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BACKGROUND: Adenoid cystic carcinoma (ACC) is a malignancy for which currently no therapies are approved by the FDA. Thus, there is an urgent need to identify novel treatments. Although imaging is the standard to evaluate responses to experimental drugs, accurate radiologic assessments can be challenging. CT and MRI may lead to an underestimation of the tumor burden, whereas PET is limited by the slow growth rate of ACC. Here, we demonstrate that liquid biopsy to detect ACC-derived cell-free DNA can serve as a complementary marker for assessing tumor burden and therapeutic futility.PATIENTS AND METHODS: We investigated 47 blood samples from 15 patients with advanced ACC who received all-trans retinoic acid in a phase II clinical trial and determined the kinetics of circulating tumor DNA (ctDNA) over time. We established two independent methods for ctDNA detection: an unbiased approach based on low-pass whole genome sequencing (lpWGS) (<1x) and a targeted sequencing approach focused on known somatic mutations.RESULTS: lpWGS performed better in detecting the ctDNA than targeted sequencing (in 47 vs. 20 % of patients who provided plasma samples, respectively), and has the advantage of not requiring a prior knowledge of the mutational landscape of the tumor. Overall, the presence of ctDNA and higher tumor fraction pointed toward a correlation with shorter progression-free survival and time spent on therapy as well as higher probability of progressive versus stable disease, although statistical significance was not achieved, possibly due to the limited size of the patient cohort.CONCLUSION: Our findings suggest that ctDNA may serve as an additional tool for therapeutic guidance in ACC patients.