Molecular characterization of a large unselected cohort of metastatic colorectal cancers in relation to primary tumor location, rare metastatic sites and prognosis

<b>Background:</b> We have reported that <i>BRAF</i> V600E mutations and microsatellite instability-high (MSI-H) are more prevalent in a population-based cohort of metastatic colorectal cancer (mCRC) patients than has been reported from clinical trials or hospital-based patient groups. The aim was to explore if other mutations in mCRC differ in prevalence between these cohorts in relation to mismatch repair status and primary tumor location and if presence of bone or brain metastases is associated with any mutations. <b>Material and methods:</b> A population-based cohort of 798 mCRC patients from three regions in Scandinavia was used. Forty-four cancer related genes were investigated in a custom designed Ampliseq hotspot panel. Differences in survival were analyzed using the Kaplan–Meier estimator and the Cox regression analysis. <b>Results:</b> Determination of mutations was possible in 449/501 patients for 40/44 genes. Besides <i>BRAF</i> V600E, seen in 19% of the tumors, none of the other mutations appeared more prevalent than in trial cohorts. <i>BRAF</i> V600E and MSI-H, seen in 8%, were associated with poor prognosis as was right-sided primary tumor location (39%) when compared to left-sided and rectum together; however, in a multivariable regression, only the <i>BRAF</i> mutation retained its statistical significance. No other mutations were associated with poor prognosis. ERBB2 alterations were more common if bone metastases were present at diagnosis (17% vs. 4%, <i>p</i> = .011). No association was found for brain metastases. Fifty-two percent had an alteration that is treatable with an FDA-approved targeted therapy, chiefly by EGFR-inhibitor for RAS wild-type and a check-point inhibitor for MSI-H tumors. <b>Conclusions:</b> Right-sided tumor location, <i>BRAF</i> V600E mutations, but no other investigated mutation, and MSI-H are more commonly seen in an unselected cohort than is reported from clinical patient cohorts, likely because they indicate poor prognosis. Half of the patients have a tumor that is treatable with an already FDA-approved targeted drug for mCRC.

**背景**：本团队此前已有报道，相较于临床试验或医院来源的患者队列数据，基于人群的转移性结直肠癌（metastatic colorectal cancer, mCRC）患者队列中，BRAF V600E突变与微卫星高度不稳定（microsatellite instability-high, MSI-H）的检出率更高。本研究旨在探讨：转移性结直肠癌患者的其他突变检出率在不同队列间是否存在差异，且该差异是否与错配修复状态、原发肿瘤部位相关；同时明确确诊时伴骨或脑转移是否与某类突变存在关联。
**材料与方法**：本研究纳入来自斯堪的纳维亚半岛3个地区的798例转移性结直肠癌患者组成的基于人群的队列。采用定制化Ampliseq热点基因检测面板，对44个癌症相关基因进行突变检测。采用Kaplan-Meier估计法与Cox回归分析，对生存差异进行统计学分析。
**结果**：本研究成功对40/44个基因在449/501例患者中完成突变检测。除在19%的肿瘤中检出的BRAF V600E突变外，其余突变的检出率均未高于临床试验队列的报道数据。BRAF V600E突变（检出率8%）、MSI-H表型（检出率8%）与原发肿瘤位于右侧（占比39%，相较于左侧结肠与直肠的总和）均与不良预后相关；但在多变量回归分析中，仅BRAF V600E突变仍保留统计学显著性，其余突变均未与不良预后存在关联。确诊时伴骨转移的患者中，ERBB2基因改变的检出率更高（17% vs. 4%，*p*=0.011）；未发现脑转移与任何突变存在关联。本队列中52%的患者携带可经美国食品药品监督管理局（Food and Drug Administration, FDA）批准的靶向治疗药物干预的肿瘤分子改变，其中主要包括针对RAS野生型患者的表皮生长因子受体（Epidermal Growth Factor Receptor, EGFR）抑制剂，以及针对MSI-H肿瘤的免疫检查点抑制剂。
**结论**：相较于临床患者队列的报道数据，未经筛选的人群队列中，原发肿瘤位于右侧、BRAF V600E突变以及MSI-H表型的检出率更高，其余受试突变则无此现象，这可能与上述分子特征或肿瘤部位提示不良预后有关。本研究中半数患者的肿瘤可通过已获FDA批准的转移性结直肠癌靶向治疗药物进行干预。