ctDNA Detects Endometrial Cancer Recurrence Risk Beyond Standard Markers

Female reproductive system diseases. Uterus cancer and endometrial malignant tumor as a uterine medical concept. 3d illustration: © Crystal Light - stock.adobe.com

Findings from a real-world study revealed that using circulating tumor DNA (ctDNA) monitoring in patients with endometrial cancer along with traditional prognostic risk factors can better identify patients with early-stage disease at risk of recurrence and determine optimal treatments.¹

Recurrence-free survival (RFS) was worse in patients who tested ctDNA positive at their first test point (HR, 6.2; P =.0006) and longitudinally (HR, 15.5; P <.0001), respectively. Recurrence rates were 58% and 52% for patients who tested as ctDNA-positive at the first time point and longitudinally.

Only 6% of the ctDNA-negative patients at the first time point experienced disease recurrence, and no patients who were ctDNA-negative longitudinally had disease recurrence.

“Presence of ctDNA detection post-surgery was highly prognostic of worse clinical outcome and remained the only significant risk factor for recurrence when adjusted for clinicopathological risk factors, such as [mismatch repair (MMR) status], p53 status, and risk group,” study authors wrote.

ctDNA positivity was also correlated with high-risk histology or sarcoma, and patients with high-risk histology and ctDNA-positive had shorter RFS compared with those who were ctDNA-negative (HR, 9.5; P =.007).

Finding New Risk Markers

The study, published in Gynecologic Oncology, evaluated the Signatera bespoke mPCR-NGS test in 267 plasma samples from 101 patients with stage I endometrial cancer. Postsurgery, patients were monitored for ctDNA for a median of 6.8 months (range, 0.37-19.1). The median patient age was 67 years (range, 32-88).

All patients underwent whole-exome sequencing, and TP53 was determined to be the most common genetic mutation in the ctDNA-positive patient population, followed by ARID1A and PIK3CA. In patients who were ctDNA-negative, the most common mutations were PTEN, PIK3CA, ARID1A, and TP53. Further, 47 patients (46.5%) had p53 altered status, and 54 patients (53.5%) had p53 wild-type status. A total of 20 patients (19.8%) were MMR-deficient, while 81 patients (80.2%) were MMR-proficient.

Altered p53 status was associated with higher ctDNA levels compared to wild-type status; however, positive ctDNA was associated with worse RFS regardless of p53 status, indicating the importance that ctDNA could have in stratifying endometrial cancer care beyond the current paradigms. 

Notably, when stratifying patients by risk group, patients who were considered low-risk but were still ctDNA-positive longitudinally had worse RFS compared with patients who were clinically considered high-risk and ctDNA-positive. This is potentially due to the higher rates of adjuvant treatment that high-risk patients would receive compared with low-risk patients.

“This suggests that ctDNA status could help identify high-risk molecular disease even in clinically lower risk categories of patients, potentially impacting treatment decisions,” study authors wrote.

“This study provides clinical validation of Signatera as a powerful postsurgical biomarker of recurrence risk for patients with endometrial cancer,” said Minetta Liu, MD, chief medical officer of oncology at Natera, in a press release.² “Use of Signatera in clinical workflows may help physicians and patients tailor their adjuvant treatment decisions based on direct evidence of molecular residual disease.”

REFERENCES:

1. Recio F, Scalise CB, Loar P, et al. Post-surgical ctDNA-based molecular residual disease detection in patients with stage I uterine malignancies. Gynecol Oncol. Published online January 22, 2024. doi:10.1016/j.ygyno.2023.12.025

2. New study validates Signatera in endometrial cancer. News release. Natera, Inc. February 5, 2024. Accessed February 7, 2024. http://tinyurl.com/z2s9rzxb