Prognostic and predictive role of EGFR pathway alterations in biliary cancer patients treated with chemotherapy and anti-EGFR

The association of anti-EGFR to gemcitabine and oxaliplatin (GEMOX) chemotherapy did not improve survival in biliary tract carcinoma (BTC) patients. Multiple mechanisms might be involved in the resistance to anti-EGFR. Here, we explored the mutation profile of EGFR extracellular domain (ECD), of tyrosine kinase domain (TKD), and its amplification status. EGFR mutational status of exons 12, 18–21 was analyzed in 57 tumors by Sanger sequencing. EGFR amplification was evaluated in 37 tumors by Fluorescent In Situ Hybridization (FISH). Kaplan-Meier curves were calculated using the log-rank test. Six patients had mutations in exon 12 of EGFR ECD and 7 in EGFR TKD. Neither EGFR ECD nor TKD mutations affected progression free survival (PFS) or overall survival (OS) in the entire population. In the panitumumab plus GEMOX (P-GEMOX) arm, ECD mutated patients had a worse OS, while EGFR TKD mutated patients had a trend towards shorter PFS and OS. Overall, the presence of mutations in EGFR or in its transducers did not affect PFS or OS, while the extrahepatic cholangiocarcinoma (ECC) mutated patients had a worse prognosis compared to WT. Nineteen out of 37 tumors were EGFR amplified, but the amplification did not correlate with survival. ECC EGFR amplified patients had improved OS, whereas the amplification significantly correlated with poor PFS (p = 0.03) in gallbladder carcinoma patients. The high molecular heterogeneity is a predominant feature of BTC: the alterations found in this work seem to have a prognostic impact rather than a predictive role towards anti-EGFR therapy.

抗EGFR（anti-EGFR）联合吉西他滨与奥沙利铂（GEMOX）化疗方案治疗胆道癌（biliary tract carcinoma, BTC）患者，未能改善其生存结局。抗EGFR治疗的耐药机制可能涉及多种途径。本研究对表皮生长因子受体（EGFR）胞外域（EGFR extracellular domain, ECD）、酪氨酸激酶域（tyrosine kinase domain, TKD）的突变谱及其扩增状态进行了探究。本研究通过桑格测序对57例肿瘤标本的EGFR 12号外显子及18~21号外显子的突变状态进行分析；采用荧光原位杂交（Fluorescent In Situ Hybridization, FISH）对37例肿瘤标本的EGFR扩增情况进行评估，并通过对数秩检验计算卡普兰-迈耶曲线。本研究中共6例患者存在EGFR ECD的12号外显子突变，7例存在EGFR TKD突变。在全部研究人群中，无论是EGFR ECD还是TKD突变，均未对无进展生存期（progression free survival, PFS）或总生存期（overall survival, OS）产生影响。在帕尼单抗联合GEMOX（P-GEMOX）治疗组中，携带EGFR ECD突变的患者总生存期更差，而携带EGFR TKD突变的患者则呈现出无进展生存期与总生存期缩短的趋势。总体而言，EGFR或其下游信号转导分子存在突变，并未对无进展生存期或总生存期产生影响；但相较于野生型（WT）患者，肝外胆管癌（extrahepatic cholangiocarcinoma, ECC）突变患者的预后更差。37例肿瘤标本中，19例存在EGFR扩增，但该扩增与患者生存结局无相关性。肝外胆管癌伴EGFR扩增的患者总生存期得到改善，而在胆囊癌患者中，EGFR扩增与较差的无进展生存期显著相关（p=0.03）。胆道癌具有高度的分子异质性，这是其主要特征：本研究中发现的基因改变，似乎对抗EGFR治疗具有预后评估价值，而非预测价值。