Personalized Circulating Tumor DNA Biomarkers Dynamically Predict Treatment Response and Survival In Gynecologic Cancers

Abstract

BackgroundHigh-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.Methods and FindingsTumor 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.ConclusionsDetection 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.

A genomic case study of desmoplastic small round cell tumor: comprehensive analysis reveals insights into potential therapeutic targets and development of a monitoring tool for a rare and aggressive disease

“…These results are in agreement with imaging exams (CT scan and PET scan) showing no signs of disease and also with good overall clinical condition of the patient and highlight the applicability of using genomic rearrangement for building personalized tool for patient surveillance. After defining the genomic breakpoint of EWS-WT1 fusion, DSRCT patients can benefit from a highly specific test that has the advantage of a rapid turnaround time and potentially higher sensitivity in detecting disease progression earlier than imaging exams or other cancer antigens measurements, as reported for other tumor types [36, 37]. Monitoring through liquid biopsy is particularly attractive for solid tumors, which cannot be repeatedly sampled without more invasive procedures.…”

Genomic Analysis of Uterine Lavage Fluid Detects Early Endometrial Cancers and Reveals a Prevalent Landscape of Driver Mutations in Women without Histopathologic Evidence of Cancer: A Prospective Cross-Sectional Study

“…Specificity of each assay was first validated by quantitative PCR. Next, sensitivity and lower limits of detection were established by digital droplet PCR (RainDance Technologies, Billerica, MA), as we have previously described [25]. When no tumor DNA was available, positive controls were synthesized and used for these reactions as 300–500 bp gBlocks Gene Fragments (Integrated DNA Technologies, Coralville, IA).…”

Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

“…We and others have previously shown that TP53 mutations can be detected in ctDNA from patients with advanced HGSOC and that, in a small number of patients studied, changes in ctDNA levels correlated with other clinical response measurements including CA-125 [21,28–30]. However, in HGSOC the relationship of ctDNA to tumour volume, dynamic ctDNA changes during chemotherapy, and the relationship of early changes to outcomes during chemotherapy have not been characterised.…”