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Home , Tamoxifen, Triphenylethylene

■ BY STEVEN R. GOLDSTEIN, MD OBGMANAGEMENT

Reducing the risk of : Key trials and their impact on practice

An expert sifts the data regarding chemopreventive options and expands on current guidelines for screening of users.

ore than 28,000 additional breast mine risk, takes into account could be prevented over 5 nongenetic (nulliparity, age at menarche) Myears if all eligible women were and genetic (family history) factors,as well as given tamoxifen.1 the number of previous breast biopsies. It This is just one of several important find- assigns a smaller relative risk to women over ings highlighted in the studies covered in this age 50. A Web-based version, available at review of breast cancer risk assessment and http://bcra.nci.nih.gov/brc, is useful for cal- chemopreventive options. culating a woman’s risk of developing inva- Because Ob/Gyns often treat tamoxifen sive disease over the next 5 years, as well as users who experience uterine bleeding and over her remaining lifetime. worry about their risk of endometrial cancer Limitations of the Gail model. Unfor- (see “Endometrial screening and tamoxifen tunately, the data on which the model is based users: Going beyond the ACOG opinion,” were collected in the late 1970s and early 1980s. page 46), it is crucial that we have the latest CONTINUED data on preventive therapies for breast can- KEY POINTS cer—which include not only tamoxifen, but also, potentially, and aromatase ■ In the Breast Trial, women inhibitors—so that we may facilitate proper taking tamoxifen experienced a 49% overall work-up and monitoring. reduction in invasive breast cancer; the relative risk of endometrial cancer was 4.01 for women over 50 and 1.21 for women younger than 50. Assessing risk:

The need for a new model ■ The risk of serious adverse effects with tamoxifen lthough a number of breast cancer risk- use appears to be lower in women under age 50. Aassessment models are available based on individual risk factors (TABLE 1), estimates ■ Preclinical animal data suggest that, like based on combinations of factors are prefer- tamoxifen, raloxifene has potent able. The Gail model,2 widely used to deter- effects on breast tissue.

■ ■ Dr. Goldstein is professor, obstetrics and gynecology, New York Because aromatase inhibitors block the University School of Medicine; and director, gynecologic ultra- peripheral conversion of to sound, and codirector, densitometry, New York University , they inhibit both initiation and Medical Center, New York, NY. promotion of breast cancer. Thus, they may be more effective than selective receptor

July 2003 • OBG MANAGEMENT 39 modulators in preventing the disease. TABLE 1 Breast cancer risk factors and their relative risks19

RELATIVE RISK <2 RELATIVE RISK 2–4 RELATIVE RISK >4 Age 25 to 34 at Age >35 at first birth Gene mutations first live birth First-degree relative Lobular carcinoma in situ Early menarche with breast cancer Late Nulliparity Atypical Proliferative benign disease Radiation exposure Postmenopausal obesity Prior breast cancer use Hormone replacement therapy

FIGURE 1 threshold adopted for the Breast cancer risk in raloxifene users Breast Cancer Prevention Trial (BCPT)—loses some credibility. 4.0 Placebo Consider this example: Raloxifene A 50-year-old nulliparous Caucasian woman experi- 3.0 3.0 enced menarche at age 11, has no first-degree relatives %) with a history of breast can- cer, and has never had a 2.0 1.8 breast biopsy. The Gail model would assign her a risk of developing breast 1.2 Breast cancer risk ( cancer of 1.2% in the next 5 0.8 1.0 0.7 years and 10.8% over her 0.6 0.6 0.4 lifetime. However, if the same patient had had 3

0.0 breast biopsies, her risk 0 >0 to <5 5 to 10 >10 to <20 would rise to 1.8% in the Serum estradiol level (pmol/L) next 5 years and 15.8% for her lifetime (placing her in Reprinted with permission from: Cummings SR, Duong T, Kenyon E, et al. Serum the high-risk category), level and risk of breast cancer during treatment with raloxifene. JAMA. 2002;287:216-220. Copyright © 2002 American Medical Association. All rights reserved. even if none of the biopsies revealed hyperplasia. Biomarkers. Objective find- Today, the greater ease of breast histopatho- ings that are patient-specific but which corre- logic assessment by fine-needle aspiration late closely with breast cancer development and outpatient core-needle biopsy has are needed. increased the rate of tissue sampling, creating Biomarkers have been proposed; among confusion as to what constitutes a biopsy. them: ultrasensitive measurement of serum Thus, the cutoff of 1.66% for high risk—the estradiol levels in postmenopausal women.3

40 OBG MANAGEMENT • July 2003 Reducing the risk of breast cancer: Key trials and their impact on practice

TABLE 2 Results of tamoxifen trials

10 11 BREAST CANCER ROYAL MARSDEN ITALIAN 7 PREVENTION TRIAL Number of participants 13,388 2,471 5,408 Age ≤50 40% 62% 36% One first-degree relative 55% 55% 18% with breast cancer >2 first-degree relatives with 13% 17% 2.5% breast cancer HRT users 0% 42% 8% Woman-years of follow-up 46,858 12,355 20,731 Cancer incidence/1,000 Placebo 6.8 5.0 2.3 Tamoxifen 3.4 4.7 2.1

In the Multiple Outcomes of Raloxifene Breast Cancer Prevention Trial: Evaluation (MORE),4 the women who had Tamoxifen reduces cancer incidence the greatest reduction in breast cancer during n 1992, the National Surgical Adjuvant treatment had the highest baseline serum IBreast and Bowel Project launched a pre- estradiol levels (FIGURE 1)—although the base- vention trial using tamoxifen: the Breast line levels of all subjects were well within the Cancer Prevention Trial.7 A total of 13,388 postmenopausal range of 20 pmol/L or less. women aged 35 or older and at high risk for breast cancer were enrolled at numerous sites Chemoprevention: throughout the United States and Canada. The rationale for tamoxifen The Gail model was utilized to deter- ata from preclinical animal and in vitro mine which women had sufficient risk—that Dstudies led to the use of tamoxifen, a is, a risk of developing invasive breast cancer selective modulator within the next 5 years of 1.66% or greater— (SERM), for primary prevention of breast to be included in the trial.2 Subjects were ran- cancer in healthy women. The drug was domly assigned to receive placebo or tamox- shown to inhibit mammary tumors in mice ifen (20 mg/d) for 5 years. and rats and suppress hormone-dependent The trial was terminated in April 1998, breast cancer cell lines in vitro.5 14 months before its planned completion, Clinical data from the Early Breast Cancer due to the striking reduction in new-onset Trialists Collaborative Group also helped spur breast cancer in the tamoxifen group. The prevention trials with tamoxifen.6 Besides data safety monitoring board felt it would be decreasing the risk of recurrent breast cancer, unethical to allow one half of the partici- tamoxifen reduced the risk of contralateral, pants, who were deemed to be at high risk, to new-onset breast cancer by 47% after 5 years of continue taking placebo in light of the dra- adjuvant treatment (P = .00001) and by 26% matic reduction in both invasive and nonin- after 2 years of treatment (P = .004). This, vasive breast cancer with tamoxifen use. along with tamoxifen’s favorable effects on The overall incidence of breast cancer in skeletal remodeling and levels, led to a the tamoxifen group was 3.4 cases per 1,000, series of chemopreventive trials in the United compared with 6.8 cases per 1,000 in the States and Europe (TABLE 2). placebo group. Overall, the reduction in

July 2003 • OBG MANAGEMENT 41 FIGURE 2 Breast Cancer Prevention Trial: Tamoxifen reduces incidence of breast cancer

50 46 Placebo 39 Tamoxifen 40

33 30 30 24 24 21

20 16 16 Number of cases

8 9 10 4

0 1234 5 6 Year of the trial

The rate of cancer reduction for tamoxifen compared with placebo for years 1 through 6 was 33%, 55%, 39%, 49%, 69%, and 55%, respectively.

Reprinted from Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;90(18):1371-1388, by permission of Oxford University Press. invasive breast cancer was 49% (P<.000001). Tamoxifen’s other effects in healthy The reductions were 44% for women in the women. The BCPT offered the first large- group aged 35 to 49 years, 51% for those scale data on the effects of tamoxifen in aged 50 to 59, and 55% for those 60 years healthy women.7 (All previous studies includ- and older (FIGURE 2). ed only women with breast cancer.) Several Tamoxifen decreased the incidence of secondary endpoints merit consideration. noninvasive breast cancer (ductal carcinoma Endometrial cancer risk. Researchers found in situ) by 50%. (Expanded use of mam- the relative risk (RR) of endometrial cancer mography has led to greater detection of this associated with tamoxifen therapy in healthy cancer. Most such lesions are estrogen- women was 2.53 (95% confidence intervals receptor–positive.8) In addition, tamoxifen [CI], 1.35, 4.97). When this figure was calcu- reduced breast cancer risk in women with a lated for the different age groups, it rose to history of lobular carcinoma in situ by 56% 4.01 (95% CI, 1.70, 10.90) in women over 50, and atypical hyperplasia by 86%. Overall, and declined to 1.21 for women ages 49 and tamoxifen decreased the occurrence of under (95% CI, 0.41, 3.60). estrogen-receptor–positive tumors by 69%, Thromboembolic event risk. The same age but had no impact on tumors that were distinction was seen in relation to throm- estrogen-receptor–negative. boembolic events. There were no statistically

42 OBG MANAGEMENT • July 2003 Reducing the risk of breast cancer: Key trials and their impact on practice

significant increases in pulmonary emboli or In addition, the FDA required that the deep venous in women 49 years of package insert advise women to consult a age or under. Although it is unclear whether health-care professional for breast cancer risk the trial was sufficiently powered for this par- assessment and state that only women at high ticular endpoint, the likelihood that serious risk should take the drug (again, without adverse events will limit the potential benefits defining high risk). of tamoxifen appears to be lower in women In 2002, the FDA added a “black box” under the age of 50. This has significant clin- warning to tamoxifen labeling that was ical consequences for physicians caring for directed at use of the drug for prevention perimenopausal patients. rather than treatment. This warning con- No change in incidence of other cancers. cerned the occurrence of uterine sarcomas. Overall, the incidence of invasive cancers other The incidence of these cancers was found to than those of the breast and was the be 0.17 per 1,000 women taking tamoxifen, same for the tamoxifen and placebo groups. compared with 0.015 per 1,000 controls.9 Other outcomes. The relative risk of death Underuse of tamoxifen? A recent study by from any cause was 0.81 (95% CI, 0.56–1.16). Freedman et al1 calculated the number of There was a slight increase in the risk of women 35 to 79 years of age who were eligi- myocardial infarction (RR, 1.11; 95% CI, ble for tamoxifen chemoprevention based on 0.65–1.92) and a slight decrease in the devel- FDA criteria. They further calculated the opment of severe angina (RR, 0.93; 95% CI, number of women who would have a positive 0.40–2.14) in tamoxifen users, although nei- benefit-risk ratio for tamoxifen use, and con- ther of these was statistically significant. cluded that, among white women alone, The overall relative risk of fractures at roughly 28,492 additional breast cancers various sites (hip, spine, radius) was 0.81 could be prevented or deferred if these indi- (95% CI, 0.63–1.05). viduals took tamoxifen for the next 5 years. A statistically significant increase was found in the number of women with European trials fail to confirm who then underwent surgery. That benefit of tamoxifen relative risk was 1.57 (95% CI, 1.16–2.14). The Royal Marsden Trial was one of 2 European trials that failed to replicate the FDA approves tamoxifen BCPT results.10 This British study involved for primary prevention 2,471 healthy women between the ages of 30 ased on the BCPT results, the US Food and 70 who had a family history of breast Band Drug Administration (FDA) cancer. The immediate follow-up was 70 approved tamoxifen in October 1998 for pri- months. No statistically significant decrease mary prevention of breast cancer in women at in breast cancer was found with tamoxifen high risk for the disease. It recommended that use, compared with placebo. tamoxifen be limited to high-risk women One possibility for the discrepancy may be because of the potentially serious side effects that eligibility for the Royal Marsden Trial was seen in clinical trials. based predominantly on a strong family histo- The FDA did not define high risk, but ry of breast cancer. It also included a much recommended that prophylactic use of larger proportion of women under age 50 tamoxifen be based on a thorough evaluation (62%, compared with only 40% in the BCPT). of a woman’s personal, family, and medical Probably most importantly, 42% of the women histories, as well as her age and understand- received hormone replacement therapy ing of the risks and benefits of treatment. (HRT) along with tamoxifen during the trial. CONTINUED

July 2003 • OBG MANAGEMENT 43 Endometrial screening and tamoxifen users: Going beyond the ACOG opinion

ith the rising use of tamoxifen has come an breast cancer about to begin tamoxifen therapy. Each Wincreased need for vigilance for signs of woman received transvaginal ultrasound; if the endometrial cancer. To address the issue, the endometrial echo was greater than 4 mm, office hys- American College of Obstetricians and Gynecologists teroscopy was performed. Of the study population, (ACOG) released a committee opinion on the subject 17.4% had initial benign polyps of the . in April 2000.1 All polyps were removed, tamoxifen therapy initiated, In the opinion, ACOG observed that screening and follow-up carried out through 5 years. tests have not increased the early detection of Among the women with no initial polyp (whom I endometrial cancer in women using tamoxifen and would classify as “squeaky clean”), 0.7% developed may lead to more invasive and costly diagnostic atypical hyperplasia over the 5-year study period— procedures. ACOG also recommended that Ob/Gyns: compared with 11.7% of those who had an initial • Educate women taking tamoxifen on the risks of polyp removed. In addition, 11.7% of squeaky clean endometrial proliferation, hyperplasia, and cancer and patients experienced polyp formation, compared with stress the importance of annual gynecologic exams. 17.6% of those with initial polyps. Thus, the 17.4% • Closely monitor these patients for signs of with initial benign polyps had 18 times the risk of the endometrial hyperplasia or cancer. squeaky clean group for developing atypical hyperpla- • Encourage patients to promptly report abnormal sia while on tamoxifen therapy. vaginal symptoms, including bloody discharge, spot- These findings have caused me to rethink my ting, staining, or leukorrhea. approach toward endometrial surveillance for women • Investigate any abnormal , bloody taking tamoxifen.4 discharge, spotting, or staining. Here is my current practice: • Limit tamoxifen therapy to 5 years, as no benefit • When patients are diagnosed with breast cancer has been established beyond this time frame. and scheduled to begin tamoxifen therapy, I perform • Initiate proper gynecologic management and pretreatment screening. reassess the use of tamoxifen if the patient • If no initial endometrial polyps are found, I follow develops atypical endometrial hyperplasia. ACOG’s recommendations. Further interventions are • Consider resuming tamoxifen therapy following unnecessary (unless abnormal symptoms develop), hysterectomy for endometrial carcinoma, in consul- since these patients are at no more risk for endome- tation with the physician responsible for the trial cancer than women not taking tamoxifen. woman’s breast care.1 • For patients with an initial polyp (ie, the high-risk Screening tests help determine risk. In light of group), I remove the polyp prior to starting tamoxifen data published over the last 5 years, I now perform treatment and monitor them throughout the course of endometrial screening on patients about to begin therapy, periodically utilizing transvaginal ultrasound tamoxifen therapy—a practice that differs from the and saline infusion sonohysterography. ACOG opinion outlined above. Here is why: REFERENCES 2 Work published by Berliere et al in 1998 and 1. Committee on Gynecologic Practice, American College of Obstetricians and updated in 20003 suggest that, among women on Gynecologists. ACOG Committee Opinion #232: Tamoxifen and Endometrial Cancer. Washington, DC: ACOG; April 2000. tamoxifen therapy, there exists a group at high risk 2. Berliere M, Charles A, Galant C, Donnez J. Uterine side effects of tamoxifen: a and a group at low risk for developing complex need for systematic pretreatment screening. Obstet Gynecol. 1998;91(1):40-44. 3. Berliere M, Radikov G, Galant C, Piette P, Marbaix E, Donnez J. Identification of atypical hyperplasia of the endometrium. women at high risk of developing endometrial cancer on tamoxifen. Eur J Cancer. Berliere and her group studied 575 asymptomatic 2000;36(suppl 4):S35-S36. 4. Goldstein SR. Controversy about uterine effects and safety of SERMs: the saga postmenopausal women with recently diagnosed continues. Menopause. 2002;9:381-384.

46 OBG MANAGEMENT • July 2003 Reducing the risk of breast cancer: Key trials and their impact on practice

The Italian prevention study also failed to In addition, preclinical animal data sug- confirm the findings of the BCPT.11 Because it gest that, like tamoxifen, raloxifene has potent recruited participants from the general popu- antiestrogen effects on breast tissue.12 lation, the overall risk of breast cancer was The MORE trial involved 7,705 post- significantly lower than in the BCPT. menopausal women up to age 80 with estab- Compliance rates in the Italian study were lished who were randomized to quite low: Approximately 26% of the subjects receive raloxifene or placebo. Bone mineral dropped out. Furthermore, the Italian trial density and fracture incidence were the pri- included considerably fewer women over age 60 (12% versus 30% in the BCPT). Because they block both initiation Raloxifene: and promotion of breast cancer, aromatase Another cancer preventive? inhibitors may be more effective than ike tamoxifen, raloxifene is a SERM. It is a Lbenzothiophene derivative; tamoxifen SERMs in preventing breast cancer. comes from the family. Like tamoxifen, raloxifene was originally investigated as a treatment for advanced mary endpoints; breast cancer was a second- breast cancer. Preclinical studies indicated ary endpoint. At 4 years, raloxifene significant- that it had an antiproliferative effect on estro- ly reduced the incidence of all invasive breast gen-receptor–positive mammary tumors and cancers by 72%, compared with placebo (RR estrogen-receptor–positive human breast can- = 0.28; 95% CI, 0.17–0.46).16 It reduced the cer cell lines.12 However, in the 1980s, a small incidence of invasive estrogen-receptor–posi- phase II trial revealed that it had no further tive tumors by 84%, compared with placebo antitumor effects in postmenopausal women (RR = 0.16; 95% CI, 0.09–0.30), but had no with advanced breast cancer in whom tamox- effect on estrogen-receptor–negative tumors. ifen therapy had failed.13 The incidence of vaginal bleeding, breast Interest in raloxifene revived after tamox- pain, and endometrial cancer in the ralox- ifen’s neoplastic effects on the uteri of post- ifene group did not differ significantly from menopausal women became evident.14 As a those of the placebo group. (Because women SERM, raloxifene exhibits estrogen- in the MORE trial were older and did not activity on bone remodeling and lipid metab- enter the study with an increased risk for olism. In December 1997, it won FDA breast cancer, these findings are not necessar- approval for the prevention of osteoporosis in ily applicable to younger, high-risk women.) postmenopausal women. Its indication was Like tamoxifen, raloxifene slightly extended to treatment in October 1999. increased the risk of thromboembolic disease, Studies found that raloxifene was similar including . Pulmonary to placebo in its effects on the endometrium of embolism developed in 1.1% of women in the postmenopausal women.15 There were no dif- raloxifene group, compared with 0.5% of sub- ferences in endometrial thickness, endolumi- jects in the placebo group (P = .003). nal masses, proliferation, or hyperplasia. This Currently, there is no approved indication corroborated previous findings that raloxifene for raloxifene in premenopausal women. causes neither endometrial hyperplasia nor SERM compounds, which are structurally cancer and is not associated with vaginal bleed- similar to clomiphene citrate, seem to have ing or increased endometrial thickness (as different effects in premenopausal and post- measured by transvaginal ultrasound). menopausal women, as tamoxifen did in the

July 2003 • OBG MANAGEMENT 47 Reducing the risk of breast cancer: Key trials and their impact on practice

BCPT. Further study in the premenopausal inhibiting the initiation process, they would population or with concomitant use of low- reduce levels of genotoxic metabolites of estra- dose estrogen may be forthcoming. diol by lowering estradiol concentration in tis- sue. They also would inhibit tumor promotion Ongoing clinical trials by lowering tissue levels of estradiol—thus STAR. To directly compare the safety and blocking cell proliferation. However, because efficacy of tamoxifen and raloxifene in reduc- they are not selective, aromatase inhibitors ing breast cancer risk among healthy women, would have an antiestrogen effect on bone and the Study of Tamoxifen and Raloxifene lipid and would induce vasomo- (STAR) has been enrolling postmenopausal tor symptoms. ■ women 35 years of age or older who are at increased risk for breast cancer. This study REFERENCES 1. Freedman AN, Graubard BI, Rao SR, McCaskill-Stevens W, Ballard-Barbash R, began in 1999 and is expected to run for at Gail MH. Estimates of the number of US women who could benefit from tamox- least 7 years. It seeks to enroll 22,000 partici- ifen for breast cancer chemoprevention. J Natl Cancer Inst. 2003; 95:526-532. 2. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of pants in its randomized, double-blind investi- developing breast cancer for white females who are being examined annually. J gation. Participants will receive a daily dose of Natl Cancer Inst. 1989;81:1879-1886. 3. Ruffin MT, August DA, Kelloff GJ, Boone CW, Weber BL, Brenner DE. Selection raloxifene (60 mg) or tamoxifen (20 mg). criteria for breast cancer chemoprevention subjects. J Cell Biochem Suppl. 1993;17G:234-241. RUTH. Raloxifene Use and the Heart 4. Cummings SR, Duong T, Kenyon E, et al. Serum estradiol level and risk of breast (RUTH) is a double-blind, placebo-con- cancer during treatment with raloxifene. JAMA. 2002;287:216-220. 5. Jordan VC, Allen KE. Evaluation of the antitumor activity of the trolled trial of 60 mg of raloxifene that will antiestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carci- include 10,000 women. Primary endpoints noma mode. Eur J Cancer. 1980;16:239-251. 6. Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen are coronary disease and invasive breast can- and of cytotoxic therapy on mortality in early breast cancer: an overview of 61 ran- cer. Trial enrollment ended in August 2000, domized trials among 28,896 women. N Engl J Med. 1988;319:1681-1692. 7. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast and the study is expected to conclude in 2006. cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;90:1371-1388. 8. Bur ME, Zimarowski MJ, Schnitt SJ, Baker S, Lew R. Estrogen receptor immuno- Aromatase inhibitors: histochemistry in carcinoma in situ of the breast. Cancer. 1992;69:1174-1181. Another route of prevention 9. Nolvadex [package insert]. Wilmington, Del: AstraZeneca Pharmaceuticals; 2002. he evidence that estrogens facilitate breast 10. Powles T, Eeles R, Ashley S, et al. Interim analysis of incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomized chemoprevention trial. Lancet. Tcancer development in animals and 1998;352:98-101. women is substantial, although the precise 11. Veronesi U, Maisonneuve P, Costa A, et al. Prevention of breast cancer with tamox- ifen: preliminary findings from the Italian randomized trial among hysterec- mechanism is unknown.17 The most com- tomized women. Italian Prevention Study. Lancet. 1998;352:93-97. 12. Hol T, Cox MB, Bryant HU, Draper MW. Selective estrogen receptor modulators monly held theory is that estrogen stimulates and postmenopausal women’s health. J Women’s Health. 1997;6:523-531. proliferation of breast cells. Thus, it statisti- 13. Buzdar AU, Marcus C, Holmes F, Hug V, Hortobagyi G. Phase II evaluation of cally increases the chances for genetic muta- LY156758 in . Oncology. 1988;45:344-345. 14. Neven P, Muylder X, Van Belle Y, Vanderick G, De Mylder E. Hysteroscopic fol- tions that could result in cancer. low-up during tamoxifen treatment. Eur J Obstet Gynecol Reprod Biol. Aromatase inhibitors block peripheral 1990;35:235-238. 15. Goldstein SR, Scheele WH, Rajagopalan SK, Wilke JL, Walsh BW, Parsons AK. A conversion of androstenedione to estrogens. 12-month comparative study of raloxifene, estrogen, and placebo on the post- In premenopausal patients, the primary site menopausal endometrium. Obstet Gynecol. 2000;95:95-103. 16. Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction of this action is in the . In post- in postmenopausal women treated with raloxifene: 4-year results from the MORE menopausal women, it occurs predominantly trial. Breast Cancer Res Treat. 2001;65:125-134. 17. Santen RJ, Yue W, Nftolin F, Mor G, Berstein L. The potential of aromatase in extraovarian sites, including the adrenal inhibitors in breast cancer prevention. Endocrine-Related Cancer. 1999;6:235-243. 18. Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of glands, adipose tissue, , muscle, and skin. breast cancer. J Clin Oncol. 2001;19:881-894. Because of their dual role, (blocking both 19. Bilimoria MM, Morrow M. The woman at increased risk for breast cancer: evalu- the initiation and promotion of breast cancer), ation and management strategies. CA Cancer J Clin. 1995;45:263-278. aromatase inhibitors may be more effective Dr. Goldstein serves on gynecology advisory boards for Eli Lilly and Company, than SERMs in preventing breast cancer.18 By Pfizer, AstraZeneca, and P&G Pharmaceuticals.

48 OBG MANAGEMENT • July 2003