennifer Lin KPNW; Celeste Machen, KPNW; Michael Maciosek, HPIER; Catherine McCarty, MCRF; Jennifer McCance, KPCO; Richard Meenan, KPNW; Alex Menter, KPCO; Jill Mesa,KPNW; Paul Meier, HFHS; Anousheh Mirabedi, KPNC; Judith Morse, KPNC; Kristin Muessig,KPNW; Andrew Nelson, HPIER; Carsie Nyirenda, KPCO; Maureen O'Keeffe Rosetti, KPNW; Kim Olson, KPNW; Suzanne O'Neill, Georgetown University; Adedayo Onitilo, MCRF; Brian Owens, HPIER;Pamala Pawloski, HPIER; Alanna Rahm, KPCO; C. Sue Richards, OHSU; Denise Schwarzkopf, KPNW; Caitlin Senger, KPNW; Carol Somkin KPNC; Amy Stone-Murai, KPHI;Nagendra Tirumali, KPNW; Laurie VanArman, HPIER; David Veenstra, University of Washington; Aleli Vinoya, KPHI; Carmel Wax, KPNW; Elizabeth Webber, KPNW; Jennifer Webster, KPNW; Evelyn Whitlock KPNW; Andrew Williams, KPHI; Carmen Wong, KPHI; Chan Zeng, KPCO; Sarah Zuber, KPNW. 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