Selective estrogen receptor modulators (SERMs) and retinoids in breast cancer chemoprevention.
Tamoxifen has been shown to decrease the risk of invasive breast cancer by 49% and noninvasive breast cancer by 50%. Tamoxifen is also associated with a threefold increased risk of endometrial cancer. Raloxifene, a second-generation selective estrogen receptor modulator (SERM), has not been associated with endometrial cancer risk, and is currently under study in a large, multi-institutional, randomized Study of Tamoxifen and Raloxifene (STAR) for breast cancer prevention in postmenopausal women. A pilot trial of raloxifene in premenopausal women to assess the safety, tolerability, effects on bone mineral density, mammographic density, and other biological endpoints is ongoing. The retinoids have been shown to decrease mammary tumors in rodent carcinogenesis models. The Italian trial of fenretinide (4-HPR) in women with stage I breast cancer randomized women to fenretinide or no intervention. This study did not show an overall effect of decreasing the risk of contralateral breast cancer. However, a protective effect was suggested in premenopausal women. It has been suggested that this effect may be related to insulin-like growth factor 1 (IGF-1), which has been shown to be modulated by fenretinide in premenopausal but not postmenopausal women. Pilot studies of SERMs alone and in combination with retinoids or other agents provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women. These studies can provide information as to both the pathophysiology of carcinogenesis and the mechanism of action of chemopreventive agents, and help select agents and doses for testing in large randomized studies.
Zujewski
JoAnne
J
Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. zujewski@nih.gov
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000517:prevention & control*; D005260:Female; D017313:Fenretinide / Q000627:therapeutic use*; D006801:Humans; D015994:Incidence; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015337:Multicenter Studies as Topic; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology; D018570:Risk Assessment; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D013629:Tamoxifen / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D017313:Fenretinide; D020849:Raloxifene Hydrochloride; D007334:Insulin-Like Growth Factor I