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ASCO SPECIAL ARTICLE
A m e r i c a n S o c i e t y o f C l i n i c a l O n c o l o g y T e c h n o l o g y
A s s e s s m e n t o f P h a r m a c o l o g i c I n t e r v e n t i o n s f o r B r e a s t
C a n c e r R i s k R e d u c t i o n I n c l u d i n g T a m o x i f e n , R a l o x i f e n e ,
a n d A r o m a t a s e I n h i b i t i o n
By Rowan T. Chlebowski, Nananda Col, Eric P. Winer, Deborah E. Collyar, Steven R. Cummings, Victor G. Vogel III, Harold J. Burstein, Andrea Eisen, Isaac Lipkus, and David G. Pfister for the American Society of Clinical Oncology Breast Cancer Technology Assessment Working Group Objective: To update an evidence-based technology
Risk/benefit models suggest that greatest clinical ben-
assessment of chemoprevention strategies for breast
efit with least side effects is derived from use of tamox-
cancer risk reduction.
ifen in younger (premenopausal) women (who are less
Potential Interventions: Tamoxifen, raloxifene, aro-
likely to have thromboembolic sequelae and uterine
matase inhibition, and fenretinide.
cancer), women without a uterus, and women at higher
Outcomes: Outcomes of interest include breast can-
breast cancer risk. Data do not as yet suggest that
cer incidence, breast cancer–specific survival, overall
tamoxifen provides an overall health benefit or in-
survival, and net health benefit.
creases survival. In all circumstances, tamoxifen use
Evidence: A comprehensive, formal literature review
should be discussed as part of an informed decision-
was conducted for relevant topics. Testimony was col-
making process with careful consideration of individu-
lected from invited experts and interested parties. The
ally calculated risks and benefits. Use of tamoxifen
American Society of Clinical Oncology (ASCO) prescribed
combined with hormone replacement therapy or use of
technology assessment procedure was followed.
raloxifene, any aromatase inhibitor or inactivator, or
Values: More weight was given to published ran-
fenretinide to lower the risk of developing breast cancer is
domized trials.
not recommended outside of a clinical trial setting. This
Benefits/Harms: A woman’s decision regarding
technology assessment represents an ongoing process
breast cancer risk reduction strategies is complex and
and recommendations will be updated in a timely matter.
will depend on the importance and weight attributed to
Validation: The conclusions were endorsed by the
information regarding both cancer- and noncancer-
ASCO Health Services Research Committee and the
related risks and benefits.
ASCO Board of Directors.
Conclusions: For women with a defined 5-year pro-
Sponsor: American Society of Clinical Oncology.
jected breast cancer risk of > 1.66%, tamoxifen (at 20
J Clin Oncol 20:3328-3343. 2002 by American
mg/d for 5 years) may be offered to reduce their risk.
Society of Clinical Oncology.
THE WORKING group (Appendix) reviewed the liter- Cancer Lit, PubMed, and scientific Internet sites (selected by link ature and, in a series of meetings and conference calls, frequency). References were searched for the period from the lasttechnology assessment (June 1999) through March 2002 using the considered recommendations from the original 1999 tech- following search terms: tamoxifen, raloxifene, aromatase inhibitors, nology assessment.1 The technology assessment was limited retinoids and breast cancer, breast cancer risk reduction, and breast to breast cancer chemoprevention. By this definition, surgi- cancer risk communication. Of the 3,733 references identified and cal and lifestyle interventions were excluded from consid- reviewed at least by title, 119 are referenced in the current report.
eration but have been reviewed elsewhere.2,3 Published information was updated by including key investigators inthe Working Group and inviting corporate entities to provide emerging The technology assessment followed previously described proce- dures.1 A comprehensive literature review incorporated MEDLINE, Conclusions of this technology assessment are outlined From the American Society of Clinical Oncology, Alexandria, VA. Submitted May 25, 2002; accepted May 25, 2002.
Address reprint requests to American Society of Clinical Oncology,
For women with a 5-year projected breast cancer risk of Health Services Research Department, 1900 Duke St, Suite 200, Ն 1.66%, tamoxifen (at 20 mg/d for 5 years) may be offered Alexandria, VA 22314; email: guidelines@asco.org. to reduce risk. Consideration of tamoxifen is appropriate for This article was published online ahead of print at www.jco.org. the goal of lowering the short-term risk of developing breast 2002 by American Society of Clinical Oncology.
0732-183X/02/2015-3328/$20.00
cancer. Risk/benefit models suggest that greatest clinical Journal of Clinical Oncology, Vol 20, No 15 (August 1), 2002: pp 3328-3343 Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
Copyright 2002 American Society of Clinical Oncology. All rights reserved.
ASCO TECHNOLOGY ASSESSMENT: BREAST CANCER RISK REDUCTION UPDATE 2002 Table 1. Conclusions
comes under tamoxifen influence needs to be translated into absolute terms for each woman. In all circumstances, For women with a 5-year projected breast cancer risk of Ն 1.66%, tamoxifen use should be discussed as part of an informed tamoxifen (at 20 mg/d for 5 years) may be offered to reduce risk.
decision-making process with careful consideration of risks Consideration of tamoxifen is appropriate for the goal of lowering the short-term risk of developing breast cancer. Risk/benefit models suggestthat greatest clinical benefit with least side effects are derived from use of tamoxifen in younger (premenopausal) women (who are less likely tohave thromboembolic sequelae and uterine cancer), women without a Use of raloxifene to lower breast cancer risk is not uterus, and women at higher breast cancer risk. Data do not as yet recommended. Raloxifene should be reserved for its ap- suggest that tamoxifen provides overall health benefit or increases proved indication to prevent or treat bone loss in postmeno- Risk/benefit calculation for tamoxifen use is challenging with no simple scale to weigh the disparate clinical outcomes that vary in their morbidity and mortality risk. To inform potential tamoxifen users, therelative risk of all outcomes under tamoxifen influence need to be Use of any aromatase inhibitor or aromatase inactivator translated into absolute terms for each woman, considering outcomes to lower breast cancer risk is not recommended.
under tamoxifen influence. In all circumstances, tamoxifen use shouldbe discussed as part of an informed decision-making process with careful consideration of risks and benefits.
Use of fenretinide to lower breast cancer risk is not Use of raloxifene to lower breast cancer risk is not recommended.
Raloxifene should be reserved for its approved indication to prevent ortreat bone loss in postmenopausal women.
Use of any aromatase inhibitor or aromatase inactivator to lower breast Clinical trials evaluating potential chemoprevention agents either alone or in combination are encouraged. Use of tamoxifen in combination with hormone replacement Use of frenretinide to lower breast cancer risk is not recommended.
therapy (HRT) is not recommended outside of a clinical trial Clinical trials evaluating potential chemoprevention agents either alone or setting, given the uncertainty regarding long-term side effects of the combination and the association of HRT with Placebo controls are appropriate for breast cancer risk reduction trials increased breast cancer risk in observational studies. Use of since no intervention has been demonstrated to favorably impact net tamoxifen in combination or sequentially with raloxifene or aromatase inhibitors for breast cancer risk reduction has Use of tamoxifen in combination with hormone replacement therapy outside of a clinical trial setting is not recommended given uncertainty either not been studied or studies have yet to be reported.
regarding long-term side effects of the combination and the association Placebo controls are appropriate for breast cancer risk of hormone replacement therapy with increased breast cancer risk in reduction trials since no intervention has been demonstrated to have a favorable impact on net health or survival.
Use of tamoxifen for risk reduction in combination or sequentially with This technology assessment represents an ongoing pro- other agents (such as raloxifene or aromatase inhibitors) has either notbeen studied or studies have not yet been reported.
cess, and the Working Group will continue to monitor data This technology assessment represents an ongoing process, and we will and update recommendations in a timely manner. The basis continue to monitor data and update recommendations in a timely for these recommendations follow. Clinical evidence is benefit with least side effects are derived from use oftamoxifen in younger (premenopausal) women (who are Clinical Evidence Relevant to Tamoxifen’s Effect on less likely to have thromboembolic sequelae and uterine cancer), women without a uterus, and women at higher Tamoxifen’s influence on breast cancer in risk reduction breast cancer risk. Data do not as yet suggest that tamoxifen Tamoxifen is the only agent approved by the provides an overall health benefit or increases survival.
United States Food and Drug Administration (FDA) for Risk/benefit calculation for tamoxifen use is challenging.
breast cancer risk reduction. Four randomized trials are There is no simple scale to weigh the disparate clinical prospectively evaluating tamoxifen (Nolvadex; AstraZen- outcomes that vary in their morbidity and mortality risk. To eca, Wilmington, DE) for breast cancer risk reduction.4-7 At inform potential tamoxifen users, the relative risk of out- the last technology assessment, three trials had reported Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
Copyright 2002 American Society of Clinical Oncology. All rights reserved.
Table 2. Randomized, Prospective Trials of Tamoxifen for Primary Breast Cancer Risk Reduction
NOTE. Total cancers include invasive breast cancers and ductal carcinoma-in-situ but excludes lobular cancer-in-situ. Active, blinded follow-up continues for all but NSABP P1. The Royal Marsden trial involves 8 years of tamoxifen therapy; all others involve 5 years of therapy.
Abbreviations: NSABP, National Surgical Adjuvant Breast and Bowel Project; IBIS, International Breast Cancer Intervention Study; CA, cancer; Tam, tamoxifen; OR, odds ratio; 95% CI, 95% confidence interval; LCIS, lobular carcinoma-in-situ; HRT, hormone replacement therapy; DVT, deep venous thrombosis; PE, pulmonaryembolism; DCIS, ductal carcinoma-in-situ; ADH, atypical ductal hyperplasia; NR, not reported.
outcome with 479 breast cancers observed. A meta-analysis The IBIS-1 trial randomized 7,154 women at increased of these studies, of which the National Surgical Breast and breast cancer risk to tamoxifen or placebo. The primary end Bowel Project (NSABP) P-1 trial contributed the largest point was breast cancer development (invasive and ductal proposition of entered patients, identified a significant 42% carcinoma-in-situ) and the secondary end point was devel- reduction in relative risk (RR) of developing breast cancer opment of endometrial and other cancers. A relatively associated with tamoxifen use (RR, 0.58; 95% confidence young population (median age, 50.8 years) at increased breast cancer risk that was identified using a newly devel- The absolute risk reduction in these trials was less than 2 oped risk assessment tool was randomized to tamoxifen (20 per 100 women given tamoxifen for 5 years. The absolute mg/d for 5 years) or placebo. Tamoxifen significantly risk reduction anticipated in an individual woman depends decreased the risk of breast cancer development (odds ratio, on her calculated breast cancer risk, with women at higher 0.67; 95% CI, 0.49 to 0.91; P ϭ .01), based on distribution risk having greater potential benefit. For instance, the average 65-year-old woman with no family history has an Concurrent HRT use was permitted in the IBIS-1 study, anticipated risk reduction of 1 per 100, while a 50-year-old was used by over 40% of participants, and had no detri- woman with two affected siblings and two prior biopsies but mental effect on tamoxifen-associated breast cancer risk no germline mutation has an anticipated risk reduction of reduction. As in P-1, tamoxifen use in IBIS-1 reduced only receptor-positive breast cancers and had no influence on the The initial report of the International Breast Cancer receptor-negative cancers seen. A recent observational Intervention Study (IBIS-1) comparing tamoxifen with study reporting a tamoxifen-associated increase in receptor- placebo and updates of the two other European chemopre- negative breast cancers9 will require further evaluation.
vention tamoxifen trials7 substantially increase information A meta-analysis7 now including the four randomized regarding tamoxifen’s influence on breast cancer risk (Ta- tamoxifen trials with updated results10 from all three Euro- bles 2 and 3). Currently, 738 breast cancers have been pean trials identified a 38% reduction in breast cancer with reported in the four randomized tamoxifen trials, 54% more tamoxifen (odds ratio, 0.62; 95% CI, 0.42 to 0.89). These than available at the last technology assessment.
results support a significant influence of tamoxifen on Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
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ASCO TECHNOLOGY ASSESSMENT: BREAST CANCER RISK REDUCTION UPDATE 2002 (Cont’d)
reducing short-term breast cancer risk, with a magnitude of increased breast cancer risk in observational studies11,12 and effect somewhat smaller than seen in the P-1 trial.
uncertainties regarding long-term effects of combined HRT Tamoxifen’s influence on survival in risk reduction trials. and tamoxifen use argue against routine use of such a None of the four tamoxifen trials was designed to assess combination in a risk reduction setting. However, further tamoxifen’s influence on survival. Available data do not yet evaluation of combined HRT and tamoxifen use remains an suggest that tamoxifen favorably influences overall health or survival in the risk reduction setting. Currently, the Tamoxifen’s influence on contralateral breast cancer in number of deaths are closely comparable in the tamoxifen In the last published Early Breast Cancer and control arms of the prevention trials.7 All three Euro- Trialists Cooperative Group (EBCTCG) analysis of adju- pean trials continue blinded follow-up and will provide vant trials,13 a 47% reduction in relative risk of contralateral additional information on tamoxifen and breast cancer breast cancer was associated with 5 years of tamoxifen use development, carry-over effects after tamoxifen discontin- (RR, 0.53; SD, 0.09; P Ͻ .00001), providing further support uation, and breast cancer–specific survival and overall for a tamoxifen effect on new breast cancer development.
The EBCTCG 2000 update identified 553 contralateral breast cancers and reported that contralateral breast cancer ence with combined tamoxifen and HRT for breast cancer risk reduction was seen only in women who had an initial risk reduction. The Royal Marsden Hospital Trial included receptor-positive tumor.14 Supporting this observation is a 523 women using both tamoxifen and HRT; subgroup recent report that women who develop receptor-negative analysis found no interaction on breast cancer develop- breast cancer are likely to develop receptor-negative con- ment.5 In the Italian study,6 a subgroup analysis found tamoxifen significantly reduced breast cancer risk only in Tamoxifen duration for risk reduction. women receiving HRT, an analysis based on only nine IBIS trials, which provide the most evidence on risk cancers. The large IBIS-1 trial reported comparable tamox- reduction, the duration of tamoxifen use was 5 years.4,7 ifen-associated risk reduction in women with or without Indirect information on tamoxifen duration in this setting concurrent HRT use. In IBIS-1, combined HRT and tamox- comes from follow-up of the NSABP B-14 trial in adjuvant ifen was not associated with a greater short-term increase in disease, which found no additional benefit on contralateral endometrial cancer or vascular events compared with ta- breast cancer for continued tamoxifen use beyond 5 years.16 Tamoxifen’s effects on benign breast disease. Although no interaction between HRT and tamoxifen on cern that tamoxifen’s effect on breast cancer risk may only breast cancer was identified, the association of HRT with reflect early therapy of invasive disease has been addressed Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
Copyright 2002 American Society of Clinical Oncology. All rights reserved.
Table 3. Quantity of Data Relevant to Breast Cancer Risk Reduction by Chemoprevention Agents
No. of risk reduction randomized prospective trials No. of breast cancers reported in prospective, randomized No. of breast cancers reported in randomized trials from Effect of interventions on breast cancer risk No. of adjuvant breast cancer trials reported No. of new contralateral breast cancers reported in Effect of intervention on contralateral breast cancer risk Maximum follow-up available for toxicity information, Abbreviation: N/A, not available.
NOTE. Breast cancer in these reports includes both invasive breast cancer and ductal carcinoma-in-situ but excludes lobular carcinoma-in-situ.
*Results from a secondary analysis of a randomized osteoporosis trial.
†Based on Early Trialist report (Early Trialist 1998) for 5 years of tamoxifen use with 252 breast cancers seen.
by an analysis of benign breast disease in the P-1 trial. In Tamoxifen’s effects in women with prior breast disease. this setting, tamoxifen was associated with a significant Women with a history of ductal carcinoma-in-situ20 or reduction in both the total number of biopsies and in the lobular carcinoma-in-situ are at recognized increased breast proportion of specimens from these biopsies showing atyp- cancer risk and are reasonable candidates for tamoxifen ical hyperplasia, typical hyperplasia, adenosis, cysts, and use.4 Women with prior receptor-positive invasive breast cancer who have either not received tamoxifen or received Tamoxifen’s effects in women with BRCA1/BRCA2 mu- tamoxifen for less than 5 years are also at increased breast The NSABP has evaluated the effect of tamoxifen cancer risk and can potentially benefit from tamoxifen.21,22 on breast cancer risk in P-1 participants with inherited Tamoxifen in African-American women. effectiveness in breast cancer risk reduction in African- BRCA1 or BRCA2 mutations.18 Of 288 women who devel- American women has been inferred from a retrospective oped breast cancers, 19 had either BRCA1 or BRCA2 analyses involving 58 contralateral breast cancers seen in mutations. Tamoxifen reduced breast cancer risk in women NSABP adjuvant trials,23 where a 52% reduction in relative with BRCA2 mutations, in whom tumors were largely risk of contralateral breast cancer was observed (RR, 0.48; receptor-positive (RR, 0.38; 95% CI, 0.06 to 1.56), but not in women with BRCA1 mutations (RR, 1.67; 95% CI, 0.32to 10.70), in whom tumors were more commonly receptor- Other Positive and Negative Effects of Tamoxifen Use negative. However, a matched case-control study reported New information on tamoxifen has emerged from the significant protection against contralateral breast cancer in NSABP P-1 study, the EBCTCG 2000 update, and meta- carriers of BRCA1 mutations treated with tamoxifen (odds analyses of published literature.24,25 The effects of tamox- ratio, 0.38; 95% CI, 0.19 to 0.74), while contralateral ifen reflect more than 20 years of clinical trial use.
cancers in BRCA2 mutation carriers were less influenced (odds ratio, 0.63; 95% CI, 0.20 to 1.50).19 results from trials comparing 5 years of tamoxifen use to no The extremely limited number of subjects in these therapy in more than 8,000 women with early breast reports and the mixed results seen preclude reliable cancer.14 Although not published, presented results in- assessment of tamoxifen effects in this setting. Given the formed the National Cancer Institute’s Adjuvant Breast overall number of identified mutation carriers, this im- Cancer Consensus Conference.26 In the EBCTCG update, portant issue is unlikely to be resolved by further time-dependent effects of tamoxifen use were identified.
Five years of tamoxifen substantially reduced the risk for Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
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ASCO TECHNOLOGY ASSESSMENT: BREAST CANCER RISK REDUCTION UPDATE 2002 breast cancer recurrence and contralateral cancer that per- and identified risk, tamoxifen use for breast cancer risk sisted for 5 to 10 years after termination of tamoxifen use.
reduction is relatively contraindicated and not recom- In addition, increased endometrial cancer risk was also mended in women with a history of deep vein thrombosis, persistent, supporting a previously identified trend.13,25,27 pulmonary embolus, stroke, or transient ischemic attack.
Publication of the EBCTG update is needed to fully evalu- creases endometrial cancer risk in postmenopausal women Tamoxifen and quality of life, depression, and cognition. with a uterus by approximately two- to four-fold.4,7 In the Tamoxifen use is associated with more frequent hot flashes EBCTG update, tamoxifen-associated excess mortality re- and vaginal discharge.4 Development of cataracts also is lated to endometrial cancer was approximately one death more frequent (RR, 1.14; 95% CI, 1.01 to 1.29) with per 1,000 postmenopausal women with a uterus treated.14 tamoxifen use, with the absolute risk increasing by 3 per New information on tamoxifen-related endometrial cancers comes from a case-control study with 309 endometrial Tamoxifen did not adversely influence questionnaire- cancers. Long-term tamoxifen users who developed endo- assessed depression risk,28 quality of life,29 or several other metrial cancer had a relatively unfavorable prognosis re- psychosocial or social functions.30,31 Other risk reduction lated to histology (more common malignant mixed meso- trials have yet to report on these parameters.
dermal tumors or sarcomas of the endometrium) and higher Tamoxifen’s effects on cognition are not resolved. A stage.37 Endometrial cancer risk with tamoxifen was neuroimaging study compared levels of myoinositol (a glial increased by prior estrogen use and obesity.38 Despite marker) in women receiving tamoxifen, HRT, or no hor- ongoing trials, use of progestins to mitigate tamoxifen’s monal treatments. A significant time-dependent reduction in effects on the endometrium, as widely used in HRT myoinositol was seen with tamoxifen, consistent with ago- regimens, is not recommended given progestin’s activity nist action on brain predictive of a favorable neuroprotec- tive effect.32,33 In a cross-sectional study of nursing home Prospective evaluation did not support the routine use of residents, women who reported past tamoxifen use had less either endometrial biopsy41 or transvaginal ultrasound42 in frequent Alzheimer’s disease and greater activities of daily ongoing monitoring for women with history of breast cancer living compared with women who had never used tamox- receiving tamoxifen. Recommended follow-up for women ifen.34 However, in an observational study using mailed receiving tamoxifen includes a yearly gynecologic exami- questionnaires, current users complained of somewhat more nation and timely work-up of vaginal bleeding.
memory problems,35 although no decrease in cognitive Tamoxifen and gastrointestinal cancers. function was seen. Additional studies using sensitive meth- meta-analysis of randomized trials identified increased gas- odologies that delineate memory and recall abilities are trointestinal and colorectal malignancies associated with tamoxifen use,24 a nested case-control study found no Tamoxifen and cardiovascular events. increase in colorectal cancer among tamoxifen users,43 so P-1 trial, cardiovascular events, including myocardial in- farctions, were similar in women receiving tamoxifen or placebo regardless of pre-existing coronary heart disease.36 ated with a modest, nonsignificant reduction in fractures compared with placebo in the P-1 trial4 and with signifi- clude deep venous thrombosis, pulmonary embolism, cantly fewer fractures compared with anastrozole in an stroke, and transient ischemic attack. A recent meta-analysis adjuvant trial.44 Whether the latter represents a positive of published tamoxifen trials found the incidence of both tamoxifen effect, a negative aromatase inhibitor effect, or venous thromboembolic events and strokes to be signifi- some combination remains to be determined.
cantly greater in women receiving tamoxifen.24 TheEBCTG update confirmed prior estimates of tamoxifen- associated excess mortality related to vascular events, Clinical Evidence Relevant to Raloxifene’s Effect on largely pulmonary emboli of approximately one death per 1,000 postmenopausal women treated for 5 years.14 Sincenearly half of thromboembolic events seen in the IBIS trial Two ongoing, randomized, prospective trials are evalu- occurred within 3 months of surgery or fracture,7 tamoxifen ating raloxifene (Evista; Lilly, Indianapolis, IN) and breast use should be carefully re-evaluated in women using tamox- cancer risk,45,46 but neither has reported clinical outcome.
ifen in a risk reduction setting after such events. Given Data on raloxifene’s influence on breast cancer come common protocol exclusions for vascular events (Table 2) almost exclusively from the Multiple Outcomes of Ralox- Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
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Table 4. Status of Selected Ongoing Randomized Trials for Primary Breast Cancer Risk Reduction With Clinical Outcome End Points
NOTE. Studies with these agents for women with ductal carcinoma-in-situ are not included.
ifene Evaluation (MORE) study, in which 7,705 postmeno- baseline estradiol levels greater than 10 pmol/L had a pausal women with osteoporosis were randomized to ralox- 6.8-fold higher rate of breast cancer than women with ifene at 60 or 120 mg/d or placebo for 4 years and undetectable levels (P ϭ .005 for trend).47 In addition, the monitored for breast cancer development from the safety raloxifene-associated reduction in breast cancer risk was database. At the last technology assessment, a total of 54 largely in women with the highest baseline estradiol levels, breast cancers (39 invasive) were reported. The MORE which suggests that individualized stratification for breast study has been updated47-49 with the most recent report, cancer risk reduction interventions may be possible. This including 77 verified breast cancers of which 59 were hypothesis will require prospective confirmation.
invasive.49 Raloxifene use (combining both dosage arms) Study of Tamoxifen and Raloxifene and Raloxifene for continues to be associated with a significant reduction in Use in the Heart: Definitive raloxifene outcome trials. relative risk of developing invasive breast cancers (RR, Definitive assessment of raloxifene’s influence on breast 0.28; 95% CI, 0.09 to 0.30), especially estrogen receptor– cancer awaits the results from two ongoing randomized positive breast cancers. The absolute reduction in risk of trials (Table 4). The Study of Tamoxifen and Raloxifene developing breast cancer was 1.4 per 100 women given (STAR) trial has randomized more than 13,000 women of a 22,000 recruitment target and is scheduled to report out- The MORE study continues to follow women under an come in 2008 or 2009.45 The Raloxifene for Use in the amended design. Reconsented participants have been con- Heart (RUTH) study has completed recruitment with 10,011 tinued on the original treatment assignment, with those on postmenopausal women and has added breast cancer to the 120-mg/d arm receiving a reduced dose of 60 mg/d (the cardiac disease as a second primary study end point.46 FDA-approved osteoporosis dose). Clinical outcome will be The RUTH trial, with baseline breast cancer risk assess- evaluated at 6 and 8 years after entry.
ment, periodic serial mammography, and randomization Cautions regarding interpretation of the raloxifene data to either raloxifene 60 mg/d or placebo, will report breast expressed in the previous technology assessment are still cancer outcomes in 2005 after completion of the fourth- applicable. A meta-analysis of several randomized trials with 10,575 women (including the MORE trial) previously Pending results of the outcome trials (Table 4), there is reported a smaller (55%) relative reduction in breast cancer currently insufficient evidence to support routine use of risk in the raloxifene arms.50 The current status of an raloxifene for breast cancer risk reduction.
updated report of breast cancer development in these ralox- Raloxifene use in women with resected breast cancer. ifene randomized trials is not available.
Raloxifene reduces mammographic breast density51 and In an intriguing subgroup analysis conducted in 7,290 of breast cancer proliferative indices.52 However, as raloxifene the MORE participants, the placebo group women with has limited activity against advanced breast cancer when Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
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ASCO TECHNOLOGY ASSESSMENT: BREAST CANCER RISK REDUCTION UPDATE 2002 used after tamoxifen53 and does not decrease and may technology assessment, but they have been reviewed increase hot flash frequency,54 there is no basis for substi- elsewhere.66,67 Anastrazole, letrozole, and exemestane tuting raloxifene for tamoxifen in the treatment of adjuvant are all in randomized trials for adjuvant breast cancer breast cancer patients experiencing menopausal symptoms.
therapy. Information from these studies will inform Currently, there are no published data regarding sequen- tial tamoxifen and raloxifene use or use of raloxifene with There is interest in evaluating aromatase inhibitors for HRT. Preclinical studies demonstrating raloxifene stimula- breast cancer risk reduction because estrogen levels are tion of tamoxifen-resistant breast cancers in athymic mice55 strongly related to higher breast cancer risk in postmeno- and raloxifene cross-resistance with tamoxifen53 suggest pausal women68 and estrogen levels are greatly reduced by caution in raloxifene use in women with resected breast cancer who have completed tamoxifen adjuvant therapy.
The Anastrazole, Tamoxifen Alone and Combined trial. Relevant to breast cancer risk reduction are results from an Other Positive and Negative Effects of Raloxifene Use adjuvant trial involving the aromatase inhibitor anastrozole Raloxifene’s toxicity profile remains largely as previ- (Arimidex; AstraZeneca). The Anastrazole, Tamoxifen ously described.1 Published information on raloxifene is alone and Combined (ATAC) trial44 is an international, based on 4 years of use and is limited to postmenopausal multicenter, randomized, double-blind trial that randomized women. Emerging reports regarding raloxifene effects are 9,366 patients with early-stage breast cancer to three treat- ment arms: tamoxifen 20 mg/d, anastrazole 1 mg/d, or the combination for 5 years. Primary study end points included raloxifene 60 mg/d for osteoporosis prevention and therapy disease-free survival and safety/tolerability; new (contralat- in postmenopausal women.56 The disproportionately greater eral) breast cancer primary tumors were a secondary end decrease in vertebral fractures relative to bone density point. Anastrazole, but not the anastrazole plus tamoxifen increase seen with raloxifene57 supports use of clinical combination, was superior to tamoxifen in disease-free outcomes rather than intermediate markers for definitive survival after a median follow-up of 33.4 months (discussed In the ATAC trial, anastrazole use was also associated cardiovascular events when examined as a secondary end with a significant 58% reduction in new contralateral breast point in the previously mentioned MORE trial.58 Raloxifene primary tumors (RR, 0.42 and 95% CI, 0.22 to 0.79 for is associated with a three-fold increase in potentially life- anastrazole compared with tamoxifen groups; P Ͻ .0068).
threatening vascular events (RR, 3.1; 95% CI, 1.5 to 6.2 for The absolute reduction in risk of developing a new con- venous thrombolic events),59 comparable to the risk of these tralateral breast cancer associated with anastrozole com- events with either tamoxifen or HRT use.60 pared with tamoxifen was less than 1%. Currently, 62 new The suggestion from preclinical and early clinical trials61 invasive contralateral breast cancers have occurred in the that raloxifene will have little influence on the endometrium ATAC trial. In comparison, the tamoxifen-associated rela- awaits determination of endometrial cancer rates in ongoing tive risk reduction of 49% in contralateral cancers reported longer-term randomized clinical trials. Raloxifene reduced in the NSABP B-14 adjuvant trial, which provided strong uterine leiomyomas in one randomized trial62 and may impetus for the P-1 trial, was based on the distribution of 83 reduce risk of pelvic floor surgery as well.63 contralateral cancers.70 In the ATAC trial, women on the Given the preclinical studies consistent with neuroprotec- anastrozole arm had significantly fewer vascular and endo- tion,64 raloxifene’s influence on cognition has receivedpreliminary evaluation, with a trend toward less decline in metrial events71 but more musculoskeletal events and frac- tures compared with those on the tamoxifen arm.44,71 Because there are no data on the long-term effects of aromatase inhibitor therapy, these agents should not beused in primary prevention for breast cancer outside of a Clinical Evidence Relevant to the Effect of Aromatase Inhibition on Breast Cancer Risk Reduction Proposed breast cancer risk reduction trials of aro- No full-scale randomized trials evaluating aromatase inhibitor use for primary breast cancer risk reduction (anastrozole, letrozole) and inactivators (exemestane) in have been conducted. A comprehensive comparative advanced breast cancer66 and the emerging effects of review of this class of agents is beyond the scope of this anastrozole on contralateral breast cancer risk44 support Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
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further evaluation of anastrazole and other agents in this studies identified a risk of dementia in estrogen users of 0.71 class for breast cancer risk reduction (Table 4).
(95% CI, 0.53 to 0.96) compared with nonusers.65 However,a randomized trial of estrogen therapy for mild to moderate Alzheimer’s disease showed no effect of 1 year Fenretinide’s influence on contralateral breast cancer risk of therapy on disease progression or on global, cognitive, has been evaluated in one randomized, prospective trial in or functional outcomes.80 The Women’s Health Initiative nearly 3,000 women with early-stage breast cancer. Al- Memory Study will address the question of HRT’s effect though fenretinide had no effect on contralateral breast on cognitive function in a large population of healthy cancer development in the overall study population, a posthoc analysis suggested reduced contralateral breast Observational findings on HRT and epithelial ovarian cancer risk in premenopausal women.72 The agent was cancer are mixed, but a recent large case-control study well tolerated, with diminished dark-vision adaption and associated users of HRT regimens with estrogen alone or dermatologic disorders being the most common adverse sequentially added progestins with increased ovarian events.73 A fenretinide and tamoxifen combination is A full discussion of the risks and benefits of HRT is beyond the scope of the current technology assessment.
Observational studies suggest an association with long-term HRT use and an approximate 35% reduction in primary A practical issue when considering tamoxifen for breast cardiovascular events.76 However, randomized prospective cancer risk reduction is how to balance tamoxifen use clinical trials have recently evaluated HRT’s influence on against the potential benefits of HRT on chronic disease risk clinical end points, including cardiac and vascular events. In and overall mortality. Issues related to combined tamoxifen these trials, HRT use did not result in secondary prevention and HRT use have been discussed previously (see “Tamox- of coronary vascular disease (CVD) or cerebral vascular ifen use with HRT” section, above).
events.83,84 In the large population (Ͼ 27,000) of generally No full-scale randomized clinical trials of HRT have healthy postmenopausal women randomized to HRT or prospectively evaluated HRT’s influence on primary pre- placebo in the ongoing Women’s Health Initiative, interim vention of coronary heart disease or either coronary heart analysis found an increase in the number of myocardial disease–associated mortality or all-cause mortality.
infarctions, strokes, and thromboembolic events in the More recent observational studies suggest an association initial years for women receiving HRT as compared with with HRT use and an increase in breast cancer risk of placebo.85 Continued follow-up of such trials will provide approximately 30%,12 especially for longer use (Ͼ 5 years) definitive assessment of HRT’s influence on CVD and and for regimens with progestins.11,39 Translated into abso- overall mortality. Results from the Women’s Health Initia- lute risk, approximately six excess breast cancers would be anticipated in 1,000 women using HRT for 10 years.75 Use Review of this emerging body of information has led of HRT is associated with an approximate three-fold in- several agencies, including the American Heart Association, crease in life-threatening vascular events and, when used to alter their recommendations regarding HRT. The Asso- without progestins, increased endometrial cancer risk.76 ciation’s recommendations for HRT and CVD now state The approved indications for estrogens used as HRT that “firm recommendations for primary prevention await include symptoms associated with moderate to severe randomized clinical trial results and there is insufficient data menopause and prevention and management of osteoporo- to suggest that HRT should be initiated for the sole purpose sis. Although HRT is often proposed for improving overall health and reducing mortality, recent estimates of HRT’s This technology assessment takes no position regard- influence on mortality are largely based on purported effects ing HRT use in postmenopausal women. However, rec- on cardiac events stemming from observational study re- ommendation of HRT use for cardiovascular disease risk sults and lipid profile influence.77,78 The established effects reduction and overall health or survival benefit should be of HRT in preventing osteoporosis have a relatively small approached using the same risk/benefit algorithm out- impact on mortality because life-threatening fractures tend A favorable effect of HRT on cognition has been pre- dicted from preclinical and observational studies,79 but the Assessment of breast cancer risk is the first step in data are somewhat mixed. A meta-analysis of observational considering tamoxifen use.3,78,88 The most useful model Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
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ASCO TECHNOLOGY ASSESSMENT: BREAST CANCER RISK REDUCTION UPDATE 2002 available for breast cancer risk assessment89 was developed COMPARISON OF QUANTITATIVE APPROACHES FOR by Gail et al90 (the Gail model) and adjusted to take into consideration the lower breast cancer risk of Hispanic Survey research has identified some reluctance of women women. Rockhill et al91 used data from white women in the to favorably consider tamoxifen for breast cancer risk Nurses Health Study to address this Gail model’s validity.
reduction.95,96 The current status of methods to communi- In their analyses, the model did well in predicting breast cate risk and benefits of tamoxifen in a risk reduction setting cancer risk in subgroups of women (“calibration”) but had are outlined below in a discussion of approaches to estimate only modest ability to discriminate whether an individual positive and negative effects of tamoxifen. The global woman would or would not develop breast cancer (“dis- effects of tamoxifen use for breast cancer risk reduction criminatory accuracy”). Since tamoxifen’s influence on have been estimated using approaches that differ in clinical breast cancer risk is limited to receptor-positive disease, outcomes considered, assumed duration of tamoxifen effect, development of improved approaches to more accurately the perspective of analysis (individual v society v third-party assess an individual woman’s risk of developing receptor- payer), assigned values of risks and benefits, and method- positive tumors is a priority research issue.
ologies used for integrating outcomes (Table 5).
The Gail model does not incorporate information needed to assess germline mutation carrier status or several other Gail Model to Estimate Positive and Negative Effects of high-breast-cancer-risk situations, such as prior thoracic radiation.92 Thus, additional information must be collected The only model currently available in a format allowing to determine whether use of the Gail model is appropriate.
calculation of an individual risk/benefit assessment for Issues related to genetic susceptibility testing and, in tamoxifen use was developed by Gail et al.97 Using infor- particular, evaluation for BRCA1 and BRCA2 are reviewed mation from a variety of sources, this model generates elsewhere.78,88 Factors related to having 10% or greater risk tabular estimates of net benefit and risk of tamoxifen use in of germline mutation include the following: known BRCA1 groups of women according to 5-year breast cancer risk, and BRCA2 family mutation, breast and ovarian cancer in age, presence or absence of uterus, and race. The number of the same family member, two or more family members health outcomes either induced or prevented by 5 years of under age 50 with breast cancer, male breast cancer, one or tamoxifen use was estimated. A net benefit/risk index was more family members under age 50 with breast cancer plus derived by assigning weights to each clinical event and Ashkenazi ancestry, ovarian cancer plus Ashkenazi ances- try, and breast cancer before age 40. Women whose history Because models make assumptions about potential ben- suggests breast cancer germline mutation are not appropri- efit (greatest in women with high risk of breast cancer) and ate candidates for use of the Gail model, as their risk would greatest risk (generally older women who are at more be underestimated. Such women are candidates for genetic jeopardy for thromboembolism and uterine cancer), these models predict that young women should experience a For women without prior breast cancer or who are not at better benefit/risk ratio. Such studies do not factor in other increased risk for BRCA1/BRCA2, use of the Gail model is sequelae, such as menopausal symptoms or sexual dysfunc- appropriate as long as there are no family members with tion, that may be more problematic in younger women.
breast cancer diagnosed before age 50. In those circum- Application of the Gail model suggests that tamoxifen stances, the Claus model tables, which incorporate detailed is most beneficial in younger women at higher breast cancer risk and those without a uterus. African-American Information on breast cancer risk for both medical and women are anticipated to have less tamoxifen benefit nonmedical personnel is available from the Internet at the based largely on increased risk of a vascular event and National Cancer Institute’s PDQ breast cancer prevention site, http://www.cancer.gov/cancer_information/.
Although clinically useful, the Gail model predicted With regard to breast cancer risk assessment in the future, outcomes only in the 5-year treatment period, the assump- additional diagnostic and laboratory tests are being evalu- tions in developing the risk/benefit index have not been ated for breast cancer risk assessment. They include bone validated, and some results are sensitive to minor changes in density, mammographic breast density, circulatory estradiol weights assigned to utilities. The weights assigned to the levels, and breast cells collected by a variety of tech- clinical outcomes were neither empirically derived nor niques.94 The role of these procedures in clinical practice is preference-based and do not reflect differences in mortality, beyond the scope of the present technology assessment.
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Table 5. Summary of Analytic Approaches to Weighing the Risks and Benefits of Tamoxifen
status; impact oftamoxifen onBRCA1/2 isinferred based onER status Abbreviations: CHD, coronary heart disease; VTE, venous thrombotic events, including both pulmonary embolism (PE) and deep venous thrombosis (DVT); ER, estrogen receptor; TIA, transient ischemic attacks.
*Other clinical outcomes were included but assigned a weight of zero, which effectively excluded them from the benefit-risk index.
hood of incurring most adverse effects except for endome- use to be cost-effective overall, considering all medical event– trial cancer was based only on age not individual disease related costs compared with no tamoxifen use. Duffy and risk. Despite these concerns, the Gail model provides the Nixon101 used meta-analytic techniques to estimate the impact best available beginning framework for risk calculation.
of tamoxifen among BRCA1/BRCA2 carriers, finding tamox- New strategies and decision aids that incorporate mortal- ifen to be more effective among BRCA2 carriers (27% risk ity estimates and carry-over effects of tamoxifen are under reduction) than among BRCA1 carriers (no significant reduc- development99 and are described below.
tion). The impact of tamoxifen on BRCA1/BRCA2 carrierswas inferred by assuming that the effect of tamoxifen is Other Models to Estimate Positive and Negative Effects of dependent on estrogen receptor status, determining the proportion of estrogen receptor–positive tumors among Smith and Hillner,100 in a cost-effectiveness analysis based BRCA1 and BRCA2 mutation carriers, and computing a on tamoxifen effects seen in P-1 over 5 years, found tamoxifen weighted average for BRCA1/BRCA2 carriers.
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ASCO TECHNOLOGY ASSESSMENT: BREAST CANCER RISK REDUCTION UPDATE 2002 Markov Modeling of Clinical Outcomes emerged since the last review concerning communication of modeling, each clinical outcome is valued according to its risk to women who are at moderate breast cancer risk.
survival or quality-adjusted survival impact, with time- Women typically overestimate their risk of breast can- dependent rates and utilities assigned to each outcome.102 cer,106 emphasizing the importance of effective communi- Survival projections involve extrapolation based on as- cation of breast cancer risk in this setting. Relative risk sumptions concerning long-term effects of treatment (where describes the ratio of the risk of disease in one group information is often limited). Differences between the compared with that in another, does not take into consider- various published Markov models exploring tamoxifen ation a person’s baseline risk, and does not describe the magnitude of the absolute risk. Absolute risk varies accord- The models of Hershman et al103 and Grann et al104 ing to baseline level of risk and could be very small when predict that tamoxifen use increases life expectancy of the disease is uncommon. Overall, women should be given higher-risk women by 69 days for 35-year-olds and 27 days information that presents the risks and benefits of any for 60-year-olds. The practical application of the predictions intervention using both absolute and relative terms.107 of quality-adjusted survival in this model is limited by the How risk information is presented,108-110 worded,107 and assignment of utilities (hip fracture was assigned a lower framed111,112 may affect its interpretation.113 Framing the utility than metastatic breast cancer). Women with and benefits (ie, gains) of treatment in relative rather than without a uterus were treated equally, precluding determi- absolute terms can affect a patient’s perception of a thera- nations involving endometrial cancer risk.
py’s effectiveness,114 making the benefits of a treatment Will et al,105 using data from Canadian cancer regis- appear more favorable115 or, conversely, emphasizing its tries and vital statistics to simulate effects of tamoxifen under a range of assumptions, incorporated all P-1 Most framing studies have focused on a treatment’s effect outcomes and calculated that tamoxifen would extend life on a single outcome over a single time horizon.112 Women expectancy among women whose 5-year predicted risk deciding on tamoxifen therapy need to consider its effects (both beneficial and harmful) on several outcomes over an Col et al99 used a Markov model to address the impact of extended time horizon. A study examining patient prefer- tamoxifen among postmenopausal women at varying levels ences for communicating complex risk information117 of risk for breast and endometrial cancer and hip fracture.
found that patients preferred risk estimates framed in This model incorporates individual risk factors for both the absolute rather than relative terms, graphical and textual benefits and principal harms of tamoxifen and is the only explanations provided together, and risk estimates given published model to include residual impact of tamoxifen over more than one time horizon. In addition, use of based on the most recent EBCTCG update.14 This model contextual and graphical displays may improve understand- predicts that tamoxifen use in 50-year-old women without a ing of numerical risk/benefit information.110 Efforts are uterus results in an increased life expectancy of 1 to 4 underway to develop such platforms for general clinical use.
months, whereas women with a uterus have gains only if In sum, the communication of tamoxifen’s risks and they are at higher breast cancer risk. Tamoxifen carry-over benefits should include both absolute and relative informa-tion over a relevant time period. Attention should be paid to effects on breast and endometrial cancer risk have a strong how the information is framed and presented.
impact on the benefit/risk survival profile.
These Markov models are complex and are constrained by the quality of the informing data. Despite the limitations, each model adds insight into assessing the risks and benefitsof tamoxifen. None of the Markov models described has The recommendations of this technology assessment been assessed for validity or is available in a format update regarding tamoxifen and raloxifene are in substan- allowing for individual patient data entry. Attempts are tive agreement with two recently published guidelines underway to develop such programs for routine clinical use.
from other agencies generated under slightly differenttime frames.118,119 CHALLENGES IN COMMUNICATING TAMOXIFEN’S The Working Group expresses its gratitude to Robert F. Ozols, MD, To make informed decisions regarding breast cancer risk Trevor J. Powles, MD, and the American Society of Clinical Oncolo- reduction, women need to understand the risks and benefits gy’s Health Services Research Committee for their thoughtful review of any proposed intervention. Limited publications have of earlier drafts of the technology assessment.
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The appendix listing the members of the ASCO Risk Reduction Update Working Group is available online at 1. Chlebowski RT, Collyar DE, Somerfield MR, et al: American 18. King MC, Wieand S, Hale K, et al: Tamoxifen and breast cancer Society of Clinical Oncology technology assessment on breast cancer incidence among women with inherited mutations in BRCA1 and risk reduction strategies: Tamoxifen and raloxifene. J Clin Oncol BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 286:2251-2256, 2. Chlebowski R: Primary care: Reducing the risk of breast cancer.
19. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of 3. Chlebowski RT: Breast cancer risk reduction: Strategies for contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A women at increased risk. Annu Rev Med 51:519-540, 2002 case-control study—Hereditary Breast Cancer Clinical Study Group.
4. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant 20. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen in treatment Breast and Bowel Project P-1 study. J Natl Cancer Inst 90:1371-1388, of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353:1993- 5. Powles T, Eeles R, Ashley S, et al: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital Tamoxifen 21. Delozier T, Switsers O, Genot JY, et al: Delayed adjuvant Randomized Chemoprevention Trial. Lancet 352:98-101, 1998 tamoxifen: Ten-year results of a collaborative randomized controlled 6. Veronesi U, Maisonneuve P, Costa A, et al: Prevention of breast trial in early breast cancer (TAM-02 trial). Ann Oncol 11:515-519, cancer with tamoxifen: Preliminary findings from the Italian random- ized trial among hysterectomized women. Lancet 352:93-97, 1998 22. Gradishar WJ, Hellmund R: A rationale for the reinitiation of 7. Cuzick J: Update on new studies in Europe. Eur J Cancer 38:S20, adjuvant tamoxifen therapy in women receiving fewer than 5 years of therapy. Clin Breast Cancer 2:282-286, 2002 8. Cuzick J: A brief review of the International Breast Cancer 23. McCaskill-Stevens W, Bryant J, Costantino J, et al: Incidence of Intervention Study (IBIS), the other current breast cancer prevention contralateral breast cancer (CBC), endometrial cancer (EC) and throm- trials, and proposals for future trials. Ann NY Acad Sci 949:123-133, boembolic events (TE) in African American (AA) women receiving tamoxifen for treatment of primary breast cancer. Proc Am Soc Clin 9. Li CI, Malone KE, Weiss NS, et al: Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer. J Natl 24. Braithwaite R, Law J, Chlebowski RT, et al: A meta-analysis of vascular and neoplastic events associated with tamoxifen. Med Deci- 10. Veronesi U, Maisonneuve P, Sacchini V, et al: Tamoxifen for breast cancer among hysterectomised women. Lancet 359:1122-1124, 25. Mourits MJ, De Vries EG, Willemse PH, et al: Tamoxifen treatment and gynecologic side effects: A review. Obstet Gynecol 11. Ross RK, Paganini-Hill A, Wan PC, et al: Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen 26. National Institutes of Health: National Institutes of Health plus progestin. J Natl Cancer Inst 92:328-332, 2000 consensus development conference statement: Adjuvant therapy for 12. Chen CL, Weiss NS, Newcomb P, et al: Hormone replacement breast cancer. J Natl Cancer Inst Monogr 30:5-15, 2001 therapy in relation to breast cancer. JAMA 287:734-741, 2002 27. Bertelli G, Valenzano M, Del Mastro L, et al: Endometrial 13. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen abnormalities in breast cancer patients receiving adjuvant tamoxifen for early breast cancer: An overview of the randomised trials. Lancet persist after treatment completion. Proc Am Soc Clin Oncol 20:36a, 14. Peto R: Tamoxifen as Adjuvant Breast Cancer Therapy. Pre- 28. Day R, Ganz PA, Costantino JP: Tamoxifen and depression: sented at the NIH Consensus Development Conference on Adjuvant More evidence from the National Surgical Adjuvant Breast and Bowel Therapy for Breast Cancer, http://videocast.nih.gov, 2000 Project’s breast cancer prevention (P-1) randomized study. J Natl 15. Swain SM, Wilson J, Eleftherios M, et al: Estrogen receptor (ER) status of primary breast cancer is predictive of ER status of 29. Day R, Ganz PA, Constantino JP, et al: Health-related quality of contralateral breast cancer (CBC). Proc Am Soc Clin Oncol 21:38a, life and tamoxifen in breast cancer prevention: A report for the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin 16. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: Updated 30. Berglund G, Nystedt M, Bolund C, et al: Effect of endocrine findings from the National Surgical Adjuvant Breast and Bowel Project treatment on sexuality in premenopausal breast cancer patients: A B-14 randomized trial. J Natl Cancer Inst 93:684-690, 2001 prospective randomized study. J Clin Oncol 19:2788-2796, 2001 17. Tan-Chiu E, Costantino J, Wang J, et al: The effect of tamoxifen 31. Fallowfield L, Fleissig A, Edwards R, et al: Tamoxifen for the on benign breast disease: Findings from the Nationial Surgical Adju- prevention of breast cancer: Psychosocial impact on women participat- vant Breast and Bowel Project (NSABP) Breast Cancer Prevention ing in two randomized controlled trials. J Clin Oncol 19:1885-1892, Trial (BCPT). San Antonio Breast Cancer Symposium, 2001 (abstr 7) Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
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ASCO TECHNOLOGY ASSESSMENT: BREAST CANCER RISK REDUCTION UPDATE 2002 32. Chlebowski RT, Ernst T, Chang L, et al: Tamoxifen and 50. Jordan VC, Glusman JE, Eckert S, et al: Incident primary breast estrogen effects on brain chemistry determined by MRI spectroscopy.
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69. Winer EP, Hudis C, Burstein HJ, et al: American Society of 87. Mosca L, Collins P, Herrington DM, et al: Hormone replace- Clinical Oncology technology assessment on the use of aromatase ment therapy and cardiovascular disease: A statement for healthcare inhibitors as adjuvant therapy for women with hormone receptor– positive professionals from the American Heart Association. Circulation 104: breast cancer: Status report 2002. J Clin Oncol 20:3317-3327, 2002 70. Fisher B, Costantino J, Redmond C, et al: A randomized clinical 88. Nathanson KN, Wooster R, Weber BL: Breast cancer genetics: trial evaluating tamoxifen in the treatment of patients with node- What we know and what we need to know. Nat Med 7:552-556, 2001 negative breast cancer who have estrogen-receptor-positive tumors.
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perceptions of breast cancer risk: How you ask matters. Med Decis Downloaded from jco.ascopubs.org on May 20, 2011. For personal use only. No other uses without permission.
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Anthraxguide 09

Anthrax is an infection caused by bacteria which form protective spores to survive in extreme conditions, enabling it to survive forlong periods of time. When we come into contact with these spores an infection may result, but not always. Anthrax can be quitedifficult to contract. There are three distinct types of anthrax infection:This is the most common infection caused by skin contact,

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J Clin Endocrin Metab. First published ahead of print April 30, 2013 as doi:10.1210/jc.2012-3893 Molecular Diagnosis of 5 ␣ -Reductase Deficiency in 4 Elite Young Female Athletes Through Hormonal Screening for Hyperandrogenism Patrick Fénichel, Françoise Paris, Pascal Philibert, Sylvie Hiéronimus, Laura Gaspari,Jean-Yves Kurzenne, Patrick Chevallier, Stéphane Bermon, Nicolas Chevalie

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