Among female malignant tumors of the reproductive system, the incidence of endometrial cancer has increased, becoming a "hidden killer" threatening women's health. For patients with advanced or recurrent endometrial cancer, traditional tissue biopsy has limitations such as invasiveness and difficulty in fully reflecting tumor heterogeneity. The advent of liquid biopsy technology, particularly the utilization of circulating tumor DNA (ctDNA) gene detection, is subtly altering the current situation.

Endometrial cancer has a highly heterogeneous "molecular family". The significant differences in genetic characteristics, biological behaviors, and treatment responses among tumors of different pathological subtypes mean that a "one - size - fits - all" treatment model is difficult to meet clinical needs. In recent years, molecular typing has become the core guiding basis for the diagnosis and treatment of endometrial cancer. Meanwhile, ctDNA gene detection is gradually replacing traditional biopsy as a key tool to unlock the molecular characteristics of tumors due to its minimally invasive, real - time, and comprehensive advantages.

A large retrospective study recently published in Clinical Cancer Research has once again confirmed the core value of ctDNA gene detection in endometrial cancer. The study included 1988 patients with advanced or recurrent endometrial cancer, and genomic analysis was performed using the Guardant360 ctDNA platform. The results showed that 91.6% of the patients had at least one somatic mutation detected, with an average of 6.7 genetic changes per sample. This high detection rate challenges the previous view of insufficient sensitivity in ctDNA detection of endometrial cancer and provides solid data support for accurate clinical diagnosis and treatment.

Among the numerous gene variants detected, TP53 tops the list with a mutation rate of 64%, becoming the most common driver of endometrial cancer. Following it were PIK3CA (29%), PTEN (25%), ARID1A (20%), and KRAS (14%).

Figure 1. Profile of common gene mutations in endometrial cancer patients in the study cohort

Interestingly, TP53 mutations were more prevalent in relapsed patients (P < 0.0001), and the overall survival of patients with TP53 mutations was significantly shortened (71.2 months vs 108 months, P = 0.02), fully demonstrating the importance of this gene as a prognostic marker.

Figure 2. A, TP53 gene mutation is more significantly distributed in patients with recurrence and progression; B, TP53 mutations are associated with lower overall survival

The study has discovered that the co - mutation status of TP53 has a more significant impact on the prognosis of patients. Seventy - four percent of the 776 patients with TP53 mutations had at least one co - mutation, and the overall survival of these patients (66.4 months) was significantly lower than that of those with only a single mutation in TP53 (78.1 months, P = 0.016). Among them, patients with TP53 and PIK3CA co - mutation (P = 0.012) have the worst prognosis and become a high - risk group that needs to be focused on clinically.

This finding suggests that comprehensive analysis of gene co - mutation patterns through ctDNA testing can help doctors more accurately stratify risks and formulate individualized treatment strategies.

Figure 3. TP53 mutations and co - mutations are significantly associated with lower survival

In addition to the core driver genes, studies have revealed other important genomic features in endometrial carcinoma. In a panel assay subgroup of 83 genes, 24.3% of patients had homologous recombination repair (HRR) gene variation, with ATM (49%), CHEK1 (31%), BRCA2 (17%), and BRCA1 (14%) being the most common; Mismatch repair (MMR) gene variation was detected in 6.3% of patients, with MSH6 accounting for 71%.

In addition, gene amplification was present in 18.5% of patients, predominantly CCNE1 (40.9%), PIK3CA (22%), and EGFR (19.3%). This genomic information provides a clear target for targeted therapy. For example, patients with HRR gene mutations may benefit from PARP inhibitor therapy.

Dynamic monitoring of tumor changes is another advantage of ctDNA gene detection. In the study, continuous ctDNA testing was performed on 118 patients, and 57 newly diagnosed advanced patients were found to have obvious gene mutation evolution during treatment. Among these, the TP53 mutation is the most common acquired variant (n = 10) and the most common type of missing variant. This dynamic change not only reflects the tumor heterogeneity and evolution under treatment pressure but also provides a basis for timely adjustment of treatment options. For example, when patients develop resistance - related mutations such as CCNE1 amplification during treatment, doctors can promptly change treatment strategies to avoid delays and side effects caused by ineffective treatment.

In clinical application scenarios, ctDNA gene detection has become a "right - hand man" for the accurate diagnosis and treatment of endometrial cancer. For newly diagnosed advanced patients, molecular typing and target screening by ctDNA testing can directly guide the selection of first - line treatment. For example, immunotherapy can be prioritized for patients with MSI - H, and PI3K inhibitors can be selected for patients with PIK3CA mutations. For patients with recurrence, ctDNA detection can quickly identify the drug resistance mechanism and provide a basis for subsequent treatment plan adjustment. For patients under treatment, dynamic ctDNA monitoring can provide an early warning of disease progression, with evidence of recurrence found months before conventional imaging.

The diagnosis and treatment of endometrial carcinoma have entered the era of individualized treatment under the guidance of molecular typing. ctDNA gene detection, as the core technology of liquid biopsy, is changing the traditional diagnosis and treatment mode with its unique advantages. By analyzing the occurrence and development mechanism of tumors at the gene level, accurately predicting the prognosis of patients, guiding the selection of treatment options, and dynamically monitoring the treatment effect, ctDNA detection is providing accurate medical support for patients with endometrial cancer throughout the course of the disease.

References

Clin Cancer Res. 2024 Dec 16; 30(24):5657-5665.

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