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Updated: Dec 14, 2025
A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma
Published on: September 30, 2021
Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers
Ryosuke Okamura1,2, Razelle Kurzrock1,2, Robert J Mallory3
1Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, La Jolla, California, USA.
Abstract:
Biliary tract cancers have dismal prognoses even when cytotoxic chemotherapy is administered. There is an unmet need to develop precision treatment approaches using comprehensive genomic profiling. A total of 121 patients with biliary tract cancers were analyzed for circulating-tumor DNA (ctDNA) and/or tissue-based tumor DNA (tissue-DNA) using clinical-grade next-generation sequencing: 71 patients (59%) had ctDNA; 90 (74%), tissue-DNA; and 40 (33%), both. Efficacy of targeted therapeutic approaches was assessed based upon ctDNA and tissue-DNA. At least one characterized alteration was detected in 76% of patients (54/71) for ctDNA [median, 2 (range, 0-9)] and 100% (90/90) for tissue-DNA [median, 4 (range, 1-9)]. Most common alterations occurred in TP53 (38%), KRAS (28%), and PIK3CA (14%) for ctDNA vs TP53 (44%), CDKN2A/B (33%) and KRAS (29%) for tissue-DNA. In 40 patients who had both ctDNA and tissue-DNA sequencing, overall concordance was higher between ctDNA and metastatic site tissue-DNA than between ctDNA and primary tumor DNA (78% vs 65% for TP53, 100% vs 74% for KRAS and 100% vs 87% for PIK3CA [But not statistical significance]). Among 80 patients who received systemic treatment, the molecularly matched therapeutic regimens based on genomic profiling showed a significantly longer progression-free survival (hazard ratio [95%confidence interval], 0.60 [0.37-0.99]. P = .047 [multivariate]) and higher disease control rate (61% vs 35%, P = .04) than unmatched regimens. Evaluation of ctDNA and tissue-DNA is feasible in biliary tract cancers.
Insights
Genomic profiling of biliary tract cancers using circulating tumor DNA (ctDNA) and tissue DNA reveals actionable alterations. Molecularly matched therapies significantly improve progression-free survival and disease control rates in these patients.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Biliary tract cancers (BTCs) have poor prognoses with standard chemotherapy.
- There is a critical need for precision treatment strategies in BTCs.
- Comprehensive genomic profiling offers a path toward targeted therapies.
Purpose of the Study:
- To assess the feasibility and efficacy of using circulating-tumor DNA (ctDNA) and tissue-based tumor DNA (tissue-DNA) for genomic profiling in biliary tract cancers.
- To evaluate the concordance between ctDNA and tissue-DNA alterations.
- To determine if molecularly matched therapies based on genomic profiling improve patient outcomes.
Main Methods:
- 121 patients with BTCs underwent next-generation sequencing for ctDNA and/or tissue-DNA.
- Alterations were identified and common mutations cataloged (TP53, KRAS, PIK3CA, CDKN2A/B).
- Concordance between ctDNA and tissue-DNA was analyzed, particularly in patients with both sample types. Efficacy of targeted therapies was assessed.
Main Results:
- Genomic alterations were detected in 76% of ctDNA samples and 100% of tissue-DNA samples.
- TP53, KRAS, and PIK3CA were common alterations in ctDNA; TP53, CDKN2A/B, and KRAS in tissue-DNA.
- Molecularly matched therapies based on genomic profiling led to significantly longer progression-free survival (HR 0.60, P=.047) and higher disease control rates (61% vs 35%, P=.04) compared to unmatched regimens.
Conclusions:
- Comprehensive genomic profiling using ctDNA and tissue-DNA is feasible in biliary tract cancers.
- Genomic profiling identifies targetable alterations in a high percentage of BTC patients.
- Molecularly guided therapy demonstrates improved clinical benefit in BTC patients, highlighting the potential of precision medicine.
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