Sclafani Francesco, Rimassa Lorenza, Colombo Piergiuseppe, Destro Annarita, Stinco Sergio, Lutman Fabio R, Carnaghi Carlo, Beretta Giordano, Zanello Alessandro, Roncalli Massimo, Giordano Laura, Santoro Armando
Medical Oncology and Hematology Unit, Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milano - Italy.
Int J Biol Markers. 2015 Feb 24;30(1):e73-80. doi: 10.5301/jbm.5000097.
Inhibition of angiogenesis is an effective treatment option for metastatic colorectal cancer. Predictive biomarkers to select patients who are most likely to benefit from this therapeutic strategy are lacking. We conducted a pilot, retrospective biomarker study in a cohort of metastatic colorectal cancer patients treated with bevacizumab. The objectives of this study were to evaluate the prognostic value of biomarker expression in metastases and to compare their expression in paired tumor specimens.
Eligible patients were treated with a bevacizumab-containing therapy; from these patients, tumor tissue from metastases was available. PTEN, PI3K p110a, c-MET, and CAIX were analyzed by immunohistochemistry.
Forty-two patients received bevacizumab, 13 (31%) with first-line and 29 (69%) with second-line chemotherapy. Expression of CAIX, PI3K p110a, and c-MET in metastases did not predict objective response. PTEN loss was associated with response to treatment (p=0.02) and this association remained significant after adjusting for prognostic variables (p=0.006). However, no association with survival outcomes was found. In 32 patients (76%) with available paired specimens, we observed an equal expression between primary tumors and corresponding metastases in 75% of cases for CAIX in epithelial tumor cells, 56% for CAIX in stromal cells, 63% for PTEN, and 87% for c-MET.
PTEN loss in metastases appears to be associated with response to bevacizumab-based therapy. However, larger studies are necessary to confirm the potential role of the PI3K/AKT/mTOR pathway in modulating the therapeutic effect of bevacizumab. Tumor heterogeneity should be taken into consideration when analyzing tumor tissues for biomarker studies.
抑制血管生成是转移性结直肠癌的一种有效治疗选择。目前缺乏用于选择最有可能从该治疗策略中获益患者的预测性生物标志物。我们对一组接受贝伐单抗治疗的转移性结直肠癌患者进行了一项前瞻性、回顾性生物标志物研究。本研究的目的是评估生物标志物在转移灶中的表达的预后价值，并比较其在配对肿瘤标本中的表达。
符合条件的患者接受含贝伐单抗的治疗；从这些患者中获取转移灶的肿瘤组织。通过免疫组织化学分析PTEN、PI3K p110α、c-MET和CAIX。
42例患者接受了贝伐单抗治疗，其中13例（31%）接受一线化疗，29例（69%）接受二线化疗。转移灶中CAIX、PI3K p110α和c-MET的表达不能预测客观缓解。PTEN缺失与治疗反应相关（p=0.02），在调整预后变量后，这种相关性仍然显著（p=0.006）。然而，未发现与生存结局相关。在32例（76%）有配对标本的患者中，我们观察到在75%的病例中，上皮肿瘤细胞中的CAIX、56%的基质细胞中的CAIX、63%的PTEN以及87%的c-MET在原发肿瘤和相应转移灶中的表达相同。
转移灶中PTEN缺失似乎与基于贝伐单抗的治疗反应相关。然而，需要更大规模的研究来证实PI3K/AKT/mTOR通路在调节贝伐单抗治疗效果中的潜在作用。在分析肿瘤组织进行生物标志物研究时应考虑肿瘤异质性。
