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Multicenter Study
. 2023 Jul 6;115(7):870-880.
doi: 10.1093/jnci/djad046.

Molecular profiling and treatment pattern differences between intrahepatic and extrahepatic cholangiocarcinoma

Kristen Spencer  1 , Leontios Pappas  2 , Islam Baiev  2 , Jordan Maurer  2 , Andrea Grace Bocobo  3 , Karen Zhang  3 , Apurva Jain  4 , Anaemy Danner De Armas  4 , Stephanie Reyes  5 , Tri Minh Le  6 , Osama E Rahma  7 , Jennifer Stanton  2 , Thomas T DeLeon  8 , Marc Roth  9 , Mary Linton B Peters  10 , Andrew X Zhu  11 , Jochen K Lennerz  12 , A John Iafrate  12 , Kylie Boyhen  13 , Christine VanCott  14 , Lewis R Roberts  15 , Stacie Lindsey  16 , Nora Horick  2 , Laura Williams Goff  17 , Kabir Mody  18 , Mitesh J Borad  8 , Rachna T Shroff  19 , Robin Kate Kelley  3 , Milind M Javle  4 , Lipika Goyal  2
Affiliations
Multicenter Study

Molecular profiling and treatment pattern differences between intrahepatic and extrahepatic cholangiocarcinoma

Kristen Spencer et al. J Natl Cancer Inst. .

Abstract

Background: Treatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies.

Methods: This multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided.

Results: Among 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P < .00001). However, they were less likely to undergo molecular profiling (50.3% vs 64.3%) or receive liver-directed therapy (17.9% vs 35.7%), targeted therapy (4.7% vs 18.9%), and clinical trial therapy (10.6% vs 24.8%) (all P < .001). In patients with recurrent ECC after surgery, the molecular profiling rate was 64.5%. Patients with advanced ECC had a shorter median overall survival than those with advanced ICC (11.8 vs 15.1 months; P < .001).

Conclusions: Patients with advanced ECC have low rates of molecular profiling, possibly in part because of insufficient tissue. They also have low rates of targeted therapy use and clinical trial enrollment. While these rates are higher in advanced ICC, the prognosis for both subtypes of cholangiocarcinoma remains poor, and a pressing need exists for new effective targeted therapies and broader access to clinical trials.

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Conflict of interest statement

KS reports advisory/consultancy: QED Therapeutics, Helsinn, the Lynx Group, and Caris Life Sciences.

LP no disclosures. IB no disclosures. JM no disclosures. AGB no disclosures. KZ no disclosures. AJ no disclosures. ADD no disclosures. SR no disclosures. TML no disclosures.

OER reports research support from Merck. Speaker for activities supported by educational grants from BMS and Merck. Consultant for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, Sobi, Boehringer Ingelheim. In addition, Dr Rahma has patent “Methods of using pembrolizumab and trebananib” pending.

JS no disclosures. TTD no disclosures. MR no disclosures.

MLBP institutional funding from Taiho, AstraZeneca, Exelixis, BeiGene, Berg, Merck, Bayer, Nucana, Lilly, and Helsinn Therapeutics; personal consulting fees from Agios. MLBP reports National Cancer Institute (K08CA248473).

AXZ reports advisory/consultancy: Sanofi-aventis, Lilly, Merck, Eisai, Sirtex. Employment: I-MAB Biopharma.

JKL no disclosures.

JKL reports National Institutes of Health (NIH) (R37 CA225655).

AJI no disclosures. KB no disclosures. CV no disclosures.

LRR reports research funding (to their institution) from Bayer, Boston Scientific, Exact Sciences, Fujifilm Medical Sciences, Gilead Sciences, Glycotest Inc, RedHill Biopharma, TARGET PharmaSolutions, and QED Therapeutics; and service on scientific advisory committees or as a consultant for AstraZeneca, Bayer, Eisai, Exact Sciences, Gilead Sciences, Global Life Science Consulting, GRAIL Inc, Hepion, MedEd Design LLC, Medscape, Novartis Venture Fund, Pontifax, Roche, and The Lynx Group.

SL no disclosures. NH no disclosures.

LWG reports advisory/consultancy: QED, Genentech, Merck, AstraZeneca, Exelixis, Boehringer Ingelheim. Research Funding: BMS, Agios, ASLAN, BeiGene, Basilea, Merck.

KM reports Stock and Other Ownership Interests: CytoDyn; Consulting or Advisory Role: Celgene, Genentech/Roche, AstraZeneca, Ipsen, Boston Scientific, Incyte (Inst), QED Therapeutics; Research Funding: FibroGen (Inst), Senhwa Biosciences (Inst), MedImmune (Inst), Agios (Inst), ArQule (Inst), Taiho Pharmaceutical (Inst), Gritstone Bio (Inst), Incyte (Inst), Merck (Inst), Vyriad (Inst), Turnstone Bio (Inst), AstraZeneca (Inst), Basilea (Inst).

MB no relevant disclosures.

RTS reports funding from Bayer, Bristol-Myers Squibb, Exelixis, IMV Inc, Loxo, Novocure, NUCANA, Pieris, QED Therapeutics, Rafael Pharmaceuticals, Seagen, and Taiho.

honoraria for serving on scientific advisory committees or as a consultant from AstraZeneca, Boehringer Ingelheim Pharma, CAMI, Clovis, Genentech, Incyte, Merck, QED Therapeutics, Servier, Taiho, Zymeworks, and Syros.

RKK reports research funding (to institution) from Agios, Astra Zeneca, Bayer, BMS, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Loxo Oncology, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, Taiho; honoraria for serving on scientific advisory committees or as a consultant from Agios, Astra Zeneca, Exelixis, Ipsen, Merck (to institution) and from Exact Sciences, Gilead, and Kinnate (to self).

MMJ reports research funding (to institution) from Merck, EMD Serono, Novartis, Eli Lilly, Astra Zeneca, Genentech, Transthera, Meclun, BMS, Incyte, QED, Taiho, Servier, Oncosil, Basilea, Nucana and to self or as advisory board/DSMB member from Incyte, Zymeworks, Mundi Pharma, Nucana, MORE health and Origimed.

LG reports research funding (to their institution) from Adaptimmune, Bayer, Merck, Macrogenics, Genentech, Novartis, Incyte, Loxo Oncology, Relay Therapeutics, QED, Taiho Oncology, Leap Therapeutics, Bristol Myers Squibb, Nucana, and Servier; honoraria (to self) for serving on scientific advisory committees or as a consultant from Alentis Therapeutics AG, Black Diamond, Basilea, Genentech, Exelixis, Kinnate, H3Biomedicine, Incyte Corporation, QED Therapeutics, Sirtex Medical Ltd, The Servier Group, SIRTEX, Taiho Oncology, TranstheraBio, and participation on data safety monitoring boards for AstraZeneca. LG receives funding from the American Cancer Society Clinical Scientist Development Grant 134013‐CSDG‐19‐163‐01‐TBG, the NIH/NCI Gastrointestinal Cancer SPORE P50 CA127003, V Foundation for Cancer Research Translational Grant, and the Cholangiocarcinoma Foundation Andrea Marie Fuquay Research Fellowship.

Figures

Figure 1.
Figure 1.
Study consort diagram. Of 1039 patients screened, 847 patients with cholangiocarcinoma (CCA) met eligibility for inclusion in the study, including 611 (72.1%) patients with intrahepatic cholangiocarcinoma (ICC) and 236 (27.9%) with extrahepatic cholangiocarcinoma (ECC). Molecular profiling was performed during routine clinical care in 64.3% of patients with advanced ICC and 50.3% of patients with advanced ECC. CCA-HCC = mixed cholangiocarcinoma-hepatocellular carcinoma.
Figure 2.
Figure 2.
Profile of targeted therapy received in intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma. Spectrum of targeted therapies received by patients with intrahepatic cholangiocarcinoma (ICC) and patients with extrahepatic cholangiocarcinoma (ECC) during the course of their clinical care. Patients with ICC primarily received FGFR-, EGFR- and IDH1-targeted therapies, and patients with ECC predominantly received EGFR-targeted therapy, followed equally by FGFR-, HER2-, PI3K-, IDH1-, BRAF-, and MAPK-targeted therapies. BRAF = v-raf murine sarcoma viral oncogene homolog B1; EGFR = epidermal growth factor receptor; FGFR = fibroblast growth factor receptor; IDH1 = isocitrate dehydrogenase 1; MAPK = mitogen-activated protein kinase; PI3K = phosphatidylinositol-3 kinase.
Figure 3.
Figure 3.
Overall survival in intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma. Overall survival (OS) in patients with intrahepatic cholangiocarcinoma (ICC) compared with patients with extrahepatic cholangiocarcinoma (ECC) from the time of diagnosis and from the time of diagnosis of advanced disease. Patients with ICC lived longer with advanced disease than patients with ECC.
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