Handbook of Genetic Counseling/Tamoxifen - Selective Estrogen Response Modifiers (SERMS)

Tamoxifen - Selective Estrogen Response Modifiers (SERMS)

Risk Reduction Agents for Breast Cancer

Why Estrogen is Important

 * Estrogen is a sex steroid hormone important for many physiologic processes
 * Affects growth, differentiation, and function of reproductive system
 * Maintains bone density and protects against osteoporosis
 * Thought to be cardioprotective, largely through its effects on blood lipids
 * Regulates reproductive behavior by effects in the brain
 * Estrogen effects are mediated through their binding to nuclear proteins called estrogen receptors (ER)
 * Binding activates receptor dimerization which activates or represses transcription depending on other tissue specific co-factors
 * ER-mediated transcription is stimulated through at least 2 transactivation domains called AF-1 and AF-2 (AF-1 is hormone-independent, whereas AF-2 is hormone-dependent)
 * There are two types of estrogen receptors: ER-alpha and ER-beta
 * The exact role of ER-beta in breast cancer is unknown
 * The role of ER-alpha is well defined
 * Maximum transcriptional activation requires both AF-1 and AF-2
 * Prolonged stimulation of breast ductal epithelium by estrogen can contribute to the development and progression of breast cancer
 * The role of hormone therapy in the treatment of metastatic breast cancer was first demonstrated in 1895 by Dr. George Beatson in Glasgow, Scotland
 * He performed a bilateral oophorectomy in a 33 year old woman with advanced cancer who lived 4 years before dying of recurrent disease
 * Approximately 50%-70% of women benefit from hormonal therapy if their tumors are positive for both ER and PR (progesterone)
 * Only 11% benefit if their tumors are negative for both types

What is a Selective Estrogen Response Modifier (SERM)?

 * SERMS have estrogen agonist effects in some tissues and antagonist effects in others
 * SERMS bind competitively to the ERs; AF-2 is not activated, but AF-1 remains active and receptor dimerization and nuclear localization occur
 * SERMS can initiate transcription in the presence of certain accessory proteins and result in the expression of some estrogen-responsive genes
 * The effect depends on the tissue and the gene
 * Ideally, we want an anti-estrogen effect in the breast and endometrium and estrogenic effects on lipid profiles, the CNS, skeletal, vagina and cardiovascular systems.
 * It is the anti-estrogenic effects in the CNS and vagina that cause menopausal side effects
 * Three categories of SERMS
 * Triphenylethylene derivatives like tamoxifen
 * Other nonsteroidal compounds like raloxifene
 * Steroidal compounds that have more complete antiestrogenic activity

Tamoxifen (Nolvadex; AstraZeneca Pharmaceuticals)

 * History and Background
 * Synthesized in the 1960s
 * The first chemotherapy to be approved for the prevention of any cancer
 * Approved by the FDA in 1977 for treatment of advanced breast cancer
 * Has demonstrated efficacy in the treatment of both premenopausal and postmenopausal patients with metastatic breast cancer as well as adjuvant treatment in post-menopausal patients following mastectomy, axillary dissection, and breast irradiation
 * Indicated as preventative treatment to reduce the incidence of breast cancer in high-risk patients and to reduce the risk of contralateral breast cancer
 * Most effective in patients who are ER+, PR+, and postmenopausal
 * Approved dose is 20mg daily for 5 years
 * Taking tamoxifen for longer than 5 years is not thought to be more effective than 5 years of therapy
 * Also used to treat men who have breast cancer
 * Approved in 1998, for reducing incidence of breast cancer in high-risk women
 * Approximately 1/3 of ER+ cancers are resistant to Tamoxifen
 * The Estrogen Effects of Tamoxifen
 * Anti-estrogen effect in breast, CNS, and vagina mucosa
 * Positive estrogen effect in liver (reducing cholesterol), bone, and endometrium
 * Acquired tamoxifen resistance is a cause of treatment failure in breast cancer
 * The mechanism of acquired tamoxifen resistance is not well defined
 * Mouse studies showed that tamoxifen-resistant tumors remained estrogen dependent in vivo but the resistance was associated with the ability of tamoxifen to stimulate tumor growth
 * Altered metabolism of tamoxifen was also seen in the tumor
 * Preclinical Studies
 * Decreased the incidence of mammary tumors in rodents, but increased the risk of liver tumors. There has been no increase in liver cancer in humans.
 * Clinical Trials: 3 randomized trials of tamoxifen as a chemopreventive agent
 * National Surgical Adjuvant Bowel and Breast Project (NSABP): Breast Cancer Prevention Trial (BCPT)
 * A landmark trial that was stopped early by the independent safety monitoring committee due to promising results
 * A trial of Tamoxifen (20mg daily for 5 years) versus placebo in 13,388 healthy women at risk for developing invasive breast cancer
 * A randomized, prospective, double-blind study that began June 1st 1992
 * Enrollment ended September 30, 1997
 * Study was terminated and results disclosed March 24, 1998
 * Eligibility criteria
 * Age 60 or older
 * Or age 35-59 with a 5-year predicted risk of developing breast cancer using the Gail model of 1.66%
 * Or over 35 years with a diagnosis of lobular carcinoma in situ
 * Results:
 * With a median follow-up of 54.6 months, tamoxifen decreased the overall risk of developing invasive breast cancer by 49% and non-invasive breast cancer by 50%
 * Breakdown of risk reduction:
 * 44% in women aged 49 years or younger
 * 51% in women 50-59 years
 * 55% in women 60 years or older
 * 56% in women with a history of LCIS
 * 86% in women with atypical hyperplasia
 * The reduction of breast cancer was limited to the reduction of ER+ breast cancer. No difference was seen in the occurrence of ER- tumors
 * The occurrence of ER+ tumors was decreased by 69%
 * 96% of participants were Caucasian
 * There was no difference in mortality between the tamoxifen-treated and placebo groups in the trial
 * A meta-analysis of 30,000 women in 55 trials with ER+ or unknown tumor status showed a mortality reduction of 26% during 5 years of follow up
 * Royal Marsden Tamoxifen Breast Cancer Prevention Study
 * From 1986 to 1996, 2494 women were randomized to tamoxifen (20mg daily) or placebo for 8 years
 * Eligibility:
 * Age between 30 and 70 with at least one first-degree relative under age 50 with breast cancer
 * Or one first-degree relative with bilateral breast cancer
 * Or one affected first-degree relative of any age plus another affected first- or second-degree relative
 * Or a benign breast biopsy and a first-degree relative with breast cancer
 * Use of hormone replacement therapy was allowed
 * 41% of women in the study received HRT which is a potential confounding factor
 * Results
 * At 70 months follow up, no difference in the incidence of breast cancer was seen
 * Italian Randomized Trial of Breast Cancer Prevention in Hysterectomized Women
 * In 1992, this trial of tamoxifen (20mg daily for 5 years) versus placebo began
 * Ended in 1997 with 5408 women with low to normal risk of breast cancer
 * The goal was to recruit 20,000 women
 * Half of the women recruited had already had an oophorectomy, which is known to reduce the risk of breast cancer, so only 3986 were available for evaluation
 * Eligibility: Healthy women age 35-70 who had a hysterectomy
 * Results: At median of 46 months follow up, there was no difference in the number of breast cancer cases in treatment versus control arms.
 * How do we explain the discrepancy of the 3 trials?
 * The studies are dissimilar in design, population enrolled, and eligibility criteria
 * The two European trials together, had fewer than half the number of breast cancer cases of the NSABP
 * The Italian trial had a high dropout rate
 * Royal Marsden study likely had large number of mutation carriers based on eligibility criteria
 * BCPT was largest and did not allow HRT: the influence of HRT on the potential effect of tamoxifen chemoprevention is unclear
 * There could be differences in compliance
 * Benefits of Tamoxifen
 * Fewer bony fractures due to slower bone loss
 * Lower blood cholesterol
 * Risks of Tamoxifen
 * Side effects similar to the onset of menopause
 * Hot flashes, vaginal discharge, dryness or itching, and irregular menses
 * Headaches, fatigue, nausea and/or vomiting, and skin rash
 * Serious side effects
 * Endometrial cancer (Risk ratio = 2.53 in Tamoxifen group in NSABP trial)
 * No endometrial cancer deaths occurred in the NSABP trial
 * All endometrial cancers were Stage I
 * Deep Vein Thrombosis (1.6x higher in NSABP trial)
 * Pulmonary embolism (3x higher in NSABP trial)
 * Stroke
 * Cataract development
 * Most serious adverse events have occurred in women over age 50

Other SERMS

 * Raloxifene (Evista; Eli Lilly and Co)
 * Background
 * A nonsteroidal compound; a benzothiophene derivative
 * Binds to ER with an affinity equal to that of estradiol
 * Unlike Tamoxifen, does not stimulate uterine tissue
 * There is a raloxifene response element that was identified in the promoter region of certain genes which could contribute to some of its functional differences
 * Has estrogenic effects on bone, lipid metabolism, and blood clotting
 * The MORE (Multiple Outcomes of Raloxifene Evaluation) Study
 * Study Design
 * 7704 postmenopausal women with osteoporosis were followed for a median of 40 months
 * Women taking estrogen or who had a history of breast cancer were excluded
 * Randomized, double-blind study of raloxifene (60mg or 120mg per day) versus placebo
 * Results
 * The primary endpoint was that raloxifene reduced the risk of osteoporosis progressing as seen by the preservation of bone mineral density, the reduction of bone turnover, and the decreased incidence of vertebral fractures
 * Approved in the US in 1997 for the prevention of osteoporosis
 * Raloxifene also decreased the incidence of invasive breast cancers by 76% among postmenopausal women with osteoporosis during 3 years of treatment
 * The risk reduction was similar for both doses of raloxifene and was confined to ER+ tumors
 * 13 cases of breast cancer were confirmed among the 5129 women assigned to raloxifene versus 27 among the 2576 women assigned to the placebo (RR=0.24)
 * Raloxifene decreased the risk of ER+ breast cancer by 90%
 * Raloxifene increased the risk of venous thromboembolic disease (RR=3.1), but did not increase the risk of endometrial cancer.
 * Study of Tamoxifen and Raloxifene (STAR) trial
 * Large, multi-institutional, randomized, double-blind study for breast cancer prevention in postmenopausal women which began in June 1999
 * Will randomize 22,000 postmenopausal women at increased risk for developing breast cancer to tamoxifen (20mg daily) or raloxifene (60mg daily) for 5 years
 * Women must be postmenopausal and at least 35 years old
 * Increased risk is defined as LCIS treated by local excision only or at least a 1.66% projected 5-year probability of developing invasive breast cancer
 * Designed to see if raloxifene is more or less effective than tamoxifen in reducing the chance of developing breast cancer in women at increased risk of developing the disease
 * STAR trial information
 * NCI (800) 422-6237 or cancertrials.nci.nih.gov
 * NSABP www.nsabp.pitt.edu
 * Anticipated time of final analysis is 2006
 * NCI pilot trial is being done to evaluate the safety of 2 years of raloxifene therapy in high-risk premenopausal women.
 * Toremifene (Fareston: Schering Corp)
 * Very similar to tamoxifen; also a triphenylethylene; differs by only a single chlorine atom
 * First synthesized in 1981; first clinical trials done in 1982
 * Trials have been done to compare tamoxifen and toremifene
 * Response rates are similar
 * Median times to progression and overall survival were not significantly different
 * Some studies have found a slightly higher incidence of undesirable effects in the tamoxifen treatment group, but these differences are not statistically significant
 * There is no clinical data to imply that it causes endometrial carcinoma, although it may unmask pre-existing endometrial tumors
 * Approved for use as first-line therapy for postmenopausal women with ER+ advanced breast cancer in 1997 in the U.S.

Chemoprevention for BRCA1/2 Mutation Carriers

 * Will Tamoxifen be as effective in mutation carriers as it is in other women who are at increased risk of breast cancer?
 * The risk of BRCA1 tumors appears to be associated with estrogen related risk factors and oophorectomy reduces risk of hereditary breast cancer suggesting tamoxifen may be effective
 * From 10 studies, 83% of BRCA1 breast tumors have been found to be ER-, whereas 76% of BRCA2 breast tumors were ER+
 * If chemoprevention is needed for at least 10 years to produce and effect, new chemoprevention agents will need to be developed for women in their 30s, as the breast cancer risk curves are steepest between 40 and 50 years of age.
 * Mary-Claire King's report of the NSABP trial (2001)
 * The main outcome measure was to compare the incidence of breast cancer among BRCA1/2 mutation carriers who were receiving tamoxifen versus placebo
 * Design and Method
 * Peripheral white blood cells were stored from study participants in the NSABP trial in anticipation of the identification of BRCA1/2
 * Genomic analysis of BRCA1/2 was done for 288 breast cancer cases
 * 19 carriers were identified
 * 5/8 BRCA1 mutation carriers had taken tamoxifen
 * RR=1.67; 95% confidence interval, 0.32-10.7
 * 3/11 BRCA2 mutation carriers had taken tamoxifen
 * RR=0.38; 95% confidence interval, 0.06-1.56
 * The power to detect a moderate protective effect was low
 * The results were not statistically significant
 * Tamoxifen reduced the risk of breast cancer in BRCA2 mutation carriers by 62%, but did not reduce the risk of breast cancer in BRCA1 mutation carriers
 * Must consider that tamoxifen use began at age 35 or older
 * It is not known if tamoxifen use at a younger age would reduce breast cancer incidence in BRCA1 mutation carriers.
 * King concludes that for women who have not yet developed breast cancer, genotype at BRCA1 and BRCA2 has a major impact on the expected effect of tamoxifen in reducing incidence of primary breast cancer
 * Steven Narod's case-control study (2000)
 * Results contrast with the results of the NSABP trial, but sample size is much greater
 * The aim of the study was to see if tamoxifen protects against contralateral breast cancer in BRCA1/2 mutation carriers since it is known to do so in the general population
 * Study Design
 * Compared 209 women with bilateral breast cancer and BRCA1/2 mutations (cases) and 384 women with unilateral breast cancer and BRCA1/2 mutations (controls) in a matched case-control study.
 * Results
 * Tamoxifen use was reported by 10.5% of the 209 bilateral cases and 21.1% of the 384 unilateral controls
 * Tamoxifen protected against contralateral breast cancer for carriers of BRCA1 and BRCA2 mutations
 * In women who used tamoxifen for 2-4 years, the risk of contralateral breast cancer was reduced by 75%

The Future of Chemoprevention

 * To develop hormonally active agents with more favorable toxicity profiles
 * Currently SERMS, aromatase inhibitors, and novel hormonal contraceptive regimens are being researched
 * Anti-estrogen drugs called ERDs are estrogen receptor down-regulators and act by decreasing the number of active estrogen receptors on a cell or by decreasing their level of responsiveness to estrogen
 * On April 25th 2002, the FDA approved an ERD called Faslodex (fulvestrant) for postmenopausal women with advanced ER+ disease for whom tamoxifen is no longer effective
 * Given as a monthly intramuscular injection
 * Side effects:
 * Nausea, vomiting, constipation, diarrhea, headache, and hot flashes
 * Aromatase inhibitors
 * They lower the amount of estrogen being produced by the body, rather than block estrogen's ability to "turn on" cancer cells
 * In post-menopausal women, androgen is converted to estrogen by aromatase
 * Aromatase inhibitors block this conversion and are often used by women who have already tried other anti-estrogen therapies
 * Examples
 * Arimidex (anastrozole)
 * Femara (letrozole)
 * Aromasin (exemestane)
 * To develop agents for the prevention of ER- breast cancer
 * Approximately 1/3 of invasive cancers are ER-
 * Women under 50 years old are more than twice as likely to have an ER- tumor as women over 50
 * Do the majority of pre-cancerous mammary epithelial cells progress from an estrogen-dependent phenotype to an estrogen-independent phenotype later in the carcinogenesis process? Or does it arise de novo?
 * To define the precise molecular changes that characterize the progression of a normal breast epithelial cell through premalignancy and malignancy
 * Then can search for agents to reverse these changes or prevent malignant transformation from occurring
 * To develop biological markers of breast cancer risk and progression
 * Biomarkers could be used to refine short-term risk assessments
 * Could be used to predict response to specific classes of preventive agents