Endocrine therapy is standard of care for estrogen-receptor positive (ER+) breast cancer, but only about half of women respond. At present, there is no method for identifying the women who are likely — and also unlikely — to respond.

But a new approach looks to be useful: it involves a trial of estrogen and then imaging that measures the function of estrogen receptors in the cancer cells.

This functional testing of estrogen receptors on breast cancer cells was perfectly accurate in predicting endocrine therapy response in 43 postmenopausal women with advanced ER+ disease, say researchers from  Washington University, St. Louis, Missouri, led by Farrokh Dehdashti, MD.

“There is an unmet clinical need to develop more precise predictive biomarkers. The results of this study are extremely promising,” they conclude.  

The study was published online February 2 in Nature Communications.

For the study, the women were first infused with a radioactive progestin analog – 21-[18F]fluorofuranylnorprogesterone (FFNP) — that binds progesterone receptors. About 40 minutes later, they had a PET scan to assess its uptake, an indication of progesterone receptor abundance.

The women were then given three 200 mg doses of estradiol over 24 hours.

The FFNP infusion and PET scan were repeated the next day.

Estradiol will cause cancer cells with functional estrogen receptors to produce more progesterone receptors, so increased uptake of the radioactive analogue indicates functional estrogen receptors that will respond to endocrine therapy. If estrogen receptors are not functional, and therefore not amenable to endocrine therapy (ET), estradiol will not upregulate progesterone receptors.

The results proved the theory. FFNP uptake increased more than 6.7% in 28 subjects, and a median of 25.4%; all 28 women responded to subsequent ET, including 15 partial responses and 13 women with stable disease at 6 months.

Median survival was not reached after a median follow up of 27.1 months.

Uptake increased no more than 6.7% in 15 subjects and, in fact, fell a median of 0.7% from baseline; none of these women responded to ET. Median survival was 22.6 months.

“We observed 100% agreement between the response to estrogen challenge and the response to hormone therapy…This method should work for any therapy that depends on a functional estrogen receptor, and it could provide valuable information to oncologists deciding how best to treat their patients,” Dehdashti said in a press release.

A larger multicenter confirmation trial is in the works.

Oncology needs “to get away from empiric therapies and make therapy more individualized” to save patients from the morbidity and expense of ineffective treatment and wasting time when other options are available, Dehdashti told Medscape Medical News.

“It would be a good thing if we could identify endocrine-resistant patients,” said Charles Shapiro, MD, a professor and director of translational breast cancer research at Mount Sinai Hospital in New York City.

However, he wondered “about the exportability to less resource-intensive community settings where most oncology care occurs. This technology, assuming the results are confirmed in a larger study, [needs] a cost-effectiveness analysis” vs the empiric approach, Shapiro told Medscape Medical News.

The women taking part in this study were a median of 60 years old and most had metastatic disease. PET imaging extended from the base of the skull to the upper thighs, with data derived from bone, lung, breast, and other tumor sites. ET options included aromatase inhibitors, fulvestrant, and tamoxifen in combination with other agents.

Almost three quarters of the women had prior systemic treatment, most often a hormone therapy-based regimen. Prior treatment had no effect on FFNP uptake.

There were no adverse events with the radiotracer, but the estradiol made a few women nauseous, among other transient discomforts, the team reported.

The work was funded by the National Cancer Institute and Washington University. Shapiro and Dehdashti have disclosed no relevant financial relationships. Several investigators reported consulting fees and/or other ties to a number of companies, including Pfizer, Merck, Avid Radiopharmaceutical, and Radius Health.

Nat. Commun. Published February 2, 2021. Full text

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from the Newhouse School at Syracuse University. He is an award-winning medical journalist who has worked for several major news outlets before joining Medscape, including McClatchy and Bloomberg, and an MIT Knight Science Journalism fellow. Email: [email protected]

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