Suzuki Shuhei, Saito Yosuke, Saito Koki, Yamada Yuta, Takahashi Koshi, Kumanishi Ryosuke, Fukui Tadahisa, Yoshioka Takashi
Yamagata Hereditary Tumor Research Center, Yamagata University, 1-4-12 Kojirakawa, Yamagata 990-8560, Japan.
Department of Clinical Oncology, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Curr Issues Mol Biol. 2024 Dec 23;46(12):14476-14486. doi: 10.3390/cimb46120869.
Epidermal growth factor receptor (EGFR) inhibition is crucial in treating RAS wild-type metastatic colorectal cancer, yet current testing methods may miss rare RAS variants affecting treatment efficacy. We analyzed 4122 colorectal cancer patients receiving anti-EGFR antibodies from the Center for Cancer Genomics and Advanced Therapeutics database, identifying 54 patients (1.3%) with rare RAS variants undetectable by standard testing. These patients showed significantly lower response rates to anti-EGFR therapy (28.3%) compared to RAS wild-type cases (44.6%, = 0.003). Disease control rates were also lower in rare variant cases (60.9%) versus wild-type cases (80.0%). Most common rare variants included Q22K, A59E, and A11_G12insGA. Comprehensive genomic profiling revealed additional alterations in (90.7%), (87.0%), and non-V600E mutations (25.9%). Our findings suggest that rare RAS variants predict poor anti-EGFR therapy response, highlighting the potential benefit of comprehensive genomic profiling before treatment initiation. This study provides real-world evidence supporting the clinical relevance of rare RAS variants in treatment decision-making for colorectal cancer. Future studies should focus on developing cost-effective comprehensive testing strategies and evaluating alternative treatment approaches for patients with rare RAS variants.
表皮生长因子受体（EGFR）抑制在治疗RAS野生型转移性结直肠癌中至关重要，但目前的检测方法可能会遗漏影响治疗效果的罕见RAS变异。我们分析了来自癌症基因组学与先进治疗中心数据库的4122例接受抗EGFR抗体治疗的结直肠癌患者，确定了54例（1.3%）携带标准检测无法检测到的罕见RAS变异的患者。与RAS野生型病例（44.6%，P = 0.003）相比，这些患者对抗EGFR治疗的缓解率显著更低（28.3%）。罕见变异病例的疾病控制率（60.9%）也低于野生型病例（80.0%）。最常见的罕见变异包括Q22K、A59E和A11_G12insGA。全面基因组分析揭示了BRAF（90.7%）、NRAS（87.0%）和非V600E BRAF突变（25.9%）中的其他改变。我们的研究结果表明，罕见RAS变异预示着抗EGFR治疗反应不佳，凸显了在开始治疗前进行全面基因组分析的潜在益处。本研究提供了真实世界证据，支持罕见RAS变异在结直肠癌治疗决策中的临床相关性。未来的研究应专注于开发具有成本效益的全面检测策略，并评估针对罕见RAS变异患者的替代治疗方法。
