独立于原发性肿瘤部位进行一线靶向治疗最佳选择的分子超选择：对RAS野生型转移性结直肠癌进行的随机FIRE-3研究的探索性分析。
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.
作者信息
Weiss Lena, Stintzing Sebastian, Stahler Arndt, Benedikt Westphalen C, von Weikersthal Ludwig Fischer, Decker Thomas, Kiani Alexander, Vehling-Kaiser Ursula, Al-Batran Salah-Edin, Heintges Tobias, Lerchenmüller Christian A, Kahl Christoph, Seipelt Gernot, Kullmann Frank, Heinrich Kathrin, Holch Julian Walter, Alig Annabel, Jung Andreas, Modest Dominik Paul, Heinemann Volker
机构信息
Department of Medicine III, LMU Klinikum, University of Munich, Munich, Germany.
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany.
出版信息
Eur J Cancer. 2025 May 15;221:115399. doi: 10.1016/j.ejca.2025.115399. Epub 2025 Apr 4.
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.
引言
分子诊断在转移性结直肠癌（mCRC）的治疗指导中起着关键作用。当前指南建议根据RAS、BRAF和DNA错配修复（MMR）状态等生物标志物进行分层，以在抗表皮生长因子受体（EGFR）和抗血管内皮生长因子（VEGF）治疗之间做出选择。
材料与方法
这项回顾性分析评估了随机FIRE-3研究，该研究比较了RAS野生型患者一线使用FOLFIRI联合西妥昔单抗与FOLFIRI联合贝伐单抗的治疗效果。本分析纳入了199例RAS/BRAF野生型、MMR功能正常的肿瘤患者。所有患者均成功进行了二代测序（NGS），并使用先前发表的PRESSING研究方法将患者分层为超选择组（无预定义基因改变）或基因改变亚组。
结果
与贝伐单抗相比，根据PRESSING-3进行的超选择与基于抗EGFR治疗的生存获益相关（38.5个月对27.5个月；风险比[HR]0.68；95%置信区间[CI]，0.44 - 1.05；P = 0.08）。在右侧和左侧肿瘤中均观察到这一获益（HR分别为0.58和0.70）。与所有亚组中的超选择患者相比，基因改变患者的生存率较低。在这个预后不良的亚组中，应用西妥昔单抗和贝伐单抗的总生存期（OS）相当（全队列：HR 1.04；95% CI，0.61 - 1.79）。同样，这一发现与原发肿瘤部位无关（左侧肿瘤：HR 1.10；95% CI，0.59 - 2.07；右侧肿瘤：HR 1.05；95% CI，0.31 - 3.55）。
结论
二代测序促成的分子超选择可取代原发肿瘤部位，作为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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