Ye Peng, Zhang Meizhuo, Fan Shuqiong, Zhang Tianwei, Fu Haihua, Su Xinying, Gavine Paul R, Liu Qiang, Yin Xiaolu
Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, China.
Research & Development Information, AstraZeneca R&D, Shanghai, China.
PLoS One. 2015 Nov 20;10(11):e0143207. doi: 10.1371/journal.pone.0143207. eCollection 2015.
Current drug development efforts on gastric cancer are directed against several molecular targets driving the growth of this neoplasm. Intra-tumoral biomarker heterogeneity however, commonly observed in gastric cancer, could lead to biased selection of patients. MET, ATM, FGFR2, and HER2 were profiled on gastric cancer biopsy samples. An innovative pathological assessment was performed through scoring of individual biopsies against whole biopsies from a single patient to enable heterogeneity evaluation. Following this, false negative risks for each biomarker were estimated in silico. 166 gastric cancer cases with multiple biopsies from single patients were collected from Shanghai Renji Hospital. Following pre-set criteria, 56 ~ 78% cases showed low, 15 ~ 35% showed medium and 0 ~ 11% showed high heterogeneity within the biomarkers profiled. If 3 biopsies were collected from a single patient, the false negative risk for detection of the biomarkers was close to 5% (exception for FGFR2: 12.2%). When 6 biopsies were collected, the false negative risk approached 0%. Our study demonstrates the benefit of multiple biopsy sampling when considering personalized healthcare biomarker strategy, and provides an example to address the challenge of intra-tumoral biomarker heterogeneity using alternative pathological assessment and statistical methods.
目前针对胃癌的药物研发工作主要针对驱动该肿瘤生长的几个分子靶点。然而，胃癌中常见的肿瘤内生物标志物异质性可能导致患者选择存在偏差。对胃癌活检样本进行了MET、ATM、FGFR2和HER2分析。通过对单个活检样本与同一患者的全活检样本进行评分，进行了一项创新的病理评估，以实现异质性评估。在此之后，利用计算机模拟估计了每种生物标志物的假阴性风险。从上海仁济医院收集了166例来自单一患者的多次活检的胃癌病例。按照预先设定的标准，56%至78%的病例在分析的生物标志物中显示低异质性，15%至35%显示中等异质性，0%至11%显示高异质性。如果从单个患者收集3次活检样本，检测生物标志物的假阴性风险接近5%（FGFR2除外：12.2%）。当收集6次活检样本时，假阴性风险接近0%。我们的研究证明了在考虑个性化医疗生物标志物策略时多次活检采样的益处，并提供了一个利用替代病理评估和统计方法应对肿瘤内生物标志物异质性挑战的例子。
