Study of Ras Mutations’ Prognostic Value in Metastatic Colorectal Cancer: STORIA Analysis

Cancers (Basel). 2020 Jul; 12(7): 1919.
Published online 2020 Jul 16. 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, p < 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.

Cancers (Basel). 2020 年 7 月；12(7): 1919.
发表于 2020 年 7 月 16 日。DOI：10.3390/cancers12071919

背景：结直肠癌（CRC）是西方国家男女性别中癌症特异性死亡的第二大原因。KRAS 突变发生在约 50% 的转移性结直肠癌（mCRCs）中。特定 KRAS 突变的预后价值尚未得到充分探索和明确。

方法：本研究纳入了 240 例 KRAS 野生型及 206 例 KRAS/NRAS 突变型连续不可切除的 mCRC 患者，其 Eastern Cooperative Oncology Group（ECOG）体能状态评分为 0 或 1，年龄小于 80 岁，预期寿命大于 3 个月。DNA 从石蜡包埋的福尔马林固定肿瘤组织中提取，并使用 Oncomine Solid Tumour DNA 测序试剂盒（Thermo Fisher Scientific，Waltham，MA，美国）进行测序。数据使用 Torrent Suite 软件 v5.0（Thermo Fisher Scientific）进行分析。主要结局为分析不同 KRAS 突变在总生存期（OS）方面的预后作用。

结果：在年龄（<65 岁 vs. ≥65 岁）、性别（男性 vs. 女性）、分级（G1/G2 vs. G3）、原发肿瘤侧（左侧 vs. 右侧）、pT 和 pN 方面，最常见的突变（p.G12D、p.G12V、p.G13D、p.G12A、p.G12C 和 p.G12S）之间没有显著差异。中位随访 25.6 个月时，KRAS 突变患者中死亡 77 例，野生型患者中死亡 94 例。确定了三个同质性预后组：野生型患者（组 A，中位生存期：27.5 个月）、p.G13D/p.G12A/p.G12V/p.G12D 突变型（组 B，中位生存期：17.3 个月）和 p.G12C/p.G12S 突变型（组 C，中位生存期：5.0 个月，根据 Log Rank 检验，p < 0.0001）。多因素分析显示，转移侵袭和 p.G12C/p.G12S KRAS 突变组 C（与其他突变相比）是独立的生存预后变量。

结论：本研究表明，KRAS 突变是负性预后因素，p.G12C/p.G12S 变异呈现最差的临床病程。这些信息表明 KRAS 突变之间存在明显差异，并在 p.G12C/p.G12S 转移性结直肠癌患者中测试增强的或创新的疗法策略将具有重要意义。