Evaluating Risks, Benefits of Hormone Therapy for Women at High Risk for or with a History of Breast Cancer

Dec 20, 2011


Jamie H. Von Roenn, MD
Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Breast cancer is the most common malignancy diagnosed in women.1Theadoption of screening guidelines and advances in adjuvant therapy haveled to significant improvements in survival for these women. As aresult, an increasing number of premenopausal women survive breastcancer and subsequently experience debilitating menopausal symptoms.These include urogenital complaints (recurrent urinary tractinfections, urinary urgency, vaginal dryness, and dyspareunia),vasomotor symptoms (hot flashes and night sweats), and central symptoms(insomnia, memory loss, and mood alterations) that may detract from thewoman’s overall sense of well-being and interfere with herdaily activities.

Clinical trials in women with a history of breast cancer haveidentified moderately effective therapies for vasomotor symptoms,including selective serotonin and norepinephrine reuptake inhibitorsand gabapentin.2Topical lubricants improve vaginal dryness anddecrease sexual concerns for some women with urovaginal symptoms.

Hormone replacement therapy (HRT), either estrogen alone or combinationestrogen/progesterone, is the most effective means to treat thesesymptoms and protects against the accelerated bone loss that may occurwith treatment-induced menopause. However, the results from theWomen’s Health Initiative study and others outline thepotential harm of HRT.3,4Healthy postmenopausal women with a uterustreated with combination estrogen and progesterone have an increasedrisk of breast cancer and breast cancer mortality. Postmenopausal womenwith a prior hysterectomy treated with a short to moderate duration ofestrogen alone have an overall decrease in the risk of developingbreast cancer. For women with a history of breast cancer, there islimited data. It is unclear whether estrogen for a short duration at alow dose, or estrogen in concert with tamoxifen, are reasonablerecommendations for women with debilitating menopausal symptoms.

In the feature that follows, the authors discuss the available dataregarding the use of hormone replacement therapy for women at high riskfor breast cancer as well as for those women with a history of breastcancer. While there is conflicting data from previously publishedtrials, HRT in women with prior breast cancer requires carefulevaluation of the risks and benefits and patient understanding of theavailable data.

1. Siegel R, Ward E, Brawley O, et al. CA Cancer J Clin.2011;61:212-36.
2. Loprinzi CL, Sloan J, Stearns V, et al. J Clin Oncol.2009;27:2831-7.
3. Chlebowski RT, Anderson GL, Gass M, et al. JAMA.2010;304:1684-92.
4. Stefanick ML, Anderson GL, Margolis KL, et al. JAMA.2006;295:1647-57.

Dr. Von Roenn is a Professorof Medicine at NorthwesternUniversity’s Feinberg School of Medicine, member of theRobert H. Lurie Comprehensive Cancer Center, and Medical Director ofNorthwestern Memorial Hospital’s Home Hospice Program. Sheserves on ASCO’s Cancer Education Committee and ProfessionalDevelopment Committee and is on the ASCO Connection Editorial Board.

A Favorable Approach to the Use of Hormone Therapy

Julia A. Files, MD
Mayo Clinic, Phoenix

Sandhya Pruthi, MD
Mayo Clinic, Rochester

A majority of breast cancers diagnosed occur in postmenopausal womenand are hormone receptor-positive. Epidemiologic studies and one of thelargest randomized controlled trials conducted in women have shown anincrease in breast cancer risk following five years of combinedestrogen-progestin (E+P) therapies compared to placebo and estrogen (E)alone.1,2More recently, a large prospective study on hormone therapy(HT) and breast cancer risk also showed that breast cancer risk wasgreater among users of combination hormone therapy than users ofestrogen-only formulations. Risk was also greater if the hormonetherapy was initiated around the time of menopause rather than later inlife.3

The North American Menopause Society recommends that HT be offered atthe lowest effective dose for the shortest duration possible to womenwho are experiencing moderate to severe menopausal symptoms.4Women athigh risk for the development of breast cancer (those with a personalor family history of breast cancer, Gail Model > 1.66%, orpersonal history of precancerous breast lesion or BRCAmutation) mayrequest systemic HT for management of moderate to severe menopausalsymptoms. Physicians face the dilemma posed by the goal of minimizingrisk of disease while trying to preserve quality of life. If HT isprescribed, it requires that the physician engage the patient incollaborative decision-making to choose the therapy that provides themost acceptable risk versus benefit for the individual patient.

Risksfor women with a BRCA mutation
Recently, there has been discussion surrounding the use of HT andfuture risk of breast cancer in women with a BRCA mutation.Risk-reducing salpingo-oophorectomy is associated with decrease inoverall mortality as well as breast and ovarian cancer-specificmortality, but may result in an exacerbation of moderate to severemenopausal symptoms.5Several studies looking at short-term HT(systemic E+P and E alone) use in patients who have a BRCAmutationhave not found an increase in breast cancer risk and the use may evenbe associated with a decrease in risk.6,7Further, a study of womenwith a BRCAmutation who had undergone bilateral prophylacticoophorectomy and subsequent use of short-term HT reported that HT didnot negate the breast cancer risk reduction following this procedure.8

Womenwith a prior diagnosis
The decision to use HT in women with a prior diagnosis of breast canceris more complex. Although observational studies and randomized trialsof hormone therapy in breast cancer survivors have shown conflictingresults, the use of systemic HT in women with a previous diagnosis ofbreast cancer (especially combined E+P) cannot be endorsed.1,9,10

Genitourinary atrophy (GUA) is a consequence of estrogen deficiency andis often worsened by the administration of aromatase inhibitors. Manywomen with a history of breast cancer suffer significant symptomsassociated with GUA.11Several recent overviews on the management ofurogenital atrophy in women with a history of breast cancer havehighlighted treatment with low-dose vaginal 17 B-estradiol (vaginalestradiol tablets 10 ug or vaginal estradiol ring) after appropriatedisclosure to the patient.12Appropriate dosing of local estrogentherapy is critical as although estrogen administered vaginally areassociated with delivery of a lower dose over a year, it can lead tosystemic levels equal to those achieved by oral or transdermal products.

The lowest effective dose for achieving resolution of clinical symptomswithout systemic effect is the goal. Best results may be achievedthrough the use of a low-dose vaginal estrogen tablet once a week incombination with daily use of vaginal lubricants and/or moisturizers.The long-term safety of these preparations are not known, and it maynot be possible to ever design a large enough study that will be ableto effectively evaluate vaginal preparations and breast cancer risk orrecurrence. In addition, a critical factor to note is that many womendiscontinue or are non-compliant with their anti-estrogen therapies dueto negative quality-of-life symptoms. In the large chemopreventiontrials (STAR, MAP.3), low-dose vaginal estrogen preparations wereallowed on study for management of symptoms associated with GUA.13,14The decision to initiate low-dose vaginal estrogen needs to beindividualized and made jointly with the oncologist.11,12The role ofHT in women with a prior diagnosis of breast cancer should be limitedto local therapy for the treatment of GUA.

In summary, the evidence at present does not support the use ofsystemic estrogen in patients with a diagnosis of breast cancer. Thedecision to use low-dose local vaginal estrogen in women at high riskor with a history of breast cancer should be done on an individualizedbasis and be made collaboratively with the patient, understanding thebenefits and risks as well as taking into account the impact on qualityof life.

1. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet.1997;350:1047-59.
2. Rossouw JE, Anderson GL, Prentice RL, et al. JAMA.2002;288:321-33.
3. Beral V, Reeves G, Bull D, et al. J Natl Cancer Inst.2011;103:296-305.
4. Santen RJ, Allred DC, Ardoin SP, et al. J Clin Endocrinol Metab.2010;95(7 Suppl 1):s1-s66.
5. Domchek SM, Friebel TM, Singer CF, et al. JAMA.2010;304:967-75.
6. Eisen A, Lubinski J, Gronwald J, et al. J Natl Cancer Inst.2008;100:1361-7.
7. Domchek SM. J Clin Oncol.2011;29:(suppl; abstr 1501).
8. Rebbeck TR, Friebel T, Wagner T, et al. J Clin Oncol.2005;23:7804-10.
9. von Schoultz E, Rutqvist LE. J Natl Cancer Inst.2005;97:533-5.
10. Holmberg L, Iversen OE, Rudenstam CM, et al. J Natl Cancer Inst.2008;100:475-82.
11. Files JA, Ko MG, Pruthi S. Mayo Clin Proc.2010;85:560-6; quiz 566.
12. Pruthi S, Simon JA, Early AP. Breast J.2011;17:403-8.
13. Vogel VG, Costantino JP, Wickerham DL, et al. JAMA.2006;295:2727-41.
14. Goss PE, Ingle JN, Alés-Martinez JE, et al. N Engl JMed. 2011;364:2381-91.

Dr. Files is an AssistantProfessor of Medicine and a physician in theWomen’s Health Internal Medicine Division at Mayo Clinic,Phoenix, Arizona. Her research interest is women’s health.

Dr. Pruthi is an Associate Professor of Medicine and a consultant inthe Department of Medicine, the Division of General Internal Medicine,and the Breast Diagnostic Clinic at Mayo Clinic, Rochester, Minnesota.Her research interests include breast diseases and women’shealth.

Caution: Menopausal Hormone Therapy after Breast Cancer

Rowan T. Chlebowski, MD, PhD
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center

Deepu Madduri, MD
Harbor-UCLA Medical Center

Any consideration of menopausal hormone therapy in patients with breastcancer for climacteric symptom management should begin with a clearunderstanding of the potential risk of breast cancer recurrence andpremature death, as breast cancer safety for any hormonal approach inthis setting is not established.1,2

Based on randomized clinical trial settings, hormone therapy regimenscommonly used in women without breast cancer differ in their effects onbreast cancer incidence. For postmenopausal women with a uterus,combined estrogen plus progestin increases breast cancer incidence,3delays diagnosis,3,4and nearly doubles breast cancer mortality.5Incontrast, estrogen alone in postmenopausal women with priorhysterectomy, at least for moderate duration use, reduces breast cancerincidence.6,7It is unknown how these findings relate to hormonetherapy use and recurrence risk in women with diagnosed breast cancer.

Risksoutweigh benefits for those with early-stage breast cancer
The adverse influence of estrogen deprivation on climacteric symptomsand sexual dysfunction from breast cancer therapy are wellrecognized.1,8,9While systemic hormone therapy is effective forclimacteric symptom management, use in randomized clinical trialsettings results in adverse breast cancer outcome. The HABITS trial(Hormonal Replacement after Breast Cancer—Is It Safe?)randomly assigned 434 women with early-stage breast cancer who hadclimacteric symptoms to either physician-directed hormone therapy or nosuch therapy. The trial was stopped early when hormone therapy morethan doubled recurrence risk (HR: 2.4, 95% CI [1.3-4.2]).10

A parallel study, the Stockholm Trial, randomly assigned 378 patientswith early-stage breast cancer to one of several defined hormonetherapy regimens or no hormone therapy. As hysterectomy was common inthis population, 73% received either estradiol alone or a“spacing out” estradiol regimen involving 14 daysof progestin per 91-day cycle. Although events were limited (11 vs. 13,respectively), recurrences were not increased on hormone therapy.11Unfortunately, such combination regimens with fewer days of progestinexposure are reported less effective in abrogating estrogen-associatedendometrial cancer risk.12

Finally, the LIBERATE trial randomly assigned 3,148 women withearly-stage cancer therapy and vasomotor symptoms to the hormonal agenttibolone, which reduces climacteric symptoms and increases bone densitybut not breast density, or no hormonal therapy. Recurrence risk wassubstantially increased (HR: 1.4, 95% CI [1.14-1.70]), especially inthe tibolone group also receiving aromatase inhibitors (HR: 2.4, 95% CI[1.01-5.0]).13

While observational, largely retrospective reports of menopausalhormone therapy and breast cancer recurrence have reported safety,major design limitations, including frequent absence of balancedrestaging at hormone therapy initiation and reports based onretrospective clinical experiences, preclude reliable conclusions.14

Managingurogenital systems
For sexually active women with breast cancer, sexual dysfunctionassociated with vaginal dryness represents a difficult managementproblem.1,15Simple non-hormone–based intervention, includingvaginal lubricants, moisturizers, and dilator use, should be theinitial approach.16Vaginal lubricants not containing hormones haveproven effective in randomized clinical trials for some women, butothers may need local estrogen therapy for relief.17,18However, acommonly prescribed sustained-release estradiol vaginal ring(Estring®) results in absorption sufficient to change lipidprofile comparable to full-dose oral estrogens.19An approach withpotentially lower estrogen absorption would be non-hormonal lubricantinter-vaginally and a titrated-down dose of intermittent estrogen creamon the more sensitive external genitalia.1

Given the adverse signals regarding aromatase inhibitor use andestrogen addition from the LIBERATE trial,13postmenopausal women withlimiting symptoms related to vaginal atrophy should be switched totamoxifen if local estrogen therapy is being considered. Unlike anaromatase inhibitor, tamoxifen reduces breast cancer recurrence risk inboth low- and high-estrogen environments.20While there is concernregarding endometrial cancer with combination estrogen plus tamoxifen,in the IBIS-I prevention trial endometrial cancers were not increasedwith that combination compared to tamoxifen alone,21and in the ItalianTamoxifen Prevention Trial tamoxifen influence on breast cancer was notblocked by menopausal hormone therapy.22

Managingvasomotor symptoms
For vasomotor symptoms, several selective serotonin reuptakeinhibitors, including venlafaxine, provide substantial relief inapproximately half of users.16,23Mindfulness training holds excitingpotential for coping with hot flash symptoms in the future. Sincedistress to climacteric symptoms reflects both the physical symptomseverity and the women’s psychological reactions to them,24arecent randomized trial evaluated mindfulness training-based stressreduction on hot flash distress. In the trial, while hot flashfrequency did not differ among the randomization group (measured byskin temperature monitoring), the mindfulness training group hadsignificantly better quality of life, subjective sleep quality, andlower anxiety and perceived stress.25

Premenopausalwomen with a BRCA1/2mutation
For premenopausal women with a BRCA1/2 mutationmanaged withprophylactic salpingo-oophorectomy, safety had been reported forsystemic hormone therapy regarding breast cancer risk.26,27However,caution is still advised as largely retrospective experiences involveshort duration exposure and very few breast cancer events.28

In summary, regardless of the severity of climacteric symptoms,consideration of systemic combined hormone therapy must be cautiouslyapproached given the substantial increase in recurrence risk seen withits use in randomized clinical trialsettings. While local vaginal estrogen regimens are effective for womenwith vaginal dryness, their safety with respect to recurrence risk hasnot been established. Non-hormone–based therapies provide anattractive alternative warranting further study.

1. Kwan KW, Chlebowski RT. Clin Breast Cancer.2009;9:219-24.
2. Melisko ME, Goldman M, Rugo HS. J Cancer Surviv.2010;4:247-55.
3. Chlebowski RT, Hendrix SL, Langer RD, et al. JAMA.2003;289:3243-53.
4. Chlebowski RT, Anderson G, Pettinger M, et al. Arch Intern Med.2008;168:370-7.
5. Chlebowski RT, Anderson GL, Gass M, et al. JAMA.2010;304:1684-92.
6. Stefanick ML, Anderson GL, Margolis KL, et al. JAMA.2006;295:1647-57.
7. LaCroix AZ, Chlebowski RT, Manson JE, et al. JAMA.2011;305:1305-14.
8. Hickey M, Saunders C, Partridge A, et al. Ann Oncol.2008;19:1669-80.
9. Panjari M, Bell RJ, Davis SR. J Sex Med.2011;8:294-302.
10. Holmberg L, Iverson OE, Rudenstam CM, et al. J Natl Cancer Inst.2008;100:475-82.
11. von Schoultz E, Rutqvist LE. J Natl Cancer Inst.2005;97:533-5.
12. Furness S, Roberts H, Marjoribanks J, et al. Cochrane Database SystRev. 2009;(2):CDOOO402.
13. Kenemans P, Bundred NJ, Foidart JM, et al. Lancet Oncol.2009;10:135-46.
14. Col NF, Kim JA, Chlebowski RT. Breast CancerRes. 2005;7;R535-40.
15. Hill EK, Sandbo S, Abramsohn E, et al.
16. Carter J, Goldfrank D, Schover LR. J Sex Med.2011;8:549-59.
17. Bygdeman M, Swahn M. Maturitas.1996;23:259-63.
18. Nachtigall LE. Fertil Steril.1994;61:178-80.
19. Naessen T, Rodriguez-Macias K, Lithell H. J Clin Endocrinol Metab.2001;86:2757-62.
20. Early Breast Cancer Trialists’ Collaborative Group.Lancet.2011;378:771-84.
21. Cuzick J, Forbes JF, Sestak I, et al. J Natl Cancer Inst.2007;99:272-82.
22. Veronesi U, Maisonneuve P, Rotmensz N, et al. J Natl Cancer Inst.2007;99:727-37.
23. Pachman DR, Jones JM, Loprinzi CL. Int J Womens Health.2010;2:123-35.
24. Santoro N, Sherman S. New interventions for menopausal symptoms.Bethesda, MD: National Institutes of Health, U.S. Dept. of Health andHuman Services, 2006.
25. Carmody JF, Crawford S, Salmoirago-Blotcher E, et al. Menopause.2011;18:611-20.
26. Rebbeck TR, Friebel T, Wagner T, et al. J Clin Oncol.2005;23:7804-10.
27. Eisen A, Lubinski J, Gronwald J, et al. J Natl Cancer Inst.2008;100:1361-7.
28. Chlebowski RT, Prentice RL. J Natl Cancer Inst.2008;100:1341-3.

Dr.Chlebowski is a Professor in Residence at David Geffen School ofMedicine at UCLA, Chief of the Division of Medical Oncology/Hematologyat Harbor-UCLA Medical Center, and an investigator at the Los AngelesBiomedical Research Institute. He is a member of the Journal ofClinical Oncology Editorial Board and has served on various ASCOcommittees, including the Breast Cancer Risk Reduction Expert Panel.

Dr.Madduri is a Fellow in the Division of Medical Oncology/Hematologyat Harbor-UCLA Medical Center.


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