Molecular and clinical determinants of targeted therapy (TT) outcomes in biliary tract cancer (BTC): Analysis of a prospectively maintained next generation sequencing (NGS) biorepository.
Authors: Cowzer Darren , Walch Henry S. , Atri Pranita , Shah Farheen , Huq Risha , Khalil Danny N. , Park Wungki , Yeh Randy , Do Richard K. G. , Basturk Olca , Shia Jinru , Berger Michael F. , O'Reilly Eileen M. , Jarnagin William R. , Schultz Nikolaus , Gonen Mithat , Solit David B. , Abou-Alfa Ghassan K. , Chatila Walid Khaled , Harding James J. 
Published: January 2025

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Background:
BTCs are genomically diverse. TT have established antitumor activity in a subset of pts that harbour actionable alterations; however, most patients (pts) do not respond to or experience acquired resistance on TT. We sought to explore genomic mechanisms of response across the spectrum of BTCs.
Methods:
We leveraged a prospectively maintained cohort of pts with histologically confirmed BTC who underwent molecular profiling using an FDA authorized, targeted, NGS assay. Additional clinicopathologic information was retrospectively extracted with an aim to describe the genomic profile and clinical actionability using OncoKB, to explore outcomes for pts treated with TT, and to nominate innate and acquired genomic mechanisms of resistance.
Results:
N = 1254 pts had molecular profiling: 61.2% intrahepatic (iCCA), 16.8% extrahepatic cholangiocarcinoma (eCCA), 22.1% gallbladder cancer (GBC). MSI
high
was observed in 2.1% and the median TMB was 3.3 (range: 0-74.6 muts/mb). Among MSS tumors, the most frequently altered genes were
TP53
(36%),
CDKN2A
(21%),
ARID1A
(18%),
KRAS
(17%), and
IDH1/2
(16%). Genomic profiles differed significantly based on anatomic subsite. Oncogenic drivers were mostly clonal except for
ERBB2
amplifications and mutations, which were subclonal in 19%, and 28% of cases respectively. OncoKB level 1/2 events observed in 32.2% (iCCA 40%, eCCA 15%, and GBC 22%). Progression-free survival (PFS) for pts with these oncogenic drivers:
IDH
,
FGFR2
,
ERBB2,
BRAF V600E
, MSI
high
, and TMB
high
from start of matched TT (N=164) is listed in the table. Clinical factors or co-occurring genomic alterations did not impact outcomes. Profiling of paired pre- and post-progression samples (N=25) nominated pathway reactivation in
FGFR2
,
BRAF
,
NTRK,
and
ERBB2
driven tumors with emergence of recurrent oncogenic
FGFR2
,
RAS
,
MEK
, and
MET
alterations, respectively, as well as off target
MYC
amplification and
CDKN2A
loss. Loss of the oncogenic driver at progression was only observed for
ERBB2
driven tumors.
Conclusions:
Acknowledging the limitations of the study design, matched TT in a real-world, prospectively maintained cohort offers meaningful PFS, most notably in those pts with MSI
high
BTC treated with immunotherapy. In those with acquired resistance to TT, alterations predicted to reactivate the primary oncogenic pathway were identified. ERBB2 heterogeneity and loss is predicted to be a mechanism of resistance to HER2 targeted therapy.

Outcomes for BTC treated with matched TT.

Target
Median PFS, months (95% CI)

IDH1/2
(N = 72)

4.2 (2.9-6.8)

FGFR2
(N=37)

7.4 (6.5-9.4)

ERBB2
(N =22)

8.2 (2.95-16.7)

MSI
high
(N = 14)

NR (10.15-NR)

TMB
high
(N=12)

2.69 (1.64-NR)

BRAF
V600E (N=7)

16.6 (3.7-NR)