Long-Term Toxicities of Selective Estrogen-Receptor Modulators and Antiaromatase Agents

May 1, 2003

Hormonal therapies have longplayed an important role inthe treatment of metastaticand early-stage breast cancer. Afterdemonstrating equivalent efficacy andless toxicity than high-dose estrogen,tamoxifen-a selective estrogen-receptormodulator (SERM)-has beenwidely used for the treatment of metastaticbreast cancer.[1] Multiple randomizedadjuvant trials subsequently demonstrated that patients treated withtamoxifen experienced fewer breastcancer recurrences, leading to its widespreaduse in the adjuvant setting.[2]

Hormonal therapies have longplayed an important role inthe treatment of metastaticand early-stage breast cancer. Afterdemonstrating equivalent efficacy andless toxicity than high-dose estrogen,tamoxifen-a selective estrogen-receptormodulator (SERM)-has beenwidely used for the treatment of metastaticbreast cancer.[1] Multiple randomizedadjuvant trials subsequently demonstrated that patients treated withtamoxifen experienced fewer breastcancer recurrences, leading to its widespreaduse in the adjuvant setting.[2]In women with ductal carcinoma insitu, tamoxifen reduced the incidenceof subsequent invasive and noninvasivecancers.[3] Finally, the NationalSurgical Adjuvant Breast and BowelProject (NSABP) P-1 trial demonstratedthat tamoxifen could reduce a woman'slikelihood of being diagnosed withbreast cancer.[4] The benefits derivedfrom a course of treatment with tamoxifenare quite clear, but they must beconsidered in light of potential sideeffects.Because of its size and its doubleblindednature, the NSABP P-1 trialrepresents the most definitive sourceof toxicity data for tamoxifen. Thetrial demonstrated an increased riskof uterine cancer, cataracts, andvenous thromboembolic events intamoxifen-treated women as comparedto placebo. There was also anonsignificant increase in stroke riskin the tamoxifen group, mostly inwomen over age 50. Additionally,the drug was found to cause an increasein uncomfortable hot flashes,genitourinary symptoms, and difficultywith sexual functioning.[5]Agents DevelopedAfter Tamoxifen
Raloxifene (Evista), anotherSERM, is currently approved by theUS Food and Drug Administration(FDA) for the prevention and treatmentof osteoporosis. In the MultipleOutcomes of Raloxifene Evaluation(MORE) trial, a lower than expectednumber of breast cancers developedin the raloxifene arm, suggesting thatthe drug may have efficacy in termsof breast cancer risk reduction.[6]These results led to the ongoing Studyof Tamoxifen and Raloxifene(STAR), which is randomizing highriskpostmenopausal women totamoxifen vs raloxifene for breastcancer prevention. However, raloxifenehas not been effective in thetreatment of metastatic breast cancer,and the drug is not currentlyindicated for use in treatment or riskreduction of breast cancer.Anastrozole (Arimidex), letrozole(Femara), and exemestane (Aromasin),the three third-generation aromataseinhibitors available in theUnited States, have gained FDA approvalfor the treatment of metastaticbreast cancer. Anastrozole has alsobeen approved for use in the adjuvantsetting. These drugs prevent theperipheral conversion of adrenal androgens into estrogen, leading to amarked reduction in estrogen levelsin postmenopausal women.In recent years, the third-generationaromatase inhibitors have beenused increasingly in the treatment ofwomen with metastatic breast cancer.Short-term toxicity data indicatethat all three agents are well tolerated.[7-9] Given the relatively shortduration of therapy in the advanceddiseasesetting, long-term toxicitydata are not available from trials inwomen with metastatic breast cancer.Ultimately, the adjuvant trialswill provide long-term toxicity datafor women who have taken an aromataseinhibitor for 5 years, but atthis time, no study is sufficientlymature to provide this much-neededinformation.Difficult Comparison
In their review article in this issueof ONCOLOGY, Mortimer and Urbancompare the long-term toxicitiesof the aromatase inhibitors and theselective estrogen-receptor modulators.This comparison is madedifficult by the relative paucity oflong-term toxicity data for the aromataseinhibitors, especially for thedrugs letrozole and exemestane. Asthe authors point out, most of theavailable data comes from trials inthe metastatic setting, in which womenwere treated with these agents forrelatively short periods of time. Tomake up for this, the authors haveprovided important preclinical and/or preliminary data. Although suchdata are extraordinarily useful forhypothesis generation, they cannotsubstitute for rigorous clinical data.The Anastrozole, TamoxifenAlone or in Combination (ATAC)trial supplies the only data we haveregarding the long-term use of thearomatase inhibitors.[10] This trialrandomized postmenopausal womenwith early-stage breast cancer to anastrozole,tamoxifen, or the combinationof the two. Anastrozole gainedFDA approval for use in the adjuvantsetting based on the efficacy resultsfrom this trial, which showed that at33 months' follow-up, patients in theanastrozole arm displayed significantly superior disease-free survival anda significantly lower incidence of contralateralbreast cancers than did thetamoxifen arm.ATAC toxicity data revealed thatuterine cancer, hot flashes, venousthromboembolic events, and ischemiccerebrovascular events were significantlymore common in the tamoxifengroup, whereas osteopenia and fractureswere significantly more commonin the anastrozole group. In a substudylooking at quality of life, there wereno overall differences between thegroups in quality-of-life measures, butthere was a suggestion of more sexualside effects in women treated withanastrozole.[11]Effects on Bone
Prior studies have also suggestedthat the aromatase inhibitors andtamoxifen have different effects onbone mineral density and fracturerisk. Data suggest that the effect oftamoxifen on bone mineral densitydepends on menopausal status, withpostmenopausal women experiencinga positive impact on bone densityand premenopausal women tendingto experience bone loss when treatedwith this agent.[12] Love et al demonstrateda significant increase inbone mineral density in postmenopausalwomen with node-negativebreast cancer treated with tamoxifencompared to those treated with placebo.[13] The NSABP preventionstudy demonstrated a nonsignificantreduction in hip, radius, and spinefractures in women treated withtamoxifen compared to those treatedwith placebo.[4] However, thesegroups were not separated by menopausalstatus. Of note, tamoxifen doesnot have an indication for the preventionor treatment of osteoporosis.The aromatase inhibitors effectivelylower estrogen levels in postmenopausalwomen to below thelower limits of detection in most assays.The ATAC trial represents theonly data to date concerning the longtermeffects of aromatase inhibitorson bone density. At 33 months'median follow-up, there were significantlymore fractures in the anasedtrozole group than in the tamoxifengroup.[10] This increase in fracturerisk was also seen in the updatedtoxicity analysis.Further work will be necessary tofully quantify the fracture risk in patientstreated with anastrozole, as wellas to develop strategies to preventthis complication. Studies looking atthe use of bisphosphonates to reducethe risk of osteopenia and fractures inwomen treated with aromatase inhibitorsare currently in progress. There iscurrently almost no clinical informationregarding the effect of letrozoleor exemestane on bone density, especiallyafter prolonged administrationof the drugs. Further conclusions regardingthe effect of these agents onbone density cannot be drawn untildata from adjuvant studies using thesedrugs becomes available.Cardiovascular Effects
The authors also discuss differencesin cardiovascular mortalityamong patients treated with tamoxifenand the aromatase inhibitors.Postmenopausal hormone-replacementtherapy and tamoxifen haveboth been shown to have a beneficialeffect on lipid profiles, which wasbelieved to lead to a reduction incardiovascular mortality. With theresults of the Women's HealthInitiative[14] and the Heart and Estrogen/Progestin Relacement Study(HERS),[15] estrogen-replacementtherapy is no longer believed to bebeneficial in the primary or secondaryprevention of heart disease.Likewise, the NSAPB P-1 preventiontrial has not suggested a reducedrisk of cardiovascular disease in patientstreated with tamoxifen.[4] Furthermore,the Early Breast CancerTrialists' overview analysis examinedthe rates of non-breast/endometrialcancer-related deaths and found no differencebetween tamoxifen and placebo groups.[2] A subanalysis of onlycardiovascular deaths again revealedno differences between the groups.Conclusions
As the authors point out in theirconclusion, the majority of postmenopausalwomen with hormone receptor-positive, early-stage breast cancerwill die of other causes. After manythousands of patient-years of experiencewith tamoxifen, the side-effectprofile of this drug is well understood.Early evidence suggests that the aromataseinhibitors probably avoidsome of the more serious toxicitiesassociated with tamoxifen use, suchas uterine cancer and venous thromboembolism.However, there is virtuallyno information availableconcerning the side effects of theseagents when they are used for 5 years.Clinicians and patients alike await theavailability of long-term toxicity data.This information will be indispensableas postmenopausal women andtheir physicians consider adjuvanttreatment decisions in the years ahead.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Ingle JN, Ahmann DL, Green SJ, et al:Randomized clinical trial of diethylsilbestrolversus tamoxifen in postmenopausal womenwith advanced breast cancer. N Engl J Med304:16-21, 1981.

2.

Early Breast Cancer Trialists’ CollaborativeGroup: Tamoxifen for early breast cancer:An overview of the randomized trials. Lancet351:1451-1467, 1998.

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Fisher B, Dignam J, Wolmark N, et al:Tamoxifen in treatment of intraductal breastcancer: National Surgical Adjuvant Breast andBowel Project B-24 randomised controlled trial.Lancet 353:1993-2000, 1999.

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Day R, Ganz PA, Costantino JP, et al: Healthrelatedquality of life and tamoxifen in breast cancer prevention: A report from the National SurgicalAdjuvant Breast and Bowel Project P-1 study. JClin Oncol 17:2659-2669, 1999.

6.

Ettinger B, Black DM, Mitlak BH, et al:Multiple Outcomes of Raloxifene Evaluation(MORE) Investigators. Reduction of vertebralfracture risk in postmenopausal women withosteoporosis treated with raloxifene: Resultsfrom a 3-year randomized clinical trial. JAMA282:637-645, 1999.

7.

Bonneterre J, Buzdar A, Nabholtz JM, etal: Anastrozole is superior to tamoxifen as firstlinetherapy in hormone receptor positiveadvanced breast carcinoma. Cancer 92:2247-2258, 2001.

8.

Buzdar A, Douma J, Davidson N, et al:Phase III, multicenter, double-blind, randomizedstudy of letrozole, an aromatase inhibitor,for advanced breast cancer versus megestrolacetate. J Clin Oncol 19:3357-3366, 2001.

9.

Dirix L, Piccart M, Lohrisch C, et al: Efficacyof and tolerance to exemestane versus tamoxifen infirst-line hormone therpay of postmenopausal metastaticbreast cancer patients: A European Organizationfor the Research and Treatmetn of Cancer(EORTC Breast Group) phase II trial with Pharmaciaand Upjohn (abstract 114). Proc Am Soc ClinOncol 20:29a, 2001.