title: Personalized Circulating Tumor DNA Biomarkers Dynamically Predict Treatment Response and Survival In Gynecologic Cancers.
abstract: BACKGROUND
  High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment. Circulating tumor DNA (ctDNA) represents a theoretically powerful biomarker for detecting otherwise occult disease. We therefore explored the use of personalized ctDNA markers as both a surveillance and prognostic biomarker in gynecologic cancers and compared this to current FDA-approved surveillance tools.
  
  
  RESULTS
  Tumor and serum samples were collected at time of surgery and then throughout treatment course for 44 patients with gynecologic cancers, representing 22 ovarian cancer cases, 17 uterine cancer cases, one peritoneal, three fallopian tube, and one patient with synchronous fallopian tube and uterine cancer. Patient/tumor-specific mutations were identified using whole-exome and targeted gene sequencing and ctDNA levels quantified using droplet digital PCR. CtDNA was detected in 93.8% of patients for whom probes were designed and levels were highly correlated with CA-125 serum and computed tomography (CT) scanning results. In six patients, ctDNA detected the presence of cancer even when CT scanning was negative and, on average, had a predictive lead time of seven months over CT imaging. Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival.
  
  
  CONCLUSIONS
  Detection of residual disease in gynecologic, and indeed all cancers, represents a diagnostic dilemma and a potential critical inflection point in precision medicine. This study suggests that the use of personalized ctDNA biomarkers in gynecologic cancers can identify the presence of residual tumor while also more dynamically predicting response to treatment relative to currently used serum and imaging studies. Of particular interest, ctDNA was an independent predictor of survival in patients with ovarian and endometrial cancers. Earlier recognition of disease persistence and/or recurrence and the ability to stratify into better and worse outcome groups through ctDNA surveillance may open the window for improved survival and quality and life in these cancers.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
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, United States of America.
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, United States of America.
authors.forename: Sanya
authors.initials: S
authors.lastname: Anand
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Sebra
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Sandra
authors.initials: S
authors.lastname: Catalina Camacho
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Leopold
authors.initials: L
authors.lastname: Garnar-Wortzel
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Navya
authors.initials: N
authors.lastname: Nair
authors.affiliation: Department of Biostatistics, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Erin
authors.initials: E
authors.lastname: Moshier
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Wooten
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Uzilov
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Prasad-Hayes
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Zakashansky
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Beddoe
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
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, United States of America.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Dottino
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D018394:CA-125 Antigen / Q000097:blood; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D059472:Exome / Q000235:genetics; D005260:Female; D005833:Genital Neoplasms, Female / Q000097:blood* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000235:genetics; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy / Q000401:mortality
chemical_list: D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D004273:DNA, Neoplasm