Barratt P L, Seymour M T, Stenning S P, Georgiades I, Walker C, Birbeck K, Quirke P
Academic Unit of Pathology, School of Medicine, University of Leeds, Leeds, UK.
Lancet. 2002 Nov 2;360(9343):1381-91. doi: 10.1016/s0140-6736(02)11402-4.
Present clinical algorithms assign adjuvant chemotherapy according to prognosis, but clinical decision-making would be greatly improved if reliable predictive markers were available to identify which subsets of patients benefit most from treatment. We examined molecular markers in preserved tissue from patients with Dukes' B or C colon cancer randomised to receive, or not, adjuvant fluorouracil, and assessed each marker's prognostic and predictive value.
Formalin-fixed paraffin-embedded paired normal and tumour samples were obtained from 393 patients with colon cancer from the UK AXIS trial of postoperative portal vein infusion fluorouracil versus control. We measured loss of heterozygosity (LOH) and microsatellite instability at four loci: P53 (17p13), D18S61 (18q22.3), D18S851 (18q21.1), and DP1 (5q21). The prognostic value of each marker was assessed with the log-rank test, and the predictive value by comparison of treatment hazard ratios with the chi(2) test for heterogeneity (CSH).
In 228 (58%) patients informative for LOH at D18S61, this marker was significantly predictive: benefit from fluorouracil was significantly greater in patients retaining heterozygosity than in those with LOH (CSH p=0.02). Conversely, LOH at D18S61 was a significant prognostic marker of improved outcome in untreated patients. 314 (80%) patients were informative for LOH at at least one of the three 17p and 18q sites, of whom half retained heterozygosity at one or more site. The effect of chemotherapy in these patients was striking (hazard ratio 0.45, 95% CI 0.28-0.73), whereas chemotherapy had no effect in patients with no retained heterozygosity (0.91; 0.56-1.48), CSH p=0.039.
Retention of heterozygosity at one or more 17p or 18q sites was associated with the ability to benefit from adjuvant fluorouracil. These results support the principle of developing molecular markers as predictive factors in treatment decisions.
目前的临床算法根据预后分配辅助化疗，但如果有可靠的预测标志物来识别哪些患者亚组从治疗中获益最大，临床决策将得到极大改善。我们检测了随机接受或不接受辅助氟尿嘧啶治疗的杜克B期或C期结肠癌患者保存组织中的分子标志物，并评估了每个标志物的预后和预测价值。
从英国AXIS试验（术后门静脉输注氟尿嘧啶与对照组）的393例结肠癌患者中获取福尔马林固定石蜡包埋的配对正常和肿瘤样本。我们在四个位点测量杂合性缺失（LOH）和微卫星不稳定性：P53（17p13）、D18S61（18q22.3）、D18S851（18q21.1）和DP1（5q21）。每个标志物的预后价值用对数秩检验评估，预测价值通过比较治疗风险比与异质性卡方检验（CSH）来评估。
在228例（58%）D18S61位点LOH信息明确的患者中，该标志物具有显著预测性：保留杂合性的患者从氟尿嘧啶中获益显著大于LOH患者（CSH p=0.02）。相反，D18S61位点的LOH是未治疗患者预后改善的显著预后标志物。314例（80%）患者在三个17p和18q位点中的至少一个位点有LOH信息，其中一半在一个或多个位点保留杂合性。化疗对这些患者的效果显著（风险比0.45，95%CI 0.28 - 0.73），而在没有保留杂合性的患者中化疗无效（0.91；0.56 - 1.48），CSH p=0.039。
在一个或多个17p或18q位点保留杂合性与从辅助氟尿嘧啶中获益的能力相关。这些结果支持将分子标志物开发为治疗决策预测因素的原则。
