title: 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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY ; Department of Obstetrics/Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Olga
authors.initials: O
authors.lastname: Camacho-Vanegas
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Nolan
authors.initials: N
authors.lastname: Priedigkeit
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Catalina
authors.initials: C
authors.lastname: Camacho
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Elena
authors.initials: E
authors.lastname: Pereira
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Leopold
authors.initials: L
authors.lastname: Garnar-Wortzel
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Dagny
authors.initials: D
authors.lastname: Miller
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Bojan
authors.initials: B
authors.lastname: Losic
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Hardik
authors.initials: H
authors.lastname: Shah
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Jun
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Pratik
authors.initials: P
authors.lastname: Lahiri
authors.affiliation: Prognosys Biosciences, San Diego, CA.
authors.forename: Mark
authors.initials: M
authors.lastname: Chee
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Eric
authors.initials: E
authors.lastname: Schadt
authors.affiliation: Department of Obstetrics/Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Peter
authors.initials: P
authors.lastname: Dottino
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018394:CA-125 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000097:blood*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D057285:Precision Medicine; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D012008:Recurrence
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D004273:DNA, Neoplasm; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D002945:Cisplatin