Clinical Impact of Sub-Clonal RAS/BRAF Alterations in Liquid Biopsies From Patients With Advanced or Metastatic CRC.

Peter Gibbs, Khalid Abubaker, Danyi Wang, Zheng Feng, Jawad Hamad, Jiemin Liao, Christopher Stroh, Soetkin Vlassak, Kathrin Heinrich, Adnan Khattak, Juergen Scheuenpflug
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Abstract

Introduction: Colorectal cancer (CRC), a global health concern, requires effective treatments. Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies are used for RAS wild-type and BRAFV600 mutation-negative metastatic CRC (mCRC) but are not indicated for RAS mutant CRC. Evidence suggests CRC patients with sub-clonal RAS/BRAF mutations in tumor tissue may benefit from anti-EGFRs. We assessed the outcomes of patients with sub-clonal RAS/BRAF mutated advanced/mCRC receiving anti-EGFRs using liquid-based GuardantINFORM real-world clinical-genomic analysis.

Patients and methods: GuardantINFORM analyzed US patients with advanced CRC with BRAFV600/KRAS/NRAS mutations who received anti-EGFR therapies within 90 days after a Guardant360 test. Primary endpoints were time-to-next treatment (TTNT) and overall survival (OS) (compared across RAS/BRAF mutation clonality cut-offs of 0.3-0.8 using the Cox proportional hazards model).

Results: In GuardantINFORM, 446 patients initiated anti-EGFR therapy within 90 days after the Guardant360 test, and 11%, 9%, and 1% had BRAFV600E, KRAS, or NRAS mutations, respectively; median distribution of RAS/BRAF clonality was 0.84 (IQR, 0.57-1.00). The data show that patients harboring sub-clonal RAS/BRAF mutations benefited from anti-EGFR therapy to a degree similar to patients without RAS/BRAF mutations. For cut-offs of 0.3 to 0.8, sub-clonal RAS/BRAF had similar TTNT to patients without RAS/BRAF mutations, while clonal RAS/BRAF had a significantly shorter TTNT. For cut-offs of 0.3 to 0.7, sub-clonal RAS/BRAF had similar OS to RAS/BRAF mutations not detected, while clonal RAS/BRAF had a significantly shorter OS.

Conclusion: Consistent with tumor tissue biopsy data, patients with CRC harboring sub-clonal RAS/BRAF mutations as assessed by liquid biopsy may derive benefit from anti-EGFR therapy, warranting further investigation.

晚期或转移性结直肠癌患者液体活检中亚克隆RAS/BRAF改变的临床影响
结直肠癌(CRC)是一个全球性的健康问题,需要有效的治疗。抗表皮生长因子受体(anti-EGFR)单克隆抗体用于RAS野生型和BRAFV600突变阴性转移性CRC (mCRC),但不适用于RAS突变型CRC。有证据表明,肿瘤组织中存在亚克隆RAS/BRAF突变的结直肠癌患者可能受益于抗egfr。我们使用基于液体的guarantinform现实世界临床基因组分析评估了亚克隆RAS/BRAF突变的晚期/mCRC患者接受抗egfr的结果。患者和方法:GuardantINFORM分析了在Guardant360检测后90天内接受抗egfr治疗的BRAFV600/KRAS/NRAS突变的美国晚期结直肠癌患者。主要终点是到下一次治疗的时间(TTNT)和总生存期(OS)(使用Cox比例风险模型比较RAS/BRAF突变克隆截断值为0.3-0.8)。结果:在GuardantINFORM中,446名患者在Guardant360检测后90天内开始抗egfr治疗,分别有11%、9%和1%的患者发生BRAFV600E、KRAS或NRAS突变;RAS/BRAF克隆的中位分布为0.84 (IQR, 0.57-1.00)。数据显示,携带亚克隆RAS/BRAF突变的患者从抗egfr治疗中获益的程度与没有RAS/BRAF突变的患者相似。当截断值为0.3 ~ 0.8时,亚克隆RAS/BRAF的TTNT与没有RAS/BRAF突变的患者相似,而克隆RAS/BRAF的TTNT明显更短。对于截断值0.3 ~ 0.7,亚克隆RAS/BRAF的OS与未检测到的RAS/BRAF突变相似,而克隆RAS/BRAF的OS明显更短。结论:与肿瘤组织活检数据一致,液体活检评估的携带亚克隆RAS/BRAF突变的结直肠癌患者可能从抗egfr治疗中获益,值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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