直肠癌新辅助放化疗反应的预测性分子标志物研究进展

doi:10.3877/cma.j.issn.2095-3224.2021.06.011

局部进展期直肠癌的标准治疗方案是新辅助放化疗后的根治性手术，但是直肠癌患者对新辅助放化疗的反应表现为从病理完全缓解到无肿瘤消退不等，并且目前尚不清楚不同患者对新辅助放化疗的反应具有如此高的变异性的背后机制。由于应用临床病理和放射学预测新辅助放化疗反应缺乏足够的敏感性和特异性，所以它们的应用具有一定的局限性。此外，虽然分子生物标记物有在早期预测患者对新辅助放化疗的反应的可能，然而因为还没有到达临床水平，所以只有将不同类型的生物标志物，包括临床病理和影像学特征，以及与肿瘤生物学的联系机制一起整合起来，开发出一种最佳的、可靠的生物标志物模型，才能够更准确地预测对新辅助放化疗的反应。在这里，我们回顾了最近在组织和血液为基础的分子生物标志物研究的进展，并阐明它们在预测直肠癌对新辅助放化疗反应方面的潜力。

关键词: 直肠肿瘤, 新辅助放化疗, 病理完全反应, 预测

The standard of care in locally advanced rectal cancer is neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery. However, patients with locally advanced rectal cancer have been shown to present different treatment responses. The utility of clinicopathological and radiological features are limited due to lack of adequate sensitivity and specificity. What's more, although molecular biomarkers have the potential to predict response to nCRT at an early time point, none have currently reached the clinic. Hence, only by integrating diverse types of biomarkers including clinicopathological and imaging features, identification of mechanistic link to tumor biology to develop a sensitive and cost-effective molecular biomarker panel can we predict the response to nCRT accurately. In the present study, we review the recent advance in tissue-and blood-based molecular biomarker research and illustrate their potential in predicting nCRT response in rectal cancer.

Key words: Rectal neoplasms, Neoadjuvant chemoradiotherapy, Pathologic complete response, Predict

表1 最常用的肿瘤退化分级（tumor regression grade，TRG）系统

作者	TRG	描述
Mandard等^［3］	1	无残留癌细胞（完全消退）
	2	极少量残留癌细胞
	3	主要是纤维化，但残留的癌细胞增多
	4	残留的癌细胞多于纤维化
	5	无退行性变化
Dworak等^［4］	0	没有消退
	1	明显肿瘤肿块伴纤维化和/或血管病变
	2	以纤维化为主，癌细胞或癌细胞群较少
	3	有或无黏液物质的纤维组织中很少有癌细胞
	4	没有肿瘤细胞，只有纤维化肿块（完全消退）
Wheeler等^［5］	1	无癌细胞或癌细胞只残留在显微镜下，有明显的纤维化（完全消退）
	2	可见明显纤维化，但肉眼可见肿瘤肿物
	3	很少或没有纤维化，肉眼可见大量的肿瘤肿块
Ryan等^［6］	1	没有或很少有癌细胞残留（完全消退）
	2	残留有癌细胞但以纤维化为主
	3	无纤维化和/或残留大量癌细胞

表1 最常用的肿瘤退化分级（tumor regression grade，TRG）系统

作者	TRG	描述
Mandard等^［3］	1	无残留癌细胞（完全消退）
	2	极少量残留癌细胞
	3	主要是纤维化，但残留的癌细胞增多
	4	残留的癌细胞多于纤维化
	5	无退行性变化
Dworak等^［4］	0	没有消退
	1	明显肿瘤肿块伴纤维化和/或血管病变
	2	以纤维化为主，癌细胞或癌细胞群较少
	3	有或无黏液物质的纤维组织中很少有癌细胞
	4	没有肿瘤细胞，只有纤维化肿块（完全消退）
Wheeler等^［5］	1	无癌细胞或癌细胞只残留在显微镜下，有明显的纤维化（完全消退）
	2	可见明显纤维化，但肉眼可见肿瘤肿物
	3	很少或没有纤维化，肉眼可见大量的肿瘤肿块
Ryan等^［6］	1	没有或很少有癌细胞残留（完全消退）
	2	残留有癌细胞但以纤维化为主
	3	无纤维化和/或残留大量癌细胞

表2 基因表达谱对结直肠癌新辅助放化疗敏感性的预测

第一作者	年份	例数	基因名称	基因功能	评价指标	P值
Ma^［30］	2018	152	TACC3	细胞增殖与癌细胞转移	pCR	0.001
Kim^［37］	2019	60	KLF5	细胞增殖和分化	pCR	0.048
Zhang^［34］	2017	175	Pim-3	细胞凋亡	pCR	0.001
Bowden^［35］	2018	111	酸性神经酰胺酶	细胞凋亡	pCR	0.003
Chang^［31］	2018	172	SERPINB5	癌细胞转移	DSS、MeFS	＜0.043
Ferrandon^［32］	2020	33	COASY	细胞周期	pCR	0.009
Yan^［33］	2019	83	RAD18	DNA修复	pCR	＜0.05
Martinez-Useros^［36］	2018	74	DEK	DNA修复，细胞凋亡和分化	pCR	0.023

表2 基因表达谱对结直肠癌新辅助放化疗敏感性的预测

第一作者	年份	例数	基因名称	基因功能	评价指标	P值
Ma^［30］	2018	152	TACC3	细胞增殖与癌细胞转移	pCR	0.001
Kim^［37］	2019	60	KLF5	细胞增殖和分化	pCR	0.048
Zhang^［34］	2017	175	Pim-3	细胞凋亡	pCR	0.001
Bowden^［35］	2018	111	酸性神经酰胺酶	细胞凋亡	pCR	0.003
Chang^［31］	2018	172	SERPINB5	癌细胞转移	DSS、MeFS	＜0.043
Ferrandon^［32］	2020	33	COASY	细胞周期	pCR	0.009
Yan^［33］	2019	83	RAD18	DNA修复	pCR	＜0.05
Martinez-Useros^［36］	2018	74	DEK	DNA修复，细胞凋亡和分化	pCR	0.023

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Progresses of predictive molecular biomarker for response to neoadjuvant chemoradiation in rectal cancer

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Progresses of predictive molecular biomarker for response to neoadjuvant chemoradiation in rectal cancer