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American Society of Clinical Oncology Technology Assessment on Breast Cancer Risk Reduction Strategies: Tamoxifen and Raloxifene

From the American Society of Clinical Oncology, Alexandria, VA.

Address reprint requests to American Society of Clinical Oncology, Health Services Research Department, 225 Reinekers Lane, Suite 650, Alexandria, VA 22314; email guidelines{at}asco.org

ABSTRACT

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 Table 1 for a summary of conclusions.)

SPONSOR: American Society of Clinical Oncology.

BREAST CANCER REPRESENTS the leading cause of cancer and the second leading cause of cancer death for women in the United States. Despite improvements in therapies and widespread application of early-detection procedures, annual mortality from this disease has remained unchanged until perhaps recently.¹ In this context, the report from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1² investigators about the effect of tamoxifen (Nolvadex; Zeneca, Wilmington, DE) on the incidence of breast cancer in a population at increased risk demands particular attention.

The results of the NSABP P-1 trial² has led the United States Food and Drug Administration (FDA) to approve the use of tamoxifen to "reduce the incidence of breast cancer in women at high risk" for this disease.³ These events, together with early reports on the effects of another selective estrogen receptor modulator (SERM), raloxifene (Evista; Eli Lilly and Company, Indianapolis, IN),^4-6 have prompted the American Society of Clinical Oncology (ASCO) to conduct a technology assessment of tamoxifen and raloxifene for use as breast cancer risk-reduction strategies.

Technology Assessment Process

A technology assessment is a process for determining whether a procedure is appropriate for broad-based conventional usage in clinical practice. The process used in this technology assessment followed defined ASCO policies and procedures; these policies and procedures are similar to those published elsewhere^7,8 and used for the development of ASCO Clinical Practice Guidelines. For a technology assessment, a Working Group composed of the majority of the ASCO Health Services Research Committee (HSRC) and selected ad hoc members, rather than a designated expert panel, conducts the literature review and analyzes the outcomes-based evidence. Testimony is collected from invited experts and interested parties. After evaluating this information, the Working Group defines specific questions and provides a report outlining conditions under which the proposed procedures are warranted, to assist both physicians and patients in making informed decisions regarding the technologies or procedures.

The Working Group for this assessment was composed of core members from the HSRC and ad hoc members who provided needed content expertise in relevant disciplines, which included medical oncology, gynecology and gynecologic oncology, radiation oncology, surgical oncology, genetics, endocrinology, basic biology, pharmacology, epidemiology, statistics, and prevention (Appendix A). Both academic and community practitioners were represented, as were major investigators in the most relevant clinical trials.

Input from the nonmedical community, including patients and advocacy groups, was sought. Deborah Collyar, President, Patient Advocates in Research, served as Co-Chair of the Working Group, and three additional patient advocates were among the Working Group members. In addition, input from other identified patient representatives/advocacy groups with interest in this question was sought through an informal and exploratory solicitation of representative, selected, national, breast cancer advocacy groups. Some national groups declined participation. Responses received from patient representatives/advocacy groups by January 31, 1999, were considered in the development of the report (see Acknowledgments).

Literature Review and Data Collection

The literature on randomized clinical trials that directly address the issue of breast cancer risk reduction using tamoxifen and/or raloxifene is limited, with data from three trials involving tamoxifen^2,9,10 and two involving raloxifene^4,6,11 presented within the past year. Other reports concerning these agents might be expected to provide critical information regarding both therapeutic efficacy and side effects. Therefore, a comprehensive, formal literature review was conducted with the OncoView program (Pracon, Reston, VA) (which incorporates MEDLINE, Cancer Lit, and selected scientific Web sites on the Internet). The literature review sought references from 1990 to 1998 on tamoxifen, tamoxifen and 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. A parallel search was performed for raloxifene.

More weight was given to publications that described randomized trials. Of 2,134 clinical references identified and considered, 102 are referenced in this report. Given the emerging nature of the evidence, attempts were made to update the primary published information, particularly for the major clinical trials involving tamoxifen and raloxifene. This was done by including key investigators on the Working Group and inviting relevant corporate entities to submit the most current clinical evidence in writing (see Acknowledgments).

Consensus Development Based on Evidence

The Working Group identified specific questions to be addressed by the technology assessment, developed a strategy for completing the technology assessment, and reviewed the available literature and evidence. The process included three face-to-face meetings of available Working Group members over a 4-month period and circulation of primary information and draft forms of the technology assessment to all Working Group members, with opportunity for comment. The technology assessment satisfied ASCO policy-defined internal review procedures. The content of the technology assessment and the resulting manuscript were reviewed and approved by the HSRC and by the ASCO Board of Directors before dissemination.

The Working Group did not attempt to codify established practice. Group members reviewed the available evidence and added their best clinical judgment to make final recommendations.

Major Questions Posed

The technology assessment Working Group developed a series of questions about breast cancer risk-reduction strategies with tamoxifen and raloxifene. These questions are listed below and were answered after a review of the relevant evidence for each drug in this report.

• Is there strong or credible evidence to conclude that tamoxifen or raloxifene will reduce the risk of developing breast cancer?

• Is there strong or credible evidence to conclude that tamoxifen or raloxifene will reduce the risk of dying from breast cancer for women who do not have breast cancer?

• Is there strong or credible evidence to conclude that there is a net health benefit and improvement in overall survival associated with tamoxifen or raloxifene use for women who do not have breast cancer if taken to reduce the risk of this disease?

In addition, the effective and responsible communication by physicians of issues regarding breast cancer risk reduction to women considering use of these agents was also addressed on a preliminary basis.

Technology Assessment and Conflict of Interest

All members of the Working Group complied with ASCO policy on conflict of interest, which requires disclosure of any interest (financial or otherwise) that might be construed as constituting an actual, potential, or apparent conflict. Members completed ASCO's disclosure form and were asked to reveal ties to companies developing products that might potentially be affected by promulgation of the technology assessment report. Information was requested regarding employment, consultant status, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. The Co-Chairs of the Working Group, the Chair of the HSRC, and the Director of the ASCO Health Services Research Department reviewed these disclosures on a case-by-case basis.

Technology Assessment Revision Dates

The technology assessment initiated by this report represents an ongoing process. At annual intervals, the Working Group chairpersons and two members designated by the chairpersons will determine the need for revisions to the technology assessment based on an examination of current literature. The entire Working Group will be reconvened to discuss potential changes every 3 years, or more frequently if new information suggests that more timely modification is warranted. When appropriate, the Working Group will recommend revisions in the technology assessment to the HSRC and the ASCO Board for review and approval.

TAMOXIFEN

Tamoxifen and Breast Cancer: Background
There is considerable clinical experience with tamoxifen citrate (Nolvadex) in breast cancer therapy since it was approved by the FDA for use in advanced disease in 1978.¹² The most recent worldwide overview of the Early Breast Cancer Trialists' Cooperative Group (EBCTCG) confirmed the efficacy of tamoxifen as adjuvant therapy in women with estrogen receptor–positive cancers.¹³ This analysis, which included 29,441 patients with receptor-positive or receptor-unknown breast cancer, demonstrated that use of adjuvant tamoxifen for 5 years reduced breast cancer recurrence by 47%, with a corresponding reduction in overall mortality of 26% (P < .00001).

In the EBCTCG overview,¹³ tamoxifen given for different durations was associated with a reduction in the incidence of contralateral breast cancer (P < .00001, based on 854 contralateral breast cancers), and there was a significant trend for increased benefit (fewer contralateral cancers) with longer tamoxifen duration (up to 5 years).¹³ In the subgroup of 7,427 patients who received adjuvant tamoxifen for 5 years, the proportional risk of contralateral breast cancer was reduced by 47%, with 93 versus 159 events for those allocated to tamoxifen versus control, respectively (P < .00001). Most recently, the NSABP reported¹⁴ that tamoxifen reduced invasive breast cancer by 45% in the ipsilateral breast when it was used as an adjuvant to resection and radiation in patients with ductal carcinoma-in-situ (DCIS). These data are consistent with early reports^15-17 that suggested an effect of tamoxifen against subclinical breast cancer and that supported prospective evaluation of tamoxifen in women at risk for breast cancer.

Tamoxifen in Randomized Breast Cancer Prevention Trials
NSABP P-1 clinical trial. The Breast Cancer Prevention Trial (NSABP P-1) was a double-blind, randomized, placebo-controlled, clinical trial with a primary objective to determine whether 5 years of tamoxifen therapy at a 20 mg/d would reduce the incidence of invasive breast cancer in women at increased risk for this disease.² Women who were 60 years of age or older or who had lobular carcinoma-in-situ (LCIS) were deemed at sufficient risk to be eligible; other eligible women had to be at least 35 years of age and had to have a 5-year predicted risk of breast cancer development of 1.66%, as determined by the previously validated¹⁸ Gail model.¹⁹ To determine risk, the Gail model considers age, number of first-degree relatives with breast cancer, number of previous breast biopsies, presence of atypical hyperplasia, age of first live birth, and age at menarche. The average risk of breast cancer for women in P-1, as measured in the Gail model for women, was 3.2%.

In total, 13,388 women were randomized to receive tamoxifen or placebo. Through the duration of the trial, 78% of participants continued on therapy. When the trial was terminated on the recommendation of the independent monitoring committee, tamoxifen was found to have reduced the relative risk (RR) of invasive cancer by 49% (P < .00001), with cumulative incidence rates through 69 follow-up months of 43.4 versus 22.0 per 1,000 women in the placebo and tamoxifen groups, respectively. In the tamoxifen group, there was a 1.3% risk of developing breast cancer at 5 years (89 cancer cases). In the placebo group, there was a 2.6% risk of developing breast cancer at 5 years (175 cancer cases). Overall absolute risk reduction at 5 years was 1.3%.

The decreased breast cancer risk was seen in all age groups: women 49 years or younger (44% reduction), women 50 to 59 years of age (51% reduction), and women 60 years or older (55% reduction). All breast cancer risk reduction was seen in the occurrence of receptor-positive tumors, with no difference in the incidence of receptor-negative tumors diagnosed in the two groups. The incidence of noninvasive breast cancer was also decreased by tamoxifen to a comparable degree (50% reduction in RR, P < .002).

Breast cancer risk reduction was seen in women with a history of LCIS (56% reduction) and in those with atypical hyperplasia (86% reduction) as well, but these RR reductions are based on a limited number of events (Table 2).

These data provided the basis for the FDA-approved indication for tamoxifen (Nolvadex) to "reduce the incidence of breast cancer in women at a high risk" for this disease. In this context, high risk was defined according to the P-1 eligibility criteria, ie, women at least 35 years of age with a 5-year predicted risk of breast cancer development of 1.66%, as calculated by the Gail model.

The significant reduction (P < .00001) in breast cancer incidence (both invasive and noninvasive) associated with tamoxifen in the P-1 trial is consistent with the efficacy of tamoxifen in other breast cancer treatment settings.^5,12-14 The P-1 results provide confirmation of the observed effect on new breast cancer incidence reported in the adjuvant setting, where a significant (P < .00001) reduction in contralateral breast cancer was associated with adjuvant tamoxifen use.¹³ The large number of cases of breast cancer in these trials and the consistency of the findings make a compelling case that tamoxifen treatment does reduce the incidence of new breast cancers.

European clinical trials. Two randomized European trials have also evaluated the use of tamoxifen to reduce the risk of breast cancer.^9,10 The United Kingdom (UK) and Italian prevention studies differed from the P-1 trial in that they were smaller (entering 2,471 and 5,408 women, respectively, v 13,388 for the P-1 trial), had fewer breast cancer events (P-1, n = 368; UK study, n = 70; Italian study, n = 41), permitted concurrent hormone replacement therapy (HRT), and included populations of different risk (Table 3). Of interest, these studies reported no effect of tamoxifen on the incidence of breast cancer.

Issues of study size and population characteristics, concurrent HRT use, and differential compliance have been offered to explain the discrepancy in results. However, other, as-yet-unidentified factors may be involved as well.^20,21 With respect to hormonal factors, of the UK trial participants, 42% had "ever received" HRT and 26% received HRT while on study. No P-1 participants received HRT while on study, but 33% had "ever received" HRT.² In the Italian trial, HRT use was permitted and an effect of tamoxifen on breast cancer risk was seen only in the subgroup receiving HRT,¹⁰ an observation based on extremely small numbers. Even taken together, the limited number of breast cancers in the two European studies precludes reliable evaluation of any interaction between HRT and tamoxifen.

The lack of tamoxifen effect in the Italian trial is not surprising given its small size, low-risk population (48% with bilateral oophorectomy and no breast cancer risk factor requirement), and limited compliance, with only 149 participants completing 5 years of treatment.

The apparently contradictory results of the UK trial are more difficult to explain. The UK trial was initiated as a feasibility trial rather than a definitive outcome trial and subsequently received extended follow-up. It involved a younger population (62% < 50 years old v 39%, for the UK v P-1 trial, respectively) with much stronger family histories of breast cancer (96% with first-degree relatives with breast cancer v 76%, for the UK and P-1 trials, respectively). The UK trial also used a different statistical model to estimate breast cancer risk.²² Whereas the American and European studies are dissimilar in some regard, the strikingly negative results seen in the younger patient population with a strong family history in the UK trial have no current explanation aside from the somewhat unlikely play of chance, since the study was designed to have a power of 90% to detect a 50% reduction^9,20 in breast cancer. Alternatively, the UK trial included an overrepresentation (compared with the P-1 trial) of younger women who, because of their family history (not necessarily involving BRCA1/2), may have been at greater risk for the development of tumors not influenced by tamoxifen use.

The investigators of the P-1 trial are planning to test a subgroup of their participants for mutations in the BRCA1 and BRCA2 genes in order to determine whether tamoxifen lowered the breast cancer incidence in women who carry these high-risk alleles. However, the attributable risk for breast cancer caused by BRCA1/2 in the population at large is relatively low.²³ Furthermore, the determination of BRCA1/2 alone cannot be used to determine reliably the comparative "genetic" risk for the P-1 and UK study populations. Thus, while addressing a specific important question, direct gene testing of BRCA1/2 is unlikely to explain fully the discrepancy in the P-1 and UK studies. However, clarification of whether tamoxifen is effective in younger individuals with identified genetic abnormalities that place them at substantial breast cancer risk is of considerable importance in light of the increasing attention being given to prophylactic mastectomy^24,25 in this setting.

Breast Cancer Mortality and Tamoxifen
Reliable information on the effect of tamoxifen on overall or breast cancer–specific mortality is not available. Projections from the experience of tamoxifen use in the adjuvant setting suggest that a favorable impact on survival could be anticipated, as a reduction in breast cancer recurrence at 5 years is associated with reduced mortality at 10 years.¹³ However, the magnitude of any mortality influence cannot be reliably projected in a risk reduction setting based on mortality reductions seen in the adjuvant setting.^13,26,27 For example, the noninvasive breast cancers prevented by tamoxifen would be expected to have little potential to cause death.

More information on the survival issue will be available as the International Breast Cancer Intervention Study continues accrual (currently exceeding 4,000 women) to a placebo-controlled tamoxifen risk reduction trial. Longer follow-up may also provide information on the potential interaction of tamoxifen and HRT on breast cancer risk as well as their potential impact on other diseases. P-1 will not be helpful in this regard, because women on the placebo arm were allowed to cross over to tamoxifen before survival end points could be reasonably determined, and because P-1 participants will be candidates for subsequent breast cancer risk reduction trials.

Tamoxifen in Other Breast Cancer Situations
DCIS and tamoxifen. Women with a history of DCIS were not eligible for the P-1 trial, but they are at identified risk for both a second primary breast cancer and recurrent invasive disease. The 3.3% risk of contralateral breast cancer alone in women with DCIS is comparable to the 5-year risk of all invasive breast cancer in the placebo arm of the P-1.² In DCIS patients treated with lumpectomy and radiation, tamoxifen reduced subsequent invasive cancers by 47% (3.4% v 2.1% incidence for placebo and tamoxifen, respectively). When all new breast cancer events are considered, the 5-year incidence rate (including contralateral second primary tumors) in women with DCIS is reduced from 13% to 8.8% by tamoxifen, a statistically significant reduction of 44%.¹⁴

Delayed adjuvant tamoxifen. Another frequent clinical question concerns the role of tamoxifen in women with a history of breast cancer who have not received adjuvant tamoxifen. These patients remain at risk for clinical breast cancer recurrence for at least 10 to 15 years after diagnosis.^13,28 They are also at risk for contralateral breast cancer development at a rate of approximately 0.6% per year.^13,28 In the EBCTCG overview, the receptor status of the original cancer was not predictive of subsequent risk reduction of contralateral disease in this setting. A tamoxifen-associated reduction in contralateral breast cancer in women with receptor-negative primary tumors was comparable to that seen in women with receptor-positive primary tumors.¹³

The effect of "delayed" adjuvant tamoxifen use on breast cancer recurrence has been addressed in a French National Cancer Center Trial.^29,30 A total of 524 breast cancer patients who had received no hormonal treatment and who had been diagnosed at least 2 years earlier were randomized to receive either tamoxifen or control. A 38% reduction in recurrence (P = .06) was seen.²⁹ Delayed adjuvant tamoxifen therapy has also been studied in a group of 140 breast cancer patients who were recruited from 2 months to 10 years after diagnosis; a favorable effect on survival (P < .05) was reported for tamoxifen. However, this result was based on only 14 total deaths.³¹

Endometrial Cancer and Tamoxifen
In the NSABP P-1 trial, the risk of invasive endometrial cancer for women without a hysterectomy was significantly increased in the tamoxifen compared with placebo groups, with an RR of 2.53 (95% confidence interval [CI], 1.35 to 4.97) and a rate of endometrial cancer development of 2.29 per 1,000 women years on tamoxifen. The increase was seen almost exclusively in women older than 50 years of age.² The best available information^2,32,33 suggests that endometrial cancers in tamoxifen-treated women are not more aggressive than those occurring in other circumstances. Nonetheless, in this setting, endometrial cancer represents a risk of great concern among many women evaluating the risks and benefits of taking tamoxifen.

The EBCTCG overview indicates that use of tamoxifen for approximately 2 years doubles—and for 5 years, quadruples—the risk of endometrial cancer. This increased risk is associated with an excess of death from endometrial cancer of about one to two per 1,000 postmenopausal women treated with tamoxifen who have a uterus.¹³ Providing one context for these results are three large adjuvant trials of tamoxifen that included both contralateral breast cancer and endometrial cancer incidence as outcomes. In these adjuvant trials, the increase in endometrial cancer was about half as large as the decrease in contralateral breast cancer,^33-35 and endometrial cancer less commonly results in a fatal outcome. Such results obviously depend on the absolute risk for the two diseases, which would differ in otherwise healthy women compared with women with breast cancer treated in an adjuvant setting.

For women receiving tamoxifen, a variety of follow-up and screening procedures have been proposed^36-38 to reduce the risk of endometrial cancer. These procedures include gynecologic examination, Pap smear, transvaginal sonography, endometrial biopsy, and office hysteroscopy.^36-40 However, these approaches represent expert opinion rather than evidence-based recommendations, as the effectiveness of such strategies in preventing deaths from endometrial cancer has not been established. There is a high frequency of endometrial proliferation associated with tamoxifen administration.⁴¹ A lack of endometrial proliferation, as measured by transvaginal sonography, may provide some assurance of safety for continued tamoxifen use,⁴² but data are lacking that such screening procedures provide clinical benefit. The American College of Obstetricians and Gynecologists recommends the approach used in the P-1 trial: annual gynecologic evaluations, including Pap smears and pelvic examinations with careful history, and thorough evaluation of any abnormal bleeding for all women receiving tamoxifen.³⁶

Coronary Heart Disease and Tamoxifen
The NSABP P-1 study is the first large clinical trial of tamoxifen in which cardiovascular mortality events represented a prospective study end point.² No benefit of tamoxifen on such events was seen. Of the 133 ischemic heart disease events identified, 62 occurred in the placebo group and 71 in the tamoxifen group (not significant). How does the negative result of tamoxifen on coronary heart disease (CHD) events in the P-1 trial compare with prior reports on this question?

For more than a decade, tamoxifen has consistently been described as favorably influencing the lipid profile, which has been used as an intermediate marker of CHD effect.^43,44 As recently summarized by Bilimoria et al,⁴⁵ tamoxifen decreases serum levels of total cholesterol (-13%) and low-density lipoprotein cholesterol (-19%); however, unlike estrogen, tamoxifen does not increase the levels of high-density lipoprotein cholesterol (not significant). More recently, homocysteine reduction as a marker of reduced CHD risk has been described with tamoxifen as well.⁴⁶

Clinical evidence of tamoxifen's effect on actual CHD-related outcome is summarized below and in Table 4. Tamoxifen use has been associated with a reduction in CHD events in retrospective reports of three randomized trials.^34,47-49 The effect of tamoxifen on CHD events and/or deaths in these adjuvant trials was modest. In a comparison of tamoxifen and the control intervention in the Scottish trial^34,48 with 1,070 patients, 25 CHD events were seen among control patients, compared with 10 CHD events (fatal myocardial infarction) among tamoxifen-treated patients. In the Scandinavian trial⁴⁹ with 2,365 patients, 14 events were seen among control patients, compared with 12 events (cardiac disease as cause-specific mortality) among tamoxifen-treated patients. In NSABP B-14 trial with 2,553 patients, 22 "definite or probable" CHD-related deaths were seen among control patients, compared with 19 among tamoxifen-treated patients. In addition to the relatively low number of observed CHD events seen in these trials, in none of these trials were CHD events a prospective study end point. Because these trials represent no more than 14% of patients entered onto tamoxifen adjuvant breast cancer trials,¹³ reporting bias may have influenced the available literature, with smaller studies, and especially those reporting no effect of tamoxifen on CHD, less likely to be submitted or published.

In the large EBCTCG overview, with more than 36,000 patients and long-term follow-up, it is reported that mortality rates for causes "not attributed to breast or endometrial cancer" (reasonably anticipated to be largely CHD-related in this age group) are nearly identical (ratio of rates, 0.99) in patients receiving tamoxifen or control as adjuvant intervention.¹³ In the trials that contributed to the overview, CHD events and mortality were not prospective study end points; however, the completely negative results cannot easily be reconciled with a favorable tamoxifen effect on CHD events. Thus, the best currently available clinical evidence does not support a significant beneficial effect of tamoxifen on CHD outcome.

The limitations of depending on secondary markers or selected studies in which CHD is not a predetermined study end point are illustrated by recent results from the Heart and Estrogen/Progestin Replacement Study.⁵⁰ Evidence of a favorable impact on secondary CHD markers, including lipid profile and meta-analysis of observational reports, had strongly suggested that HRT should decrease the number of cardiac events among women with established coronary disease by 35% to 50%.^51,52 However, when 2,763 postmenopausal women with heart disease were randomized to receive either HRT or placebo for secondary CHD prevention, no differences between groups in myocardial infarction or CHD death were seen. In fact, increased CHD events were seen in the HRT group for the first 2 years of treatment, presumptively mediated through effects on coagulation. In this case, a hormone intervention (HRT) that favorably influenced lipid profile had no beneficial effect on cardiac events, and "experimentation trumped observation."⁵² Thus, although lipid profile is an established CHD risk factor whose modulation by lipid-reducing agents is associated with reduced CHD events, the same relationship remains to be established for hormonal therapies that improve lipid profile but increase vascular events.

Bone Density, Fractures, and Tamoxifen
Bone density loss, osteoporosis, and fracture risk represent a threat to general health as postmenopausal women age.^53,54 In the postmenopausal breast cancer patients who used tamoxifen as adjuvant therapy, bone mineral density (BMD) preservation has been reported in several observational studies.^55-59 However, few randomized trials involving tamoxifen have included BMD or fracture risk as prospective end points. Love et al^55,57,58 have compared the effects of placebo and tamoxifen for up to 5 years on serial lumbar spine BMD. With tamoxifen, a modest increase of 0.8% in lumbar spine BMD (P = .06) was seen, whereas a decrease of 0.7% in BMD was associated with placebo, and mean regression lines significantly (P < .0005) favored a beneficial tamoxifen effect in this setting. In another randomized trial, tamoxifen was compared with toremifene citrate (Fareston; Schering Corporation, Kenilworth, NJ) for its effects on BMD in 30 postmenopausal breast cancer patients.⁶⁰ After 12 months, tamoxifen reduced bone turnover and increased BMD in the lumbar spine (2%) and femoral neck (1%), whereas toremifene did not increase BMD.

In contrast to FDA-approved drugs with indications for osteoporosis prevention (including estrogen, alendronate, and raloxifene), tamoxifen has not been evaluated in any prospective studies in women with osteoporosis. The modest increases in BMD associated with tamoxifen in observational studies seem inferior to those seen with agents specifically indicated for use in bone preservation or in osteoporosis.

The P-1 trial is the only prospective evaluation of tamoxifen and fracture risk and provides some suggestive evidence for a favorable tamoxifen influence on this gold standard end point. Initially, fractures of the hip and radius (Colles' fracture) were defined as primary fracture events, with spine fractures and fractures of the lower radius added later.² Overall, fewer fractures at these four sites were seen in the tamoxifen group compared with the placebo group (111 fracture events for tamoxifen v 137 events for placebo), a reduction that was of borderline statistical significance (RR, 0.81; 95% CI, 0.63 to 1.05). Because nearly 40% of the P-1 population was 35 to 49 years old, this younger population, with little fracture risk, may have contributed to the borderline results.

In contrast to the results with postmenopausal women, the effect of tamoxifen on BMD in premenopausal women has been mixed, with studies reporting either loss^61,62 or no difference in BMD⁶³ for tamoxifen compared with placebo groups.

Several additional issues should be recognized when considering the use of an intervention that targets bone preservation. Postmenopausal women at particular fracture risk, such as those with decreased BMD and/or osteoporosis, represent an easily identifiable subgroup, given the increasing general clinical availability of BMD determinations.⁵³ In addition, prospective observational studies have identified a strong association between low BMD and reduced risk of breast cancer development. In prospective observational studies, women in the highest BMD quartile were found to have substantially (RR of between 2.0 and 7.0) increased risk of developing breast cancer compared with women with BMD who were in the lowest quartile.^64,65 The influence of BMD on breast cancer risk is comparable in magnitude to components included in the Gail model and could substantially alter a woman's calculated risk for breast cancer development and her decision regarding the most appropriate therapy.

Vascular Events and Tamoxifen
In the P-1 trial, vascular events (including stroke, transient ischemic attack, pulmonary embolism, and deep vein thrombosis) were, in aggregate, more common for women receiving tamoxifen versus placebo (110 events for tamoxifen v 77 events for placebo). Of these categories, pulmonary embolism and stroke are of greatest concern. Pulmonary embolism was three times as frequent in the tamoxifen group as compared with the placebo group (RR, 3.01; 95% CI, 1.15 to 9.27). Strokes were nearly twice as frequent among women 50 years of age in the tamoxifen group (RR, 1.75; 95% CI, 0.98 to 3.20).

These results of tamoxifen on vascular events are similar to those seen with HRT.^66,67 They are also consistent with prior experiences with using tamoxifen in patients with established breast cancer⁶⁸ and should be incorporated into the risk benefit calculation for women considering tamoxifen for breast cancer risk reduction.

Cataracts and Tamoxifen
An additional risk identified during the course of the prevention trial was excess risk of cataracts and cataract surgery observed among women in the tamoxifen group. Both "development of cataracts" (RR, 1.14; 95% CI, 1.01 to 1.29) and "undergoing cataract surgery" (RR, 1.57; 95% CI, 1.16 to 2.14) were more common in the tamoxifen group and reached statistical significance.

Mental and Cognitive Effects and Tamoxifen
No adverse effects on depression or mental function were seen in the P-1 trial. A serially applied, established screening questionnaire⁶⁹ identified no influence of tamoxifen on depression score in this setting.^2,70,71 Similarly, the mental component score of the Medical Outcomes Study Short Form 36 was not changed by tamoxifen use in P-1.^2,71

These results are encouraging; however, tamoxifen's long-term impact on cognitive function remains a concern that has not been addressed with sensitive methodology. Roles for estrogen in neuronal maintenance⁷² and improved cognitive function in postmenopausal women have been described.^73-77 Conversely, detailed neuropsychologic function testing has recently identified cognitive impairment in women receiving either conventional or high-dose chemotherapy together with tamoxifen.⁷⁸ Although the contribution of tamoxifen to cognitive dysfunction in this setting is not known, studies of this issue are ongoing with sensitive cognition measures, including neuroimaging techniques.

Menopausal Symptoms and Other Side Effects
In general, relatively few differences in measured side effects were associated with tamoxifen use in the P-1 trial.² However, both bothersome hot flashes (46% v 29%) and vaginal discharge (29% v 13%) were significantly more common in the tamoxifen group. Additional information has been collected in the P-1 population regarding other side effects that could affect quality of life. This information, when published, should inform healthy women considering tamoxifen use for breast cancer risk reduction, but it may not fully address the potential impact of tamoxifen use on all parameters of quality of life.

Implications of the P-2 Study Design
The National Institutes of Health is supporting the Study of Tamoxifen and Raloxifene trial, which will compare these two agents for breast cancer risk reduction in postmenopausal women without a placebo control (NSABP P-2 trial). However, other studies with eligibility criteria that directly overlap those of the P-2 trial are continuing to incorporate placebo controls. The Women's Health Initiative is also a National Institutes of Health–supported multicenter study that has just completed randomization of more than 27,500 postmenopausal women to long-term HRT or placebo use; it is continuing to randomize women to a calcium and vitamin D versus placebo trial that will include over 35,000 participants.⁷⁹ Given the all-cause mortality end point, definitive results are anticipated in the year 2005. The Women's International Study of Long Duration Oestrogen after Menopause is beginning entry of postmenopausal women in Europe onto a larger trial of similar design.⁸⁰ In another study, the National Cancer Institute of Canada is initiating a multicenter trial comparing idoxifene (another SERM) with placebo in postmenopausal women, with end points of breast cancer and fracture. All of these trials, with placebo controls, include women with a 1.66% 5-year risk of breast cancer.

The continuing use of placebo controls in other risk reduction trials highlights the current unanswered issues concerning use of such interventions, especially when the influence on net health benefit remains to be determined.^81,82

Breast Cancer Risk and Tamoxifen
Is there currently strong or credible evidence to conclude that tamoxifen will reduce the risk of developing breast cancer? An extensive body of clinical information from randomized trials supports a role for tamoxifen in both clinical and subclinical breast cancer. This information, together with the strongly positive and appropriately powered NSABP P-1 trial conducted in a population at increased risk for the disease, supports a role for tamoxifen therapy in reducing the risk of breast cancer.

For women with a defined 5-year projected risk of breast cancer of 1.66%, which corresponds to eligibility requirement of the P-1 study, tamoxifen may be offered to reduce their risk. Consideration of tamoxifen use is appropriate if the primary goal of therapy is to lower the risk of breast cancer rather than focus on other health-related issues. In all circumstances, tamoxifen use should be discussed as part of an informed decision-making process, with careful consideration of risks and benefits.

Given the relatively modest level of increased risk required for entry onto the NSABP P-1 trial, and the continuum of risk associated with breast cancer development, there is some concern with identifying a woman at "high risk" based largely on age or general risk factors. Women in the P-1 trial, on average, were at twice the original risk profile of 1.66%. Among this group of women with a higher risk profile, the absolute risk reduction (2.6% to 1.3%) was modest. This, coupled with the negative results from the UK trial and the Italian trial (both used different risk criteria), makes careful risk assessment for each woman imperative. It should be emphasized that although the reduction in relative risk of breast cancer development among patients treated with tamoxifen in the P-1 trial was similar across all age and other risk groups, the absolute risk reduction should be lower as risk decreases.

Although much thought went into the NSABP's use of the 1.66% increased risk threshold, it should be viewed as a starting point rather than as the definitive criterion. In addition, the question regarding the impact that tamoxifen may have in lowering the risk of developing breast cancer in women with known genetic predispositions (BRCA1, BRCA2) has not yet been addressed. At this time, however, the Working Group has no other data on which to base a definition of increased risk.

The NSABP P-1 results show that tamoxifen reduces the incidence of breast cancer for a period of several years in women identified as being at increased risk. Although inferences can be made from the experience with tamoxifen in adjuvant treatment, it is not currently known whether there is a reduced risk of breast cancer incidence beyond the initial period of therapy or in the lifetime breast cancer risk that women may face.

Tamoxifen's adverse effects are greatest in women older than 50 years old, especially in women with a uterus. While younger women experienced fewer life-threatening effects, there is less information from breast cancer trials regarding the long-term effects of tamoxifen among younger women as compared with the more commonly treated postmenopausal population. For example, only 159 (2.4%) of the women randomized to tamoxifen in the P-1 trial were younger than 40 years of age. Issues regarding tamoxifen effectiveness in this setting in younger individuals with strong family histories may be answered, in part, with further follow-up of ongoing trials and genetic analysis of P-1 participants.

Ethnic minorities were underrepresented in the P-1 trial,² and the difficulty in achieving representative participation in such prevention trials is recognized.^82,83 Representative participation in future prevention efforts is strongly encouraged. Nevertheless, given comparable effects of tamoxifen in other breast cancer settings, it is reasonable to apply the same criteria for tamoxifen use across all ethnic groups at the present time.

Given the combined results of NSABP trials P-1² and B-24,¹⁴ women with a history of atypical hyperplasia and/or noninvasive breast cancer (both LCIS and DCIS) may be candidates for consideration of tamoxifen use. Similarly, women with a history of invasive breast cancer who have not received hormonal therapy, regardless of receptor status, may also be candidates for tamoxifen, given the results of the EBCTCG overview¹³ (contralateral breast cancer incidence decrease with tamoxifen regardless of the primary tumor's receptor status) and the preliminary information on the effect of "delayed" adjuvant tamoxifen therapy on breast cancer recurrence risk.^29-31

Evidence supporting a tamoxifen influence on CHD events and mortality is limited. More evidence is needed before CHD risk reduction can be considered an evidence-based component of the decision-making process regarding tamoxifen use in postmenopausal women. The need for more evidence is underscored by the negative results of the P-1 trial on CHD events² (as the only randomized trial prospectively evaluating this issue), the completely negative EBCTCG overview results¹³ on non–cancer-associated mortality, the limitations of the three reports of tamoxifen use in randomized trials in which cardiac end points were evaluated; and the demonstrated unreliability of lipid profile change as a surrogate marker to predict a clinical cardiac event.

With respect to tamoxifen's influence on osteoporotic fracture risk, tamoxifen has been observed to consistently increase BMD in postmenopausal women to a moderate degree. Tamoxifen was associated with fracture reduction of borderline statistical significance,² but it has not been directly compared with interventions that are approved by the FDA for prevention of postmenopausal bone loss. No prospective studies have been conducted on the effect of tamoxifen in women with osteoporosis, and its reported magnitude of influence on BMD is modest.

In summary, taken in the context of the extensive clinical experience with tamoxifen in a variety of breast cancer settings, the data from the NSABP P-1 trial are sufficiently compelling to conclude that women at increased risk of breast cancer should be offered tamoxifen for periods up to 5 years. However, as discussed further below, there is currently insufficient data to determine whether tamoxifen provides an overall health benefit and increased chance for survival. Such information, and the apparently contradictory results from two smaller studies, suggests that it is reasonable and ethical to continue controlled studies of this issue.

A woman's decision regarding tamoxifen use in breast cancer risk reduction will depend on the importance and weight attributed to the information provided regarding both cancer and non–cancer-related risks. The short-term benefits of tamoxifen in terms of breast cancer risk reduction will outweigh the symptoms and risks of endometrial cancer, thromboembolism, and stroke for a specific group of women. The most appropriate identification of this group depends on careful risk assessment, which should be performed as part of each patient assessment. Full discussion of indications, risks, benefits, and alternatives is recommended as part of the informed consent process.

Is there strong or credible evidence to conclude that tamoxifen will reduce the risk of dying from breast cancer for women who do not have breast cancer? Not at this time. None of the tamoxifen trials that target breast cancer risk reduction currently provides reliable information on the effect of tamoxifen on breast cancer-associated mortality. The effect of tamoxifen use before a diagnosis of breast cancer on the risk of dying of breast cancer cannot be determined from the NSABP P-1 trial because women in the placebo arm were allowed to cross over to tamoxifen before survival influence could be determined. For this reason, other trials with placebo arms must eventually serve as the source of information to address these important questions. While a favorable impact on mortality could be anticipated based on projections from the use of tamoxifen in the adjuvant setting, definitive evidence of survival benefit in the risk reduction setting is not available.

Is there strong or credible evidence to conclude that there is a net health benefit and an improvement in overall survival associated with tamoxifen use for women who do not have breast cancer, if tamoxifen is taken to reduce the risk of this disease? The best available clinical evidence indicates that any discussion of benefit should focus primarily on tamoxifen's effect on breast cancer reduction. There is no currently available evidence to indicate that long-term net health benefit, and specifically mortality reduction, is associated with tamoxifen use in this setting.

RALOXIFENE

Raloxifene and Breast Cancer: Background
Based on initial laboratory studies and subsequent clinical evaluation, raloxifene (Evista) has received FDA approval for the prevention of osteoporosis in postmenopausal women.⁸⁴ Raloxifene (originally LY156758 and keoxifene) is a SERM that has undergone extensive basic and preclinical evaluation.^5,85

Reports of raloxifene use in patients with established breast cancer are quite limited. In contrast to tamoxifen, for which efficacy in a range of breast cancer settings has been documented,^13-15,86 reports of the use of raloxifene in established breast cancer consists of two clinical reports that include only 32 postmenopausal patients treated for advanced disease. In one study, a dose of 200 mg/d resulted in no objective tumor response in 14 patients with tamoxifen-resistant disease.⁸⁷ In a more recent trial, a raloxifene dose of 300 mg/d resulted in three objective responses in 18 patients with receptor-positive metastatic breast cancer.⁸⁸ Other studies of raloxifene in a variety of breast cancer settings are currently ongoing. Results from such experiences may significantly influence future recommendations regarding raloxifene use and warrant ongoing attention. However, at the present time, only the most preliminary information regarding raloxifene's influence on clinical breast cancer is available.

Raloxifene and Breast Cancer Incidence in Randomized Trials
The influence of raloxifene on breast cancer incidence has been reported from several ongoing trials. The largest randomized trial to address the issue of breast cancer risk and raloxifene is the Multiple Outcomes of Raloxifene Evaluation (MORE) study, in which 7,705 postmenopausal women with existing osteoporosis were randomized to receive either raloxifene at 60 or 120 mg/d or placebo. Breast cancer is being monitored in the MORE study, and initial reports show a 70% reduction in the incidence of invasive breast cancer with raloxifene treatment compared with placebo after a mean follow-up period of 33 months. This finding is based on only 32 breast cancers.⁴ It should be emphasized that this study was designed as an osteoporosis trial; breast cancer risk was not specifically addressed at entry, nor was breast cancer development a primary outcome measure. Breast cancer incidence is a primary study end point of the Study of Tamoxifen and Raloxifene trial, which is comparing tamoxifen and raloxifene (described above).

A partially overlapping meta-analysis, reviewing data from nine raloxifene trials (including MORE) involving 10,575 patients, was presented at the 1998 ASCO Annual Meeting¹¹ as well and was recently updated.⁶ In this analysis, after a mean follow-up period of 40 months, raloxifene was associated with a 55% reduction in the relative risk of developing invasive breast cancer compared with placebo use, based on 67 breast cancers. Raloxifene reduced the incidence of estrogen receptor–positive but not estrogen receptor–negative cancers. The MORE study continues, and further updates of the MORE study and associated pooled analyses of other raloxifene trials should be informative. Because current information on the effect of raloxifene on breast cancer incidence is limited to abstract presentations, further detailed evaluation is precluded.

Endometrial Cancer and Raloxifene
Preclinical studies suggest that raloxifene may have limited effects on endometrial proliferation. Raloxifene has low estrogenic activity in the rodent uterus⁸⁶ and inhibits tamoxifen-stimulated human endometrial cancer in athymic mice.⁸⁹ Information regarding the influence of raloxifene on the endometrium in humans is now becoming available. In these clinical reports, endometrial thickness was unchanged during raloxifene therapy at doses up to 150 mg/d, compared with placebo.^90,91

It has not yet been established whether animal models and clinical endometrial proliferation are reliable predictors of endometrial cancer risk, especially in the context of the limited duration of raloxifene clinical trial follow-up. An analysis, with relatively few events, in the MORE study population indicated a trend toward fewer endometrial cancers in the raloxifene as compared with placebo populations.⁴ Definitive assessment of the clinical influence of raloxifene on endometrial cancer awaits the maturation of results from ongoing randomized trials.

CHD and Raloxifene
Although a number of large-scale clinical trials of raloxifene are currently underway, given the recent FDA approval of raloxifene for prevention of bone loss, only limited clinical trial information on raloxifene's influence on other diseases is available.

Raloxifene has consistently been described as favorably influencing lipid profile, a potential intermediate marker of CHD's influence.⁹² Raloxifene decreases serum levels of total cholesterol (-3.9% to 5.2 %)^90,93 and low-density lipoprotein cholesterol (-5.5% to 12.0%)^90,93,94 and also reduces the level of fibrinogen.⁹⁴ Unlike estrogen,⁹⁵ raloxifene does not increase levels of high-density lipoprotein cholesterol.^90,93,94 In a small randomized trial, raloxifene significantly decreased fasting levels of plasma homocysteine (-16%) at 150 mg/d, whereas raloxifene 60 mg/d had no significant effect compared with placebo in healthy postmenopausal women.⁹⁶ Of course, the caution regarding extrapolation of change in intermediate end points of CHD risk to reduction in clinical CHD outcome, which has been identified for both HRT and tamoxifen,^5,13,52 applies to this agent as well.

Full-scale clinical trials are in progress to define the relationship between raloxifene use and CHD events. The Raloxifene Use for the Heart trial will enroll about 10,000 postmenopausal women to assess the effects of raloxifene on cardiovascular outcomes, with results anticipated in 4 to 6 years.⁹⁷ However, at present, clinical information on raloxifene's influence on CHD clinical events and/or CHD-associated mortality is not available.

Bone Density, Fractures, and Raloxifene
Information supporting the currently approved indication of raloxifene for the prevention of osteoporosis in postmenopausal women is supported by a placebo-controlled, double-blind study with 601 postmenopausal women and BMD as the primary study end point. Participants in this trial were randomized to receive 30, 60, or 150 mg of raloxifene or placebo daily. Women who received any of the raloxifene doses had significant increases in BMD of the lumbar spine, hip, and total body compared with baseline, whereas women on placebo showed decreases in BMD.⁹⁰ At 24 months, the mean difference (± SE) in change in BMD between women receiving 60 mg of raloxifene versus placebo was 2.4% + 0.4%, a significant (P < .001) difference. Influence on fractures was not included in reports from this trial. Raloxifene has also been compared with conjugated estrogens (Premarin, 0.625 mg/d; Wyeth-Ayerst, Philadelphia, PA) in a randomized trial of 51 postmenopausal women. A somewhat greater effect on BMD was seen with estrogen (3.2% BMD increase with estrogen v 1.3% with raloxifene).

The MORE study, described above, which included 7,705 women (mean age, 66.5 years) with existing osteoporosis, was a prospective evaluation of raloxifene's effect on fracture risk. Raloxifene at 60 or 100 mg/d was associated with a significantly reduced fracture rate compared with placebo.⁴

Taken together, such information supports an established role for raloxifene in osteoporosis prevention and perhaps even in therapy for women with established osteoporosis who are postmenopausal. As an approved therapy for the prevention of postmenopausal bone loss, raloxifene represents an alternative to estrogen and the bisphosphonate alendronate (Fosamax; Merck, West Point, PA) in this context. Use of raloxifene is currently limited to postmenopausal women, because there are no published data on the use of or toxicity profile with raloxifene in premenopausal populations.

Vascular Events and Raloxifene
In clinical trials, raloxifene use seems to increase the risk of thromboembolic events by approximately three-fold.⁴ Although results from direct comparative clinical trials are not available, the effect of raloxifene in this regard seems to be similar to that of estrogen^50,98 and tamoxifen.²

Menopausal Symptoms and Other Side Effects
Available information clearly indicates that raloxifene does not relieve estrogen deficiency symptoms. In a pooled analysis from several clinical trials involving raloxifene and placebo, hot flashes were significantly greater for women taking raloxifene 60 mg/d (25%) than for women taking placebo (18%).⁹⁷ However, in an osteoporosis prevention trial with 601 postmenopausal women, there were no significant differences in the proportion of women reporting hot flashes across the raloxifene and placebo groups.⁹⁰ Ongoing clinical trials will clarify whether raloxifene influences the frequency or severity of estrogen deficiency symptoms.

Currently there is no reliable clinical information regarding raloxifene's influence on mental function based on sensitive cognition measures.

Breast Cancer Risk and Raloxifene
Is there strong or credible evidence to conclude that raloxifene will reduce the risk of developing breast cancer? Preliminary reports from studies targeting osteoporosis as the major end point indicate that raloxifene may be associated with a reduced risk of developing breast cancer in postmenopausal women. This suggestion is based on a relatively small number of breast cancer events. It is premature to recommend raloxifene use to lower the risk of developing breast cancer outside of a clinical trial setting.

At the present time, data are insufficient to recommend raloxifene as a treatment for established breast cancer or to use it in combination with tamoxifen, or sequentially after tamoxifen in an adjuvant setting. Because there is limited evidence of raloxifene's efficacy against established breast cancer, and because, like tamoxifen, raloxifene is associated with hot flashes, there is no basis for substituting raloxifene for tamoxifen in the treatment of adjuvant breast cancer patients experiencing menopausal symptoms.

Is there strong or credible evidence to conclude that raloxifene will reduce the risk of dying from breast cancer for women who do not have breast cancer? There is no evidence at this time. A number of large clinical trials are currently underway, with monitoring of breast cancer risk, to assess raloxifene's influence on osteoporotic fracture risk and CHD events. These trials are not sufficiently mature to provide survival information, particularly data on mortality related to breast cancer development.

Is there strong or credible evidence to conclude that there is a net health benefit and an improvement in overall survival associated with raloxifene use for women who do not have breast cancer, if raloxifene is taken to reduce the risk of this disease? As outlined above, there is currently insufficient evidence to recommend use of raloxifene to reduce the risk of breast cancer. When raloxifene is used for the established indication of osteoporosis prevention, the limited duration of follow-up of available clinical information is insufficient to determine net health benefit.

Raloxifene has been demonstrated to increase BMD, and it may lower fracture risk as well. The full clinical toxicity profile is in the process of being described in the ongoing clinical trials. The best available evidence indicates that raloxifene is not associated with endometrial proliferation, as determined by change in endometrial thickness, but definitive information on raloxifene's effect on endometrial cancer development is not yet available. The number of thromboembolic events seems to be increased with raloxifene use to a comparable degree seen for HRT and tamoxifen use. On the basis of available information, the use of raloxifene should currently be reserved for its approved indication to prevent bone loss in postmenopausal women.

Currently, an extremely large number of postmenopausal women are entering, or are continuing to be followed on, randomized clinical trials evaluating raloxifene's effect on a wide range of clinical end points. Results from such experiences may influence future recommendations regarding raloxifene use and warrant ongoing attention.

TOPICS TO CONSIDER WHEN COMMUNICATING RISK

The optimal way to communicate information about risks and benefits of interventions such as tamoxifen, aimed at breast cancer risk reduction, presents a new medical challenge and is beyond the scope of the current technology assessment. Perspectives regarding these issues are likely to vary greatly among both physicians and patients. The topics summarized in Table 5 provide a preliminary framework to consider during discussions with women regarding this issue. They were identified with input from a solicitation of advocate groups (Appendix B).

APPENDIX B

ACKNOWLEDGMENTS

The Working Group wishes to express its gratitude to Carolyn Clancy, Martee L. Hensley, Scott Lippman, and Richard Love for their thoughtful reviews of earlier versions of the technology assessment. The Working Group is also grateful to Jennifer J. Padberg and Dayna E. Olson for editorial assistance.

Unpublished, relevant clinical evidence was submitted for review to the Working Group by Zeneca Pharmaceuticals, by A. Costa and U. Veronesi for the Italian Tamoxifen Prevention Study, and by R. Day, P. Ganz, and D.L. Wickerham for the NSABP.

The Working Group thanks the following national and regional advocacy groups for their participation in providing input on these important issues: Adelphi New York State Breast Cancer Hotline, Adelphi, NY; Breast Cancer Coalition of North Carolina, Chapel Hill, Chapel Hill, NC; Breast Cancer Action, San Francisco, CA; Capital Region Action Against Breast Cancer, Newtonville, NY; Alamo Breast Cancer Foundation, San Antonio, TX; and, Y-Me, Tulsa, OK.

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