Selective Estrogen-Receptor Modulators in 2001

September 1, 2001

Tamoxifen (Nolvadex), a selective estrogen-receptor modulator, or SERM, is currently the endocrine therapy of choice for all stages of hormone-responsive breast cancer. Only tamoxifen has been approved by the US Food and

A number of issues remain tobe clarified concerning the use of selective estrogen-receptor modulators (SERMs) in the treatment andprevention of breast cancer. These considerations include identification of theideal agent; the appropriate target population, particularly for chemopreventionwith SERMs; the duration of use; the age at which to begin therapy; and a properrisk/benefit calculation.

The prototype SERM, tamoxifen (Nolvadex), has been a landmark in the historyof breast cancer treatment. The ability of this drug to reduce both recurrencesand deaths when used in the adjuvant setting are well known,[1] and thedemonstration that it could reduce primary breast malignancies was a milestonein 20th-century medical oncology.[2] Tamoxifen, however, is associated with anincreased risk of endometrial carcinoma, cataracts, menopausal symptoms, andthrombotic events. Drs. O’Regan and Gradishar did not specifically address theissue of thrombosis, but this concern becomes particularly important aftermenopause, especially in women aged 60 years and over.

Risk/Benefit Calculations

Gail and colleagues have shown that it is possible to calculate the risk vsbenefit of tamoxifen use in a way that considers reduction in breast cancerincidence and osteoporotic fractures along with increased risk of thromboticevents, endometrial cancer, and cataracts.[3] Clinicians who are consideringprescribing tamoxifen for risk reduction should be cognizant of this strategy.They should also be aware that the calculation of net benefit or risk isconditioned by the weights assigned by either the patient or her clinician tothe individual benefits and risks.

Using this strategy, it is relatively easy to show that all premenopausalwomen with a 5-year risk of invasive breast cancer of 1.66% or greater derive apositive net benefit from the use of tamoxifen for risk reduction. It is alsoclear that net benefit is more difficult to demonstrate in postmenopausal women,particularly among those with an intact uterus, and especially in light of therising baseline risks of thromboembolic events associated with increasing age.Nevertheless, women at a moderate to high risk of invasive breast cancer who areolder than 50 years still derive net benefit from using tamoxifen for riskreduction. Additional research is needed to identify the best strategy forcommunicating the relative risks/benefits and a net benefit calculation for theentire at-risk population.

Large Studies of TamoxifenRisk/Benefit

The largest, and perhaps most informative, review of the association betweenexposure to tamoxifen and development of endometrial carcinoma appears in theNational Surgical Adjuvant Breast and Bowel Project (NSABP) report on studyB-14.[4] This evaluation suggests that tamoxifen-associated endometrialcarcinomas can occur over prolonged periods after the administration oftamoxifen. Unlike the information cited by Drs. O’Regan and Gradishar, thesedata suggest that endometrial tumors associated with tamoxifen may not merelyoccur after short durations of therapy. Importantly, however, the Breast CancerPrevention Trial showed that endometrial cancer incidence was not increasedamong menstruating, premenopausal women; the increase in risk was confined onlyto nonmenstruating, postmenopausal women.

It is unlikely that cases of genetically transmitted breast cancer accountfor the absence of demonstrated benefit in the Royal Marsden Pilot Study. Narodand colleagues from the Hereditary Breast Cancer Clinical Study Group recentlyreported a reduction in the risk of contralateral breast cancer in carriers ofeither BRCA1 or BRCA2 mutations, and the reported reduction among BRCA1 carrierswas actually greater than that seen in the Breast Cancer Prevention Trial.[5]The reason that the Royal Marsden trial did not see a beneficial effect oftamoxifen is most likely the small number of estrogen-receptor tumors thatoccurred and the consequential low power to detect a difference betweentamoxifen and placebo treatments.

I disagree with the statement by Drs. O’Regan and Gradishar that the RoyalMarsden trial had a 90% power to detect a decrease in breast cancerincidence.[6] Our published calculations indicate that the power of the RoyalMarsden trial was nearer to 40%. They are quite correct, however, in saying thatthe high proportion of women in the Italian study who underwent premenopausaloophorectomy probably accounts for tamoxifen’s inability to add to thereduction in breast cancer risk already resulting from the prophylactic surgery.

The authors are also correct in pointing out that tamoxifen is associatedwith an increase in hot flashes and vaginal dryness. It is reassuring that,while these symptoms do occur with increased frequency among women takingtamoxifen, they can be controlled with available medications. Also, weight gainand depression have not been observed to occur with increased frequency in womentaking tamoxifen for breast cancer risk reduction,[7] contrary to widely heldbeliefs.

Other SERMs and SERDs

Clinicians must exercise caution in interpreting the results of the MultipleOutcomes of Raloxifene (MORE) trial, since the eligible women who have low bonemineral density also have a substantially lower increased risk of breastcancer.[8] We do not yet know whether the use of raloxifene in women atincreased risk of invasive breast cancer will result in the same reduction inrisk seen among women with osteoporosis. The Study of Tamoxifen and Raloxifene(STAR) trial will provide important outcome data to address this questiondirectly. It is also important to recall that in women taking raloxifene in theMORE trial, the incidence of thrombosis increased threefold[9]—an increaseequivalent to that seen in the Breast Cancer Prevention Trial.

The most recently presented data regarding the efficacy of selectiveestrogen-receptor downregulators (SERDs) show an equal degree of benefit whencomparing fulvestrant (ICI 182,780, Faslodex) with tamoxifen in treating womenwith advanced breast cancer, although the duration of benefit may be longer withthe SERD.[10] Further evaluations will be necessary before we can judge withcertainty whether SERDs offer an advantage over SERMs in either the treatment ofbreast cancer or the reduction of breast cancer risk.

Future Outlook

A number of issues remain to be resolved in the epidemiology and clinicalmanagement of breast cancer. We have not yet identified the optimal clinicaltrial design to evaluate putative risk-reduction agents. We simply do not havethe resources of time, money, or eligible patients to conduct trials of the sizeof the Breast Cancer Prevention Trial (ie, 13,388 subjects in the NSABP P-1trial) or the STAR trial (a projected 22,000 subjects in the NSABP P-2 trial).Identification of appropriate intermediate markers would facilitate the designof more economical trials. Clinicians also need more efficient methods ofidentifying and recruiting the appropriate patients for theseinterventions.[11,12]

The availability of aromatase inhibitors, pure antiestrogens, and third- andfourth-generation SERMs holds promise for an ever-expanding array of potentialagents to use for both breast cancer treatment and risk reduction. Additionaltrials will be necessary to identify the proper sequence of SERMs, hormonereplacement therapy, aromatase inhibitors, and other agents for the optimalmanagement of breast cancer risk. Finally, it is quite possible that new agentsthat target coactivators and corepressors of estrogen receptor action will soonbe identified and will need to be incorporated into our armamentarium for boththe reduction of breast cancer risk and the treatment of early breastcancer.[13]

References:

1. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for earlybreast cancer: An overview of the randomized trials. Lancet 351:1451-1467, 1998.

2. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention ofbreast cancer: Report of the National Surgical Adjuvant Breast and Bowel ProjectP-1 Study. J Natl Cancer Inst 90:1371-1388, 1998.

3. Gail, MH, Costantino JP, Bryant J, et al: Weighing the risks and benefitsof tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst91:1829-1846, 1999.

4. Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer intamoxifen-treated breast cancer patients: Findings from the National SurgicalAdjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86:527-537,1994.

5. Narod SA, Brunet, JS, Ghadirian P, et al, for the Hereditary Breast CancerClinical Study Group: Tamoxifen and risk of contralateral breast cancer inBRCA-1 and BRCA-2 mutation carriers: A case-control study. Lancet 356:1876-1881,2000.

6. Costantino JP, Vogel VG: Results and implications of the Royal Marsden andother tamoxifen chemoprevention trials: An alternative view. Clinical BreastCancer 2:41-46, 2001.

7. Day R, Ganz PA, Costantino JP, et al: Health-related quality of life andtamoxifen in breast cancer prevention: A report from the National SurgicalAdjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 17:2659-2669, 1999.

8. Lucas FL, Cauley JA, Stone RA, et al: Bone mineral density and risk ofbreast cancer: Differences by family history of breast cancer. Study ofOsteoporotic Fractures Research Group. Am J Epidemiol 148:22-29, 1998.

9. Cummings SR, Eckert S, Krueger KA, et al: The effect of raloxifene on riskof breast cancer in postmenopausal women: Results from the MORE randomizedtrial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281:2189-2197, 1999.

10. Howell A, Robertson JFR, Quaresma Albano J, et al: Comparison of efficacyand tolerability of fulvestrant (Faslodex) with anastrazole (Arimidex) inpost-menopausal women with advanced breast cancer-preliminary results(abstract). Breast Cancer Res Treat 64:27, 2000.

11. Vogel VG: High-risk populations as targets for breast cancer preventiontrials. Prev Med 20:86-100, 1991.

12. Vogel VG (ed): Management of Patients at High-Risk for Breast Cancer.Cambridge, Mass, Blackwell Science, p 63-93, 2000.

13. Osborne CK, Zhao H, Fuqua SAW: Selective estrogen receptor modulators:Structure, function, and clinical use. J Clin Oncol 18:3172-3186, 2000.