New Genetic Insights into Who Should Receive Radiotherapy for Uterine Cancer

Cancer deaths have generally declined in developed countries over recent decades, but not for every cancer. In the United States, deaths from endometrial cancer, the most common uterine cancer, have increased over the past 20 years. This has prompted major efforts to improve diagnosis and treatment, particularly in early-stage disease.

Recent research suggests that some patients with early-stage endometrial cancer are undertreated when decisions rely only on traditional clinicopathological features, such as anatomical spread or pathological grade. Ignoring molecular and genomic characteristics can produce suboptimal outcomes, highlighting the need for a more integrated approach.

International guidelines updated in 2021 state that adjuvant radiotherapy treatment decisions should incorporate molecular classification. This may help identify more accurately which patients could benefit from treatment.

An analysis supporting this recommendation appeared on March 14, 2024, in JAMA Oncology. It found that molecular classification can identify patients likely to benefit from adjuvant radiotherapy who did not receive it under traditional clinicopathological assessment. Dr. Otilia Ciobanu and colleagues wrote, "Without precise genomic guidance, molecularly aggressive disease may be missed," the report states.

What Are the Main Guideline Changes?

Recently updated guidelines incorporate molecular classification to support more personalized management of endometrial cancer.

The PORTEC-1 and PORTEC-2 clinical trials informed the updated recommendations:

1. Patients with DNA polymerase-epsilon (POLE)-mutated tumors should not receive adjuvant radiotherapy because of their more favorable prognosis.
2. Patients with no specific molecular profile should receive vaginal brachytherapy (internal radiotherapy) only, because their prognosis is intermediate.
3. p53-mutant tumors, used as an indicator of TP53-mutated disease with an unfavorable prognosis, should be treated with conventional external-beam pelvic radiotherapy.

How Common Are Undertreatment and Overtreatment?

The current analysis, focusing on patients without mismatch repair deficiency , included 153 women with stage I endometrioid endometrial cancer and compared their documented adjuvant radiotherapy regimens with molecular classification-based strategies.

The women underwent surgical resection and contributed tumor samples to The Cancer Genome Atlas, but radiotherapy decisions had been made before molecular classification.

After accounting for molecular classification, the researchers concluded:

• 96 patients (63%) were undertreated, and 16 (10%) were overtreated.
• Undertreatment generally occurred in stage IA, low-grade disease, while overtreatment was more frequent in high-grade disease.

Specifically, patients with no specific molecular profile who received no adjuvant radiotherapy were considered undertreated (72%, or 70 of 97). Patients with p53-mutant endometrial cancer who did not receive external-beam pelvic radiotherapy were also considered undertreated (90%, or 26 of 29).

Patients with DNA polymerase-epsilon-mutated tumors receiving any adjuvant radiotherapy were considered overtreated (37%, or 10 of 27), as were patients with no specific molecular profile who received external-beam pelvic radiotherapy (6%, or 6 of 97).

Molecular classification also showed a greater likelihood of aggressive disease in Black patients. For example, p53 mutations were more common (22%) among Black patients. Of the 25 Black patients, 72% (18 of 25) were considered undertreated.

What Can We Learn?

This analysis highlights molecular classification's potential to reduce disparities in outcomes, particularly for aggressive cancers. It enables more personalized treatment based on genetic characteristics and helps identify the most appropriate treatment for each patient.

Without precise genomic guidance, cancers with aggressive molecular characteristics may be difficult to identify correctly. Such guidance may enable earlier identification and more effective management, potentially improving survival and quality of life.

Integrating molecular classification into treatment may therefore improve equity and effectiveness in oncology, supporting better-informed genetic decisions and better outcomes.