化疗诱导转移性结直肠癌中突变型向野生型的逆转。

Chemotherapy-induced Reversion of Mutant to Wild-type in Metastatic Colorectal Cancer.

机构信息

Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan;

Department of Surgery, Yokohama City University, Yokohama, Japan.

出版信息

Anticancer Res. 2022 May;42(5):2625-2635. doi: 10.21873/anticanres.15740.

DOI:10.21873/anticanres.15740

PMID:35489751

Abstract

BACKGROUND/AIM: Secondary mutation of mutated RAS, induced by chemotherapy, is thought to be rare. However, introduction of liquid biopsy (LB) has made it possible to monitor RAS status in patients' plasma throughout the course of chemotherapy for metastatic colorectal cancer (mCRC), and disappearance of the RAS mutation (RAS-mt), i.e., the NeoRAS-wt phenomenon, has been reported and is receiving attention, especially with respect to treatment implications.

PATIENTS AND METHODS

A prospective study of 129 patients undergoing chemotherapy for mCRC (RAS-wt, n=65; RAS-mt, n=64) was carried out. Plasma RAS status was monitored in these patients by LB. Relations between secondary genetic change, chemotherapy, and 6-month disease outcomes were analyzed. The effect of anti-EGFR mAb therapy on NeoRAS-wt mCRC was also examined.

RESULTS

NeoRAS-wt was detected in 27 (43.5%) RAS-mt patients overall and in all patients with a G12S or Q61H mutation. First-line treatment was more effective among NeoRAS-wt patients than non-NeoRAS-wt patients (70.9% vs. 48.6% overall response rate, p=0.087), and the time from treatment to LB was shorter in this group. Six-month outcomes were significantly better in the NeoRAS-wt group (p<0.001), and conversion to NeoRAS-wt was found to be predictive of a good outcome (OR=7.886, 95% CI=2.458-25.30; p<0.001). Anti-EGFR mAb therapy was found to restrict disease progression in NeoRAS-wt patients.

CONCLUSION

Conversion to NeoRAS-wt is relatively frequent, and it may predict good responses to treatment. Anti-EGFR mAb therapy was effective for our NeoRAS-wt patients. Detection of NeoRAS-wt by LB may significantly change the indication for anti-EGFR mAb therapy and the mCRC treatment strategy.

摘要

背景/目的：化疗诱导的突变 RAS 的继发突变被认为很少见。然而，引入液体活检（LB）使得监测转移性结直肠癌（mCRC）患者化疗过程中的 RAS 状态成为可能，并且已经报道并引起关注的是 RAS 突变（RAS-mt）的消失，即 NeoRAS-wt 现象，特别是在治疗意义方面。

患者和方法

对 129 名接受 mCRC 化疗的患者（RAS-wt，n=65；RAS-mt，n=64）进行了一项前瞻性研究。通过 LB 监测这些患者的血浆 RAS 状态。分析了继发遗传变化、化疗与 6 个月疾病结局之间的关系。还检查了抗 EGFR mAb 治疗对 NeoRAS-wt mCRC 的影响。

结果

总体而言，在 27 名（43.5%）RAS-mt 患者中检测到 NeoRAS-wt，并且在所有 G12S 或 Q61H 突变患者中均检测到 NeoRAS-wt。NeoRAS-wt 患者的一线治疗比非 NeoRAS-wt 患者更有效（总体反应率为 70.9%比 48.6%，p=0.087），并且该组从治疗到 LB 的时间更短。NeoRAS-wt 组的 6 个月结局明显更好（p<0.001），并且发现转换为 NeoRAS-wt 可预测良好的结局（OR=7.886，95%CI=2.458-25.30；p<0.001）。发现抗 EGFR mAb 治疗可限制 NeoRAS-wt 患者的疾病进展。