美国《临床肿瘤杂志》：只有这种基因突变的食管癌使用吉非替尼才有效

2017-05-26 08:46:24桓兴医讯

美国《临床肿瘤杂志》2017年5月24日在线先发

http://ascopubs.org/doi/full/10.1200/JCO.2016.70.3934

食管癌EGFR基因拷贝数畸变与使用吉非替尼的关系

目的

吉非替尼是表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，“食管癌吉非替尼试验”表明，在晚期食管癌化疗后疾病进展的患者中，相对于安慰剂，用吉非替尼可以延长无进展生存期，在少数患者中观察到有快速持久的缓解。因此，我们推测，通过EGFR通路上的基因畸变可能可以甄别出吉非替尼获益的患者。

方法

我们对“食管癌吉非替尼试验”进行了一项预先设定的盲法分子分析，按照EGFR拷贝数增益（CNG）、EGFR、KRAS、BRAF以及PIK3CA突变状况，比较吉非替尼与安慰剂的疗效。采用预先设定的标准，用原位荧光杂交（FISH）技术检测EGFR拷贝数增益（CNG），将染色体多体或扩增判定为EGFR FISH阳性。

结果

349名患者有生物标记物数据，在EGFR FISH阳性肿瘤（20.2%）中，吉非替尼与安慰剂相比，总生存期延长（死亡风险比[HR]，0.59；95%CI，0.35-1.00；P=0.05）。在EGFR FISH阴性肿瘤中，吉非替尼与安慰剂相比较，总生存期无差异（死亡风险比HR，0.90；95%CI，0.69-1.18；P=0.46）。EGFR扩增患者（7.2%）用吉非替尼获益最大（死亡风险比HR，0.21；95%CI，0.07-0.64；P=0.006）。对于EGFR、KRAS、BRAF以及PIK3CA突变的患者，或者对于其他任何突变对比无突变的患者，用吉非替尼的总生存期与用安慰剂无差异。

结论

通过FISH技术评价EGFR拷贝数增益（CNG）可以甄别出使用吉非替尼可能获益的食管癌患者，进行二线治疗。本研究结果表明，在EGFR FISH阳性、特别是EGFR扩增的食管癌的不同类型中，应当进行抗EGFR治疗的前瞻性临床试验研究。

Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer

DOI: http://dx.doi.org/10.1200/JCO.2016.70.3934

Purpose

The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib.

Methods

A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification.

Results

Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none.

Conclusion

EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

《桓兴医讯》南南和北北