Next-generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance

Daniel Ahn, Milind Javle, Chul W. Ahn, Apurva Jain, Sameh Mikhail, Anne M. Noonan, Christina Wu, Rachna T. Shroff, James L. Chen, Tanios Bekaii-Saab

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum–based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. METHODS: Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). RESULTS: When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P =.0004) and OS (P ≤.0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. CONCLUSIONS: In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66.

Original languageEnglish (US)
Pages (from-to)3657-3666
Number of pages10
JournalCancer
Volume122
Issue number23
DOIs
StatePublished - Dec 1 2016

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Biliary Tract Neoplasms
Drug Therapy
Mutation
Cyclin-Dependent Kinase Inhibitor p16
gemcitabine
Neoplasms
Disease-Free Survival
Survival
Biomarkers
Genes
Surveys and Questionnaires
Proteins
Genomic Instability
Platinum
Proportional Hazards Models
DNA Repair
Paraffin
Formaldehyde
Therapeutics
Joints

Keywords

  • biliary tract cancer
  • gemcitabine and platinum–based therapy response
  • next-generation sequencing
  • tumor somatic variants

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Next-generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance. / Ahn, Daniel; Javle, Milind; Ahn, Chul W.; Jain, Apurva; Mikhail, Sameh; Noonan, Anne M.; Wu, Christina; Shroff, Rachna T.; Chen, James L.; Bekaii-Saab, Tanios.

In: Cancer, Vol. 122, No. 23, 01.12.2016, p. 3657-3666.

Research output: Contribution to journalArticle

Ahn, Daniel ; Javle, Milind ; Ahn, Chul W. ; Jain, Apurva ; Mikhail, Sameh ; Noonan, Anne M. ; Wu, Christina ; Shroff, Rachna T. ; Chen, James L. ; Bekaii-Saab, Tanios. / Next-generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance. In: Cancer. 2016 ; Vol. 122, No. 23. pp. 3657-3666.
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title = "Next-generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance",
abstract = "BACKGROUND: Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum–based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. METHODS: Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). RESULTS: When genes with an incidence > 10{\%} were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P =.0004) and OS (P ≤.0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. CONCLUSIONS: In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66.",
keywords = "biliary tract cancer, gemcitabine and platinum–based therapy response, next-generation sequencing, tumor somatic variants",
author = "Daniel Ahn and Milind Javle and Ahn, {Chul W.} and Apurva Jain and Sameh Mikhail and Noonan, {Anne M.} and Christina Wu and Shroff, {Rachna T.} and Chen, {James L.} and Tanios Bekaii-Saab",
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T1 - Next-generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance

AU - Ahn, Daniel

AU - Javle, Milind

AU - Ahn, Chul W.

AU - Jain, Apurva

AU - Mikhail, Sameh

AU - Noonan, Anne M.

AU - Wu, Christina

AU - Shroff, Rachna T.

AU - Chen, James L.

AU - Bekaii-Saab, Tanios

PY - 2016/12/1

Y1 - 2016/12/1

N2 - BACKGROUND: Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum–based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. METHODS: Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). RESULTS: When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P =.0004) and OS (P ≤.0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. CONCLUSIONS: In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66.

AB - BACKGROUND: Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum–based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. METHODS: Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). RESULTS: When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P =.0004) and OS (P ≤.0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. CONCLUSIONS: In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66.

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KW - gemcitabine and platinum–based therapy response

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