扩增作为转移性结直肠癌抗表皮生长因子受体抗体治疗预测生物标志物的验证

Validation of Amplification as a Predictive Biomarker for Anti-Epidermal Growth Factor Receptor Antibody Therapy in Metastatic Colorectal Cancer.

作者信息

Raghav Kanwal, Loree Jonathan M, Morris Jeffrey S, Overman Michael J, Yu Ruoxi, Meric-Bernstam Funda, Menter David, Korphaisarn Krittiya, Kee Brian, Muranyi Andrea, Singh Shalini, Routbort Mark, Chen Ken, Shaw Kenna R M, Katkhuda Riham, Shanmugam Kandavel, Maru Dipen, Fakih Marwan, Kopetz Scott

机构信息

Kanwal Raghav, Jonathan M. Loree, Jeffrey S. Morris, Michael J. Overman, Ruoxi Yu, Funda Meric-Bernstam, David Menter, Krittiya Korphaisarn, Brian Kee, Mark Routbort, Ken Chen, Kenna R.M. Shaw, Riham Katkhuda, Dipen Maru, and Scott Kopetz, The University of Texas MD Anderson Cancer Center, Houston, TX; Andrea Muranyi, Shalini Singh, and Kandavel Shanmugam, Ventana Medical Systems, Tucson, AZ; and Marwan Fakih, City of Hope Comprehensive Cancer Center, Duarte, CA.

出版信息

JCO Precis Oncol. 2019 Dec;3:1-13. doi: 10.1200/PO.18.00226.

DOI:10.1200/PO.18.00226

PMID:35100667

Abstract

PURPOSE

amplification has been implicated in resistance to therapy with anti-epidermal growth factor receptor antibodies (anti-EGFRabs) in metastatic colorectal cancer (mCRC). The purpose of the study was to validate the predictive impact of amplification in mCRC.

PATIENTS AND METHODS

We analyzed patients with wild-type mCRC across two distinct cohorts. In cohort 1 (n = 98), amplification was tested in tumor tissue using dual in situ hybridization ( amplification: ratio, 2.0 or greater). Cohort 2 (n = 70) included 16 patients with amplification and 54 nonamplified controls identified by next-generation sequencing ( amplification: four or more copies) who had received prior anti-EGFRabs. The primary end point was progression-free survival (PFS) on treatment with anti-EGFRab therapy, which was estimated and compared using the Kaplan-Meier method and log-rank test.

RESULTS

Median PFS in cohort 1 on anti-EGFRab-based therapy was significantly shorter in patients with amplification compared with nonamplified patients (2.8 8.1 months, respectively; hazard ratio [HR], 7.05; 95% CI, 3.4 to 14.9; < .001). These findings were validated in cohort 2 (median PFS for amplified nonamplified: 2.8 9.3 months, respectively; HR, 10.66; 95% CI, 4.5 to 25.1; < .001). The median PFS on therapy without anti-EGFRabs was similar among -amplified and nonamplified patients in both cohort 1 (9.7 11.1 months, respectively; HR, 1.01; 95% CI, 0.4 to 2.4; = .97) and cohort 2 (9.6 11.3 months, respectively; HR, 1.21; 95% CI, 0.5 to 3.1; = .66). In multivariable analyses, amplification emerged as a single independent predictor of poor PFS on anti-EGFRab therapy in both cohort 1 (HR, 6.48; 95% CI, 3.1 to 13.6; < .001) and cohort 2 (HR, 10.1; 95% CI, 4.3 to 23.9; < .001).

CONCLUSION

amplification in wild-type mCRC seems to be a predictive biomarker for lack of efficacy of anti-EGFRab therapy. Screening patients with wild-type mCRC for amplification should be considered before anti-EGFRab treatment to guide therapy and to identify patients for early referral to clinical trials.

摘要

目的

扩增与转移性结直肠癌（mCRC）患者对抗表皮生长因子受体抗体（抗EGFR抗体）治疗的耐药性有关。本研究的目的是验证扩增在mCRC中的预测作用。

患者与方法

我们分析了来自两个不同队列的野生型mCRC患者。在队列1（n = 98）中，使用双重原位杂交技术检测肿瘤组织中的扩增情况（扩增：比率为2.0或更高）。队列2（n = 70）包括16例经下一代测序鉴定为扩增的患者和54例未扩增的对照患者（扩增：四个或更多拷贝），这些患者均接受过抗EGFR抗体治疗。主要终点是接受抗EGFR抗体治疗的无进展生存期（PFS），采用Kaplan-Meier法和对数秩检验进行估计和比较。

结果

在队列1中，接受基于抗EGFR抗体治疗的扩增患者的中位PFS显著短于未扩增患者（分别为2.8个月和8.1个月；风险比[HR]，7.05；95%CI，3.4至14.9；P <.001）。这些结果在队列2中得到验证（扩增患者与未扩增患者的中位PFS分别为2.8个月和9.3个月；HR，10.66；95%CI，4.5至25.1；P <.001）。在队列1（分别为9.7个月和11.1个月；HR，1.01；95%CI，0.4至2.4；P =.97）和队列2（分别为9.6个月和11.3个月；HR，1.21；95%CI，0.5至3.1；P =.66）中，未接受抗EGFR抗体治疗的扩增患者和未扩增患者的中位PFS相似。在多变量分析中，扩增在队列1（HR，6.48；95%CI，3.1至13.6；P <.001）和队列2（HR，10.1；95%CI，4.3至23.9；P <.001）中均成为抗EGFR抗体治疗中PFS较差的单一独立预测因素。