精准化疗--以培美曲塞为例

化疗药副作用巨大，尤应提倡精准治疗；精准治疗就是要摆脱癌种用药桎梏，而要以生物标志物为中心制定治疗方案，像用靶向药一样用化疗药。

/ C* L: ]# Z& _- Z现以培美曲塞为例：
5 V1 i4 P# \% G- E
: k1 y, X1 ?% ^" d. S一、胸苷酸合成酶 thymidylate synthase是预测NSCLC培美曲塞疗效的生物标志物

3 G; L+ z8 c3 D! u& r1、《Expression of thymidylate synthase predicts clinical outcomes of pemetrexed-containing chemotherapy for non-small-cell lung cancer: a systemic review and meta-analysis》:“Results: Eight studies were included in the meta-analysis. Better response usually appeared in NSCLC patients with a lower expression of TS [RR = 2.06 95 % confidence intervals (CI) 1.44, 2.96]. There was a significant association between TS expression and outcomes of pemetrexed-based chemotherapy for NSCLC (PFS: HR = 0.63 95 % CI 0.52, 0.76; OS: HR = 0.74, 95 % CI: 0.63, 0.88). In addition, no evidence of publication bias was observed.”
& X' e4 y; c+ U' G9 D7 ^
( N, x9 p; [2 x: X/ n) S! i2、《Thymidylate synthase expression as a predictive biomarker of pemetrexed sensitivity in advanced non-small cell lung cancer》 “Results: TYMS overexpression was detected in 61 % of patients and low expression in 39 %. The response rate for patients with low TYMS expression was 0.29 compared with 0.03 in patients with overexpression (P = 0.025). A significant benefit was observed in patients with low expression both in time to progression (average TTP = 56 vs. 23 months, P = 0.001) and in overall survival (average OS = 60 vs. 25 months, P = 0.002).”
/ G( j' B. W7 \$ i; p
3、《胸苷酸合成酶在非小细胞肺癌中的表达与培美曲塞疗效相关性研究》：“目的评价胸苷酸合成酶(TS)在非小细胞肺癌(NSCLC)中的表达与培美曲塞疗效的相关性。方法选择经病理检查确诊的106例复治晚期NSCLC患者,予培美曲塞500 mg/m2,静脉滴注,第1天,每3周1次,采用免疫组化方法分析TS蛋白表达,并采用半定量组织评分方法进行评价。结果 TS表达与培美曲塞疗效呈正相关(P=0.02)。TS低表达患者较TS高表达者有较长的中位无进展生存期(PFS),分别为4.8、3.4个月,差异有统计学意义(P=0.01)。在腺癌患者中TS低表达患者较TS高表达者有较长的中位PFS,分别为4.8、3.8个月,以及中位总生存期(OS),分别为21.4、10.0个月,差异有统计学意义(P=0.03)。结论 TS在NSCLC中的表达与培美曲塞疗效显著相关。TS表达的预测作用在未来的随机研究中值得进一步探讨。”

二、胸苷酸合成酶 thymidylate synthase也是预测其他癌种培美曲塞疗效的生物标志物

  R5 B0 n) K3 l& s1 I2 S1、《Thymidylate synthase predicts poor response to pemetrexed chemotherapy in patients with advanced breast cancer》 “Pemetrexed is a candidate chemotherapy regimen for anthracycline- and taxane-pretreated advanced breast cancer. However, to the best of our knowledge, no efficient treatment efficacy biomarkers have been identified. In the present study, the potential correlation between thymidylate synthase (TYMS) expression and clinical response to pemetrexed was examined in advanced breast cancer. A retrospective collection was performed by using 77 advanced breast cancer subjects, who received at least three cycles of pemetrexed treatment in the Second Hospital of Shandong University hospital. TYMS expression was detected using immunohistopathological staining. The correlations between TYMS and therapeutic efficacies of different chemotherapy treatment were analyzed. The objective response rate (ORR) and disease control was 31.17 and 64.94%, respectively. Immunohistochemical staining demonstrated that TYMS expression was observed in the cytoplasm and nuclei of breast cancer cells. High TYMS expression was observed in 32 specimens. Elevated TYMS expression was correlated with higher histological grade and lymph node metastasis (P<0.05). Furthermore, significantly higher TYMS expression was observed in treatment-resistant patients than response ones (P<0.05). Patients with low expression level of TYMS exhibit significantly higher ORR. Cox regression analysis indicated that elevated TYMS expression was a detrimental factor for pemetrexed treatment for advanced breast cancer patients. The present results suggested that TYMS expression levels predicts therapeutic sensitivity of pemetrexed chemotherapy in advanced breast cancer, indicating that it may be a useful biomarker to choose chemotherapy regimens.”
0 {0 h0 J8 i$ K
2、《胸苷合成酶表达在培美曲塞治疗晚期卵巢癌患者效果评估中的意义》 “目的探讨胸苷酸合成酶(TS)表达在培美曲塞治疗晚期复发卵巢癌患者效果评估中的意义。方法回顾性分析2010年7月2014年7月我院80例接受培美曲塞联合奈达铂化疗的晚期复发卵巢癌患者,其中实验组为40例经免疫组化检测TS表达阴性的患者,对照组40例为未经TS酶检测,分析疗效。结果实验组:完全缓解(CR)2例,部分缓解(PR)21例,稳定(SD)8例,进展(PD)9例,对照组:CR 1例,PR 13例,SD 7例,PD 19例。实验组的总有效率、疾病控制率和1年生存率分别为57.5%、77.5%、60.0%,对照组分别是35.0%、52.5%、37.5%,两组差异有统计学意义(P<0.05)。结论 TS可能成为预测晚期卵巢癌患者对培美曲塞敏感性的指标,TS表达阴性卵巢癌患者可能从含培美曲塞的化疗方案中获益。”
6 A; I- c  l9 i  w% d, |5 I3 _3 h
3、《胃癌中胸苷酸合成酶与培美曲塞/雷替曲塞敏感性的初步研究》 “目的探讨胃癌组织中胸苷酸合成酶(TS)mRNA表达与培美曲塞或雷替曲塞药物敏感性之间的关系。方法收集50例经病理确诊的新鲜人胃癌标本,采用三维微组织块培养法(HDRA)进行两种药物的体外敏感试验;实时荧光定量PCR检测对应胃癌石蜡组织中TS mRNA水平。结果新鲜胃癌组织对培美曲塞或雷替曲塞的敏感性以及胃癌石蜡组织中TS mRNA水平均与临床病理特征无明显相关性。培美曲塞敏感组与耐药组的TS mRNA相对表达量分别为6.72±1.34和15.39±2.43(P=0.002);雷替曲塞敏感组与耐药组的TS mRNA相对表达量分别为7.96±1.70和14.14±2.37(P=0.028)。结论胃癌石蜡组织TS mRNA水平与新鲜胃癌组织对培美曲塞或雷替曲塞的敏感性呈负相关,TS在胃癌应用新型抗叶酸代谢类药物个体化治疗中具有潜在的指导价值。”
  {; X4 d0 V) A, S% @& J6 P
0 [& a1 S- e& O4 q* O1 d此外，《FDA approved fused-pyrimidines as potential PI3K inhibitors: a computational repurposing approach》这篇论文介绍，培美曲塞与pik3ca的Dock score 是 -10.6 kcal/mol，超过pik3ca靶向药阿培利司。培美曲塞给药方式静脉、腔体灌注、鞘内注射，生物利用度超过阿培利司。目前上市的pik3ca靶向药都是口服药；因此培美曲塞非常适合需要pik3ca抑制剂灌注的使用场景（如pik3ca突变为主驱动因素的患者需要灌注治疗积液或者鞘内注射治疗软脑膜病灶）