Genomic landscape of treatment refractory metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) is a complex and heterogeneous disease with few standard and targeted treatment options. Next-generation sequencing of tumor tissue was performed to identify cancer driver mutations to discover possible personalized treatment options, as targeted treatment possibilities are limited for this patient population. Results of genomic sequencing in patients with treatment-refractory mCRC are described in this retrospective analysis. Clinico-pathological characteristics and genomic sequence results of consecutive patients with refractory mCRC, referred to the Experimental Cancer Therapy Unit (ECTU) at Department of Oncology, Herlev &amp; Gentofte Hospital in the period from 1 October 2015 to 14 December 2018 were reviewed in this retrospective analysis. Tumor tissue from the patients was analyzed by next-generation sequencing using the Oncomine Comprehensive primer panel to detect actionable variants of cancer driver mutations and microsatellite instability status. From August 2018 tumor mutational burden was also analyzed. A total of 80 patients with treatment-refractory mCRC and in a fairly good performance were referred to the ECTU during this period. Genomic sequencing of tumor tissue was performed for all 80 patients and a cancer driver mutation was identified in 90% (<i>n</i> = 72) of the patients. A total of 31.3% (<i>n</i> = 25) of the patients received therapy either as targetable therapy outside an available trial (<i>n</i> = 2), FDA approved therapy (<i>n</i> = 2), or treatment in phase 1 or 2 trials, independent of the genomic signature 26.3% (<i>n</i> = 21). Most mCRC patients refractory to standard anti-neoplastic therapies, presented with a cancer driver mutation, however, only a few of these mutations gave rise to matched therapies as only 2.5% of the patients from this period received targeted therapy.

转移性结直肠癌（metastatic colorectal cancer, mCRC）是一种复杂且具有高度异质性的疾病，目前可用的标准化治疗与靶向治疗方案均较为有限。鉴于该患者群体的靶向治疗选择受限，研究人员通过对肿瘤组织进行二代测序（next-generation sequencing, NGS）以鉴定癌症驱动突变，从而探索潜在的个体化治疗策略。本回顾性分析旨在描述经治难治性转移性结直肠癌患者的基因组测序结果。
本研究回顾了2015年10月1日至2018年12月14日期间，丹麦赫勒夫与根托夫特医院肿瘤学部实验性癌症治疗科（Experimental Cancer Therapy Unit, ECTU）收治的连续性难治性mCRC患者的临床病理特征与基因组测序结果。研究采用Oncomine综合引物组对患者的肿瘤组织进行二代测序，以检测癌症驱动突变的可操作变异及微卫星不稳定（microsatellite instability, MSI）状态；自2018年8月起，还新增了肿瘤突变负荷（tumor mutational burden, TMB）的检测分析。
本研究周期内共有80例体能状态较好的难治性mCRC患者转诊至ECTU。所有80例患者均接受了肿瘤组织基因组测序，其中90%（n=72）的患者检出了癌症驱动突变。总计31.3%（n=25）的患者接受了靶向治疗：包括2例在现有临床试验之外的可靶向治疗、2例FDA获批疗法，以及26.3%（n=21）的Ⅰ/Ⅱ期临床试验治疗（无需匹配基因组特征）。尽管多数经标准抗肿瘤治疗失败的难治性mCRC患者均可检出癌症驱动突变，但其中仅有极少数突变可匹配对应治疗方案——本研究周期内仅2.5%的患者接受了靶向治疗。