Idoxifene

BOSTON—Favorable results from treatment trials have brought considerable attention to targeted cancer prevention. Meanwhile, research continues to identify proteins important for cancer development and progression, expanding the list of agents that might one day be suitable for healthy individuals at high risk of developing certain types of cancer. Investigators discussed many of these agents and their targets at the recent Molecular Targets and Cancer Therapeutics International Conference, organized by the American Association for CancerResearch, theNationalCancer Institute, and the European Organisation for Research and Treatment of Cancer. The well-known successes of targeted therapies for breast cancer have revolutionized cancer care. Now researchers are looking to apply similar strategies to prevention. “Therapeutic interventions related to the estrogen receptor and HER2/neu have prepared the way for exploiting these same targets in breast cancer prevention,” said Karen A. Johnson, MD, PhD, MPH, of the National Cancer Institute in Bethesda, Md. The benefits of anti-HER2/neu therapies such as trastuzumab are linked to overexpression of HER2 in breast tissue. “It follows that HER2-positive DCIS [ductal carcinoma in situ] is an appropriate setting to study the effect of trastuzumab for a high-risk tissue abnormality short of invasive cancer,” said Johnson. Other investigators are examining the activity of lapatinib, a dual kinase inhibitor, for its effect on DCIS that overexpresses HER2, the epidermal growth factor receptor, or both. Phase 3 prevention studies have shown that drugs that target the estrogen receptor (ER)—including tamoxifen, raloxifene, and idoxifene—

Recent clinical data on selective estrogen receptor modulators (SERMs) have provided the basis for reassessment of the SERM concept. The molecular basis of SERM activity involves binding of the ligand SERM to the estrogen receptor (ER), causing conformational changes which facilitate interactions with coactivator or corepressor proteins, and subsequently initiate or suppress transcription of target genes. SERM activity is intrinsic to each ER ligand, which accomplishes its unique profile by specific interactions in the target cell, leading to tissue selective actions. We discuss the estrogenic and anti-estrogenic effects of early SERMs, such as clomiphene citrate, used for treatment of ovulation induction, and the triphenylethylene, tamoxifen, which has ER antagonist activity in the breast, and is used for prevention and treatment of ER-positive breast cancer. Since the development of tamoxifen, other triphenylethylene SERMs have been studied for breast cancer prevention, including droloxifene, idoxifene, toremifene, and ospemifene. Other SERMs have entered clinical development more recently, including benzothiophenes (raloxifene and arzoxifene), benzopyrans (ormeloxifene, levormeloxifene, and EM-800), lasofoxifene, pipendoxifene, bazedoxifene, HMR-3339, and fulvestrant, an anti-estrogen which is approved for breast cancer treatment. SERMs have effects on tissues containing ER, such as the breast, bone, uterine and genitourinary tissues, and brain, and on markers of cardiovascular risk. Current evidence indicates that each SERM has a unique array of clinical activities. Differences in the patterns of action of SERMs suggest that each clinical end point must be evaluated individually, and conclusions about any particular SERM can only be established through appropriate clinical trials.