Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Department of Pathology, Henry Ford Health System, Detroit, MI, USA.
Mod Pathol. 2020 Sep;33(9):1832-1843. doi: 10.1038/s41379-020-0560-x. Epub 2020 May 6.
Mutations in RAS occur in 30-50% of metastatic colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR therapy. Consequently, mCRC biomarker guidelines state RAS mutational testing should be performed when considering EGFR inhibitor treatment. However, a small subset of mCRCs are reported to harbor RAS amplification. In order to elucidate the clinicopathologic features and anti-EGFR treatment response associated with RAS amplification, we retrospectively reviewed a large cohort of mCRC patients that underwent targeted next-generation sequencing and copy number analysis for KRAS, NRAS, HRAS, BRAF, and PIK3CA. Molecular testing was performed on 1286 consecutive mCRC from 1271 patients as part of routine clinical care, and results were correlated with clinicopathologic findings, mismatch repair (MMR) status and follow-up. RAS amplification was detected in 22 (2%) mCRCs and included: KRAS, NRAS, and HRAS for 15, 5, and 2 cases, respectively (6-21 gene copies). Patients with a KRAS-amplified mCRC were more likely to report a history of inflammatory bowel disease (p < 0.001). In contrast, mutations in KRAS were associated with older patient age, right-sided colonic origin, low-grade differentiation, mucinous histology, and MMR proficiency (p ≤ 0.017). Four patients with a KRAS-amplified mCRC and no concomitant RAS/BRAF/PIK3CA mutations received EGFR inhibitor-based therapy, and none demonstrated a clinicoradiographic response. The therapeutic impact of RAS amplification was further evaluated using a separate, multi-institutional cohort of 23 patients. Eight of 23 patients with KRAS-amplified mCRC received anti-EGFR therapy and all 8 patients exhibited disease progression on treatment. Although the number of KRAS-amplified mCRCs is limited, our data suggest the clinicopathologic features associated with mCRC harboring a KRAS amplification are distinct from those associated with a KRAS mutation. However, both alterations seem to confer EGFR inhibitor resistance and, therefore, RAS testing to include copy number analyses may be of consideration in the treatment of mCRC.
RAS 突变发生在 30-50%的转移性结直肠癌（mCRC）中，与抗 EGFR 治疗的耐药性相关。因此，mCRC 生物标志物指南规定，在考虑 EGFR 抑制剂治疗时应进行 RAS 突变检测。然而，据报道，一小部分 mCRC 存在 RAS 扩增。为了阐明与 RAS 扩增相关的临床病理特征和抗 EGFR 治疗反应，我们回顾性分析了一组接受 KRAS、NRAS、HRAS、BRAF 和 PIK3CA 靶向下一代测序和拷贝数分析的大型 mCRC 患者队列。作为常规临床护理的一部分，对 1271 名患者中的 1286 例连续 mCRC 进行了分子检测，结果与临床病理发现、错配修复（MMR）状态和随访相关。在 22 例（2%）mCRC 中检测到 RAS 扩增，分别包括 15、5 和 2 例 KRAS、NRAS 和 HRAS（6-21 个基因拷贝）。患有 KRAS 扩增 mCRC 的患者更有可能报告炎症性肠病病史（p<0.001）。相比之下，KRAS 突变与患者年龄较大、结肠右侧起源、低分化、黏液组织学和 MMR 熟练程度相关（p≤0.017）。4 例 KRAS 扩增 mCRC 患者无伴发 RAS/BRAF/PIK3CA 突变，接受 EGFR 抑制剂治疗，均未显示临床影像学反应。使用另一组 23 例多机构患者队列进一步评估了 RAS 扩增的治疗影响。23 例 KRAS 扩增 mCRC 患者中有 8 例接受了抗 EGFR 治疗，所有 8 例患者在治疗过程中均出现疾病进展。尽管 KRAS 扩增 mCRC 的数量有限，但我们的数据表明，与携带 KRAS 扩增的 mCRC 相关的临床病理特征与与 KRAS 突变相关的特征不同。然而，这两种改变似乎都赋予了 EGFR 抑制剂耐药性，因此，在 mCRC 的治疗中可能需要进行 RAS 检测，包括拷贝数分析。
