317P - Targeted next generation sequencing (NGS) of cell free (cf) DNA in biliary tract cancer (BTC)

Background

Despite up to 40% of BTC patients (pts) harboring actionable alterations amenable to precision medicine, routine tumor genotyping can be challenging due to limited tissue and other factors. NGS of cfDNA may aid in genotyping, detecting minimal residual disease (MRD), and prognosticating in metastatic disease.

Methods

A real-world, prospective genotyping protocol was employed to collect cfDNA in BTC pts treated at Memorial Sloan Kettering (MSK) from 2016 to 2023. Samples were analyzed using a CLIA approved, cfDNA targeted NGS assay. Matched tumor samples were analyzed using an FDA authorized targeted NGS assay. OncoKB was used to annotate actionability. The primary objectives were to define the molecular profile, level of actionability, and concordance to matched tumor genotyping. Secondary objectives included impact of MRD and variant allele frequency (VAF) on outcomes. VAF_high was defined as greater than the median VAF_max detected in all samples.

Results

170 BTC pts had genotyping of cfDNA with 270 samples. 98 (58%) had a paired genotyped tumor sample. Alterations identified in cfDNA were TP53 (29%), FGFR2 (16%), ARID1A (13%), CDKN2A (11%), KRAS(11%). OncoKB level 1/2 alterations were identified in 19% pts. Total concordance between cfDNA and tissue was high for level 1/2 alterations (100% IDH1, 99% BRAF, 99% ERBB2 muts, 99% ERBB2 amps, 92% FGFR2 fusions). Evaluating positive calls only, the critical success index was 100% IDH1, 86% BRAF, 83% ERBB2 muts 80% ERBB2 amps, 38% FGFR2 fusions. For MRD, resected pts (n=23) persistently negative had a trend to longer OS than those with positive cfDNA within 12 months of surgery (38.7 (27-NR) vs 10.8 (2.4-NR); p=0.3). In pts with treatment naïve locally advanced/metastatic BTC (n=60) that had VAF_high detected there was a statistically significant worse median OS (14.1 (95% CI 5.4-19.9) vs. 32.0 (95% CI 13.8-39.9) months (HR 3.1 (95%CI 1.5-6.6) p=0.002)) and PFS (4.5 (95% CI 2.2-6.5) vs. 11.8 (95% CI 5.4-18.4) (HR 2.7 95%CI1.5-5.1, p=0.002).

Conclusions

Molecular profiling of cfDNA from BTC pts identifies Level 1/2 gene alterations with concordance highest for single nucleotide variants. Worse outcomes were observed in those with detectable cfDNA following surgery and high levels of VAF at late stages of disease.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

D. Khalil: Financial Interests, Personal, Advisory Board: AbbVie. A. Cercek: Financial Interests, Personal, Advisory Board: Bayer, GSK, Janssen, Merck, Seagen, Pfizer; Financial Interests, Personal, Stocks/Shares: Haystack; Financial Interests, Personal, Royalties, Pending patent neoadjuvant PD1 blocked in mismatch repair deficient solid tumors: Memorial Sloan Kettering; Financial Interests, Personal, Royalties, Pending patent for HAI FUDR in DPD metastatic colorectal cancer: Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Invited Speaker, Clinical trial funding: Seattle Genetics; Financial Interests, Institutional, Invited Speaker, Clinical trial: GSK. E.M. O'Reilly: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, BioNTech, Merck, AstraZeneca, Novartis, FibroGen, Astellas, Tempus, Merus, BMS, Berry Genomics, Exelixis, Incyte, Neogene, Sevier, Thetis, Vector, Yiviva; Financial Interests, Personal, Advisory Board, +Spouse: Ipsen; Financial Interests, Personal, Advisory Board, Spouse: Genentech/Roche, Eisai; Financial Interests, Personal, Advisory Board, + spouse: Autem; Financial Interests, Institutional, Invited Speaker: Genentech/Roche, Arcus, Elicio, AstraZeneca, Pertzye; Financial Interests, Personal and Institutional, Invited Speaker: BioNTech; Financial Interests, Institutional, Research Grant: Parker Institute; Non-Financial Interests, Other, Scientific and Medical Advisory Board: Pancreas Cancer Action Network; Non-Financial Interests, Member of Board of Directors: National Pancreas Foundation; Other, Editor: American Society of Clinical Oncology, American Association of Cancer Research (AACR). G.K. Abou-Alfa: Financial Interests, Personal, Advisory Board: AstraZeneca, Autem, Berry Genomics, Boehringer Ingelheim, Eisai, Exelixis, Genentech/Roche, Incyte, Ipsen, Merck, Novartis, Servier, Vector, Yiviva, AbbVie, BioNTech, BMS, Merus, Tempus; Financial Interests, Personal, Other, IP License: PCT/US2014/031545 filed on March 24, 2014, and priority application Serial No.: 61/804,907; Filed: March 25, 2013; Financial Interests, Institutional, Research Grant: Arcus, AstraZeneca, BioNTech, BMS, Genentech/Roche, Puma, QED, Yiviva, Agenus, Elicio, Helsinn, Parker Institute, Pertyze, Servier; Non-Financial Interests, Principal Investigator: AstraZeneca, Yiviva, QED. J.J. Harding: Financial Interests, Advisory Board: AbbVie, Boehringer Ingelheim, Debiopharm; Financial Interests, Invited Speaker: BMS; Financial Interests, Advisory Role: CytomX, Eli Lilly, Geoscience, Incyte, Novartis, AstraZeneca, Zymeworks. All other authors have declared no conflicts of interest.