Selective estrogen receptor modulating drug used the treat ER positive breast cancers.
Acts by largely or wholly by competitive binding to the estrogen receptor protein.
Tamoxifen selectively blocks estrogen in the breasts but acts like estrogen in other tissues such as bone and uterus.
Tamoxifen is US Food and Drug Administration approved for breast cancer risk reduction in premenopausal and postmenopausal women older than 35 years.
A selective estrogen-receptor modulator that binds to and inhibits the estrogen receptor, thereby blocking estrogen from binding and inhibiting estrogen-receptor mediated signaling.
Antagonizes the action of estrogen in the breast, and mimics the action of estrogens in the bone and uterus.
Two to seven fold increase in the risk of endometrial cancer and the risk increases with long-term use.
Decreases incidence of contralateral breast cancer by 47%.
Recent overview of all risk reduction trials estimate a 38% reduction in breast cancer incidence confined to estrogen receptor positive cancers.
A systematic review of 86 clinical trials found that patients with treated with tamoxifen had an objective response rate of 34%.
Adjuvant tamoxifen reduces the annual rates of breast cancer recurrence by almost half and mortality by one third.
After 10 years of follow up, approximally 22% of patients will experience a breast cancer recurrence.
Adjuvant Tamoxifen in absolute terms translates to 11.8 fewer recurrences and 9.2 fewer deaths per 100 women at 15 years, the benefits being similar for both younger and older women.
In the metastatic setting, it is effective for approximately one year,on average.
Continuing tamoxifen for 10 years, as opposed to five years, decreases the risk of recurrence and death by 3 1/2 and 2.8 percentage points, respectively.
A randomized trial for T1a and T1b breast cancers showed that tamoxifen lowers recurrence risk among small ER positive tumors (Fisher B).
Early Breast Cancer Trialists Collaborative Group (EBCTCG)-15 year update revealed 5 years of tamoxifen adjuvant therapy for postmenopausal breast cancer reduced annual breast cancer death rate by 31%, irrespective of age, addition of adjuvant chemotherapy, progesterone receptor status or other tumor characteristics.
The Early Breast Cancer Trialists’ Collaborative Group showed a small absolute gain in 5 year survival, but additional reductions were noted in years 5 through 9 and 10 through 14 which were as great as the mortality reduction during years 0-4 when tamoxifen was still being taken: The absolute reduction in breast cancer mortality produced by 5 years of tamoxifen was almost 3 times as great at 15 years as it had been only 5 years after diagnosis.
Multiple studies show that patients treated with adjuvant tamoxifen for early breast cancer showed a almost 50% reduction in the risk of recurrence during the first five years of follow-up, the period of active therapy.
In the above studies after tamoxifen was discontinued a carryover benefit during years 5 to 9 of an additional 32% reduction in risk of recurrence, and thereafter tamoxifen and control patients had parallel recurrence free survival curves.
There was a 13% absolute difference in recurrence at 15 years in the tamoxifen adjuvant studies.
Tamoxifen added to lumpectomy and radiation therapy for DCIS is more beneficial than lumpectomy and radiation alone. After 5 years the cumulative incidence of all breast cancers was 8.2% in the tamoxifen group compared with 13.2% in the placebo group.
Low-dose tamoxifen for breast cancer risk reduction in radiation-induced cancer survivors was effective in reducing established biomarkers of risk, including breast density.
Reduced breast cancer by 56% in patients with history of lobular carcinoma-in situ.
Symptoms of estrogen deficiency (hot flashes, vaginal discharge and in some cases sexual dissatisfaction) increase in about 5 to 20% of women given tamoxifen.
Common adverse effects: Hot flashes (up to 80%, 30% severe, night sweats; vaginal discharge, vaginal dryness; weight gain; muscle cramps </span>;Joint pain (20%-50%)
Complications Increased risk of DVT/PE, stroke, uterine cancer, cataracts,, Decreased bone density.
Premenopausal women treated with tamoxifen have no increased risk of uterine cancer or cataracts, as seen in the National Surgical Adjuvant Breast and Bowel Project P-1 study.
Vision changes associated with tamoxifen are rare and include cataracts; therefore, yearly eye examinations are recommended.
Up to 80% of women taking tamoxifen experience vasomotor symptoms and 30% of cases can be severe.
Contraindications to tamoxifen use:
Personal history of DVT/stroke; hypercoagulable condition; endometrial hyperplasia with atypia/endometrial cancer; current/planned pregnancy
Standard of therapy is 5 years of tamoxifen for adjuvant endocrine treatment for early-stage hormone receptor positive breast cancer.
Oxford review analysis of 194 randomized studies on adjuvant endocrine therapy for breast cancer with the administration of tamoxifen for 5 years to ER+ patients reduced annual recurrences by almost 50% and reduced breast cancer mortality by one third.
Approximately 80% of invasive breast cancers are endocrine receptor positive and appropriate for tamoxifen treatment (SEER).
After 5 years of tamoxifen therapy women are at risk for a recurrence in the ipsilateral breast and new tumors in the contralateral breast, and distant metastases at a rate of 2-3% per year.
Previous use of estrogen and obesity both increase the risk of endometrial cancer associated with tamoxifen use.
The rate of death from endometrial cancer is increased by about 1 to 2 per 1000 among post-menopausal women who have a uterus and are treated with tamoxifen.
Delayed treatment of 2 years with Tamoxifen in women with breast cancer who underwent surgery, radiotherapy, and/or adjuvant chemotherapy resulted in a 10-year disease-free survival of 83% compared to 75% in a control group. Improved outcomes from Tamoxifen treatment is seen even in patients who had delay of over 5 years before beginning therapy.
Reduces risk of breast cancer in patients with atypical hyperplasia by 86%.
Recently, a study of tamoxifen 5 mg/d vs placebo in patients with atypical hyperplasia or ductal carcinoma in situ by DeCensi et al found a 50% decreased risk of invasive cancer with fewer adverse effects than standard-dose tamoxifen.
In a small prospective study, tamoxifen reduced breast cancer occurrence by approximately 60% in BRCA2 variant carriers but did not reduce breast cancer occurrence in BRCA1 carriers, possibly because breast cancers that develop in BRCA1 carriers tend to be hormone receptor negative.
Tamoxifen has favorable effects on lipid and lipoprotein profiles by decreasing total and LDL cholesterol levels.
Lowers serum cholesterol by 13% and LDL by 19%.
Tamoxifen is associated with a small to moderate increased risk of venous thromboembolism events.
There is a higher risk of thromboembolism in older women, 4-7 events per 1000 over 5 years.
Risk of stroke 2 times more than in non-users and three times the risk for thromboembolism.
The incidence of any thromboembolic events in women with early breast cancer receiving adjuvant tamoxifen is approximally 3-4%.
More than 31% of women receiving tamoxifen experience dyspareunia.
Long term therapy associated with increased number of uterine lesions, including endometrial polyps, endometrial hyperplasia, endometrial carcinoma, leiomyomata and adenomyosis.
Extended exposure of tamoxifen of 10 years compared to the usual five years in adjuvant studies doubled the number of endometrial cancers, and significantly increases the risk of dying from it.
Tamoxifen is associated with menstrual irregularities..
Women taking tamoxifen should report any abnormal vaginal symptoms: bloody discharge, spotting, and leukorrhea.
Tamoxifen is a teratogen; therefore, contraception is strongly recommended for premenopausal women.
Tamoxifen is associated with a low but significant increased incidence of endometrial cancer of 2.2 per thousand women compared with 0.71 for placebo.
No evidence that any form of screening for endometrial cancer in tamoxifen treated patients will improve outcome.
Associated risk of endometrial cancer is 2 in 1000 and approximately 15% of these cancers.
Tamoxifen is associated with an increased risk of endometrial cancer in postmenopausal women (3.05 cancers per 1000 women older than 50 years treated with tamoxifen vs 0.76 cancers per 1000 women older than 50 years receiving placebo).
Premenopausal women treated with tamoxifen have no increased risk of uterine cancer or cataracts,
Lowers serum cholesterol by 13% and LDL by 19%.
Asymptomatic postmenopausal women receiving tamoxifen have a thicker endometrium than do controls.
Maintains bone density in postmenopausal women with a moderate reduction in the risk of fracture.
Small increase in risk of cataracts, yearly eye examinations are recommended. so that yearly eye examinations are recommended.
Associated with an increased risk of deep vein thrombophlebitis and pulmonary embolism.
Reduces fatal myocardial infarction by 60% and nonfatal myocardial infarction by 50-70%.
Use associated with emergence of breast cancer resistance.
Resistance is classified into two types: primary and secondary.
In pr imary resistance, progression occurs early within the first two years of adjuvant therapy, and subsequent lines of endocrine therapy tend to be less effective.
The most important reason for primary resistance is when the estrogen receptive is either not expressed or expressed at very low levels in the breast cancer.
Beyond the estrogen receptor other factors can contribute to resistance and include growth factor receptors such as HER2, epidermal growth factor receptor, and the fibroblast growth factor receptor all can cause resistance when they are coexpressed with the estrogen receptor.
Indicated when the estimated risk of breast cancer is greater than 1.66% at 5-years.
In high risk women reduces ER positive breast cancer by 49%.
Women taking tamoxifen who develop breast cancer are more likely to be ER negative and have a worse prognosis.
Despite its benefits in the adjuvant setting at least two thirds of women with hormone receptor positive breast cancer do not benefit from treatment, with more than 50% of relapses and more than two thirds of deaths occurring after the initial 5 years after surgery.
Patients treated with 5 years of tamoxifen in an adjuvant setting still have substantial rates of new primary tumors and relapses at all sites.
NSABP (National Surgical Adjuvant Breast and Bowel Project) B14 trial of 1150 women who received 5 years of tamoxifen and were free of recurrence randomized to continued treatment with tamoxifen or to placebo for a planned total course of 10 years.
NSABP (National Surgical Adjuvant Breast and Bowel Project) B14 trial was stopped early: due to significant advantages in disease free survival and distant disease free survival observed inpatients who stopped tamoxifen at 5 years (92% vs. 86%), and overall survival was better in the group treated with tamoxifen for just 5 years, albeit not statistically significant.
In the National Surgical Adjuvant Breast and Bowel Project P-1 study,16 5 years of standard therapy with tamoxifen 20 mg/d decreased the risk of invasive estrogen receptor positive breast cancer by approximately 50% in high-risk women, by 86% in those with atypical hyperplasia, and by 56% in those with LCIS.
International Breast Cancer Intervention Study (IBIS-1), a double blind, placebo controlled trial of females with increased risk of breast cancer, randomized 7,154 women aged 35-70 years, to tamoxifen vs placebo for 5 years: associated with a 26% reduction in incidence of estrogen receptor positive breast cancer, and for individuals that received treatment for 5 years and beyond the rate of estrogen receptor breast cancer was 44% lower in the tamoxifen arm (median 96 months).
Royal Marsden study of 2,471 women at high risk for breast cancer compared tamoxifen for 8 years to placebo revealed at 20 years (median 13 years), a 39% reduction in invasive estrogen receptor positive breast cancer for the tamoxifen group.
Italian Tamoxifen Prevention Study (ITPS) a randomized and controlled study of hysterectomized women, allowed to take hormone replacement therapy and followed for 81 months did not show reduction in breast cancer in the tamoxifen group compared to control group: reanalysis of high risk of women that did not have oophorectomy had a decreased risk of breast cancer by 82% in the tamoxifen group compared to the placebo group.
ATLAS (Adluvant Tamoxifen:Longer Against Shorter ) trial: for both recurrence and BC mortality there was little benefit during years 5-9, but after 10 years there is a significant benefit.
aTTom (Adjuvant Tamoxifen: Longer Against Shorter) trial found 10 years of tamoxifen significantly reduced the risk of recurrence from 32% 28% in 10 years or more after the diagnosis of estrogen receptor positive early breast cancer.
In the above study of 6,846 women with ER positive BC completed 5 years of tamoxifen and were randomized to stop treatment or to continue 5 more years: the risk of recurrence 5-14 years after diagnosis was 21.4% in the 10 year group and 25.1% in the 5 year group, and the risk of death was 12.2% and 15%, respectively.
Caution is advised with concurrent use of a strong CYP2D6-inhibiting selective serotonin reuptake inhibitor (eg, paroxetine and fluoxetine); citalopram and venlafaxine may be more favorable options.
Most of its anti-proliferative effects in breast cancer are mediated by the metabolites 4-hydroxy-N-methyltamoxifen and endoxifen.
Endoxifen Is much more potent than tamoxifen, as it binds to estrogen receptors with 100 fold greater affinity than tamoxifen or its most abundant metabolite 4-hydroxy-N-methyltamoxifen.
Patients who are homozygous for two variant alleles for cytochrome P450 2D6, and who are taking concomitant CYP2D6 inhibitors have low serum endoxifen concentrations.
There is insufficient evidence to recommend CYP2D6 testing when prescribing tamoxifen for risk-reduction purposes.
Endoxifen is predominately formed by the enzyme cytochrome P450 (CYP) 2D6 of which there are approximately 100 genetic variants that manifest in the population as four distinct phenotypes with extensive normal activity, intermediate reduced activity, poor with no activity and ultra-rapid with high activity metabolism.
There is an association between CYP2D6 variation and clinical outcome, such that the presence of two functional alleles associated with better clinical outcome compared to non-functional or reduced function alleles.
In a retrospective analysis of 1325 patients with stage I through III breast cancer and who were mainly postmenopausal treated with adjuvant therapy and association between CYP2D6 variation and clinical outcomes were such that two functional, CYP 2D6 alleles was associated with better clinical outcome and the presence of nonfunctional or reduced function alleles with worse outcomes (Schroth W).
Patients lacking CYP 2D6 & function had almost a twofold increased risk of developing breast cancer recurrence compared to patients with two functional CYP 2D6 alleles (Schroth W).
CYP 2D6 is an independent predictor of breast cancer outcome in postmenopausal women receiving tamoxifen for early breast cancer (Goetz).
Higher risk of relapse for adjuvant tamoxifen with lower incidence of hot flashes associated with CYP 2D6 *4/*4 genotype.
CYP2D6 poor metabolizers have a 3.8 fold higher risk for recurrence relative to extensive metabolizers in patients treated with adjuvant tamoxifen alone, but this was not seen in patients treated with tamoxifen followed by anastrozole (Goetz).
Testing for CYP2D6 enzyme should be considered when utilizing tamoxifen therapy.
5 years of adjuvant tamoxifen therapy in patients who are carriers of the wild type CYP2D6, extensive metabolizers, is similar to or perhaps superior when compared with aromatase inhibitor treatment (Punglia RS).
Presently it is uncertain whether patients that metabolize the parent drug to its active form or less likely to achieve a favorable outcome compared to patients with the ability to metabolize this agent extensively.
In a study of 119 women on Tamoxifen for a minimum of 4 months were found to be genetically defined as intermediate or poorer metabolizers of the drug and had the daily dose increased to 40 mg a day from 20 mg per day given to extensive metabolizers: Endotoxifen concentration in the intermediate and poor metabolizers groups increased substantially following the increased dose of tamoxifen- the concentration of endoxifen in the intermediate group attained approximately this same levels as the extensive metabolizers with half dose, but poor metabolizers failed to reach the levels of this group despite 40 mg per day of tqmoxifen (Irwin WJ Jr et al).
Caution should be used with the concurrent use of CYP2D6 inhibitors such as bupropion, paroxetine, and fluoxetine.
Randomized controlled studies of tamoxifen showed efficacy in 71% to 96% of patients with cyclic breast pain and 56% of those with noncyclic breast pain.
Long-term follow-up of tamoxifen prevention trials showed a higher risk cancer related mortality in the tamoxifen group despite a reduction in breast cancer incidence.