Abstract
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.
Highlights
Different strategies aimed at inhibiting EGFR with small molecules or with monoclonal antibodies have been developed over the years in many cancer types [1,2,3,4,5,6]
These premises did not reflect the success obtained in metastatic colorectal cancer (mCRC) and the scientific community agreed about the marginal role of antiEGFR therapies in biliary tract carcinoma (BTC)
The lack of efficacy obtained by the addition of panitumumab to standard chemotherapy demonstrated in the Vecti-BIL trial confirmed previous results available in literature [22,23,24]
Summary
Different strategies aimed at inhibiting EGFR with small molecules (erlotinib and gefitinib) or with monoclonal antibodies (cetuximab and panitumumab) have been developed over the years in many cancer types [1,2,3,4,5,6]. The study, which enrolled and stratified intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) including gallbladder carcinoma (GBC), revealed that the addition of panitumumab to the standard chemotherapy did not improve progression free survival (PFS), which was 5.3 months in experimental arm and 4.4 months in control arm. EGFR amplification was described in BTC [18, 19], but its prognostic role is unknown Overall, in both arms of the Vecti-BIL trial, there was a broad range of PFS and OS: in the experimental arm, PFS ranged from 1.1 to 21.3 months and OS from 2.7 to 34.9 months, while in the control arm PFS ranged between 1.1 to 15.4 months, and OS between 1.1 and 31.7 months
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