INVITED COMMENTARY

Invited Commentary: Time to Move Breast CancerChemoprevention to Center Stage

Kala Visvanathan

Published online: 6 November 2013# Springer Science+Business Media New York 2013

Abstract Breast cancer is now the most common cancerdiagnosedworldwide. There is substantial evidence that 5 yearsof treatment with chemopreventive agents, such as tamoxifen,raloxifene, and exemestane, can reduce the incidence ofhormone-positive cancers in high-risk women. Nevertheless,the uptake of these agents has been poor, even in women withatypical hyperplasia and lobular carcinoma in situ (LCIS)where the greatest benefit has been seen. There is a need fornovel approaches to ensure that chemoprevention is offered towomen at high risk. Less toxic agents are for women at modestrisk and to prevent hormone receptor-negative cancer.

Keywords Breast cancer . Chemopreventive agents .

Chemoprevention . Tamoxifen . Raloxifene . Exemestane

Introduction

A Global Concern

Breast cancer (BC) is now a global health issue, because it isthe most common cancer diagnosed among women and theleading cause of cancer death [1]. In the United States, BC isstill the most common cancer diagnosed in women [3]. Theincidence of BC is expected to increase steadily as thepopulation ages and there is overall growth as well as theadoption of cancer-related behaviors [2]. Many countrieshowever do not have the monetary resources to perform

widespread screening or to provide treatment for allwomen diagnosed with BC. In these countries, BCprevention that includes both chemoprevention—the focusof this commentary—and lifestyle modifications is likelyto have its significant impact.

The Evidence

It has been more than a decade since the first Phase III breastcancer chemoprevention trials were conducted [4]. There isnow substantial evidence that selective estrogen receptormodulators (SERMs) and aromatase inhibitors (AIs) canreduce the incidence of estrogen receptor (ER)-positive breastcancers in high-risk women. The totality of the evidence led toa stronger recommendation by the ASCO guideline panel onbreast cancer risk reduction for the use of chemopreventionagents. The recommendation now reads that chemoprevention“should be discussed” in women at high-risk for breast cancer[1]. This is instead of “may be offered,” which was thewording in the prior version [2]. A recent meta-analysis ofnine randomized, phase III trials that evaluated SERMS forprevention reported a 38 % reduction in breast cancerincidence [5] compared with the placebo (8 that included aplacebo arm), with the greatest reduction in the first 5 years.The authors calculated that over a 10-year period, 42 high-riskwomen would need to be treated to prevent one breast cancerand 53 high-risk women would need to be treated to preventone ER-positive invasive breast cancer.

Four phases III, randomized, placebo-controlled trialsranging from 2,500 to 13,000 high-risk women haveevaluated the efficacy of tamoxifen, for breast cancerreduction in both pre- and postmenopausal women. Thenames of these trials are the Breast Cancer Prevention Trial(National Surgical Adjuvant Breast and Bowel Project –NSABP-P1), International Breast Cancer Intervention Study(IBIS-1), the Royal Marsden Tamoxifen Prevention Trial, and

K. Visvanathan (*)Department of Epidemiology, Johns Hopkins Bloomberg School ofPublic Health & Johns Hopkins Sidney Kimmel ComprehensiveCancer Center, Baltimore, MD, USAe-mail: kvisvana@jhsph.edu

K. Visvanathane-mail: visvaka@jhmi.edu

Curr Obstet Gynecol Rep (2013) 2:199–201DOI 10.1007/s13669-013-0064-5

the Italian Randomized Tamoxifen Prevention Trial [6–9]. Allfour studies demonstrated a reduction in ER-positive breastcancer, which ranged between 31 % and 67 % in womenrandomized to take tamoxifen 20 mg/day compared withplacebo. Interestingly in the RoyalMarsden Trial, a significantreduction was only observed posttreatment [9]. None of thestudies were powered to detect differences in mortality,because that would have required even larger samplessizes. However, a lack of a survival benefit does notdiminish the importance of these findings, as a reductionof incidence itself is an important endpoint. This iscontrary to the treatment setting.

The STAR trial is the only randomized, clinical trial toevaluate raloxifene, another SERM specifically for breastcancer risk reduction [10]. In this study, 5 years of tamoxifen(20 mg/day) was compared with 5 years of raloxifene(60 mg/day) in postmenopausal women age ≥ 35 years and atincreased breast cancer risk [10]. After median follow-up of4.6 years, there was no difference in BC incidence betweenthe two groups. However, at median follow-up of 6 years,women who took raloxifene were 24%more likely to developBC compared with tamoxifen [11]. Raloxifene also was lesseffective in preventing noninvasive breast cancer by a similarmagnitude. These differences between tamoxifen andraloxifene are important to convey to women but does not inany way negate the use of raloxifene for breast cancerprevention. It does highlight the complexities related to choiceof agent and the need for detailed discussions on the risks andbenefits of each agent with eligible women. The use of otherSERMs, such as lasofoxifene and arzoxifene, also have beenassociated with a reduction in breast cancer incidence, but therandomized trials have only been conducted among womenwith low bone mineral density and/or osteoporosis [12, 13].

There is now more information on the longer-term adverseeffects of SERMs in the prevention setting. In the meta-analysis by Cuzick et al., a 1.7-increase in thromoboembolicdisease was observed among SERM users and a 34 %reduction in nonvertebral fractures. Serious adverse effectsassociated with tamoxifen include endometrial cancer, stroke,transient ischemic attack, venous thromboembolic disease,deep venous thrombosis, and pulmonary embolism. Inpremenopausal women, Gail et al. have shown that womenyounger than age 50 years have a lower risk of these sideeffects [14]. These findings are based on data from NSABP-P1. Longer-term follow-up data from the IBIS1 studydemonstrated that the risk of the vascular side effects declinedramatically posttreatment irrespective of age [7]. Tamoxifenis contraindicated in women who are immobilized oroverweight, because they are at higher risk of thromboembolicdisease. The risk profile for tamoxifen is significantly betterthan raloxifene, although it was less efficacious [10, 11, 15].Uterine cancer, cataracts and cataract surgery, and benignuterine hyperplasia vaginal concerns are less common in

women taking raloxifene than tamoxifen. Freedman et al. alsodemonstrated that factors, such as age, race, and level of breastcancer risk and history of hysterectomy, can impact net healthbenefits when considering tamoxifen versus raloxifene inpostmenopausal women [16]. The authors have generatedsome tables to help providers with that decision. All ofthese factors need to be considered when deciding on whichagent to recommend.

Exemestane, a steroidal aromatase inhibitor (AI), is anotheroption for breast cancer risk reduction in postmenopausalwomen [17]. MAP3 is a randomized, placebo control trial ofexemestane that was conducted in postmenopausal women.After a median follow-up of 3 years, a 73 % reduction in ER-positive breast cancers was observed among womenwho tookexemestane (25 mg/day) for 5 years compared with placebo.Women who took exemestane were more likely to haveendocrine-related events, gastrointestinal events, and musclepain. There was no difference in fractures between the groups;however, this was only ascertained by self-report. In a posthoc substudy, a statistically significant reduction in bonemineral density was observed in the exemestane groupcompared with placebo despite calcium and vitamin Dsupplementation [18]. Longer-term data are needed to furtherunderstand the magnitude of adverse events over time. Theresults from IBIS II a randomized trial comparing anastrozoleto placebo in high-risk cancer-free women also will informour understanding of the use of AI in the preventive setting.

The Challenges

Despite accumulating evidence over the past decade, very fewwomen opt to take chemoprevention or are being offered it[19, 20]. The reasons for this are multifactorial but include thefollowing challenges: 1) successful incorporation of breastcancer risk assessment into clinical practice; 2) educatingwomen about how to evaluate risks and benefits; 3) updatingproviders as new information becomes available; 4)improving the discriminatory accuracy of risk assessmenttools; 5) identifying a biomarker of treatment response; 6)the identification of additional barriers; 7) identifynonresponder and women who are likely to suffer side effectsupfront so they can be monitored more closely or given otheroptions; and 8) generate more robust estimates in BRCA1/2mutation carriers.

The lack of adherence also is likely to be a challenge. In theNSABP-P1 study, after 3 years adherence was only 79 % [6].A number of approaches are being studied to improveadherence in this setting. This includes examining geneticand metabolic predictors of response and adverse effects toSERMs and evaluating the use of low-dose tamoxifen in thepreventive setting [21].

Despite the ongoing challenges, health providers should beencouraged to assess breast cancer risk in their patients and

200 Curr Obstet Gynecol Rep (2013) 2:199–201

discuss chemoprevention with women presently at high-riskfor breast cancer. This includes women post childbearing witha strong family history and women with lobular carcinoma insitu (LCIS) or atypical ductal hyperplasia (ADH). In thesewomen, the benefits are likely to outweigh the risks.

Summary

It is important for health providers to recognize that effectivechemoprevention agents for hormone-positive breast cancernow exist and should be considered in women at high-risk.Patients can be referred to specialty clinics at most cancercenters for more nuanced discussions if needed. New agentsare needed to prevent ER-negative breast cancers and for usein the general population. Women also should be educatedabout the beneficial impact of optimizing lifestyle factors,such as physical activity and body mass index, on BC risk.

Compliance with Ethics Guidelines

Conflict of Interest Kala Visvanathan declares that he has no conflictof interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

References

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM.Estimates of worldwide burden of cancer in 2008: GLOBOCAN2008. Int J Cancer. 2010;127(12):2893–917.

2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Globalcancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

3. ACS. Cancer facts & figures 2013. Atlanta: American CancerSociety, Inc.; 2013. Contract No.: Document Number|.

4. Visvanathan K, Hurley P, Bantug E, Brown P, Col NF, Cuzick J, et al.Use of pharmacologic interventions for breast cancer risk reduction:American Society of Clinical Oncology Clinical Practice Guideline. JClin Oncol. 2013;31(23):2942–62.

5. Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, DeCensiA, et al. Selective oestrogen receptor modulators in prevention ofbreast cancer: an updatedmeta-analysis of individual participant data.Lancet. 2013;381(9880):1827–34. PMCID: 3671272.

6. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M,Cronin WM, et al. Tamoxifen for prevention of breast cancer: reportof the National Surgical Adjuvant Breast and Bowel Project P-1Study. J Natl Cancer Inst. 1998;90(18):1371–88.

7. Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, et al.Long-term results of tamoxifen prophylaxis for breast cancer–96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst.2007;99(4):272–82.

8. Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P,Viale G, et al. Tamoxifen for the prevention of breast cancer:late results of the Italian Randomized Tamoxifen PreventionTrial among women with hysterectomy. J Natl Cancer Inst.2007;99(9):727–37.

9. Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M. Twenty-yearfollow-up of the Royal Marsden randomized, double-blindedtamoxifen breast cancer prevention trial. J Natl Cancer Inst.2007;99(4):283–90.

10. Vogel VG, Costantino JP,WickerhamDL, CroninWM, Cecchini RS,Atkins JN, et al. Effects of tamoxifen vs raloxifene on the risk ofdeveloping invasive breast cancer and other disease outcomes: theNSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.JAMA. 2006;295(23):2727–41.

11. Vogel VG, Costantino JP,WickerhamDL, CroninWM, Cecchini RS,Atkins JN, et al. Update of the National Surgical Adjuvant Breast andBowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial:preventing breast cancer. Cancer Prev Res (Phila). 2010;3(6):696–706. PMCID: 2935331.

12. Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S,Reid DM, et al. Lasofoxifene in postmenopausal women withosteoporosis. N Engl J Med. 2010;362(8):686–96.

13. LaCroix AZ, Powles T, Osborne CK, Wolter K, Thompson JR,Thompson DD, et al. Breast cancer incidence in the randomizedPEARL trial of lasofoxifene in postmenopausal osteoporotic women.J Natl Cancer Inst. 2010;102(22):1706–15.

14. Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L,Helzlsouer K, et al. Weighing the risks and benefits of tamoxifentreatment for preventing breast cancer. J Natl Cancer Inst.1999;91(21):1829–46.

15. Land SR, Wickerham DL, Costantino JP, Ritter MW, Vogel VG, LeeM, et al. Patient-reported symptoms and quality of life duringtreatment with tamoxifen or raloxifene for breast cancer prevention:the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.JAMA. 2006;295(23):2742–51.

16. Freedman AN, Yu B, Gail MH, Costantino JP, Graubard BI, VogelVG, et al. Benefit/risk assessment for breast cancer chemopreventionwith raloxifene or tamoxifen for women age 50 years or older. J ClinOncol. 2011;29(17):2327–33. PMCID: 3107748.

17. Goss PE, Ingle JN, Ales-Martinez JE, Cheung AM, Chlebowski RT,Wactawski-Wende J, et al. Exemestane for breast-cancer preventionin postmenopausal women. N Engl J Med. 2011;364(25):2381–91.

18. Cheung AM, Tile L, Cardew S, Pruthi S, Robbins J, Tomlinson G,et al. Bone density and structure in healthy postmenopausal womentreatedwith exemestane for the primary prevention of breast cancer: anested substudy of the MAP.3 randomised controlled trial. LancetOncol. 2012;13(3):275–84.

19. Waters EA, McNeel TS, Stevens WM, Freedman AN. Use oftamoxifen and raloxifene for breast cancer chemoprevention in2010. Breast Cancer Res Treat. 2012;134(2):875–80.

20. Waters EA, Cronin KA, Graubard BI, Han PK, Freedman AN.Prevalence of tamoxifen use for breast cancer chemopreventionamong U.S. women. Cancer Epidemiol Biomarkers Prev.2010;19(2):443–6.

21. Decensi A, Robertson C, Guerrieri-Gonzaga A, Serrano D,Cazzaniga M, Mora S, et al. Randomized double-blind 2 × 2 trialof low-dose tamoxifen and fenretinide for breast cancer prevention inhigh-risk premenopausal women. J Clin Oncol. 2009;27(23):3749–56. PMCID: 2799048.

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