The majority of patients with breast cancer have hormone-sensitive disease, which is characterized as being estrogen-receptor positive (ER+), progesterone-receptor positive (PgR+), or both. It is well established that these two steroid receptors have significant prognostic and predictive value, and patients with hormone- sensitive disease have an overall favorable outcome and are also more likely to benefit from endocrine therapies (ETs). Nevertheless, only 55-60% of patients with ER+ disease respond to endocrine therapy (ET), and even though the presence of PgR in tumors increases the likelihood of hormone responsiveness to some degree, the selection of breast cancer patients most likely to benefit from ETs is still uncertain. The PgR gene is directly regulated by estrogen action through ER, and the measurement of PgR levels was originally proposed as a way to distinguish ER+ tumors in which ER is functional and therefore capable of mediating ET from those in which ER is non-functional. The predictive value of PgR assays for ET benefit, as typically done by immunohistochemistry (IHC), is limited by a number of factors, such as variable standards for PgR positivity and lack of reproducibility due to sampling errors. More significantly, however, PgR levels are elevated only when ER is functional and estrogen is present; menopausal estrogen levels are unlikely to be sufficient to maximally elevate PgR levels, and importantly, PgR assays are not controlled for circulating estrogen levels. We have developed a PgR based radiotracer (21-[18F]fluorofuranylnorprogesterone [FFNP]), and recently showed a significant difference in FFNP uptake in patients with PgR+ compared with PgR- breast cancer. In addition, in preclinical models, we found that the increase in FFNP uptake after estrogen treatment was both rapid and robust. Our hypothesis is that we can determine whether the ER in ER+ breast cancer is functional by measuring how tumor PgR levels change in vivo, assessed by FFNP-PET, in response to a brief dose of estradiol, This will assess directly the functional status of ER in the tumor itself and should be a much stronger predictor of benefit from ET than merely the presence of ER by IHC in a biopsy sample. The results of this study will provide data for a future multicenter trial to better assess the role of this noninvasive testin patients with ER+ breast cancer.
The overall goal is to develop a sensitive and specific, non-invasive test, based on PET imaging, that is highly predictive for benefit from endocrine therapies in breast cancer. We propose that a hormone-challenge test for functional estrogen receptor based on the change in a progesterone receptor imaging agent, (21- [18F]fluorofuranylnorprogesterone [FFNP]) uptake before and after a 1-day estradiol challenge, measured by PET, should provide a robust and highly reliable means to predict a favorable response of estrogen-receptor positive breast cancer to endocrine therapy. This improved prediction of response to ET would enable many breast cancer patients to avoid months of futile endocrine therapy or unnecessary, highly toxic chemotherapy and ultimately save costs.
