Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
Department of Medical Oncology, City of Hope National Medical Center, Duarte, California, USA.
Oncologist. 2021 Jun;26(6):469-475. doi: 10.1002/onco.13679. Epub 2021 Feb 10.
RAS short variant (SV) mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR) monoclonal antibody (EGFRmAb). However, the clinical implications for RAS amplification (RASa) as a biomarker for anti-EGFR therapy in CRC remain ill defined.
Genomic analysis was performed using the Foundation Medicine (FM) comprehensive genomic profiling database of 37,233 CRC cases. Clinical outcomes were assessed using two independent cohorts: the City of Hope (COH) cohort of 338 patients with metastatic CRC (mCRC) and the Flatiron Health-FM real-world clinicogenomic database (CGDB) of 3,904 patients with mCRC.
RASa was detected in 1.6% (614/37,233) of primarily mCRC. RASa 6-9 (n = 241, 39%), 10-19 (n = 165, 27%), and ≥ 20 (n = 209, 34%) copy number subsets had co-RAS SV/BRAF V600E in 63%/3%, 31%/0.6%, and 4.8%/0% of cases, respectively. In the COH cohort, six patients with RASa (13-54 copies) received EGFRmAb, four of six had progressive disease, two had stable disease, and median time to treatment discontinuation (TTD) was 2.5 months. Of the CGDB EGFRmAb-treated patients, those with RASa (n = 9) had median TTD of 4.7 months and overall survival (OS) of 11.4 months, those with RAS SV (n = 101) had median TTD and OS of 5.3 and 9.4 months, and those with RAS/BRAF wild-type (n = 608) had median TTD and OS of 7.6 and 13.7 months.
Patients with RASa without RAS mutations (1.1% of mCRC) may have poor outcomes on EGFRmAb, although numbers herein were small, and interpretation is confounded by combination chemotherapy. Larger independent studies are warranted to determine if RASa, including degree of amplification, may act similarly to RAS mutation as a resistance mechanism to EGFRmAb therapies.
Genomic data suggest that RAS amplification occurs as the sole RAS/RAF alteration in >1% of colorectal cancer cases and that degree of amplification inversely correlates with co-occurring MAPK pathway alterations. Preliminary clinical evidence suggests that RAS amplification may function similarly to RAS mutation as a negative predictor of benefit from anti-epidermal growth factor receptor therapies in colorectal cancer. More clinical data are needed, and comprehensive genomic profiling, including detection of RAS amplification, should be used in trial design to inform therapy selection.
结直肠癌（CRC）中 RAS 短变异（SV）突变与表皮生长因子受体（EGFR）单克隆抗体（EGFRmAb）治疗获益缺失相关。然而，RAS 扩增（RASa）作为 CRC 抗 EGFR 治疗的生物标志物的临床意义仍不明确。
采用 Foundation Medicine（FM）综合基因组分析数据库对 37233 例 CRC 病例进行基因组分析。采用两个独立队列评估临床结局：City of Hope（COH）的 338 例转移性 CRC（mCRC）患者队列和 Flatiron Health-FM 真实世界临床基因组数据库（CGDB）的 3904 例 mCRC 患者。
在主要为 mCRC 的患者中，检测到 RASa 占 1.6%（614/37233）。RASa 的 6-9（n=241，39%）、10-19（n=165，27%）和≥20（n=209，34%）拷贝数亚组中，分别有 63%/3%、31%/0.6%和 4.8%/0%的病例伴有 co-RAS SV/BRAF V600E。在 COH 队列中，6 例 RASa（13-54 拷贝）患者接受 EGFRmAb 治疗，其中 4 例疾病进展，2 例疾病稳定，中位治疗终止时间（TTD）为 2.5 个月。在 CGDB 接受 EGFRmAb 治疗的患者中，RASa（n=9）患者的中位 TTD 为 4.7 个月，总生存期（OS）为 11.4 个月，RAS SV（n=101）患者的中位 TTD 和 OS 分别为 5.3 个月和 9.4 个月，RAS/BRAF 野生型（n=608）患者的中位 TTD 和 OS 分别为 7.6 个月和 13.7 个月。
在 EGFRmAb 治疗中，RASa 而无 RAS 突变（mCRC 的 1.1%）的患者可能预后较差，尽管本研究中病例数较少，且联合化疗会影响解释，但仍需要更大规模的独立研究来确定 RASa（包括扩增程度）是否与 RAS 突变一样，作为 EGFRmAb 治疗的耐药机制。
基因组数据表明，RAS 扩增是 >1%结直肠癌病例中唯一的 RAS/RAF 改变，且扩增程度与 MAPK 通路改变的共存呈负相关。初步临床证据表明，RAS 扩增可能与 RAS 突变一样，作为结直肠癌抗表皮生长因子受体治疗获益的负预测因子。需要更多的临床数据，全面的基因组分析，包括 RAS 扩增的检测，应在临床试验设计中使用，以指导治疗选择。
