Ras突变在转移性结直肠癌中的预后价值研究：STORIA分析
Study of Ras Mutations' Prognostic Value in Metastatic Colorectal Cancer: STORIA Analysis.
作者信息
Ottaiano Alessandro, Normanno Nicola, Facchini Sergio, Cassata Antonino, Nappi Anna, Romano Carmela, Silvestro Lucrezia, De Stefano Alfonso, Rachiglio Anna Maria, Roma Cristin, Maiello Monica R, Scala Stefania, Delrio Paolo, Tatangelo Fabiana, Di Mauro Annabella, Botti Gerardo, Avallone Antonio, Nasti Guglielmo
机构信息
Department of Abdominal Oncology, SSD-Innovative Therapies for Abdominal Cancers, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via M. Semmola, 80131 Naples, Italy.
Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via M. Semmola, 80131 Naples, Italy.
出版信息
Cancers (Basel). 2020 Jul 16;12(7):1919. doi: 10.3390/cancers12071919.
BACKGROUND
Colorectal cancer (CRC) is the second most common cause of cancer-specific death in both sexes in Western countries. KRAS mutations occur in about 50% of metastatic CRCs (mCRCs). The prognostic value of specific KRAS mutations still remains unexplored and unclear.
METHODS
Two hundred and forty KRAS wild-type and 206 KRAS/NRAS mutant consecutive unresectable mCRC patients with PS Eastern Cooperative Oncology Group (ECOG) 0 or 1, aged < 80 years, and with a life expectancy >3 months entered into this study. DNA was extracted from paraffin-embedded formalin-fixed tumour tissues, and it was sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Data were analysed using the Torrent Suite Software v5.0 (Thermo Fisher Scientific). The primary outcome was the analysis of the prognostic role of different KRAS mutations in terms of overall survival (OS).
RESULTS
There were no significant differences among the most prevalent mutations (p.G12D, p.G12V, p.G13D, p.G12A, p.G12C, and p.G12S) in terms of age (<65 vs. ≥65 years), gender (male vs. female), grading (G1/G2 vs. G3), side of primary tumour (left vs. right), pT, and pN. At the median follow-up of 25.6 months, there were 77 deaths in KRAS-mutated patients and 94 in wild-type patients. Three homogeneous prognostic groups were identified: wild-type patients (group A, median survival: 27.5 months), p.G13D/p.G12A/p.G12V/p.G12D mutants (group B, median survival: 17.3 months), and p.G12C/p.G12S mutants (group C, median survival: 5.0 months, < 0.0001 according to Log Rank test). Upon multivariate analysis, metastatic involvement and p.G12C/p.G12S KRAS mutation group C (vs. other mutations) emerged as independent prognostic variables for survival.
CONCLUSIONS
We show that mutant KRAS is a negative prognostic factor and that p.G12C/p.G12S variants present the worst clinical courses. This information suggests a clear difference among KRAS mutations, and it will be useful to test potentiated and/or innovative therapeutic strategies in p.G12C/p.G12S metastatic CRC patients.
背景
在西方国家，结直肠癌（CRC）是男女癌症特异性死亡的第二大常见原因。约50%的转移性结直肠癌（mCRC）发生KRAS突变。特定KRAS突变的预后价值仍未得到充分探索且尚不明确。
方法
本研究纳入240例KRAS野生型和206例KRAS/NRAS突变的连续不可切除mCRC患者，这些患者东部肿瘤协作组（ECOG）体能状态为0或1，年龄<80岁，预期寿命>3个月。从福尔马林固定石蜡包埋的肿瘤组织中提取DNA，使用Oncomine Solid Tumour DNA试剂盒（美国马萨诸塞州沃尔瑟姆市赛默飞世尔科技公司）进行测序。数据使用Torrent Suite Software v5.0（赛默飞世尔科技公司）进行分析。主要结局是分析不同KRAS突变对总生存期（OS）的预后作用。
结果
在年龄（<65岁与≥65岁）、性别（男性与女性）、分级（G1/G2与G3）、原发肿瘤部位（左与右）、pT和pN方面，最常见的突变（p.G12D、p.G12V、p.G13D、p.G12A、p.G12C和p.G12S）之间无显著差异。在中位随访25.6个月时，KRAS突变患者中有77例死亡，野生型患者中有94例死亡。确定了三个同质的预后组：野生型患者（A组，中位生存期：27.5个月）、p.G13D/p.G12A/p.G12V/p.G12D突变体（B组，中位生存期：17.3个月）和p.G12C/p.G12S突变体（C组，中位生存期：5.0个月，根据对数秩检验<0.0001）。多因素分析显示，转移灶累及情况和p.G12C/p.G12S KRAS突变C组（与其他突变相比）是生存的独立预后变量。
结论
我们表明，KRAS突变是一个负面预后因素，且p.G12C/p.G12S变异体的临床病程最差。这一信息表明KRAS突变之间存在明显差异，这对于在p.G12C/p.G12S转移性CRC患者中测试强化和/或创新治疗策略将是有用的。
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