Assessment of Tamoxifen-Related Endometrial Changes in Premenopausal Female Patients With Diffusion-Weighted Magnetic Resonance Imaging.

PURPOSE: To evaluate tamoxifen-related endometrial changes in premenopausal female patients with diffusion-weighted magnetic resonance imaging (DWI). METHODS: This prospective study was performed on 71 premenopausal female patients (mean age, 41 years) who were receiving tamoxifen therapy. All patients underwent magnetic resonance imaging with DWI of the pelvis and hysteroscopic-guided endometrial biopsy. The apparent diffusion coefficient (ADC) values of the endometrial plate were calculated and correlated with pathological results. RESULTS: The mean ADCs of tamoxifen-related benign endometrial lesions (1.35 ± 0.19 and 1.32 ± 0.13 × 10 mm/s) were significantly higher (P = 0.001) than those of normal endometrial plate (0.95 ± 0.11 and 0.93 ± 0.11 × 10 mm/s) by both reviewers, respectively. The cutoff ADC values used to differentiate tamoxifen-related benign endometrial lesions from normal endometrium were 1.07 and 1.02 × 10 mm/s with areas under the curve of 0.94 and 0.93 and accuracy of 94.4 and 95.8 by both reviewers, respectively. The mean ADC values of endometrial polyp (EP) (1.44 ± 0.19 and 1.42 ± 0.22 × 10 mm/s) were significantly higher (P = 0.001) than those of endometrial hyperplasia (EH) (1.25 ± 0.19 and 1.23 ± 0.19 × 10 mm/s) by both reviewers, respectively. The cutoff ADC values used to differentiate EP from EH were 1.38 × 10 and 1.36 × 10 mm/s with areas under the curve of 0.81 and 0.77 and accuracy of 80% and 70% by both reviewers, respectively. There was an insignificant difference in ADC value between typical and atypical EH. The ADC values of endometrial cancer (0.80 and 0.78 × 10 mm/s) were lower than those of tamoxifen-related benign endometrial lesions. The final diagnosis was normal endometrium (n = 36), benign endometrial lesions either EH (n = 17), or EP (n = 16), and endometrial cancer in only 2 patients. CONCLUSIONS: We concluded that DWI helps in detection and characterization of different tamoxifen-related endometrial changes in the premenopausal female patients.

Assessment of Breast Cancer Patients' Knowledge and Decisional Conflict Regarding Tamoxifen Use.

Breast cancer is the most common type of female cancer. Tamoxifen, a selective estrogen receptor modulator, is widely used to decrease breast cancer recurrence and mortality among patients. However, it also increases the risk of endometrial cancer. This study aimed to assess knowledge and decisional conflict regarding tamoxifen use. Between June and October 2014, breast cancer patients using tamoxifen were consecutively screened and requested to complete a survey including the EQ-5D, Satisfaction with Decision Scale (SWD), Decisional Conflict Scale (DCS), and a self-developed, 15-item questionnaire measuring tamoxifen-related knowledge. The study sample comprised 299 patients. The mean total knowledge score was 63.4 of a possible 100.0 (range, 13.3-93.3). While 73.9% of the participants knew that tamoxifen reduces the risk of breast cancer recurrence, only 57.9% knew that the drug increases endometrial cancer risk. A higher education level (≥ college) was associated with a higher, total knowledge score (ß = 4.291; P = 0.017). A higher knowledge score was associated with a decreased DCS score (ß = -0.366; P < 0.001). A higher SWD score was also associated with decreased decisional conflict (ß = -0.178; P < 0.001). In conclusion, the breast cancer patients with higher levels of tamoxifen-related knowledge showed lower levels of decisional conflict regarding tamoxifen use. Clinicians should provide the exact information about tamoxifen treatment to patients, based on knowledge assessment results, so as to aid patients' decision-making with minimal conflict.

Hysteroscopic dynamic assessment of the endometrium in patients treated with long-term tamoxifen.

STUDY OBJECTIVE: To describe the evolutive endometrial hysteroscopic patterns in patients undergoing long-term tamoxifen treatment. DESIGN: Prospective analysis. Analysis of variance test with post hoc Bonferroni test and homogeneity test of percentages were used for hypothesis contrast between the groups. DESIGN CLASSIFICATION: Canadian task force II-2. SETTING: Four Spanish tertiary care hospitals. PATIENTS: A total of 278 patients with breast cancer diagnosed between 2002 and 2004, which completed 5-years adjuvant therapy with tamoxifen. INTERVENTIONS: Ultrasonography and hysteroscopic explorations were performed before starting the treatment and then at yearly intervals during the 5 years of adjuvant treatment. MEASUREMENTS AND MAIN RESULTS: Hysteroscopic endometrial changes were significant throughout the years of treatment. Tamoxifen-exposed endometria present five different patterns: atrophic, cystic, hypervascularized, endometrial polyp, and suspicious of malignancy. Endometrial carcinoma appeared in four patients (1.5%) that bled during the follow-up. CONCLUSION: Tamoxifen produces five different endometrial patterns that evolve dynamically throughout the 5 years of treatment.

Chemoprevention: drug pricing and mortality: the case of tamoxifen.

BACKGROUND: Tamoxifen is a prototypic cancer chemopreventive agent, yet clinical trials have not evaluated its effect on mortality or the impact of drug pricing on its cost-effectiveness. METHODS: A state-transition Markov model for a hypothetical cohort of women age 50 years was used to evaluate the effects of tamoxifen on mortality and tamoxifen price on cost-effectiveness. Incidence and mortality rates for breast and endometrial cancers were derived from Surveillance, Epidemiology and End Results statistics, and noncancer outcomes were obtained from published studies. Relative risks of outcomes were derived from the National Surgical Adjuvant Breast and Bowel Project P-1 trial. Costs were based on Medicare reimbursements. RESULTS: Projected overall mortality for women at 1.67% 5-year breast cancer risk showed little difference with or without tamoxifen, resulting in a cost-effectiveness ratio of $1,335,690 per life-year saved as a result of tamoxifen use. Adjusting for the differential impact of estrogen receptor-negative cancers, tamoxifen increased mortality for women with a uterus until the 5-year breast cancer risk reached > or =2.1%. Assigning the Canadian price for tamoxifen dramatically reduced the incremental cost (to $123,780 per life-year saved). At that price, the use of tamoxifen was less costly and more effective for women with 5-year breast cancer risks >4%. CONCLUSIONS: Tamoxifen may increase mortality in women at the lower end of the "high-risk" range for breast cancer. If prices in the U.S. approximated Canadian prices, then tamoxifen use for breast cancer risk reduction in women with a 5-year risk >3% could be a reasonable strategy to reduce the incidence of breast cancer. Because they are used by many unaffected individuals, the price of chemopreventive agents has a major influence on their cost-effectiveness.

Estimation of attributable risk for case-control studies with multiple matching.

Kuritz and Landis considered case-control studies with multiple matching and proposed an asymptotic interval estimator of the attributable risk based on Wald's statistic. Using Monte Carlo simulation, Kuritz and Landis demonstrated that their interval estimator could perform well when the number of matched sets was large (>or=100). However, the number of matched sets may often be moderate or small in practice. In this paper, we evaluate the performance of Kuritz and Landis' interval estimator in small or moderate number of matched sets and compare it with four other interval estimators. We note that the coverage probability of Kuritz and Landis' interval estimator tends to be less than the desired confidence level when the probability of exposure among cases is large. In these cases, the interval estimator using the logarithmic transformation and the two interval estimators derived from the quadratic equations developed here can generally improve the coverage probability of Kuritz and Landis' interval estimator, especially for the case of a small number of matched sets. Furthermore, we find that an interval estimator derived from a quadratic equation is consistently more efficient than Kuritz and Landis' interval estimator. The interval estimator using the logit transformation, although which performs poorly when the underlying odds ratio (OR) is close to 1, can be useful when both the probability of exposure among cases and the underlying OR are moderate or large.

Hysteroscopically targeted biopsies compared with blind samplings in endometrial assessment of menopausal women taking tamoxifen for breast cancer.

STUDY OBJECTIVE: To determine the validity of tissue sampling accomplished by hysteroscopically targeted or blind biopsies in the assessment of endometrial morbidity associated with tamoxifen treatment. DESIGN: Retrospective, unrandomized study (Canadian Task Force classification II-2). SETTING: Public hospital. PATIENTS: One hundred seventy-six menopausal women who had an endometrial stripe of more than 4 mm on transvaginal ultrasonography. INTERVENTION: Review of histopathologic reports of patients undergoing hysteroscopy followed by targeted (94 samplings) or blind (82 samplings) endometrial biopsies. MEASUREMENTS AND MAIN RESULTS: Histopathology was considered the reference test to assess endometrial morbidity, and correlates with hysteroscopic findings were made to evaluate the validity of the two sampling procedures. Overall, in 23 women (13.0%) tissue samples were insufficient for pathologic evaluation. Functional or atrophic endometrium and cystic atrophy were found in 51 (28.8%) and 37 patients (21.0%), respectively. Polyps, hyperplasias, and carcinomas were found in 38 (21.5%), 19 (10.7%), and 6 (3.3%), respectively. Blind biopsies failed to detect 5 of 5 polyps and 33 of 37 cystic atrophies, and in 34.1% of cases provided insufficient tissue for diagnosis; however, no hyperplasias or carcinomas were undetected. All specimens collected under vision were pathologically evaluable; 34 of 38 hysteroscopic reports of cystic atrophy were confirmed, and neither endometrial polyps nor hyperplasias and carcinomas were undetected. In distinguishing between normal and abnormal endometrium, hysteroscopy showed sensitivity and negative predictive value of 100% regardless of sampling modality. We found better specificity (80.0% vs 68.9%) and positive predictive value (68.9% vs 43.7%) for hysteroscopic diagnosis when tissue was collected under vision compared with blind sampling. CONCLUSION: In women taking tamoxifen, endometrial evaluation performed by blind sampling is safe in excluding hyperplasias or carcinomas. For complete understanding of tamoxifen-associated morbidity, hysteroscopy with sampling under vision has better diagnostic compliance.

Survival impact of tamoxifen use for breast cancer risk reduction: projections from a patient-specific Markov model.

The authors estimate tamoxifen's impact on life expectancy among healthy women. A Markov model compared the effects of 5 years of tamoxifen on survival among 50-year-old postmenopausal women. Scenarios were explored using alternative assumptions with regard to tamoxifen's long-term effects on breast and endometrial cancer. Postmenopausal women without a uterus had substantial life expectancy gains from tamoxifen (1 to 4 months), whereas women with a uterus had such gains only if they were at a very high breast cancer risk. If tamoxifen's impact on endometrial cancer persists after treatment is discontinued, women at high risk for endometrial cancer have life expectancy losses from tamoxifen unless they are at a very high risk for breast cancer. The authors conclude that tamoxifen use among postmenopausal women is associated with substantial life expectancy gains. However, this benefit is modulated in women at increased endometrial cancer risk and depends on assumptions concerning tamoxifen's lingering effects on breast and endometrial cancer.

Interval estimation of the attributable risk in case-control studies with matched pairs.

OBJECTIVE: The attributable risk (AR), which represents the proportion of cases who can be preventable when we completely eliminate a risk factor in a population, is the most commonly used epidemiological index to assess the impact of controlling a selected risk factor on community health. The goal of this paper is to develop and search for good interval estimators of the AR for case-control studies with matched pairs. METHODS: This paper considers five asymptotic interval estimators of the AR, including the interval estimator using Wald's statistic suggested elsewhere, the two interval estimators using the logarithmic transformations: log(x) and log(1-x), the interval estimator using the logit transformation log(x/(1-x)), and the interval estimator derived from a simple quadratic equation developed in this paper. This paper compares the finite sample performance of these five interval estimators by calculation of their coverage probability and average length in a variety of situations. RESULTS: This paper demonstrates that the interval estimator derived from the quadratic equation proposed here can not only consistently perform well with respect to the coverage probability, but also be more efficient than the interval estimator using Wald's statistic in almost all the situations considered here. This paper notes that although the interval estimator using the logarithmic transformation log(1-x) may also perform well with respect to the coverage probability, using this estimator is likely to be less efficient than the interval estimator using Wald's statistic. Finally, this paper notes that when both the underlying odds ratio (OR) and the prevalence of exposure (PE) in the case group are not large (OR < or =2 and PE < or =0.10), the application of the two interval estimators using the transformations log(x) and log(x/(1-x)) can be misleading. However, when both the underlying OR and PE in the case group are large (OR > or =4 and PE > or =0.50), the interval estimator using the logit transformation can actually outperform all the other estimators considered here in terms of efficiency. CONCLUSIONS: When there is no prior knowledge of the possible range for the underlying OR and PE, the interval estimator derived from the quadratic equation developed here for general use is recommended. When it is known that both the OR and PE in the case group are large (OR > or =4 and PE > or =0.50), it is recommended that the interval estimator using the logit transformation is used.

Benefit/risk assessment of SERM therapy: clinical trial versus clinical practice settings.

Benefit/risk assessment (B/rA) can be used in a variety of circumstances encompassing clinical practice and research settings. Subsequent to the reporting of the results from the Breast Cancer Prevention Trial (BCPT), methodology was developed to perform B/rA for the use of the selected estrogen receptor modulator (SERM), tamoxifen. Although the methodology was specifically developed and applied to the use of tamoxifen, it is a generalized procedure that can be readily modified and applied to other forms of therapy including other SERMs. Recently, the methodology has been incorporated into the Study of Tamoxifen and Raloxifene (STAR) trial, a randomized clinical trial designed to compare the chemopreventive effects of two SERMs--tamoxifen and raloxifene. The B/rA of SERMs is complex because SERMs are known to exhibit properties that can reduce or increase the incidence of several health outcomes. This paper summarizes the uses of B/rA in the clinical practice and clinical trial settings and describes the constraints of the methodology as it is being applied to the assessment of therapy with SERMs.

Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen.

BACKGROUND: Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women. METHODS: We did a nationwide case-control study on the risk and prognosis of endometrial cancer after tamoxifen use for breast cancer. Information on tamoxifen use and other risk factors for endometrial cancer was obtained from 309 women with endometrial cancer after breast cancer (cases), and 860 matched controls with breast cancer but without endometrial cancer. For 276 cases, we obtained tissue blocks of endometrial cancer to review the diagnosis, and used immunohistochemistry to examine hormone-receptor status and overexpression of p53. FINDINGS: Tamoxifen had been used by 108 (36.1%) of 299 cases and 245 (28.5%) controls (relative risk 1.5 [95% CI 1.1-2.0]). Risk of endometrial cancer increased with longer duration of tamoxifen use (p < 0.001), with relative risks of 2.0 (1.2-3.2) for 2-5 years and 6.9 (2.4-19.4) for at least 5 years compared with non-users. Endometrial cancers of stage III and IV occurred more frequently in long-term tamoxifen users (> or = 2 years) than in non-users (17.4% vs 5.4%, p=0.006). Long-term users were more likely than non-users to have had malignant mixed mesodermal tumours or sarcomas of the endometrium (15.4% vs 2.9%, p < or = 0.02), p53-positive tumours (31.4% vs 18.2%, p=0.05), and negative oestrogen-receptor concentrations (60.8% vs 26.2%, p < or = 0.001). 3-year endometrial-cancer-specific survival was significantly worse for long-term tamoxifen users than for non-users (76% for > or = 5 years, 85% for 2-5 years vs 94% for non-users, p=0.02). INTERPRETATION: Long-term tamoxifen users have a worse prognosis of endometrial cancers, which seems to be due to less favourable histology and higher stage. However, the benefit of tamoxifen on breast-cancer survival far outweighs the increased mortality from endometrial cancer. Nevertheless, we seriously question widespread use of tamoxifen as a preventive agent against breast cancer in healthy women.

Surveillance of the endometrium in tamoxifen treated women.

There is much debate about the risks and benefits of tamoxifen, most specifically about the incidence of associated endometrial cancer. Nearly all of the published trials on the subject have been criticized for methodological flaws and various forms of bias, making resolution of this controversy difficult. There is a consensus, however, that tamoxifen results in an increased incidence of both premalignant and malignant lesions of the endometrium. As the indications for tamoxifen continue to broaden, a larger number of women will be subjected to the potential adverse effects of tamoxifen. Many techniques for screening patients on tamoxifen for the development of endometrial abnormalities have been suggested. None of these methods appears to be consistently clinically or cost effective. We have reviewed the literature on endometrial surveillance in tamoxifen treated women with a focus on the larger publications reported within the past year. From this, we have provided what we hope to be safe and cost-effective recommendations for the management of these patients.

Risk assessment of the menopausal patient.

Menopause is a physiologic event that gives a woman the opportunity to become involved in a preventive health program. Menopause is not a disease; however, it does cause symptoms in a significant percentage of women. Medical evaluation with an emphasis on health maintenance and lifestyle measures is important for menopausal women. Tailoring an individual program for women, which may include HRT and other therapeutic options, is guided by the menopausal risk assessment.

American Society of Clinical Oncology technology assessment on breast cancer risk reduction strategies: tamoxifen and raloxifene.

OBJECTIVE: To conduct an evidence-based technology assessment to determine whether tamoxifen and raloxifene as breast cancer risk-reduction strategies are appropriate for broad-based conventional use in clinical practice. POTENTIAL INTERVENTION: Tamoxifen and raloxifene. OUTCOME: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefits. EVIDENCE: A comprehensive, formal literature review was conducted for tamoxifen and raloxifene on the following topics: breast cancer risk reduction; tamoxifen side effects and toxicity, including endometrial cancer risk; tamoxifen influences on nonmalignant diseases, including coronary heart disease and osteoporosis; and decision making by women at risk for breast cancer. Testimony was collected from invited experts and interested parties. VALUES: More weight was given to publications that described randomized trials. BENEFITS/HARMS/COSTS: The American Society of Clinical Oncology (ASCO) Working Group acknowledges that a woman's decision regarding breast cancer risk-reduction strategies will depend on the importance and weight attributed to the information provided regarding both cancer and non-cancer-related risks. CONCLUSIONS: For women with a defined 5-year projected risk of breast cancer of >/= 1.66%, tamoxifen (at 20 mg/d for up to 5 years) may be offered to reduce their risk. It is premature to recommend raloxifene use to lower the risk of developing breast cancer outside of a clinical trial setting. On the basis of available information, use of raloxifene should currently be reserved for its approved indication to prevent bone loss in postmenopausal women. Conclusions are based on single-agent use of the drugs. At the present time, the effect of using tamoxifen or raloxifene with other medications (such as hormone replacement therapy), or using tamoxifen and raloxifene in combination or sequentially, has not been studied adequately. The continuing use of placebo-controlled trials in other risk-reduction trials highlights the current unanswered issues concerning the use of such interventions, especially when the influence on net health benefit remains to be determined. Breast cancer risk reduction is a rapidly evolving area. This technology assessment represents an ongoing process with existing plans to monitor and review data and to update recommendations in a timely matter. (See VALIDATION: The conclusions of the Working Group were evaluated by the ASCO Health Services Research Committee and by the ASCO Board of Directors. SPONSOR: American Society of Clinical Oncology.

[Risks, benefits and costs of hormone replacement therapy in menopause]. / Risques, bénéfices et coûts du traitement hormonal substitutif à la ménopause.

Hormone replacement therapy (HRT) acts both as an effective treatment of menopausal symptoms and genital atrophy, and as an effective prevention of osteoporosis. It is also probably cardioprotective and potentially preventing cerebrovascular disease. The risk of oestrogen-induced endometrial cancer is eliminated by the addition of a progestin. An increase in breast cancer risk is however possible after 10 years or more of HRT use. This multifactorial risk-benefit balance altogether with other variables (numerous and expensive hormonal therapies, low compliance of postmenopausal women, need for monitoring, therapy-related adverse events) explain why so few global pharmaco-economic appraisals have been devoted to HRT. Computer model studies have been set up to study hypothetical cohorts of menopausal women treated for 5-10 years or more, comprising hysterectomized women (receiving an estrogen alone) and non hysterectomized women (receiving an oestrogen-progestogen therapy) compared with untreated controls. Treatment of hysterectomized women as well as non hysterectomized symptomatic menopausal women appears relatively cost-effective. In terms of mortality and morbidity, a reduction in cardiovascular disease risk and, to a smaller extent, in osteoporosis has a strikingly greater impact than the small increase in breast cancer risk related to HRT use. A significant increase in life expectancy seems associated with long-term use and the quality-adjusted life years gain, is particularly impressive, as quality of life appears distinctly improved by HRT utilization. In the future, this beneficial cost-effectiveness equation will probably be optimized thanks to the introduction of alternative and innovative replacement therapies allowing longer treatment periods without increasing the risk of breast cancer.

Antiestrogen therapy: uncertainties and risk assessment.

Tamoxifen is by far the most clinically tested antiestrogenic drug currently used as adjuvant therapy for breast cancer and it continues to provide considerable benefit in this setting. The balance from clinical trials indicates a strong association between the use of tamoxifen and an increase in uterine tumors (three to sixfold). In rats, tamoxifen is a mutagenic, genotoxic hepatocarcinogen. These actions are not related to its estrogen antagonist activity but have been shown to be as a result of metabolic activation of this drug by cytochrome P450 enzymes, resulting in irreversible binding to cellular DNA. The mechanism of endometrial cancer associated with tamoxifen treatment is unclear, although there are two plausible hypotheses: (1), tamoxifen causes damage and mutation to DNA in uterine cells or (2), it promotes the development of endometrial tumors through its estrogen agonist activity. The evidence for a genotoxic effect of tamoxifen in the uterus is highly contentious and, on balance, we have concluded that it is more likely that the estrogenic effects of tamoxifen promote tumor development.