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

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Resumen

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.

Idioma original	English (US)
Páginas (desde-hasta)	1269-1283
Número de páginas	15
Publicación	Annals of oncology : official journal of the European Society for Medical Oncology
Volumen	33
N.º	12
DOI	https://doi.org/10.1016/j.annonc.2022.09.150
Estado	Published - dic 2022

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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 : official journal of the European Society for Medical 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, M-J, 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 : official journal of the European Society for Medical Oncology, vol. 33, n.º 12, pp. 1269-1283. https://doi.org/10.1016/j.annonc.2022.09.150

@article{41f2090938bf4b4db2aadcd8c8038bba,

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 = "Humans, Cell-Free Nucleic Acids/genetics, Proto-Oncogene Proteins B-raf/genetics, Proto-Oncogene Proteins p21(ras)/genetics, Bile Duct Neoplasms/genetics, High-Throughput Nucleotide Sequencing, Mutation, Biliary Tract Neoplasms/drug therapy",

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 M-J Wu 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",

year = "2022",

month = dec,

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

language = "English (US)",

volume = "33",

pages = "1269--1283",

journal = "Annals of oncology : official journal of the European Society for Medical Oncology",

issn = "0923-7534",

publisher = "Elsevier Ltd",

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 - Humans

KW - Cell-Free Nucleic Acids/genetics

KW - Proto-Oncogene Proteins B-raf/genetics

KW - Proto-Oncogene Proteins p21(ras)/genetics

KW - Bile Duct Neoplasms/genetics

KW - High-Throughput Nucleotide Sequencing

KW - Mutation

KW - Biliary Tract Neoplasms/drug therapy

U2 - 10.1016/j.annonc.2022.09.150

DO - 10.1016/j.annonc.2022.09.150

M3 - Article

C2 - 36089135

SN - 0923-7534

VL - 33

SP - 1269

EP - 1283

JO - Annals of oncology : official journal of the European Society for Medical Oncology

JF - Annals of oncology : official journal of the European Society for Medical Oncology

IS - 12

ER -

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

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