Intratumoral Transcriptome Heterogeneity Is Associated With Patient Prognosis and Sidedness in Patients With Colorectal Cancer Treated With Anti-EGFR Therapy From the CO.20 Trial.
Intratumoral Transcriptome Heterogeneity Is Associated With Patient Prognosis and Sidedness in Patients With Colorectal Cancer Treated With Anti-EGFR Therapy From the CO.20 Trial.
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DOI：
10.1200/po.20.00050
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发表时间：
2020
影响因子：
4.6
通讯作者：
Sadanandam A
中科院分区：
文献类型：
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作者：
Fontana E;Nyamundanda G;Cunningham D;Tu D;Cheang MCU;Jonker DJ;Siu LL;Sclafani F;Eason K;Ragulan C;Bali MA;Hulkki-Wilson S;Loree JM;Waring PM;Giordano M;Lawrence P;Rodrigues DN;Begum R;Shapiro JD;Price TJ;Cremolini C;Starling N;Pietrantonio F;Trusolino L;O'Callaghan CJ;Sadanandam A
转移性结直肠癌（mCRC）被分配为转运扩增（TA）CRCAssigner亚型，对抗表皮生长因子受体（EGFR）治疗更敏感。我们评估了肿瘤内存在TA标记（TA-高/TA-低，称为TA-性分类）与接受抗EGFR治疗的CRC结局之间的关系。TA性分类在发现队列（n = 84）中定义，并在临床试验（CO.20;西妥昔单抗单药治疗组; n = 121）和其他样本中使用已建立的基于NanoString的基因表达测定法进行独立验证。采用单因素和多因素分析评估无进展生存期（PFS）、总生存期（OS）和疾病控制率（DCR）。对712例患者的772个样本进行了TA测定。患者（接受抗EGFR治疗）的TA高水平肿瘤患者的PFS显著延长（发现风险比[HR]，0.40; 95% CI，0.25至0.64; P <0.001;验证HR，0.65; 95% CI，0.45至0.93; P = 0.018），OS更长（发现HR，0.48; 95% CI，0.29至0.78; P = 0.003;验证HR，0.67; 95% CI，0.46至0.98; P = 0.04），DCR更高（发现优势比[OR]; 14.8; 95%CI，4.30 - 59.54; P < .001;验证优势比，4.35; 95%CI，2.00 - 9.09; P < .001）。使用来自转移性样本（PFS P <0.001）和患者来源的异种移植物（P = 0.042）的公开可用数据（n = 80）进一步证实了TA性分类及其与抗EGFR治疗结果的关联。在对55例RAS/BRAF野生型和左侧肿瘤患者进行的探索性分析中，TA高分级与PFS延长和缓解率升高趋势显著相关（PFS HR，0.53; 95% CI，0.28 - 1.00; P = 0.049; OR，5.88; 95% CI，0.71 - 4.55; P = 0.09; TA高缓解率为33%，TA低缓解率为7.7%）。TA分类与接受抗EGFR治疗的mCRC患者的预后相关，并可能进一步帮助了解RAS/BRAF野生型肿瘤患者的侧性价值。
Metastatic colorectal cancers (mCRCs) assigned to the transit-amplifying (TA) CRCAssigner subtype are more sensitive to anti–epidermal growth factor receptor (EGFR) therapy. We evaluated the association between the intratumoral presence of TA signature (TA-high/TA-low, dubbed as TA-ness classification) and outcomes in CRCs treated with anti-EGFR therapy. The TA-ness classes were defined in a discovery cohort (n = 84) and independently validated in a clinical trial (CO.20; cetuximab monotherapy arm; n = 121) and other samples using an established NanoString-based gene expression assay. Progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) according to TA-ness classification were assessed by univariate and multivariate analyses. The TA-ness was measured in 772 samples from 712 patients. Patients (treated with anti-EGFR therapy) with TA-high tumors had significantly longer PFS (discovery hazard ratio [HR], 0.40; 95% CI, 0.25 to 0.64; P < .001; validation HR, 0.65; 95% CI, 0.45 to 0.93; P = .018), longer OS (discovery HR, 0.48; 95% CI, 0.29 to 0.78; P = .003; validation HR, 0.67; 95% CI, 0.46 to 0.98; P = .04), and higher DCR (discovery odds ratio [OR]; 14.8; 95% CI, 4.30 to 59.54; P < .001; validation OR, 4.35; 95% CI, 2.00 to 9.09; P < .001). TA-ness classification and its association with anti-EGFR therapy outcomes were further confirmed using publicly available data (n = 80) from metastatic samples (PFS P < .001) and patient-derived xenografts (P = .042). In an exploratory analysis of 55 patients with RAS/BRAF wild-type and left-sided tumors, TA-high class was significantly associated with longer PFS and trend toward higher response rate (PFS HR, 0.53; 95% CI, 0.28 to 1.00; P = .049; OR, 5.88; 95% CI, 0.71 to 4.55; P = .09; response rate 33% in TA-high and 7.7% in TA-low). TA-ness classification is associated with prognosis in patients with mCRC treated with anti-EGFR therapy and may further help understanding the value of sidedness in patients with RAS/BRAF wild-type tumors.