Personalized Ovarian Cancer Disease Surveillance and Detection of Candidate Therapeutic Drug Target in Circulating Tumor DNA

Abstract

Retrospective studies have demonstrated that nearly 50% of patients with ovarian cancer with normal cancer antigen 125 (CA125) levels have persistent disease; however, prospectively distinguishing between patients is currently impossible. Here, we demonstrate that for one patient, with the first reported fibroblast growth factor receptor 2 (FGFR2) fusion transcript in ovarian cancer, circulating tumor DNA (ctDNA) is a more sensitive and specific biomarker than CA125, and it can also inform on a candidate therapeutic. For a 4-year period, during which the patient underwent primary debulking surgery and chemotherapy, tumor recurrences, and multiple chemotherapeutic regimens, blood samples were longitudinally collected and stored. Whereas postsurgical CA125 levels were elevated only three times for 28 measurements, the FGFR2 fusion ctDNA biomarker was readily detectable by quantitative real-time reverse transcription-polymerase chain reaction (PCR) in all of these same blood samples and in the tumor recurrences. Given the persistence of the FGFR2 fusion, we treated tumor cells derived from this patient and others with the FGFR2 inhibitor BGJ398. Only tumor cells derived from this patient were sensitive to FGFR2 inhibitor treatment. Using the same methodologic approach, we demonstrate in a second patient with a different fusion that PCR and agarose gel electrophoresis can also be used to identify tumor-specific DNA in the circulation. Taken together, we demonstrate that a relatively inexpensive, PCR-based ctDNA surveillance assay can outperform CA125 in identifying occult disease.

Liquid biopsy in ovarian cancer: recent advances on circulating tumor cells and circulating tumor DNA

“…For this purpose, they quantified total cfDNA and/or the circulating cell-free mitochondrial DNA (mtDNA) levels in some cases, or aimed at the detection of different genetic and epigenetic alterations, such as chromosomal abnormalities and specific tumor LOH, cancer-related somatic gene mutations and aberrant DNA methylation. Additionally, in a recent case study, Martignetti et al [40] detected the FGFR2-FAM76A tumor-specific fusion in cfDNA of an advanced stage serous epithelial ovarian cancer patient.…”

Preclinical Efficacy of the Auristatin-Based Antibody–Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors

“…FGFR2 aberrations have been implicated in multiple cancer types, associated with poor prognosis and resistance to cancer treatments. Oncogenic FGFR2 functions, promoted by FGFR2 overexpression, gene amplification, gene fusions, and autoactivating mutations of the receptor, have been described in several cancers, including gastric, breast, and ovarian cancer (7)(8)(9)(10)(11)(12)(13)(14). FGFR2 gene amplification is found in 4% of triple-negative breast cancers (TNBC) and appears to promote breast tumorigenicity by maintaining breast tumorinitiating cells (11,14).…”

Personalized circulating tumor DNA biomarkers dynamically predict treatment response and survival in gynecologic cancers

“…Previous studies in gynecologic malignancies have primarily evaluated the presence of ctDNA at a single time point using pelvic washes, ascites, serum and plasma [13][14][15]. As a proof-ofprinciple study to demonstrate the ability to serially track disease, we recently used a tumorspecific fusion event to demonstrate the continued presence of ctDNA, and thus minimal residual disease, in a single patient over a four-year period in the face of repeatedly normal CA125 measurements [16]. Apart from this, longitudinal studies correlating ctDNA levels with tumor burden and clinical course in gynecologic cancers are lacking.…”