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

C Peraldo-Neia, G Cavalloni, E Fenocchio, C Cagnazzo, L Gammaitoni, S Cereda, G Nasti, Maria Antonietta Satolli, Giuseppe Aprile, M Reni, A Avallone, R Spadi, T Venesio, V Martin, C Doglioni, M Frattini, M Aglietta, F Leone

Research output: Contribution to journalArticle

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. © 2018 Peraldo-Neia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Original languageEnglish
Article numbere0191593
JournalPLoS One
Volume13
DOIs
Publication statusPublished - 2018

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Biliary Tract Neoplasms
oxaliplatin
Chemotherapy
gemcitabine
Protein-Tyrosine Kinases
drug therapy
Amplification
Tumors
Drug Therapy
neoplasms
Survival
Disease-Free Survival
tyrosine
phosphotransferases (kinases)
Exons
biliary tract
carcinoma
mutation
Mutation
Cholangiocarcinoma

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Peraldo-Neia, C., Cavalloni, G., Fenocchio, E., Cagnazzo, C., Gammaitoni, L., Cereda, S., ... Leone, F. (2018). Prognostic and predictive role of EGFR pathway alterations in biliary cancer patients treated with chemotherapy and anti-EGFR. PLoS One, 13, [e0191593]. https://doi.org/10.1371/journal.pone.0191593

Prognostic and predictive role of EGFR pathway alterations in biliary cancer patients treated with chemotherapy and anti-EGFR. / Peraldo-Neia, C; Cavalloni, G; Fenocchio, E; Cagnazzo, C; Gammaitoni, L; Cereda, S; Nasti, G; Satolli, Maria Antonietta; Aprile, Giuseppe; Reni, M; Avallone, A; Spadi, R; Venesio, T; Martin, V; Doglioni, C; Frattini, M; Aglietta, M; Leone, F.

In: PLoS One, Vol. 13, e0191593, 2018.

Research output: Contribution to journalArticle

Peraldo-Neia, C, Cavalloni, G, Fenocchio, E, Cagnazzo, C, Gammaitoni, L, Cereda, S, Nasti, G, Satolli, MA, Aprile, G, Reni, M, Avallone, A, Spadi, R, Venesio, T, Martin, V, Doglioni, C, Frattini, M, Aglietta, M & Leone, F 2018, 'Prognostic and predictive role of EGFR pathway alterations in biliary cancer patients treated with chemotherapy and anti-EGFR', PLoS One, vol. 13, e0191593. https://doi.org/10.1371/journal.pone.0191593
Peraldo-Neia, C ; Cavalloni, G ; Fenocchio, E ; Cagnazzo, C ; Gammaitoni, L ; Cereda, S ; Nasti, G ; Satolli, Maria Antonietta ; Aprile, Giuseppe ; Reni, M ; Avallone, A ; Spadi, R ; Venesio, T ; Martin, V ; Doglioni, C ; Frattini, M ; Aglietta, M ; Leone, F. / Prognostic and predictive role of EGFR pathway alterations in biliary cancer patients treated with chemotherapy and anti-EGFR. In: PLoS One. 2018 ; Vol. 13.
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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. {\circledC} 2018 Peraldo-Neia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
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AU - Peraldo-Neia, C

AU - Cavalloni, G

AU - Fenocchio, E

AU - Cagnazzo, C

AU - Gammaitoni, L

AU - Cereda, S

AU - Nasti, G

AU - Satolli, Maria Antonietta

AU - Aprile, Giuseppe

AU - Reni, M

AU - Avallone, A

AU - Spadi, R

AU - Venesio, T

AU - Martin, V

AU - Doglioni, C

AU - Frattini, M

AU - Aglietta, M

AU - Leone, F

PY - 2018

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N2 - 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. © 2018 Peraldo-Neia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

AB - 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. © 2018 Peraldo-Neia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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