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Updated, expanded analysis with next generation sequencing (NGS) of biliary tract cancer confirms association between tumor somatic variants and chemotherapy resistance

Date

08 Oct 2016

Session

Poster Display

Presenters

Daniel Ahn

Citation

Annals of Oncology (2016) 27 (6): 207-242. 10.1093/annonc/mdw371

Authors

D.H. Ahn1, D. Catenacci2, C.W. Ahn3, A. Jain4, R.K. Kelley5, A.G. Bocobo5, R. Rendak2, S. Mikhail6, C. Wu6, R.T. Shroff4, M. Borad7, J.L. Chen6, M. Javle4, T. Bekaii-Saab7

Author affiliations

  • 1 Medical Oncology, The Ohio State University James Cancer Hospital, 43210 - Columbus/US
  • 2 Medical Oncology, The University of Chicago Medical Centre, Chicago/US
  • 3 Clinical Sciences, University of Texas Southwestern Medical Center at Dallas, Dallas/US
  • 4 Medical Oncology, MD Anderson Cancer Center, Houston/US
  • 5 Medical Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco/US
  • 6 Medical Oncology, The Ohio State University James Cancer Hospital, Columbus/US
  • 7 Hematology/oncology, Mayo Clinic, Phoenix/US
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Resources

Abstract 3347

Background

BTC are uncommon and associated with a dismal prognosis. Gemcitabine and platinum combination (GP) form the standard approach for treating advanced BTC with a modest improvement in survival. To identify potential biomarkers for response to GP in BTC, we used NGS to evaluate the genomic BTC landscape and specifically, identify whether mutations affecting cell cycle function and DNA repair associated with GP resistance and prognosis.

Methods

Pretreatment formalin-fixed, paraffin-embedded (FFPE) samples from 232 patients (pts) with BTC treated with GP were analyzed with a commercial targeted NGS platform. Genes with incidence >10% were included in our analysis. Cox regression models were used to determine the association between mutations, progression free survival (PFS) and overall survival (OS). Survival from start of GP was estimated using the Kaplan Meier method and compared by the log-rank test.

Results

In the 232 pts analyzed, the most common mutations included CDKN2A (28%), TP53 (31%), KRAS (23%), and ARID1A (13%). Considering genes with an incidence >10%, no individual gene was independently predictive of GP response. In pts with unresectable, advanced BTC who received GP as first-line therapy, the joint status of CDKN2A, TP53 and ARID1A were associated with PFS (P = 0.0008) and OS (P = 0.0002). 7% of pts had mutations in CDKN2A and TP53 with wild type ARID1A were identified as a poor prognostic cohort with a median PFS of 2.63 months (mos) and a median OS 5.22 mos. Pts with mutant ARID1A, regardless of the single mutational status of TP53 or CDKN2A had statistically similar PFS and OS. In a pt who exhibited mutations in all three genes, the median PFS was 20.37 mos and median OS not reached.

Conclusions

In the largest exploratory analysis of this nature to date in BTC, we found that the presence of three prevalent mutations (TP53, CKDN2A and ARID1A) represent distinct pt cohorts. These mutations are prognostic and may represent a predictive biomarker to GP therapy response. Prospective studies are needed to validate these findings, including the incorporation of novel agents that exploit the cell cycle abberations or genomic alterations observed with these mutations with GP in BTC.

Clinical trial identification

Not applicable, retrospective study

Legal entity responsible for the study

Ohio State University Wexner Medical Center

Funding

Ohio State University Wexner Medical Center

Disclosure

All authors have declared no conflicts of interest.

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