Introduction

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

Breast cancer is the most common malignancy diagnosed in women.¹ The adoption of screening guidelines and advances in adjuvant therapy have led to significant improvements in survival for these women. As a result, an increasing number of premenopausal women survive breast cancer and subsequently experience debilitating menopausal symptoms. These include urogenital complaints (recurrent urinary tract infections, 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 the woman’s overall sense of well-being and interfere with her daily activities.

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

Hormone replacement therapy (HRT), either estrogen alone or combination estrogen/progesterone, is the most effective means to treat these symptoms and protects against the accelerated bone loss that may occur with treatment-induced menopause. However, the results from the Women’s Health Initiative study and others outline the potential harm of HRT.^3,4 Healthy postmenopausal women with a uterus treated with combination estrogen and progesterone have an increased risk of breast cancer and breast cancer mortality. Postmenopausal women with a prior hysterectomy treated with a short to moderate duration of estrogen alone have an overall decrease in the risk of developing breast cancer. For women with a history of breast cancer, there is limited data. It is unclear whether estrogen for a short duration at a low dose, or estrogen in concert with tamoxifen, are reasonable recommendations for women with debilitating menopausal symptoms.

In the feature that follows, the authors discuss the available data regarding the use of hormone replacement therapy for women at high risk for breast cancer as well as for those women with a history of breast cancer. While there is conflicting data from previously published trials, HRT in women with prior breast cancer requires careful evaluation of the risks and benefits and patient understanding of the available data.

References
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 Professor of Medicine at Northwestern University’s Feinberg School of Medicine, member of the Robert H. Lurie Comprehensive Cancer Center, and Medical Director of Northwestern Memorial Hospital’s Home Hospice Program. She serves on ASCO’s Cancer Education Committee and Professional Development Committee and is on the ASCO Connection Editorial Board.

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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 women and are hormone receptor-positive. Epidemiologic studies and one of the largest randomized controlled trials conducted in women have shown an increase in breast cancer risk following five years of combined estrogen-progestin (E+P) therapies compared to placebo and estrogen (E) alone.^1,2 More recently, a large prospective study on hormone therapy (HT) and breast cancer risk also showed that breast cancer risk was greater among users of combination hormone therapy than users of estrogen-only formulations. Risk was also greater if the hormone therapy was initiated around the time of menopause rather than later in life.³

The North American Menopause Society recommends that HT be offered at the lowest effective dose for the shortest duration possible to women who are experiencing moderate to severe menopausal symptoms.⁴ Women at high risk for the development of breast cancer (those with a personal or family history of breast cancer, Gail Model > 1.66%, or personal history of precancerous breast lesion or BRCA mutation) may request systemic HT for management of moderate to severe menopausal symptoms. Physicians face the dilemma posed by the goal of minimizing risk of disease while trying to preserve quality of life. If HT is prescribed, it requires that the physician engage the patient in collaborative decision-making to choose the therapy that provides the most acceptable risk versus benefit for the individual patient.

Risks for women with a BRCA mutation
Recently, there has been discussion surrounding the use of HT and future risk of breast cancer in women with a BRCA mutation. Risk-reducing salpingo-oophorectomy is associated with decrease in overall mortality as well as breast and ovarian cancer-specific mortality, but may result in an exacerbation of moderate to severe menopausal symptoms.⁵ Several studies looking at short-term HT (systemic E+P and E alone) use in patients who have a BRCA mutation have not found an increase in breast cancer risk and the use may even be associated with a decrease in risk.^6,7 Further, a study of women with a BRCA mutation who had undergone bilateral prophylactic oophorectomy and subsequent use of short-term HT reported that HT did not negate the breast cancer risk reduction following this procedure.⁸

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

Genitourinary atrophy (GUA) is a consequence of estrogen deficiency and is often worsened by the administration of aromatase inhibitors. Many women with a history of breast cancer suffer significant symptoms associated with GUA.¹¹ Several recent overviews on the management of urogenital atrophy in women with a history of breast cancer have highlighted treatment with low-dose vaginal 17 B-estradiol (vaginal estradiol tablets 10 ug or vaginal estradiol ring) after appropriate disclosure to the patient.¹² Appropriate dosing of local estrogen therapy is critical as although estrogen administered vaginally are associated with delivery of a lower dose over a year, it can lead to systemic levels equal to those achieved by oral or transdermal products.

The lowest effective dose for achieving resolution of clinical symptoms without systemic effect is the goal. Best results may be achieved through the use of a low-dose vaginal estrogen tablet once a week in combination with daily use of vaginal lubricants and/or moisturizers. The long-term safety of these preparations are not known, and it may not be possible to ever design a large enough study that will be able to effectively evaluate vaginal preparations and breast cancer risk or recurrence. In addition, a critical factor to note is that many women discontinue or are non-compliant with their anti-estrogen therapies due to negative quality-of-life symptoms. In the large chemoprevention trials (STAR, MAP.3), low-dose vaginal estrogen preparations were allowed on study for management of symptoms associated with GUA.^13,14 The decision to initiate low-dose vaginal estrogen needs to be individualized and made jointly with the oncologist.^11,12 The role of HT in women with a prior diagnosis of breast cancer should be limited to local therapy for the treatment of GUA.

In summary, the evidence at present does not support the use of systemic estrogen in patients with a diagnosis of breast cancer. The decision to use low-dose local vaginal estrogen in women at high risk or with a history of breast cancer should be done on an individualized basis and be made collaboratively with the patient, understanding the benefits and risks as well as taking into account the impact on quality of life.

References
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 J Med. 2011;364:2381-91.

Dr. Files is an Assistant Professor of Medicine and a physician in the Women’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 in the 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’s health.

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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 breast cancer for climacteric symptom management should begin with a clear understanding of the potential risk of breast cancer recurrence and premature death, as breast cancer safety for any hormonal approach in this setting is not established.^1,2

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

Risks outweigh benefits for those with early-stage breast cancer
The adverse influence of estrogen deprivation on climacteric symptoms and sexual dysfunction from breast cancer therapy are well recognized.^1,8,9 While systemic hormone therapy is effective for climacteric symptom management, use in randomized clinical trial settings 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 had climacteric symptoms to either physician-directed hormone therapy or no such therapy. The trial was stopped early when hormone therapy more than doubled recurrence risk (HR: 2.4, 95% CI [1.3-4.2]).¹⁰

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

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

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

Managing urogenital systems
For sexually active women with breast cancer, sexual dysfunction associated with vaginal dryness represents a difficult management problem.^1,15 Simple non-hormone–based intervention, including vaginal lubricants, moisturizers, and dilator use, should be the initial approach.¹⁶ Vaginal lubricants not containing hormones have proven effective in randomized clinical trials for some women, but others may need local estrogen therapy for relief.^17,18 However, a commonly prescribed sustained-release estradiol vaginal ring (Estring®) results in absorption sufficient to change lipid profile comparable to full-dose oral estrogens.¹⁹ An approach with potentially lower estrogen absorption would be non-hormonal lubricant inter-vaginally and a titrated-down dose of intermittent estrogen cream on the more sensitive external genitalia.¹

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

Managing vasomotor symptoms
For vasomotor symptoms, several selective serotonin reuptake inhibitors, including venlafaxine, provide substantial relief in approximately half of users.^16,23 Mindfulness training holds exciting potential for coping with hot flash symptoms in the future. Since distress to climacteric symptoms reflects both the physical symptom severity and the women’s psychological reactions to them,²⁴ a recent randomized trial evaluated mindfulness training-based stress reduction on hot flash distress. In the trial, while hot flash frequency did not differ among the randomization group (measured by skin temperature monitoring), the mindfulness training group had significantly better quality of life, subjective sleep quality, and lower anxiety and perceived stress.²⁵

Premenopausal women with a BRCA1/2 mutation
For premenopausal women with a BRCA1/2 mutation managed with prophylactic salpingo-oophorectomy, safety had been reported for systemic hormone therapy regarding breast cancer risk.^26,27 However, caution is still advised as largely retrospective experiences involve short 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 cautiously approached given the substantial increase in recurrence risk seen with its use in randomized clinical trial settings. While local vaginal estrogen regimens are effective for women with vaginal dryness, their safety with respect to recurrence risk has not been established. Non-hormone–based therapies provide an attractive alternative warranting further study.

References
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 Syst Rev. 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 Cancer Res. 2005;7;R535-40.
15. Hill EK, Sandbo S, Abramsohn E, et al.
Cancer. 2011;117:2643-51.
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 and Human 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 of Medicine at UCLA, Chief of the Division of Medical Oncology/Hematology at Harbor-UCLA Medical Center, and an investigator at the Los Angeles Biomedical Research Institute. He is a member of the Journal of Clinical Oncology Editorial Board and has served on various ASCO committees, including the Breast Cancer Risk Reduction Expert Panel.

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