Genomic profiling by cell-free circulating tumor DNA in patients with recurrent adenoid cystic carcinoma (ACC) and the potential activity of selective fibroblast growth factor receptor (FGFR) inhibitors.

Abstract

e15018 Background: Few effective systemic therapies are available for adenoid cystic carcinoma (ACC). Multitargeted Tyrosine Kinase inhibitors (TKIs) as Lenvatinib and Rivoceranib can provide disease control and limited radiographic response in unselected ACC patients. Next-generation sequencing in tissue (tNGS) has identified MYB gene fusions in [patients with ACC but currently, only Notch1 mutations have an available targeted agent. The fibroblast growth factor receptor (FGFR) pathway is a downstream target of MYB. Methods: We retrospectively reviewed adult patients with a diagnosis of recurrent ACC seen at the University of Miami Sylvester Comprehensive Cancer Center between January 1, 2019 and October 31, 2020. Commercially available cell free DNA panel of 73 genes was used for analyzing circulating tumor DNA (ctDNA). Patients included had radiographically measurable disease and both tNGS and ctDNA data available. Results: Twelve patients were included. Median age at diagnosis was 54 years (28 - 68), and 69% were males. 83% of the patients had genomic abnormalities reported by tNGS, with the same number by ctDNA sequencing. Seven patients (58%) had genomic abnormalities in ctDNA of potentially therapeutic significance which were not found on tNGS, including FGFR1 amplification as well as FGFR2, BRAF, KRAS and JAK2 mutations. Three patients with FGFR genomic abnormalities only seen by ctDNA had been previously treated with Lenvatinib. One patient with primary lacrimal gland ACC metastatic to the liver and tNGS positive for NOTCH 1 had disease progression despite treatment with Lenvatinib and a NOTCH γ-secretase inhibitor. The patient’s ctDNA reported a FGFR2 mutation. The patient was started on Erdafitinib, an oral selective FGFR inhibitor, achieving a partial response at the primary site and metastatic liver lesions and remained on therapy for 7 months. Follow-up ctDNA after 3 months of therapy noted resolution of both FGFR and NOTCH abnormalities. Conclusions: Patients treated with lenvantinib or other TKIs may develop acquired resistance mutations and other genomic abnormalities. ctDNA can reveal additional therapeutic targets not present on tNGS and can be repeated serially. FGFR genomic abnormalities can be a driver mutation in patients with refractory advanced ACC and the activity of Erdafinib should be evaluated in this subset of patients with few therapeutic options.