Raloxifene For Breast Cancer Prevention Research Articles

Breast cancer chemoprevention: little progress in practice?

Breast cancer chemoprevention: little progress in practice?

Women's interest in taking tamoxifen and raloxifene for breast cancer prevention: response to a tailored decision aid.

Although tamoxifen can prevent primary breast cancer, few women use it as a preventive measure. A second option, raloxifene, has recently been approved. The objective of the study was to determine women's interest in tamoxifen and raloxifene after reading a decision aid (DA) describing the risks and benefits of each medication. Women with 5-year risk of breast cancer ≥ 1.66 from two large health maintenance organizations were randomized to receive a DA versus usual care. After reading an on-line DA that discussed the risks and benefits of tamoxifen and raloxifene, women completed measures of risk perception, decisional conflict, behavioral intentions, and actual behavior related to tamoxifen and raloxifene. 3 months following the intervention, 8.1% of participants had looked for additional information about breast cancer prevention drugs, and 1.8% had talked to their doctor about tamoxifen and/or raloxifene. The majority, 54.7%, had decided to not take either drug, 0.5% had started raloxifene, and none had started tamoxifen. Participants were not particularly worried about taking tamoxifen or raloxifene and did not perceive significant benefits from taking these drugs. Over 50% did not perceive a change in their risk of getting breast cancer if they took tamoxifen or raloxifene. After reading a DA about tamoxifen and raloxifene, few women were interested in taking either breast cancer prevention drug.

Toward a Total Cure for Acute Lymphoblastic Leukemia

REFERENCES 1. Vardy J, Wefel JS, Ahles T, et al: Cancer and cancer-therapy related cognitive dysfunction: An international perspective from the Venice cognitive workshop. Ann Oncol 19:623-629, 2008 2. McEwen B: Estrogen actions throughout the brain. Recent Prog in Horm Res 7:357-384, 2002 3. Eberling JL, Wu C, Tong-Turnbeaugh R, et al: Estrogen and tamoxifenassociated effects on brain structure and function. Neuroimage 21:364-371, 2004 4. Legault C, Maki PM, Resnick SM, et al: Effects of tamoxifen and raloxifene on memory and other cognitive abilities: Cognition in the study of tamoxifen and raloxifene. J Clin Oncol 27:5144-5152, 2009 5. Vogel VG, Costantino JP, Wickerham DL, et al: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727-2741, 2006 6. Castellon SA, Ganz PA, Bower JE, et al: Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol 26:955-969, 2004 7. Silverman DH, Dy CJ, Castellon SA, et al: Altered frontocorical, cerebellar, and basal ganglia activity in adjuvant therapy-treated survivors, 5-10 years after chemotherapy. Breast Cancer Res Treat 103:303-311, 2007 8. Paganini-Hill A, Clark LJ: Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 64:165176, 2000 9. Bender CM, Sereika SM, Berga SL, et al: Cognitive impairment associated with adjuvant therapy in breast cancer. Psychooncol 15:422-430, 2006 10. Shilling V, Jenkins V, Fallowfield L, et al: Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 13:61-66, 2004 11. Palmer JL, Trotter T, Joy AA, et al: Cognitive effects of tamoxifen in pre-menopausal women with breast cancer compared to healthy controls. J Cancer Surviv 2:275-278, 2008 12. Greendale GA, Huang MH, Wight RG, et al: Effects of menopause transition and hormone use on cognitive performance in midlife women. Neurology 72:1850-1857, 2009 13. Land SR, Wickerham DL, Costantino JP, et al: Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2742-2751, 2006

Randomized clinical trials of raloxifene

The P-1 trial of tamoxifen versus placebo for breast cancer prevention in high-risk women provided proof of the concept that chemoprevention was effective. The approval of tamoxifen for this indication in 1998 provided a pharmaceutical agent as an alternative to bilateral mastectomy and/or oophorectomy for women at high risk. Although for some women and their physicians this was a welcome alternative, fear of toxicities from tamoxifen has been a major barrier to its use. Four trials evaluating the role of raloxifene in breast cancer prevention have resulted in the recent approval by the US Food and Drug Administration for postmenopausal women with osteoporosis or at high risk of breast cancer. It has a more favorable toxicity profile than tamoxifen and provides an alternative for postmenopausal women.

Raloxifene in breast cancer prevention

Background: Raloxifene is a benzothiophene, selective estrogen receptor modulator with estrogen-agonist effects in the skeleton and the cardiovascular system but estrogen-antagonist effects in the uterus and the mammary gland. This compound was first approved in different countries for the prevention and treatment of osteoporosis. Objective/methods: We performed a literature search to review available preclinical and clinical data that has led to the recent FDA approval of raloxifene as a chemopreventive agent for breast cancer in postmenopausal women. Results/conclusions: Different placebo-controlled trials indicated that raloxifene is effective in reducing invasive breast cancer risk in postmenopausal women. In a recent comparative study, a similar efficacy between raloxifene and tamoxifen for breast cancer prevention was demonstrated, but raloxifene showed a more favorable safety profile.

International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers

Several options for cancer prevention are available for women with a BRCA1 or BRCA2 mutation, including prophylactic surgery, chemoprevention and screening. The authors report on preventive practices in women with mutations from 9 countries and examine differences in uptake according to country. Women with a BRCA1 or BRCA2 mutation were contacted after receiving their genetic test result and were questioned regarding their preventive practices. Information was recorded on prophylactic mastectomy, prophylactic oophorectomy, use of tamoxifen and screening (MRI and mammography). Two thousand six hundred seventy-seven women with a BRCA1 or BRCA2 mutation from 9 countries were included. The follow-up questionnaire was completed a mean of 3.9 years (range 1.5-10.3 years) after genetic testing. One thousand five hundred thirty-one women (57.2%) had a bilateral prophylactic oophorectomy. Of the 1,383 women without breast cancer, 248 (18.0%) had had a prophylactic bilateral mastectomy. Among those who did not have a prophylactic mastectomy, only 76 women (5.5%) took tamoxifen and 40 women (2.9%) took raloxifene for breast cancer prevention. Approximately one-half of the women at risk for breast cancer had taken no preventive option, relying solely on screening. There were large differences in the uptake of the different preventive options by country of residence. Prophylactic oophorectomy is now generally accepted by women and their physicians as a cancer preventive measure. However, only the minority of women with a BRCA1 or BRCA2 mutation opt for prophylactic mastectomy or take tamoxifen for the prevention of hereditary breast cancer. Approximately one-half of women at risk for breast cancer rely on screening alone.

Incorrect Data and Wording in: Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial

Incorrect Data and Wording in: Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial

Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention. The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial

The investigators assessed quality of life for 19,747 participants in a double-blind, randomized trial comparing tamoxifen (20 mg daily) and raloxifene (60 mg daily), both given for 5 years, for their ability to lower the risk of invasive breast cancer in postmenopausal women. Patients were followed at nearly 200 centers throughout North America for a median potential time of 4.6 years. Participants completed a 36-item symptom checklist. Quality of life was estimated using the Medical Outcomes Study Short-Form Health Survey and the Medical Outcomes Study Sexual Activity Questionnaire. Depressive symptoms were measured using the Center for Epidemiologic Studies-Depression scale, a 20-item self-report scale. The questionnaires were administered before treatment and every 6 months for 5 years. Quality-of-life scores worsened modestly over 5 years of follow up but did not differ significantly between the 2 treatment groups. Sexual function was slightly better for women assigned to tamoxifen therapy. Raloxifene-treated women reported more severe symptoms over the 5-year study period for musculoskeletal problems, dyspareunia, and weight gain. Women taking tamoxifen reported more severe symptoms from gynecologic problems and more marked vasomotor symptoms, leg cramps, and symptoms of bladder control disorders. There were no significant group differences in mental health problems, including depression. In general, differences in symptom severity between the 2 treatment groups were small.

Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention

Tamoxifen has been approved for breast cancer risk reduction in high-risk women, but how raloxifene compares with tamoxifen is unknown. To compare the differences in patient-reported outcomes, quality of life [QOL], and symptoms in Study of Tamoxifen and Raloxifene (STAR) participants by treatment assignment. STAR was a double-blind, randomized phase 3 prevention trial designed to evaluate the relative efficacy of raloxifene vs tamoxifen in reducing the incidence of invasive breast cancer in high-risk postmenopausal women. Between July 1, 1999, and November 4, 2004, 19,747 participants were enrolled at centers throughout North America, with a median potential follow-up time of 4.6 years (range, 1.2-6.5 years). Patient-reported symptoms were collected from all participants using a 36-item symptom checklist. Quality of life was measured with the Medical Outcomes Study Short-Form Health Survey (SF-36), the Center for Epidemiologic Studies-Depression (CES-D), and the Medical Outcomes Study Sexual Activity Questionnaire in a substudy of 1983 participants, median potential follow-up 5.4 years (range, 4.6-6.0 years). Questionnaires were administered before treatment, every 6 months for 60 months and at 72 months. Primary QOL end points were the SF-36 physical (PCS) and mental (MCS) component summaries. Among women in the QOL analysis, mean PCS, MCS, and CES-D scores worsened modestly over the study's 60 months, with no significant difference between the tamoxifen (n = 973) and raloxifene (n = 1010) groups (P>.2). Sexual function was slightly better for participants assigned to tamoxifen (age-adjusted repeated measure odds ratio, 1.22%; 95% CI, 1.01-1.46). Of the women in the symptom assessment analyses, the 9769 in the raloxifene group reported greater mean symptom severity over 60 months of assessments than the 9743 in the tamoxifen group for musculoskeletal problems (1.15 vs 1.10, P = .002), dyspareunia (0.78 vs 0.68, P<.001), and weight gain (0.82 vs 0.76, P<.001). Women in the tamoxifen group reported greater mean symptom severity for gynecological problems (0.29 vs 0.19, P<.001), vasomotor symptoms (0.96 vs 0.85, P<.001), leg cramps (1.10 vs 0.91, P<.001), and bladder control symptoms (0.88 vs 0.73, P<.001). No significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical health, mental health, and depression, although the tamoxifen group reported better sexual function. Although mean symptom severity was low among these postmenopausal women, those in the tamoxifen group reported more gynecological problems, vasomotor symptoms, leg cramps, and bladder control problems, whereas women in the raloxifene group reported more musculoskeletal problems, dyspareunia, and weight gain. clinicaltrials.gov Identifier: NCT00003906.

Selective estrogen receptor modulators: discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells.

Selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of approximately 12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Ral, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.

Raloxifène et tissu mammaire : du concept des SERMs à la place de ce composé en pratique clinique

Raloxifene is a second generation Selective Estrogen Receptor Modulator. It is indicated in prevention and treatment of post-menopausal osteoporosis. This drug has an estrogen agonistic effect on bone tissue, an estrogen-antagonistic effect in breast and endometrial tissue. It inhibits estrogen induced breast cells proliferation and, in animal studies, it prevents the growth of chemically induced mammary tumors. Raloxifene has a limited effectiveness in women with advanced breast cancers. The effects of raloxifene after treated breast cancer and sequential use of tamoxifene after raloxifene (or the contrary) are not known and should be tested in specific pre-clinical and clinical studies. In osteoporotic women included in the MORE trial, the risk reduction of hormone-dependent breast cancer due to raloxifene raises the issue of some effectiveness of raloxifene in breast cancer prevention. The STAR trial is currently comparing tamoxifene vs raloxifene in breast cancer prevention in women at increased risk of breast cancer. Like tamoxifene, raloxifene increases the risk of venous thrombo-embolic events. On the other hand, in a subgroup of women at increased vascular risk in the MORE trial, the reduction of cardiovascular events raises the issue of an effect of raloxifene in the prevention of coronary events. The ongoing RUTH trial is testing this assumption and it is comparing raloxifene to a placebo in women at increased vascular risk. Today, in clinical practice, before the results of ongoing trail, raloxifene should be used in the setting of osteoporosis prevention and treatment.

Prevention of breast cancer using SERMs and aromatase inhibitors.

Breast cancer is one of the most common cancers of women in the Western world. Despite modest achievements in the treatment of this disease, there is a substantial unmet medical need to reduce the occurrence of new breast cancers. In several prospective, placebo-controlled trials, the antiestrogen tamoxifen has been shown to reduce the incidence of both invasive cancer and preinvasive breast lesions. Meanwhile, numerous other selective estrogen receptor modulators (SERMs) are being developed and trials comparing tamoxifen to these agents are ongoing. The goal of these studies is not only to show superior chemopreventive efficacy of the newer SERMs, but also an improved side-effect profile. The proof-of-principle demonstrated with tamoxifen suggests that strategies inhibiting estrogen are a logical way forward in breast cancer prevention. Aromatase inhibitors, which antagonize estrogen by blocking its synthesis from androgens, offer an alternative way of preventing the effects of estrogen and its metabolites on the breast. In this paper, the available data on SERMs including tamoxifen and raloxifene in breast cancer prevention and the data pointing to the efficacy of aromatase inhibitors in this setting are outlined.

Raloxifene: recent information on skeletal and non-skeletal effects.

Raloxifene, a selective estrogen receptor modulator, is currently used for both prevention and treatment of postmenopausal osteoporosis. Recent data from the MORE (Multiple Outcomes of Raloxifene Evaluation) trial have evaluated health-related quality of life, 1-year clinical vertebral fracture reduction, and the correlation of bone mineral density and biochemical markers of bone turnover with vertebral fracture reduction. In addition, new information on the effects of raloxifene in breast cancer prevention, cardiovascular disease in high-risk women, and uterine disorders is reviewed.

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The effect on the IGF system of 60 mg and 600 mg daily of raloxifene administered for 2 weeks prior to surgery was investigated in 37 postmenopausal women with breast cancer. Raloxifene significantly decreased insulin-like growth factor (IGF-I) as compared to placebo (P < 0.05) with no dose–response relationship. No significant change was observed in IGFBP-3, while the IGF-I/IGFBP-3 molar ratio was decreased by treatment, with a statistically significant effect only for the higher dose. Given that high plasma levels of IGF-I have been suggested as a risk factor for breast cancer, these findings provide further support for the potential activity of raloxifene in breast cancer prevention. © 2001 Cancer Research Campaign http://www.bjcancer.com

Tamoxifen and raloxifene for breast cancer prevention

Tamoxifen and raloxifene for breast cancer prevention

Chemoprevention of Breast Cancer

We critically examined the literature regarding tamoxifen and raloxifene for breast cancer chemoprevention, a controversial topic of interest to all providers of health care services for women. The National Surgical Adjuvant Breast and Bowel Project showed that tamoxifen decreased the incidence of breast cancer in women at increased risk. Two European studies did not confirm this benefit. Although well-tolerated, tamoxifen chemoprevention continues to be associated with an increased risk of endometrial cancer. Raloxifene is a promising agent that has not been established to reduce the incidence of breast cancer in women at increased risk and currently should not be considered an alternative to tamoxifen outside of clinical trials. Tamoxifen results in a decreased risk of causing breast cancer in women at increased risk for having the disease. Women at increased risk are encouraged to participate in the ongoing clinical trial comparing tamoxifen and raloxifene for breast cancer prevention.

Chemoprevention of breast cancer.

Despite a recent trend toward improvement in the U.S. breast cancer mortality rate, breast cancer incidence (182,800 new cases anticipated in 2000) and mortality figures (over 40,800 anticipated deaths) remain the highest and second highest, respectively, of all cancers in U.S. women. In 1998, the selective-estrogen-receptor-modulator (SERM) tamoxifen achieved positive results in the Breast Cancer Prevention Trial (BCPT), leading to the Food and Drug Administration (FDA) approval of tamoxifen for risk reduction in women at high risk of breast cancer (the historic first FDA approval of a cancer preventive agent). This brought about a paradigm shift in new approaches for controlling breast cancer toward pharmacologic preventive regimens, called chemoprevention. This paper presents a comprehensive clinical review of breast cancer prevention study, highlighting issues of the extensive study of tamoxifen. These issues include the record of primary tamoxifen results in several breast-cancer risk-reduction settings (primary, adjuvant, and ductal carcinoma in situ [DCIS]); critical secondary BCPT risk-benefit findings (including quality of life issues) and their effects on counseling patients on use of tamoxifen for prevention; ethic minorities; optimal tamoxifen dose/duration; and potential impact on mortality and other issues involved with potential net benefit to society. Other breast-cancer chemoprevention issues reviewed here include women at high genetic risk (especially BRCA1 mutation carriers); raloxifene in breast cancer prevention; other SERMs; SERM resistance; and new agents and combinations currently in development. Very recent developments involving PPAR-gamma ligands, COX-2 inhibitors, and RXR-ligands are discussed in the section on new drug development.

MORE on raloxifene in breast cancer prevention

MORE on raloxifene in breast cancer prevention