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

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.

Unveiling resistance mechanisms to EGFR inhibitors in cholangiocarcinoma

“…Further studies are now required and preclinical investigations using patient-derived xenograft (PDX) model of CCA bearing KRAS mutation could bring a valuable tool to deciphering resistance mechanisms to targeted therapies [7]. Additionally, mutations in NRAS , BRAF , PI3KCA and even in EGFR do not seem to play a role in the inefficiency of anti-EGFR treatment in CCA patients [8].…”

The Effect of the EGFR - Targeting Compound 3-[(4-Phenylpyrimidin-2-yl) Amino] Benzene-1-Sulfonamide (13f) against Cholangiocarcinoma Cell Lines

“…Limitation associated with EGFR targeted therapies nevertheless exist, including chemoresistance. In the clinical trials also reveal a potential use of panitumumab anti-EGFR combined to gemcitabine and oxaliplatin (GEMOX) chemotherapy but it did not show to improve the overall survival of CCA patient (Peraldo-Neia et al, 2018). Other EGFR-targeted inhibitors were also used as alternative monotherapy and combination with cytotoxic agents therapy and developed for CCA also not improve survival in CCA patients in large clinical studies (Philip et al, 2006;Ramanathan et al, 2009;Gruenberger et al, 2010;Zhu et al, 2010).…”

ErBb Family Proteins in Cholangiocarcinoma and Clinical Implications

“…Also, 10.5% (6/57) and 12.3% (7/57) of BTC patients have an identified mutation in the extracellular domain (ECD) of EGFR (L443Q, S464P, K467stop, N468D, G482E, G482R, L469S) as new mutations and in the tyrosine kinase domain (TKD) of EGFR (L707S, V786M, L788H, G810S, G824S, D837N T854I, D855N), respectively; 50%, 16.7%, and 33.3% of mutated BTC were detected in patients with ICC, ECC, and GBC, respectively. Also, patients with a mutation of the ECD of EGFR revealed a worse OS, and those with maturation at the TKD of EGFR had shorter PFS and OS [ 109 ]. Moreover, new mutations of EGFR were identified in patients with BTCs, including CC (E114K, Y1069C, I425L, C818F, G203R, R669Qfs*36, V524Sfs*44) [ 110 , 111 ].…”