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.
Highlights
Gynecologic malignancies will be diagnosed in over 94,000 women in the U.S and will result in close to 29,000 deaths this year alone [1]
This study suggests that the use of personalized Circulating tumor DNA (ctDNA) biomarkers in gynecologic cancers can identify the presence of residual tumor while more dynamically predicting response to treatment relative to currently used serum and imaging studies
CtDNA was an independent predictor of survival in patients with ovarian and endometrial cancers
Summary
Gynecologic malignancies will be diagnosed in over 94,000 women in the U.S and will result in close to 29,000 deaths this year alone [1]. The development of more sensitive and accurate biomarkers will be critical for both earlier detection of disease and more effective surveillance in the post-treatment setting. In epithelial ovarian cancer, the most lethal female reproductive tract malignancy worldwide, most women will present with advanced stage disease which will be managed by surgical resection followed by combination platinum- and taxane-based chemotherapy. The only currently available serum biomarker in gynecologic malignancies, CA-125, lacks the sensitivity and specificity for monitoring treatment response and early detection of recurrence [2,3]. 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. We 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
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