Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer.
Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer.
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DOI：
10.1097/sla.0b013e31822b8cfa
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发表时间：
2011-09
影响因子：
9
通讯作者：
Pastor C
中科院分区：
文献类型：
--
作者：
Garcia-Aguilar J;Chen Z;Smith DD;Li W;Madoff RD;Cataldo P;Marcet J;Pastor C
确定与局部晚期直肠癌放化疗（CRT）肿瘤反应相关的生物标志物特征。直肠癌对新辅助CRT的反应是可变的。虽然一些患者有最小的反应，但其他患者达到病理性竞争反应（pCR），并且在他们的手术标本中没有活的癌细胞。确定反应的生物标志物将有助于选择更有可能从CRT中获益的患者。本研究包括132例接受新辅助CRT治疗的局部晚期直肠癌患者，随后进行手术。对来自治疗前肿瘤活检组织的肿瘤DNA和来自配对正常手术标本的对照DNA进行23个基因的突变和多态性筛查。将遗传生物标志物与肿瘤对CRT的反应（pCR与非pCR）相关，并确定单一或联合生物标志物与肿瘤反应的相关性。132例患者中有33例（25%）达到pCR，99例（75%）患者未达到pCR。三种个体标志物与非pCR相关; KRAS突变（p = 0.0145）、CCND 1 G870 A（AA）多态性（p = 0.0138）和MTHFR C677 T（TT）多态性（p = 0.0120）。生物标志物组合的分析显示，27名同时具有p53和KRAS突变的患者中没有一名具有pCR。此外，在同时具有p53和KRAS突变或CCND 1 G870 A（AA）多态性或MTHFR C677 T（TT）多态性的患者中（n = 52），与非pCR的相关性进一步加强; 52例患者中有51例（98%）是非pCR。这些生物标志物组合具有>70%的有效性和97%-100%的阳性预测值，预测携带这些突变/多态性谱的患者将不会实现pCR。特定的生物标志物特征与CRT的非pCR密切相关，可用于选择直肠癌患者的最佳肿瘤治疗。
To identify a biomarker profile associated with tumor response to chemoradiation (CRT) in locally advanced rectal cancer. Rectal cancer response to neoadjuvant CRT is variable. While some patients have a minimal response, others achieve a pathologic compete response (pCR) and have no viable cancer cells in their surgical specimens. Identifying biomarkers of response will help select patients more likely to benefit from CRT. This study includes 132 patients with locally advanced rectal cancer treated with neoadjuvant CRT followed by surgery. Tumor DNA from pre-treatment tumor biopsies and control DNA from paired normal surgical specimens was screened for mutations and polymorphisms in 23 genes. Genetic biomarkers were correlated with tumor response to CRT (pCR versus non-pCR), and the association of single or combined biomarkers with tumor response was determined. Thirty-three out of 132 (25%) patients achieved a pCR and 99 (75%) patients had non-pCR. Three individual markers were associated with non-pCR; KRAS mutation (p = 0.0145), CCND1 G870A (AA) polymorphism (p = 0.0138), and MTHFR C677T (TT) polymorphism (p = 0.0120). Analysis of biomarker combinations revealed that none of the 27 patients with both p53 and KRAS mutations had a pCR. Further, in patients with both p53 and KRAS mutations or the CCND1 G870A (AA) polymorphism or the MTHFR C677T (TT) polymorphism (n = 52) the association with non-pCR was further strengthened; 51 out of 52 (98%) of patients were non-pCR. These biomarker combinations had a validity of >70% and a positive predictive value of 97%–100%, predicting that patients harboring these mutation/polymorphism profiles will not achieve a pCR. A specific biomarker profile is strongly associated with non-pCR to CRT and could be used to select optimal oncologic therapy in rectal cancer patients.