Molecular profiling can safely reduce radiation for women with endometrial cancer: Clinical trial results

Endometrial cancer is the most common gynecological cancer in highly-developed countries, most often affecting women after menopause. The majority of women are diagnosed at an early stage, when treatment outcomes are generally favorable.

For women with high-intermediate risk disease, adjuvant radiotherapy—particularly vaginal brachytherapy (a form of internal radiotherapy delivered directly to the vaginal area)—is commonly used after surgery to reduce the risk of recurrence.

However, patients don’t need it equally, and some may receive more treatment than necessary, exposing them to potential side effects without added benefit. Furthermore, a small subgroup of patients seem to be undertreated when only treated with vaginal brachytherapy.

This has sparked growing interest in tailoring treatment using molecular profiling, a method that examines the genetic and biological features of a tumor to guide clinical decisions. It helps identify which patients are most likely to benefit from radiotherapy, and which can safely avoid it.

A major international study, PORTEC-4a, provides the strongest evidence yet that molecular profiling can safely reduce radiotherapy for women with early stage endometrial cancer while identifying those who would benefit from more intensive treatment.

The results, presented at ESTRO 2025, the annual congress of the European Society for Radiotherapy and Oncology (ESTRO), mark a significant step forward in personalized cancer treatment.

Endometrial cancer is the most common gynecological cancer, and its incidence is rising globally. The PORTEC trials have played a key role in refining treatment strategies, ensuring that radiotherapy is used effectively while minimizing side effects. The findings from PORTEC-4a highlight:

• More precise treatment: Molecular profiling helps tailor radiotherapy decisions based on individual tumor characteristics.
• Reduced overtreatment: Nearly half of patients in the trial safely avoided radiation without compromising cancer control.
• Improved outcomes for patients at a higher risk of recurrence: The study suggests that patients with unfavorable tumor profiles benefit from a more intensive radiation approach.

Key findings from PORTEC-4a

The randomized PORTEC-4a trial enrolled 592 women across eight European countries with (high-)intermediate risk endometrial cancer. Molecular testing classified tumors into risk categories, allowing treatment to be adapted accordingly:

• 46% of patients in the molecular-profile arm safely avoided radiotherapy.
• Patients with an unfavorable molecular profile received a more intensive radiation approach, pelvic radiotherapy, instead of vaginal brachytherapy, and the results suggest better locoregional control, with a recurrence rate of 8.4% compared to 30.5% in those who received standard treatment without molecular profiling.

“By using molecular profiling, we can tailor treatment to each patient’s individual risk,” said Dr. Anne Sophie V.M. van den Heerik, lead investigator of the PORTEC-4a trial, from The Leiden University Medical Center, The Netherlands.

“This approach allows us to safely reduce radiotherapy for many women while ensuring that those who need it receive the most effective therapy. It’s a major step towards more personalized and less invasive cancer treatment.”

The findings demonstrate that nearly half of patients can be safely spared radiotherapy while maintaining excellent survival rates. Additionally, exploratory analyses suggest that patients with an unfavorable molecular profile may benefit from a more intensive radiation approach to reduce recurrence risks.

A game-changer for precision oncology

“The PORTEC-4a trial is a game-changer,” said Prof Matthias Guckenberger, President of ESTRO, Chairman of the Department of Radiation Oncology and full Professor at the University Hospital Zurich and University of Zurich.

“This research proves that precision medicine is transforming cancer treatment. By identifying patients who have the largest benefit from radiotherapy, we can maximize its impact, improve quality of life for thousands of women worldwide, and maintain excellent cancer control.”

These findings pave the way for a more personalized approach to treating endometrial cancer, ensuring that each patient receives the most effective and least invasive treatment based on their tumor biology and risk profile.