独立于原发肿瘤的分子超选择一线靶向治疗的最佳选择：在RAS野生型转移性结直肠癌中进行的随机FIRE-3研究的探索性分析

IF 7.6 1区医学 Q1 ONCOLOGY

European Journal of Cancer Pub Date : 2025-04-04 DOI:10.1016/j.ejca.2025.115399

Lena Weiss , Sebastian Stintzing , Arndt Stahler , C. Benedikt Westphalen , Ludwig Fischer von Weikersthal , Thomas Decker , Alexander Kiani , Ursula Vehling-Kaiser , Salah-Edin Al-Batran , Tobias Heintges , Christian A. Lerchenmüller , Christoph Kahl , Gernot Seipelt , Frank Kullmann , Kathrin Heinrich , Julian Walter Holch , Annabel Alig , Andreas Jung , Dominik Paul Modest , Volker Heinemann

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引用次数: 0

摘要

导言分子诊断在指导转移性结直肠癌（mCRC）的治疗中发挥着关键作用。目前的指南建议根据 RAS、BRAF 和 DNA 错配修复（MMR）状态等生物标志物进行分层，以便在抗表皮生长因子受体（anti-EGFR）和抗血管内皮生长因子（anti-VEGF）疗法之间做出选择。材料与方法本回顾性分析评估了随机 FIRE-3 研究，该研究比较了 RAS 野生型患者接受 FOLFIRI 加西妥昔单抗和 FOLFIRI 加贝伐单抗一线治疗的效果。本分析包括199名RAS/BRAF野生型MMR熟练肿瘤患者。结果与贝伐珠单抗相比，根据PRESSING-3进行的非选择与抗EGFR治疗的生存获益相关（38.5个月对27.5个月；HR 0.68；95 % CI，0.44-1.05；P = 0.08）。在右侧和左侧肿瘤中都观察到了这种益处（HR 0.58 和 HR 0.70）。在所有亚组中，基因改变患者的生存率均低于超选患者。在这一不利亚组中，应用西妥昔单抗和贝伐单抗可获得相当的生存期（总队列：HR 1.04；95 % CI，0.61-1.79）。同样，这一结果与原发肿瘤的偏侧无关（左侧肿瘤：HR 1.10；95 % CI：0.61-1.79）：HR 1.10; 95 % CI, 0.59-2.07; 右侧肿瘤：结论下一代测序技术促进的分子超选择可以取代原发肿瘤侧位，成为 RAS 野生型 mCRC 一线治疗中靶向治疗最佳选择的决策工具。

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Molecular hyperselection for optimal choice of first-line targeted therapy independent of primary tumor sidedness: An exploratory analysis of the randomized FIRE-3 study performed in RAS wild-type metastatic colorectal cancer

Introduction

Molecular diagnostics play a pivotal role in guiding therapy for metastatic colorectal cancer (mCRC). Current guidelines recommend stratification based on biomarkers such as RAS, BRAF, and DNA mismatch-repair (MMR) status to select between anti-EGFR (epidermal growth factor receptor) and anti-VEGF (vascular endothelial growth factor) therapies.

Materials and methods

This retrospective analysis evaluated the randomized FIRE-3 study that compared first-line treatment with FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in RAS wild-type patients. The present analysis included 199 patients with RAS/BRAF wild-type MMR proficient tumors. Next-generation sequencing (NGS) was successfully performed in all patients and allowed stratification into hyperselected (no predefined genetic alterations) or gene altered subgroups using the previously published approach of the PRESSING-studies.

Results

Hyperselection according to PRESSING-3 was associated with a survival benefit from anti-EGFR-based therapy compared to bevacizumab (38.5 months vs. 27.5 months; HR 0.68; 95 % CI, 0.44–1.05; P = 0.08). This benefit was observed in both, right- and left-sided tumors, (HR 0.58 and HR 0.70). Patients with gene alterations showed inferior survival compared to hyperselected patients across all subgroups. In this unfavorable subgroup, application of cetuximab and bevacizumab were associated with comparable OS (total cohort: HR 1.04; 95 % CI, 0.61–1.79). Again, this finding was independent of primary tumor sidedness (left-sided tumors: HR 1.10; 95 % CI, 0.59–2.07; right-sided tumors: HR 1.05; 95 % CI, 0.31–3.55).

Conclusion

Molecular hyperselection facilitated by next generation sequencing could replace primary tumor sidedness as a tool of decision making for optimal choice of targeted therapy in first-line treatment of RAS wild-type mCRC

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来源期刊

European Journal of Cancer 医学-肿瘤学

CiteScore

11.50

自引率

4.80%

发文量

953

审稿时长

23 days

期刊介绍： The European Journal of Cancer (EJC) serves as a comprehensive platform integrating preclinical, digital, translational, and clinical research across the spectrum of cancer. From epidemiology, carcinogenesis, and biology to groundbreaking innovations in cancer treatment and patient care, the journal covers a wide array of topics. We publish original research, reviews, previews, editorial comments, and correspondence, fostering dialogue and advancement in the fight against cancer. Join us in our mission to drive progress and improve outcomes in cancer research and patient care.