In the past 25 years, the estrogen receptor (ER) has proven to be an important target for the treatment of breast cancer. Tamoxifen, an antiestrogen that blocks estrogen binding to the ER, has been an invaluable therapeutic advance that has opened the door for the testing of all the current antihormonal therapies. Treatment with 5 years of tamoxifen following lumpectomy or mastectomy has resulted in the survival of 400,000 breast cancer patients. The aromatase inhibitors, which block estrogen synthesis in postmenopausal patients, are proving to be superior to tamoxifen in postmenopausal patients by further reducing recurrences and side effects. However, there is a need for a new strategy to reverse the eventual development of antihormonal drug resistance. Precise application of this strategy will ensure that effective agents can ultimately be used indefinitely to maintain survivorship.

One recommendation for the long-term treatment of postmenopausal ER-positive breast cancer is to consider treatment with an aromatase inhibitor after 5 years of tamoxifen. We have addressed the consequences of long-term antihormonal therapy on the biology of breast cancer under laboratory conditions. We have discovered that the original estrogen-stimulated breast cancer cell retains the ER but creates a complex system of survival mechanisms in response to long-term antiestrogen treatment or estrogen withdrawal. Remarkably, minute concentrations of estrogen now cause rapid programmed cell death rather than growth. It is as though the estrogen ER complex has the ability to recognize the aberrant cancer cell and orders immediate destruction. Thus, a natural hormone can destroy cancer through preprogrammed mechanisms that reside in the ER.

For the first time, laboratory studies demonstrate that antihormonally resistant tumor cells are destroyed selectively by low concentrations of estrogen and remaining tumor cells are again responsive to antihormonal therapy. A window of opportunity is now available to focus the efforts of a synergistic team consisting of consumer advocates and laboratory and clinical scientists to introduce a short-term, safe, simple, and inexpensive treatment into medical practice to help patients live longer.

A team of molecular biologists, pharmacologists, basic cancer researchers, patient advocates, biostaticians, and analytical scientists will work with a team of clinical investigators and consumer advocates in a Clinical Trials Consortium (CTC) to discover the molecular mechanisms of estrogen-induced apoptosis in antihormone-resistant breast cancer. They will apply the knowledge immediately to patient care. The centerpiece of our proposal is the CTC that will determine the minimum dose of estrogen treatment necessary to cause tumor regression. The key to success is the partnership with the Y-ME National Breast Cancer Organization that will apply specifically prepared educational materials for recruitment and retention to our multisite trials and aid in sample procurement for laboratory testing of early tumor response. Working in parallel, the tripartite team of laboratory scientists at the Fox Chase Cancer Center, Georgetown University, and Translational Genomics (TGen) will create a subcellular map of the new biology of estrogen that results in the rapid apoptosis or survival of breast cancer. The tripartite team will deliver subcellular signatures of the success and failure of estrogen to produce apoptosis and identify target genes and pathways to be validated in clinical samples. Serum tests for early apoptosis will be validated by using samples acquired by the CTC in patient protocols.

Within the 5 years of the proposal, the synergistic team will establish the dose of short-term estrogen treatment necessary to be given to patients to cause tumor regression and reactivate the sensitivity of any remaining tumor cells to antihormonal therapy. Completion of the pathway map of survival and apoptosis, linked to circulating markers and tumor signatures, will enable the subsequent rational applications of small molecules that are targeted to block survival pathways. The immediate application of a new and simple clinical intervention and the strategic approach providing a platform for subsequent evaluation of novel therapies will increase response rates for patients with antihormone-resistant breast cancer. In this way, survival can be enhanced.