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ctDNA May Predict Worse Metastatic Biliary Tract Cancer Prognosis

Key Takeaway

  • Assessing circulating tumor DNA (ctDNA) in patients with metastatic biliary tract cancers (BTC) could identify patients with worse survival outcomes when treated with upfront platinum-based chemotherapy, suggests this retrospective patient analysis. The study was made available as a preprint on medRxiv on November 2 and has not yet been peer reviewed.

Why This Matters

  • BTC typically presents at an advanced stage when only 20% of tumors are resectable. The 5-year overall survival is around 4% in unresectable patients and the gains with first-line chemotherapy are modest. Most patients progress within a year.

  • There is increasing interest in the use of next-generation tumor genomic profiling and liquid biopsy to identify targetable genetic alterations. The current results suggest ctDNA could be used for genomic profiling and patient stratification in prospective, randomized trials.

Study Design

  • Sixty-seven patients with metastatic BTC who underwent ctDNA testing before first-line platinum-based chemotherapy between June 2016 and June 2020 were included. Patient charts were reviewed for response to therapy and disease control rate.

  • The variant allele frequency (VAF), or the number of mutant molecules over the total number of wild-type molecules at a specific genome location, was calculated from the ctDNA samples. The relationship between the dominant clone allele frequency (DCAF) and overall and progression-free survival was determined.

Key Results

  • The median age of the patients was 67 years, and 80.6% had intrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinoma was diagnosed in 10.4% and 9% had gallbladder cancer. The majority (68.6%) of patients received cisplatin plus gemcitabine, whereas gemcitabine was combined with another platinum-based therapy in a further 16.4%. The disease control rate was 64.4%.

  • DCAF analysis revealed that TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with the highest frequency. The median DCAF was 3%.

  • DCAF >3% was associated with worse progression-free survival (PFS) at a median of 4.7 months vs 7.7 months for DCAF ≤3% (P = .087) and significantly worse overall survival at a median of 10.8 months vs 18.8 months (P = .032).

  • Stratifying DCAF into quartiles revealed that the highest quartile, DCAF ≥10%, was associated with significantly worse PFS, at 3.0 months vs 7.0 months for the lowest quartile (P = .014), and significantly worse overall survival, at 7.0 months vs 22.2 months (P = .002).

  • After adjusting for patient age and sex, metastatic sites, size of the largest lesion, primary tumor, and CA19-9, each 1% increase in ctDNA was associated with a hazard ratio for death of 13.07 (P = .034).

Limitations

  • The study was limited by the small sample size and was a single center, retrospective analysis. Plus, the use of a targeted gene panel. In addition, there were few patients with other diagnoses than intrahepatic duct tumor.

Study Disclosures

  • The Mayo Clinic Hepatobiliary SPORE funded the statistical analysis for this project. This work was supported by the National Institutes of Health; National Cancer Institute, SPORE Project Award, SPORE Supplement Award, Mayo Clinic Center for Individualized Medicine (CIM) Precision Cancer Therapeutics Program; and Mayo Clinic Cancer Center.

  • No relevant financial relationships declared.

This is a summary of a preprint research study published on medRxiv on November 2. The study’s first author was Pedro Luiz Serrano Uson Junior, Mayo Clinic, Scottsdale, Arizona. A preprint is a preliminary version of a manuscript that has not yet been peer reviewed at a journal. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.

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