Predicting Response to Endocrine Therapy in ER-Positive Breast Cancer (2021)

MRI; imaging: MRI; imagingAccording to the American Cancer Society, nearly 70 percent of patients with breast cancer have hormone receptor-positive (HR+) disease—estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or both. Hormone therapy is designed to stop the effects of estrogen on the tumor and can be very effective for ER+ breast cancer. An assortment of drugs can be prescribed as hormone therapy, and clinicians choose a treatment regimen depending on the patient and the specifics of that person's disease. Aromatase inhibitors prevent the body from producing estrogen and are typically the first treatment of choice for hormone therapy, whereas other anti-estrogen drugs, such as fulvestrant, block the ER on cancer cells. However, there has historically been no reliable way to predict which patients will benefit, especially as the cancer advances or recurs. Furthermore, in previous research, up to 50 percent of patients with HR+ breast cancer have not responded to first-line hormone therapy, and the occurrence of non-responsiveness increased during subsequent lines of hormone therapy (Lancet 2011; doi: 10.1016/S0140-6736(11)60993-8). New research from the Washington University School of Medicine in St. Louis has found that an imaging test measuring the function of ERs in breast cancer cells can be used to distinguish between breast cancer patients who are likely, and those who are unlikely, to benefit from hormone therapy. The findings were published in Nature Communications (2021; https://doi.org/10.1038/s41467-020-20814-9). In the small 5-year Phase II clinical trial (NCT02455453), Dehdashti and colleagues utilized an imaging agent that attaches to PRs on cancer cells. The compound, 21-[18F] fluorofuranylnorprogesterone (FFNP), attaches to PRs and can be detected with a positron emission tomography (PET) scan. When ERs are stimulated, the cells respond by increasing the number of PR molecules on their surfaces; however, there is no change in PRs if the ERs are inactive. The researchers observed the change in tumor uptake of the progestin analog 21-[18F] FFNP before and after a 1-day estradiol challenge. The team hypothesized that this short-term estradiol challenge would elevate tumor PR levels only in tumors with functional ERs, thus permitting the group to recognize which tumors would respond to hormone therapy. The study included 43 postmenopausal women with ER+ breast cancer. The median patient age was 60 years. Most (86%) had metastatic disease, while 14 percent had locally advanced or locally recurrent disease. The majority (72%) already had received some form of treatment before the start of the study; most often it was a hormone therapy-based regimen. The participants underwent a PET scan using FFNP, followed by three doses of estrogen over a 24-hour period and a second PET scan a day after the estrogen treatment. The researchers then followed the participants for 6 months or greater as they underwent hormone therapy as recommended by their physicians. An increase in tumor FFNP uptake was observed in 28 patients with clinical benefit from hormone therapy, defined as no disease progression within 6 months. These patients were classified as responders, indicating that their ERs were working and had responded to the hormone by triggering an increase in PR numbers. Of the women whose tumors had responded, 13 remained stable and 15 improved. Fifteen women showed little to no change in PR numbers after estrogen treatment; these women were classified as nonresponders. Each of the women were found to experience disease progression within 6 months of initiating endocrine therapy. The median percentage change in tumor FFNP uptake among responders was 25.4 percent; in nonresponders, it was –0.7 percent. These findings demonstrate a 100 percent agreement between the response to estrogen challenge and the response to hormone therapy, even though the participants were on a variety of treatment regimens. No adverse or clinically detectable pharmacological effects were associated with FFNP administration. Additionally, there were no considerable changes in vital signs. A larger Phase II clinical trial with collaborators at other institutions to verify the results is currently being set up, according to the researchers. To gain additional insights into the study, Oncology Times spoke with lead author Farrokh Dehdashti, MD, Professor of Radiology in the Division of Nuclear Medicine of the Mallinckrodt Institute of Radiology at Washington University School of Medicine. Oncology Times: What was the rationale for designing the imaging agent, [18F] FFNP, for ER-positive breast cancer patients? What were some of the factors which posed challenges in the development of the imaging method? Dehdashti: “PR+ transcription is directly regulated by estrogen action through the ER, and the measurement of PR levels was originally proposed as a way to identify ER+ tumors with functional ER capable of mediating hormone therapy response. However, baseline tumor PR levels do not accurately predict response to hormone therapy. Accordingly, we hypothesized that the effect of a brief estradiol challenge on PR levels (measured noninvasively by PET with FFNP) would be a better biomarker of ER function and the likelihood of response to RT. “Additionally, we recognized that PET with FFNP would provide an ability to address changing ER status in previously treated patients, obviating the need for biopsy to obtain tumor tissue for in vitro analysis of ER (an invasive procedure with associated risks and morbidity). Another likely advantage would be the ability to assess the ER status of all patient lesions by an imaging test, as multiple biopsies are rarely feasible. Because several previous attempts to develop PET imaging agents for PR had failed, several factors went into the specific design of FFNP. It was designed to have high affinity for PR and low non-specific binding to be resistant to metabolic inactivation by reduction of the C-20 ketone in progestins, and to be rapidly and efficiently labeled with the short-lived PET radionuclide fluorine-18.” Oncology Times: What are the clinical impacts of the findings of this study? Dehdashti: “FFNP-PET before and after estradiol challenge can be accomplished in as little as 2 days prior to initiation of therapy and discriminates likely responders from nonresponders with high accuracy, thus allowing for risk stratification equivalent to that obtained by much longer clinical observations alone.” Oncology Times: What additional factors need to be addressed before implementing this novel methodology into the clinic? Dehdashti: “Our very encouraging single-institution results need to be confirmed by one or more larger multicenter trials, one of which has recently been funded. Ultimately, translation into the clinic will require interest by a radiopharmaceutical manufacturer, who will conduct the registration studies needed for FDA approval, and establish a production and distribution network for FFNP.” Oncology Times: Is there a potential of transferability of this methodology for any other types of treatments? Dehdashti: “It is possible that a similar strategy with PET imaging of an androgen receptor-regulated target protein before and after a hormone challenge with testosterone could be used to evaluate the function of androgen receptors in breast cancer and prostate cancer.” Dibash Kumar Das is a contributing writer.