PET imaging of progesterone receptor (PgR) response to an estradiol challenge perfectly predicted breast cancer response to hormonal therapy, a small prospective study showed.
PET with a progestin-analog tracer showed increased PgR levels, indicative of functional estrogen receptors (ERs), in 28 postmenopausal women receiving endocrine therapy for metastatic or recurrent breast cancer, and all 28 benefited from treatment. In contrast, 15 patients without an increase in PgR levels did not benefit, representing 100% sensitivity and specificity. The 28 women with endocrine-responsive tumors lived significantly longer than did the women with nonresponsive tumors, as reported in Nature Communications.
The results suggest that PET imaging with the radiolabeled progestin-receptor analog could have a role in treatment selection and monitoring, said Farrokh Dehdashti, MD, of Washington University in St. Louis.
"The fact that you can actually assess the [ER] function in the body was amazing," she told MedPage Today. "It's something that is very difficult to do. I'm really hopeful we can move to the next step and do a multicenter trial, if we can secure funding."
PET assessment of ER function should be applicable to all types of hormonal therapy for breast cancer. The strategy might also help guide therapeutic decision-making for other types of hormonally driven cancers, notably prostate cancer, Dehdashti added.
Despite the fact that 70%-80% of breast cancers are hormone-receptor (HR) positive, as many as half of HR-positive tumors do not respond to endocrine therapy. Conventional testing for ER status of breast cancers is an imperfect predictor of tumor response to endocrine therapy, Dehdashti and colleagues noted.
Recognizing that PgR transcription is regulated by ERs, researchers more than 40 years ago proposed measuring PgR levels as a means of predicting breast cancer response to endocrine therapy. However, immunohistochemistry assessment of PgR levels has limitations that can make results unreliable. Moreover, elevation of PgR levels occurs only with functional ER, and menopausal estrogen levels are probably insufficient to maximize PgR production.
Dehdashti and colleagues developed a PgR-binding progestin-analog radiotracer (21-[18F]fluoro furanyl norprogesterone, FFNP). In a preliminary evaluation, they observed significantly greater FFNP uptake in PgR-positive versus PgR-negative breast cancers with PET imaging. They subsequently reported a "rapid and robust" increase in FFNP uptake after estrogen treatment in a preclinical model of breast cancer, findings that were replicated in studies involving human breast cancer xenografts.
The accumulation of favorable experimental results led to a phase II evaluation of PET with FFNP in postmenopausal breast cancer. Investigators at Washington University's Siteman Cancer Center studied 43 women with locally advanced, locally recurrent, or metastatic HR-positive breast cancer scheduled to be treated with hormonal agents.
The patients had a median age of 60, and all but six of them had metastatic disease. The cohort included 12 patients with no prior treatment. One patient had received only chemotherapy, and the remainder have received endocrine therapy alone (n=4) or in combination with chemotherapy or targeted agents. Hormonal treatment during the study included tamoxifen, aromatase inhibitors, fulvestrant, and gonadotropin-releasing hormone agonists, and most of them received a CDK4/6 inhibitor.
Baseline PET studies showed no difference in FFNP uptake prior (standardized uptake value, SUV) to estradiol challenge in the 28 patients who had stable disease or objective response to endocrine therapy and the 15 who did not benefit from treatment. Following the 1-day estradiol challenge, FFNP increased by an average of 25.4% in the 28 patients who subsequently benefited from treatment but decreased by 0.7% in the 15 women who did not benefit (P<0.0001). The percentage change in FFNP uptake did not vary significantly according to prior therapy.
The 28 patients who benefited from hormonal therapy had at least a 7% increase in SUV for FFNP (responders), whereas none of the 15 nonresponding patients had as much as a 7% increase in SUV. The 7% threshold was associated with significantly longer overall survival (OS). After a median follow-up of 27.1 months, the estimated median OS was 22.6 months in patients who did not respond, but was not yet reached in responding patients (P<0.0001). Baseline FFNP uptake did not have a significant association with OS.
Beyond the goal of a phase III trial in breast cancer, Dehdashti said the PET imaging strategy should interest oncologists who treat prostate cancer. Androgen-receptor imaging agents already exist, so clinical interest by the genitourinary oncology community might provide impetus for formal clinical evaluation.
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Disclosures
The study was supported by the National Cancer Institute and the Albert J. Siteman Cancer Center.
Dehdashti disclosed no relevant relationships with industry. Co-authors disclosed relevant relationships with Pfizer, AstraZeneca, Eli Lilly, Novartis, Merck, Eisai, Radius Health, Avid Radiopharmaceutical, Capella Imaging, Curium Pharma, GE Healthcare, ImaginAb, Progenics Pharmaceuticals, and Siemens Healthineers.
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