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

Pereira E, Camacho-Vanegas O, Anand S, Sebra R, Catalina Camacho S, Garnar-Wortzel L, Nair N, Moshier E, Wooten M, Uzilov A, Chen R, Prasad-Hayes M, Zakashansky K, Beddoe AM, Schadt E, Dottino P, Martignetti JA - PLoS ONE (2015)

Bottom Line: 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.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.Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.

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.

Methods and findings: 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.

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Related in: MedlinePlus

Undetectable levels of ctDNA following initial treatment are associated with improved survival.Kaplan–Meier analysis of progression-free (left panel) and overall survival (right panel) between individuals with undetectable (ctDNA = 0; blue lines) and detectable ctDNA (≥ 1; red lines). Significant differences in progression-free survival (p = 0.001) and overall survival (p = 0.0194) between undetectable and detectable groups.
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pone.0145754.g003: Undetectable levels of ctDNA following initial treatment are associated with improved survival.Kaplan–Meier analysis of progression-free (left panel) and overall survival (right panel) between individuals with undetectable (ctDNA = 0; blue lines) and detectable ctDNA (≥ 1; red lines). Significant differences in progression-free survival (p = 0.001) and overall survival (p = 0.0194) between undetectable and detectable groups.

Mentions: We next assessed whether ctDNA levels following surgical resection and adjuvant therapy had prognostic significance. Pre- and post-treatment ctDNA levels were analyzed for 10 patients and compared to PFS and OS. Current clinical status, dead of disease (DOD), alive with disease (AWD) and no evidence of disease (NED), was available for all 10 patients (Table 3). Undetectable levels of ctDNA following initial adjuvant treatment were associated with both improved PFS (p = 0.0011 Kaplan Meier) and OS (p = 0.0194; Fig 3). The median PFS difference was just over 2 years (six months versus 32 months). All four patients with average post-treatment ctDNA levels ≥ 10 copies/ml are DOD, whereas the one patient with ctDNA = 5 copies/ml, who also intriguingly had very low levels of ctDNA pre-treatment, is AWD. Of the five patients with undetectable ctDNA levels post-treatment, none have died of their disease, three are AWD and two are NED. Two of the patients have already survived beyond 5 years. We noted no survival differences based on ctDNA pre-treatment values.


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

Pereira E, Camacho-Vanegas O, Anand S, Sebra R, Catalina Camacho S, Garnar-Wortzel L, Nair N, Moshier E, Wooten M, Uzilov A, Chen R, Prasad-Hayes M, Zakashansky K, Beddoe AM, Schadt E, Dottino P, Martignetti JA - PLoS ONE (2015)

Undetectable levels of ctDNA following initial treatment are associated with improved survival.Kaplan–Meier analysis of progression-free (left panel) and overall survival (right panel) between individuals with undetectable (ctDNA = 0; blue lines) and detectable ctDNA (≥ 1; red lines). Significant differences in progression-free survival (p = 0.001) and overall survival (p = 0.0194) between undetectable and detectable groups.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696808&req=5

pone.0145754.g003: Undetectable levels of ctDNA following initial treatment are associated with improved survival.Kaplan–Meier analysis of progression-free (left panel) and overall survival (right panel) between individuals with undetectable (ctDNA = 0; blue lines) and detectable ctDNA (≥ 1; red lines). Significant differences in progression-free survival (p = 0.001) and overall survival (p = 0.0194) between undetectable and detectable groups.
Mentions: We next assessed whether ctDNA levels following surgical resection and adjuvant therapy had prognostic significance. Pre- and post-treatment ctDNA levels were analyzed for 10 patients and compared to PFS and OS. Current clinical status, dead of disease (DOD), alive with disease (AWD) and no evidence of disease (NED), was available for all 10 patients (Table 3). Undetectable levels of ctDNA following initial adjuvant treatment were associated with both improved PFS (p = 0.0011 Kaplan Meier) and OS (p = 0.0194; Fig 3). The median PFS difference was just over 2 years (six months versus 32 months). All four patients with average post-treatment ctDNA levels ≥ 10 copies/ml are DOD, whereas the one patient with ctDNA = 5 copies/ml, who also intriguingly had very low levels of ctDNA pre-treatment, is AWD. Of the five patients with undetectable ctDNA levels post-treatment, none have died of their disease, three are AWD and two are NED. Two of the patients have already survived beyond 5 years. We noted no survival differences based on ctDNA pre-treatment values.

Bottom Line: 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.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.Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.

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.

Methods and findings: 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.

Show MeSH
Related in: MedlinePlus