The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer

J. E. Berchuck; F. Facchinetti; D. F. DiToro; I. Baiev; U. Majeed; S. Reyes; C. Chen; K. Zhang; R. Sharman; P. L.S. Uson Junior; J. Maurer; R. T. Shroff; C. C. Pritchard; M. J. Wu; D. V.T. Catenacci; M. Javle; L. Friboulet; A. Hollebecque; N. Bardeesy; A. X. Zhu; J. K. Lennerz; B. Tan; M. Borad; A. R. Parikh; L. A. Kiedrowski; R. K. Kelley; K. Mody; D. Juric; L. Goyal

doi:10.1016/j.annonc.2022.09.150

The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer

J. E. Berchuck, F. Facchinetti, D. F. DiToro, I. Baiev, U. Majeed, S. Reyes, C. Chen, K. Zhang, R. Sharman, P. L.S. Uson Junior, J. Maurer, R. T. Shroff, C. C. Pritchard, M. J. Wu, D. V.T. Catenacci, M. Javle, L. Friboulet, A. Hollebecque, N. Bardeesy, A. X. ZhuJ. K. Lennerz, B. Tan, M. Borad, A. R. Parikh, L. A. Kiedrowski, R. K. Kelley, K. Mody, D. Juric, L. Goyal

GI Medical Oncology

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Background: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology. Patients and methods: We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA–tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes. Results: Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E were clonal in the majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%). Conclusions: These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.

Original language	English (US)
Pages (from-to)	1269-1283
Number of pages	15
Journal	Annals of Oncology
Volume	33
Issue number	12
DOIs	https://doi.org/10.1016/j.annonc.2022.09.150
State	Published - Dec 2022

Keywords

biliary tract cancer
cell-free DNA
cholangiocarcinoma
liquid biopsy

ASJC Scopus subject areas

Hematology
Oncology

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10.1016/j.annonc.2022.09.150

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Berchuck, J. E., Facchinetti, F., DiToro, D. F., Baiev, I., Majeed, U., Reyes, S., Chen, C., Zhang, K., Sharman, R., Uson Junior, P. L. S., Maurer, J., Shroff, R. T., Pritchard, C. C., Wu, M. J., Catenacci, D. V. T., Javle, M., Friboulet, L., Hollebecque, A., Bardeesy, N., ... Goyal, L. (2022). The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer. Annals of Oncology, 33(12), 1269-1283. https://doi.org/10.1016/j.annonc.2022.09.150

Berchuck, JE, Facchinetti, F, DiToro, DF, Baiev, I, Majeed, U, Reyes, S, Chen, C, Zhang, K, Sharman, R, Uson Junior, PLS, Maurer, J, Shroff, RT, Pritchard, CC, Wu, MJ, Catenacci, DVT, Javle, M, Friboulet, L, Hollebecque, A, Bardeesy, N, Zhu, AX, Lennerz, JK, Tan, B, Borad, M, Parikh, AR, Kiedrowski, LA, Kelley, RK, Mody, K, Juric, D & Goyal, L 2022, 'The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer', Annals of Oncology, vol. 33, no. 12, pp. 1269-1283. https://doi.org/10.1016/j.annonc.2022.09.150

@article{a413540636f045259d1942186f399cca,

title = "The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer",

abstract = "Background: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology. Patients and methods: We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA–tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes. Results: Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E were clonal in the majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%). Conclusions: These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.",

keywords = "biliary tract cancer, cell-free DNA, cholangiocarcinoma, liquid biopsy",

author = "Berchuck, {J. E.} and F. Facchinetti and DiToro, {D. F.} and I. Baiev and U. Majeed and S. Reyes and C. Chen and K. Zhang and R. Sharman and {Uson Junior}, {P. L.S.} and J. Maurer and Shroff, {R. T.} and Pritchard, {C. C.} and Wu, {M. J.} and Catenacci, {D. V.T.} and M. Javle and L. Friboulet and A. Hollebecque and N. Bardeesy and Zhu, {A. X.} and Lennerz, {J. K.} and B. Tan and M. Borad and Parikh, {A. R.} and Kiedrowski, {L. A.} and Kelley, {R. K.} and K. Mody and D. Juric and L. Goyal",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = dec,

doi = "10.1016/j.annonc.2022.09.150",

language = "English (US)",

volume = "33",

pages = "1269--1283",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "12",

}

TY - JOUR

T1 - The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer

AU - Berchuck, J. E.

AU - Facchinetti, F.

AU - DiToro, D. F.

AU - Baiev, I.

AU - Majeed, U.

AU - Reyes, S.

AU - Chen, C.

AU - Zhang, K.

AU - Sharman, R.

AU - Uson Junior, P. L.S.

AU - Maurer, J.

AU - Shroff, R. T.

AU - Pritchard, C. C.

AU - Wu, M. J.

AU - Catenacci, D. V.T.

AU - Javle, M.

AU - Friboulet, L.

AU - Hollebecque, A.

AU - Bardeesy, N.

AU - Zhu, A. X.

AU - Lennerz, J. K.

AU - Tan, B.

AU - Borad, M.

AU - Parikh, A. R.

AU - Kiedrowski, L. A.

AU - Kelley, R. K.

AU - Mody, K.

AU - Juric, D.

AU - Goyal, L.

PY - 2022/12

Y1 - 2022/12

N2 - Background: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology. Patients and methods: We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA–tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes. Results: Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E were clonal in the majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%). Conclusions: These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.

AB - Background: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology. Patients and methods: We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA–tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes. Results: Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E were clonal in the majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%). Conclusions: These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.

KW - biliary tract cancer

KW - cell-free DNA

KW - cholangiocarcinoma

KW - liquid biopsy

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DO - 10.1016/j.annonc.2022.09.150

M3 - Article

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AN - SCOPUS:85140466671

SN - 0923-7534

VL - 33

SP - 1269

EP - 1283

JO - Annals of Oncology

JF - Annals of Oncology

IS - 12

ER -

The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer

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