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Targeting hormonal therapy for endometrial cancer is opening up the potential to improve outcomes without overtreating in the molecular era.

A dramatic increase in endometrial cancer cases and stark racial disparities in this trend over the past few decades sparked a revolution in care from a one-size-fits-all hysterectomy-focused approach to molecularly targeted management that accounts for more than just how tumors look under the microscope.

Four molecular subtypes emerged from findings of the , which was released in 2013:

• DNA polymerase epsilon (ultra-mutated)
• Microsatellite instability (hypermutated)
• p53 abnormal (copy-number high)
• p53 wild-type/no specific molecular subtype (NSMP; copy-number low)

For the roughly half of endometrial cancer patients who fall into the group with NSMP on subtyping and immunohistochemistry, "we can stratify based off of the aggressiveness under the microscope, but also, very importantly, the level of estrogen receptor positivity," noted Casey Cosgrove, MD, a gynecologic oncologist with the Ohio State University Comprehensive Cancer Center in Columbus.

Patients with higher levels of estrogen receptor positivity have a better outcome than those who have low or negative levels. In one , higher estrogen receptor levels had pooled hazard ratios of 0.75 for overall survival (95% CI 0.68-0.83), 0.45 for cancer-specific survival (95% CI 0.33-0.62), and 0.66 for progression-free survival (95% CI 0.52-0.85).

"And this could have incredible opportunity for us moving forward in further risk stratifying this large molecular group, where those who have a negative estrogen receptor status may need different treatment approaches," said Cosgrove. "Those that do have positive estrogen receptor responses, not only might they have a more positive outcome overall, but they also have a targeted therapy with hormonal therapies."

Grade 1 endometrioid endometrial cancer typically tends to be estrogen receptor positive and thus have a higher responsiveness to hormonal therapy, noted Ursula A. Matulonis, MD, chief of the division of gynecologic oncology at Dana-Farber Cancer Institute in Boston.

"It's important for our pathologists to do estrogen receptor testing via immunohistochemistry assay," she said. "That helps, because if the assay is 0%, then we may not use an endocrine therapy."

But beyond adding immunotherapy, hormonal therapy can be a good option for recurrent or advanced endometrial cancer, she noted.

While progestins, tamoxifen, and progestins alternating with tamoxifen have been well established for decades, CDK4/6 inhibitors with an aromatase inhibitor or fulvestrant have demonstrated "really remarkable response rates in estrogen receptor-positive advanced endometrial cancer," Matulonis said. "So that is definitely a therapy really learned from our breast cancer colleagues."

In a phase II trial by Matulonis and colleagues published in the in 2022, the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib (Verzenio) yielded nine total responses (eight confirmed) out of 30 treated patients, for an objective response rate of 30% (95% CI 14.7-49.4). All of those responses were in endometrioid adenocarcinomas. Median progression-free survival was 9.1 months, with 55.6% of patients alive without progression of disease at 6 months. The median duration of response was 7.4 months.

In the NSGO-PALEO/ENGOT-EN3 trial predominantly done in Europe among women with advanced, hormone receptor-positive endometrial cancer, the CDK inhibitor palbociclib (Ibrance) more than doubled progression-free survival when added to hormonal therapy with letrozole (8.3 vs 3.0 months). The combination achieved a disease control rate of 63.6% versus 37.8% with letrozole alone.

Other hormonal therapy combinations are also in the works, with a targeting the RNA helicase eIF4A to downregulate key factors in CDK4/6 inhibition resistance by adding novel zotatifin to abemaciclib and letrozole for recurrent endometrial cancer.

"What's exciting? Antibody-drug conjugates, antibody-drug conjugate combinations, hormonal therapies, various hormonal therapy combinations to really further increase response, further affect pathways that are important for cancer cell growth and make it 'more' and hopefully better for patients," Matulonis said.

Molecular targeting may also allow safer, less aggressive treatment.

Two international clinical trials planned under the platform are testing the safety of de-escalation of adjuvant therapy based on molecular subtyping in the randomized phase II POLEmut-BLUE trial of women with stage I-III POLE-mutated endometrial cancer: no adjuvant therapy for lower-risk disease and no adjuvant therapy or radiotherapy alone for higher-risk disease. The randomized phase III NSMP-ORANGE trial of women with estrogen receptor-positive stage II endometrial cancer with lymphovascular space invasion or stage III NSMP endometrial cancer will compare radiotherapy followed by progestin for 2 years versus adjuvant chemoradiation.

"So that's a really exciting area where molecular testing could be important for our patients in minimizing the toxicities of therapy," Cosgrove said.

However, he noted, "we're still trying to figure out what the right threshold for this estrogen receptor status is where you have these better outcomes."

"We have to make sure that we're really thoughtful before we implement it in clinical practice," he added, "because you can actually do harm if you haven't cautiously evaluated things based off of potential small numbers."

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