Feigelson Heather Spencer, Zeng Chan, Pawloski Pamala A, Onitilo Adedayo A, Richards C Sue, Johnson Monique A, Kauffman Tia L, Webster Jennifer, Nyirenda Carsie, Alexander Gwen L, Hwang Clara, Cross Deanna, McCarty Catherine A, Davis Robert L, Schwarzkopf Denise, Williams Andrew E, Honda Stacey, Daida Yihe, Kushi Lawrence H, Delate Thomas, Goddard Katrina A B
Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado, United States of America.
HealthPartners Institute for Education and Research, Bloomington, Minnesota, United States of America.
PLoS One. 2014 May 1;9(5):e94977. doi: 10.1371/journal.pone.0094977. eCollection 2014.
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.
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.
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.
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.
表皮生长因子受体（EGFR）抑制剂已被批准用于治疗转移性结直肠癌（CRC）；建议在治疗前进行KRAS突变检测。我们进行了一项非劣效性分析，以研究KRAS检测是否影响CRC患者的生存率。
我们纳入了来自七个健康计划的1186例转移性CRC病例。以2008年7月为分界点，定义两个KRAS检测时间段组：“检测前”（n = 760例）和“检测后”（n = 426例）。估计总生存期（OS），并计算两组之间的中位OS差异。生存差异的单侧95%置信区间（CI）下限用于检验检测后劣效性的零假设。构建多变量Cox回归模型以调整协变量。
检测前和检测后组的中位未调整OS分别为15.4个月（95%CI：14.0 - 17.5）和12.8个月（95%CI：10.0 - 15.2）。OS差异为 - 2.6个月，单侧95%置信下限为 - 5.13个月，小于非劣效性界值（ - 5.0个月，未调整p = 0.06），导致未能拒绝检测后时期OS的劣效性。相比之下，在调整分析中，检测后时期确定了OS非劣效性（p = 0.001）。使用2008年7月前后分界点的敏感性分析也符合非劣效性标准。
KRAS检测的实施并未影响CRC的OS。我们的数据支持使用KRAS检测来指导EGFR抑制剂用于治疗转移性CRC的给药，而不会降低OS。
