Cell-Free Tumor DNA Dominant Clone Allele Frequency Is Associated With Poor Outcomes in Advanced Biliary Cancers Treated With Platinum-Based Chemotherapy.

Purpose: This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment.
Materials and Methods: We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS).
Results: The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9.
Conclusion: DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.
Competing Interests: Jun YinEmployment: Mayo Clinic Mohamad Bassam SonbolResearch Funding: Lilly (Inst), Taiho Oncology (Inst) Daniel H. AhnStock and Other Ownership Interests: NateraConsulting or Advisory Role: Eisai, Exelixis, Genentech/Roche, Advanced Accelerator Applications, Novartis, Daiichi Sankyo/Astra ZenecaResearch Funding: Bayer, AstraZeneca Jason S. StarrConsulting or Advisory Role: Natera, Ipsen, Pfizer, Taiho Oncology, TerSera, Advanced Accelerator ApplicationsResearch Funding: Incyte (Inst), Merus (Inst), Rafael Pharmaceuticals (Inst), Molecular Templates (Inst), MacroGenics (Inst), Vedanta Biosciences (Inst), Leap Therapeutics Hani BabikerConsulting or Advisory Role: Endocyte, Celgene, Idera, Myovant Sciences, NovocureSpeakers' Bureau: Guardant Health Tanios S. Bekaii-SaabConsulting or Advisory Role: Amgen (Inst), Ipsen (Inst), Lilly (Inst), Bayer (Inst), Roche/Genentech (Inst), AbbVie, Incyte (Inst), Immuneering, Seattle Genetics (Inst), Pfizer (Inst), Boehringer Ingelheim, Janssen, Eisai, Eisai, Daiichi Sankyo/UCB Japan, AstraZeneca, Exact Sciences, Natera, Treos Bio, Celularity, SOBI, BeiGene, Foundation Medicine, Arcus Biosciences (Inst), Stemline Therapeutics, Kanaph Therapeutics, Deciphera, Illumina, Foundation MedicinePatents, Royalties, Other Intellectual Property: Patent WO/2018/183488, Patent WO/2019/055687Other Relationship: Exelixis, Merck (Inst), AstraZeneca, Lilly, Pancreatic Cancer Action Network, FibroGen, Suzhou Kintor Pharmaceuticals, 1-Globe, Imugene, Xilis, Replimune, Sun Biopharma, UpToDateOpen Payments Link: https://openpaymentsdata.cms.gov/physician/636276 Gregory J. GoresHonoraria: Sagimet Biosciences Rory SmootConsulting or Advisory Role: AstraZeneca Bolni NagaloPatents, Royalties, Other Intellectual Property: Patent “Chimeric Vesiculoviruses and Methods of Use” Mitesh J. Borad, and Bolni M. Nagalo James BogenbergerStock and Other Ownership Interests: Xpecting Diagnostics IncResearch Funding: Agios, RedHill Biopharma, Tolero Pharmaceuticals, Lexicon Aaron MansfieldHonoraria: RocheConsulting or Advisory Role: Genentech (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), AstraZeneca (Inst)Research Funding: Novartis (Inst)Travel, Accommodations, Expenses: AbbVie, Roche Kabir ModyStock and Other Ownership Interests: CytoDyn, ONCOtherapeuticsConsulting or Advisory Role: Celgene, Genentech/Roche, Merrimack, Eisai, AstraZeneca, Vicus Therapeutics, Ipsen, Boston Scientific, BTG, BTG, Exelixis, Exelixis, Incyte (Inst), QED TherapeuticsResearch Funding: FibroGen (Inst), Senhwa Biosciences (Inst), ARIAD (Inst), TRACON Pharma (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) Mitesh J. BoradStock and Other Ownership Interests: Gilead Sciences, AVEO, Intercept Pharmaceuticals, Spectrum PharmaceuticalsConsulting or Advisory Role: G1 Therapeutics, Fujifilm (Inst), Agios (Inst), Insys Therapeutics (Inst), Novartis (Inst), ArQule (Inst), Celgene (Inst), Inspyr Therapeutics, Halozyme (Inst), Pieris Pharmaceuticals (Inst), Taiho Pharmaceutical (Inst), Immunovative Therapies, Exelixis, Lynx Group, Genentech, Western Oncolytics, Klus Pharma, De Novo Pharmaceuticals, Merck, ImvaxResearch Funding: Boston Biomedical (Inst), miRNA Therapeutics (Inst), Senhwa Biosciences (Inst), MedImmune (Inst), BioLineRx (Inst), Agios (Inst), Halozyme (Inst), Celgene (Inst), Threshold Pharmaceuticals (Inst), Toray Industries (Inst), Dicerna (Inst), SillaJen (Inst), Eisai (Inst), Taiho Pharmaceutical (Inst), EMD Serono (Inst), Isis Pharmaceuticals (Inst), Incyte (Inst), Sun Biopharma (Inst), ARIAD (Inst), ImClone Systems (Inst), QED Therapeutics (Inst), Incyte (Inst), Puma Biotechnology (Inst), Adaptimmune (Inst), Merck Serono (Inst), RedHill Biopharma (Inst), Basilea (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: ArQule, Celgene, AstraZenecaNo other potential conflicts of interest were reported.