Circulating tumor DNA as a prognostic marker in high-risk endometrial cancer.
BACKGROUND
Currently, there is no reliable blood-based marker to track tumor recurrence in endometrial cancer (EC) patients. Liquid biopsies, specifically, circulating tumor DNA (ctDNA) analysis emerged as a way to monitor tumor metastasis. The objective of this study was to examine the feasibility of ctDNA in recurrence surveillance and prognostic evaluation of high-risk EC.


METHODS
Tumor tissues from nine high-risk EC patients were collected during primary surgery and tumor DNA was subjected to next generation sequencing to obtain the initial mutation spectrum using a 78 cancer-associated gene panel. Baseline and serial post-operative plasma samples were collected and droplet digital PCR (ddPCR) assays for patient-specific mutations were developed to track the mutations in the ctDNA in serial plasma samples. Log-rank test was used to assess the association between detection of ctDNA before or after surgery and disease-free survival.


RESULTS
Somatic mutations were identified in all of the cases. The most frequent mutated genes were PTEN, FAT4, ARID1A, TP53, ZFHX3, ATM, and FBXW7. For each patient, personalized ddPCR assays were designed for one-to-three high-frequent mutations. DdPCR analysis and tumor panel sequencing had a high level of agreement in the assessment of the mutant allele fractions in baseline tumor tissue DNA. CtDNA was detected in 67% (6 of 9) of baseline plasma samples, which was not predictive of disease-free survival (DFS). CtDNA was detected in serial post-operative plasma samples (ctDNA tracking) of 44% (4 of 9) of the patients, which predicted tumor relapse. The DFS was a median of 9 months (ctDNA detected) versus median DFS undefined (ctDNA not detected), with a hazard ratio of 17.43 (95% CI, 1.616-188.3). The sensitivity of post-operative ctDNA detection in estimating tumor relapse was 100% and specificity was 83.3%, which was superior to CA125 or HE4.


CONCLUSIONS
Personalized ctDNA detection was effective and stable for high-risk EC. CtDNA tracking in post-operative plasma is valuable for predicting tumor recurrence.
['Feng|Weiwei|W|0000-0002-0685-9479', 'Jia|Nan|N|', 'Jiao|Haining|H|', 'Chen|Jun|J|', 'Chen|Yan|Y|', 'Zhang|Yueru|Y|', 'Zhu|Menghan|M|', 'Zhu|Chongying|C|', 'Shen|Lifei|L|', 'Long|Wenqing|W|']
D014408:Biomarkers, Tumor D000074141:Circulating Tumor DNA D016889:Endometrial Neoplasms D005260:Female D006801:Humans D009154:Mutation D009364:Neoplasm Recurrence, Local D011379:Prognosis
Circulating tumor DNA High-risk endometrial cancer Recurrence