结直肠癌的共识分子亚群（CMS）和 FOLFIRI 联合西妥昔单抗或贝伐珠单抗一线治疗在 FIRE3（AIO KRK-0306）试验中的疗效。
Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial.
机构信息
Department of Medicine, Division of Hematology, Oncology, and Tumor Immunology (CCM), Charité Universitaetsmedizin Berlin, Berlin, Germany.
SIB Swiss Institute of Bioinformatics, Bioinformatic Core Facility, Lausanne, Switzerland.
出版信息
Ann Oncol. 2019 Nov 1;30(11):1796-1803. doi: 10.1093/annonc/mdz387.
BACKGROUND
FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined.
PATIENTS AND METHODS
In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method.
RESULTS
CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy.
CONCLUSIONS
CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.
背景
FIRE-3 比较了 KRAS 外显子 2 野生型转移性结直肠癌（mCRC）患者一线治疗中 FOLFIRI 联合西妥昔单抗或贝伐珠单抗的效果，共识分子亚群（CMS）根据四种不同亚型的基因特征对 CRC 样本进行分组。CMS 对 mCRC 治疗的相关性尚未确定。
方法
本探索性分析根据先前发表的肿瘤 CRC-CMSs 对患者进行分组。采用卡方检验比较客观缓解率（ORR）。采用 Kaplan-Meier 估计和对数秩检验比较总生存（OS）和无进展生存（PFS）时间。根据 Cox 比例风险方法估计危险比（HR）。
结果
可对意向治疗（ITT）人群中 592 例患者中的 438 例标本进行 CMS 分类（n=514）。其余 438 例样本的频率如下：CMS1（14%）、CMS2（37%）、CMS3（15%）、CMS4（34%）。对于 315 例 RAS 野生型肿瘤，频率如下：CMS1（12%）、CMS2（41%）、CMS3（11%）、CMS4（34%）。右半结肠癌与左半结肠癌的 CMS 分布如下：CMS1（27%比 11%）、CMS2（28%比 45%）、CMS3（10%比 12%）、CMS4（35%比 32%）。无论治疗如何，CMS 都是 ORR（P=0.051）、PFS（P<0.001）和 OS（P<0.001）的强预后因素。在 RAS 野生型人群中，CMS4 观察到的 OS 使 FOLFIRI 西妥昔单抗优于 FOLFIRI 贝伐珠单抗。在 CMS3 中，OS 倾向于西妥昔单抗组，而 CMS1 和 CMS2 的 OS 无差异，且不受靶向治疗影响。
结论
CMS 分类对 mCRC 具有预后意义。FIRE-3 研究中 FOLFIRI 联合西妥昔单抗与 FOLFIRI 联合贝伐珠单抗诱导的 OS 延长似乎是由 CMS3 和 CMS4 引起的。CMS 分类为 CRC 的生物学提供了更深入的见解，但目前对临床决策没有直接影响。FIRE-3（AIO KRK-0306）研究已在 ClinicalTrials.gov 注册：NCT00433927。
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