HRT after having Breast Cancer

This is a very controversial topic. Most experts now accept the fact that women can have HRT after having had breast cancer, but they must be aware of the risk, and be suffering severely to warrant the risk. Here is some of the research on the subject. I have treated over 40 women with the BHRT after they had breast cancer, with very acceptable results so far. There have been only a few recurrences, but their quality of life has improved considerably. Various anti-depressants are an acceptable alternative, with less risk of recurrence of the cancer. However, some women find the side effects of these drugs unpleasant. I have reproduced some of the research into HRT after breast cancer below, to help women make up their minds whether they want to go down this path.

ENDOCRINE DILEMMA: Managing menopausal symptoms after breast cancer

  1. John Eden⇑

+ Author Affiliations


  1. Barbara Gross Research Unit, Royal Hospital for Women and University of NSW, Locked bag 2000, Randwick, New South Wales 2031, Australia
  1. Correspondence should be addressed to J Eden; Email: j.eden@unsw.edu.au

Next Section

Abstract

Managing the symptoms of menopause after a diagnosis of breast cancer offers some unique clinical challenges. For some women, vasomotor symptoms can be severe and debilitating, and hormone therapy is at least relatively contraindicated. Non-oestrogen therapies for hot flushes include SSRIs, clonidine, gabapentin and perhaps black cohosh extracts. Vulvovaginal atrophy can usually be alleviated by simple moisturizers, although some may need specialized physiotherapy such as vaginal dilators. In a small number, topical oestrogens may be the only treatment that works. The CO2 laser may be a novel, non-oestrogen therapy to alleviate this unpleasant symptom. Bone loss can be accelerated in some patients on AIs or those who had early menopause induced by chemotherapy.

Previous SectionNext Section

Invited Author’s profile

Graphic

Dr J Eden (MB BS, MD, FRANZCOG, FRCOG, CREI) is a certificated reproductive endocrinologist and gynaecologist. He is a Conjoint Associate Professor at The University of New South Wales in Sydney. He is a visiting medical officer at the Royal Hospital for Women, Sydney, Australia where he is Director of the Sydney Menopause Centre and the Barbara Gross Research Unit. He also works at the Moree Aboriginal Health Service. John is a Director of the Women’s Health and Research Institute of Australia (WHRIA). His research interests include managing menopause after breast cancer, early menopause, polycystic ovary syndrome (PCOS), osteoporosis, biofilms, hormone replacement therapy as well as herbal medicine.

Introduction

For many menopausal women, symptoms such as hot flushes, insomnia, mood swings and vaginal dryness are problematic. Hormone replacement therapy (HRT) and topical oestrogens are highly effective and safe when used for the short-term. However, for those with a personal history of breast cancer HRT, even topical oestrogens are considered at least relatively contra-indicated. Not only that, chemotherapy can induce premature menopause, provoking severe hot flushes. Many of the endocrine therapies used to treat ER+ breast cancer (tamoxifen and aromatase inhibitors (AIs)) can aggravate or induce hot flushes. Thus many breast cancer survivors will have poor quality of life and painful, unpleasant intercourse, if not treated.

Also, menopause per se, has long been associated with osteoporosis. Early menopause, induced by chemotherapy, and the AIs can accelerate this potentially devastating bone problem. Fortunately, there are many non-controversial options, such as the bisphosphonates, available to help these women (Table 1). The management of menopausal symptoms after a diagnosis of breast cancer is much more controversial and difficult.

Health professionals working with breast cancer survivors are very aware of the quality of life issues after breast cancer. Over the last two decades, there has been much research and many clinical trials aimed at finding effective non-oestrogen therapies to help such menopausal women.

For this review, a literature search was performed using the search engine Primoa at UNSW, using the following keywords: non-hormonal, meta-analysis, antidepressant, gabapentin, hot flush, hot flash, vaginal dryness, SSRI, SNRI, clonidine, progestin, medroxyprogesterone acetate and osteoporosis. Preference was given to more recent papers and reviews.

Managing hot flushes

For many breast cancer survivors, hot flushes are a major problem. Sweats and flushes are often worse at night and so disrupt sleep, often resulting in tiredness and mood swings. Simple measures such as staying cool, avoiding stress, hot drinks, and spicy food can help a little. Many women seek safe options from their medical practitioners to reduce these unpleasant hot sensations. Fortunately, several evidence-based, non-oestrogen options are available and recently, there have been several excellent reviews and meta-analyses published on this subject (1, 2, 3).

Of course, the endocrine therapies used to treat breast cancer such as the AIs and tamoxifen often induce hot flushes. In some patients, it may be difficult to know whether their flushes are due to menopause or their drug therapy. Sometimes, the only way to find out is to temporarily stop the drug therapy for 2–4 weeks. If most of the sweating disappears, then trying a different agent or reassessing the case may be indicated. Sometimes the patient may choose not to take the drug and accept a small increased risk of recurrence or new breast cancer, rather than putting up with severe flushes.

Black cohosh and other herbals

Many women would like to use a natural product to help their menopause symptoms. Amongst the many herbal preparations offered as therapies for menopausal flushing, the two most common are phytoestrogens (soy or red clover based) and black cohosh. Nelson et al. (3) performed a meta-analysis of non-hormonal therapies for flushes, including red clover in their study. They showed that the effect of red clover extracts on hot flushes was not superior to placebo. Also, since these products are, at least theoretically oestrogenic, they should be considered relatively contraindicated in the breast cancer setting.

In contrast, black cohosh extracts are not oestrogenic and may in fact have some anti-oestrogenic properties on breast tissue (4, 5, 6). Einbond (4) exposed a number of human breast cancer cell lines to black cohosh extracts and showed inhibition of growth, particularly in those cell lines overexpressing HER2. Clinical trials in humans have shown that women taking black cohosh had no change in mammographic density or endometrial thickness over 6 months of usage (6). This would suggest a lack of oestrogenic effect on breast and uterine tissue by the extract. Furthermore, Obi et al. (5) performed a case controlled study of women using herbal extracts to manage menopausal symptoms. They found that usage of phytoestrogens or black cohosh extracts was associated with a decreased risk of breast cancer (OR 0.72, 95% CI 0.60–0.87).

Efficacy studies with black cohosh give mixed results (7). Part of the difficulty of performing meta-analyses in this area of research is heterogeneity, not just with the studies themselves but also with the different extracts. They are not all the same. Where and how the herb is grown, the extraction process and many other factors can influence the final composition of the herbal extract. Specifically, the German product, Remifemin, has at least four randomized trials (8, 9, 10, 11) showing efficacy. One trial (10) even showed equivalence with a low-dose oestradiol patch.

Concerns have been raised about occasional reports of hepatotoxicity associated with black cohosh usage. Teschke (12) has reviewed the cases and cast doubt on this association. Also, to date, no case of liver problems has been described in a patient using black cohosh for less than 6 months. In summary, a high quality black cohosh product like Remifemin would seem a reasonable starting point to help a patient who has been treated for breast cancer to try to reduce her hot flushes.

Antidepressants

The older tricyclic antidepressants commonly cause sweating and flushes as a side effect. SSRIs appear to be different in this respect. In the last few years, there have been many trials examining the efficacy of SSRIs on hot flushes and several meta-analyses have been published (2, 3, 13). It seems to be a class effect; they are all helpful in low-dosage (e.g. citalopram 20 mg). Interestingly, in the high dosage used for severe depression (e.g. citalopram 60–80 mg), excess sweating is a common side effect. It is usual to commence therapy with a half-dosage for 2–4 days to minimize start up side effects such as headache and nausea. After that, the lowest effective dose for depression seems to help reduce hot flushes (e.g. citalopram 20 mg). They are generally very well tolerated.

Paroxetine should be avoided in those patients taking tamoxifen. This SSRI has been shown to interfere with the metabolism of tamoxifen (14). Over the long term, SSRIs may inhibit sexual responsiveness and orgasm. Interestingly, a placebo-controlled, randomized trial has shown that loss of orgasm associated with SSRIs can be restored with sildenafil 50–100 mg (15). Despite these problems, SSRIs are very useful in this setting. Depression and mood swings are common after a diagnosis of breast cancer as well as hot flushes. Thus the judicious use of a low-dose SSRI may markedly improve the quality of life after breast cancer.

Clonidine

The α-blocker, clonidine, in low-dosage has been shown in meta-analyses to be superior to placebo for hot flushes (3). The usual starting dose is half a tablet twice a day, increasing if needed to 1 twice a day. The half tablet twice a day dosage usually does not affect blood pressure, whereas the 1 twice daily dosage typically lowers blood pressure by around 5 mmHg. In these low doses, side effects are uncommon but may include dizziness (due to lowering blood pressure), dry mouth (anti-cholinergic effects) and in high dosage (not used for hot flushes), it may aggravate depression. Clonidine in these doses has been used as a migraine preventive agent too and the combination of hot flushes and migraine is common during the menopause transition. Thus for some patients, this agent may help two medical conditions.

Comparative trials of venlafaxine vs clonidine

There have been three trials published comparing the antidepressant venlafaxine with clonidine (16, 17, 18). Buijs performed a crossover study of venlafaxine 75 mg vs clonidine 50 μg twice daily (one half of a 100 μg tablet). Both agents had a similar flush-reducing action (around 50% improvement) and more patients had side effects (and stopped medication) with venlafaxine than clonidine. Loibl (17) compared venlafaxine 37.5 mg twice daily with clonidine 75 μg twice daily for 4 weeks. Venlafaxine was superior to clonidine for the relief of hot flushes. Boekhout (18) used a 2:2:1 design to compare venlafaxine 75 mg, clonidine 100 μg and placebo for 12 weeks. Both active drugs were superior to placebo for hot flushes. Venlafaxine had a quicker effect than clonidine; clonidine was more effective than venlafaxine at 12 weeks and more subjects had side effects from venlafaxine (especially nausea and constipation).

Gabapentin

Gabapentin was initially developed as an anticonvulsant and was later found to have nerve-stabilizing effects making it useful for nerve pain (e.g. trigeminal neuralgia, shingles pain). It can be helpful for migraines, bipolar disorder and fibromyalgia (19, 20). There are numerous trials using gabapentin to relieve hot flushes. Three meta-analyses (2, 19, 20) have shown superiority over placebo. The usual dosage used was 900 mg daily in divided doses, although in a small number of studies much larger doses have been used.

Typically, treatment is commenced with 300 mg at night and then the dosage is increased every 4–7 days by 300 mg (in divided doses). Gabapentin is usually well tolerated. However, side effects may include dizziness, unsteadiness, fatigue and somnolence. In the setting of breast cancer, some patients develop nerve pain in surgical wounds and so gabapentin may help relieve pain as well as hot flushes. Gabapentin may also be an option for the migranous patient suffering concomitant hot flushes.

Moderate–high dose progestins

In the 1980s and 1990s, high dose progestin was one of the standard treatments for advanced breast cancer (21) and moderate to high dose progestins such as medroxyprogesterone acetate (MPA) and Megestrol were also used to relieve hot flushes (1, 22, 23). In contrast, the Women’s Health Initiative study (WHI, (24)) showed that the combination of conjugated equine oestrogen 0.625 mg and MPA 2.5 mg daily was associated with an increased risk of breast cancer (eight extra breast cancers/10 000 women/year after 5 years). This apparent paradox can be explained in several ways.

First, advanced breast cancer is likely to behave differently than very small breast cancer being stimulated by hormone therapy (HT). Second, the dose of progestin was markedly different. Sutherland et al. (25, 26) through a series of elegant experiments showed in the 1990s that low doses of progestins tended to stimulate the cell cycle of normal and malignant breast cells, in contrast to high-dose progestins which typically hurried the cell through one cell cycle and then arrested growth.

In current clinical practice, high-dose progestins are hardly ever used to treat breast cancer. As a treatment for hot flushes, high-dose progestins can cause fluid retention, glucocorticoid effects, mood swings and weight gain.

Hormone therapy

Today, the use of HT after breast cancer would seem an anathema. However, a few years ago, a number of clinical trials were performed to examine the safety of using HT after a diagnosis of breast cancer (23, 27, 28, 29).

The first was a retrospective observational study of 1122 women with a personal diagnosis of breast cancer, treated by five Sydney doctors between 1964 and 1999 (23). Two hundred and eighty six used HT after their diagnosis of breast cancer. Typically the patients were offered MPA 50–100 mg daily to relieve their hot flushes. If that did not relieve their hot flushes then oestrogen was added to the moderate dose progestin (138 took combined HT). Relative risks (RR) were determined using Cox regression analyses, adjusting to patient and tumour characteristics. One thousand one hundred and twenty two patients were followed up for an average of 6 years. The HT users had a reduced risk of recurrence (RR 0.62, 95% CI 0.43–0.87). This was a unique study that took into account the likely beneficial impact of a moderately high dose progestin in this setting.

There were two studies using ‘standard HT’ regimens of conjugated equine oestrogens and low-dose MPA, the Stockholm study (27) and the HABITS study (28). Both were terminated early. The Stockholm study was a randomized open label study with two parallel arms. Subjects had to be disease-free at time of entry and they were stratified according to tamoxifen usage, type of HT, and time since primary diagnosis. They were randomized to HT (n=188) or no HT (n=190). They recently reported on 10 year follow-up of this study group. There was no difference in new breast cancer events between the groups.

HABITS (28) was a randomized, non-placebo controlled non-inferiority trial. Cox models were used to estimate RR of a breast cancer event. Four hundred and forty seven women were randomized and 442 were followed up for a median of 4 years. Thirty nine of the 221 women on HT and 17 of the control arm experienced a new breast cancer event (HR=2.4, 95% CI 1.3–4.2). After extended follow up, there was still a significantly increased risk of a new breast cancer event in the group who used standard HT.

Finally, LIBERATE was a randomized placebo controlled trial of tibolone 2.5 mg daily given to breast cancer patients having significant hot flushes (n=3148). After a median follow up of 3.1 years, there was a higher risk of recurrence in the treatment group compared to placebo (HR=1.40, 95% CI 1.14–1.70) and so the study was terminated early. The tibolone treated group had a significant improvement of their hot flushes and high bone density than the control group.

Managing vulvo-vaginal dryness

The vagina is the most sensitive tissue in the body to oestrogen. Menopause, natural or induced, commonly results in vulvo-vaginal atrophy with concomitant loss of rugal folds, thinning and drying of the vagina epithelium. This results in clinical problems such as painful intercourse, vulval ‘burning’ sensations, and recurrent urinary tract infections. The AIs typically aggravate these problems. Tamoxifen usage is often associated with an unpleasant yellow vaginal discharge. Oncologists are reticent to prescribe topical oestrogens for fear of systemic absorption and thus an increased risk of breast cancer recurrence (especially amongst patients on AIs).

Many women are embarrassed to talk about such intimate problems. Often when the clinician raises the issue with the patient, they are greatly relieved that something can be done about it. Many respond to simple measures such as the avoidance of soap, the use of soap-free washes and water-based moisturizers (e.g. Replens). Lubricants such as olive or coconut oil or Sylk are much more effective than water-based lubricants.

Women who have had the problem for many years may develop pain in their pelvic floor muscles which become myalgic. Physiotherapy aimed at relaxing these sore pelvic floor muscles can be very helpful. Sometimes vaginal dilator therapy and/or Botox infiltrated into the muscles (under general anesthetic) is needed. In such affected women, pelvic floor exercises should be avoided, as they aggravate the problem. A bike seat will also make the soreness much worse so bike riding should be avoided.

There has been a cohort study of vaginal oestrogen usage after a diagnosis of breast cancer (31). One thousand four hundred and seventy two women with a personal diagnosis of breast cancer were recruited. Sixty-nine had used topical oestrogens after their diagnosis of breast cancer. Cox regression analysis was performed. Hormone usage was entered as a time-dependent covariate with disease–free intervals as the outcome. Subjects using topical oestrogens had a correct HR of 0.30 (95% CI 0.20–1.58). Although the numbers were small, these data were reassuring.

A novel recent development in this area is the use of a fractional, microablative CO2 laser to treat vulvo-vaginal atrophy. In one uncontrolled prospective study (32), 77 postmenopausal women were treated with the CO2 laser. Using the Female Sexual Function Index, marked and significant improvement in symptoms was seen over 12 weeks. At the moment, it is not known how long the effect lasts. The procedure itself is usually painless to perform.

Osteoporosis and breast cancer

Some breast cancer patients are at high risk of developing osteoporosis, either because of early menopause induced by chemotherapy and/or the use of AIs. Fortunately, the bisphosphonates and more recently, denosumab, have a strong track record as successful treatments for advanced breast cancer, particularly bone metastases (33, 34, 35). Typically the doses used in this situation are much higher than those used for osteoporosis. For example, in one recent randomized trial, denosumab 120 mg was compared with zoledronic acid 4 mg, given every 4 weeks as treatment for bone metastases. All took calcium and vitamin D. Denosumab was superior in delaying time to first skeletal-related event (SRE; HR 0.82, 95% CI 0.71–0.95). In general, adverse events (AEs) were similar in the two groups. Osteonecrosis of the jaw occurred infrequently (2% denosumab; 1.4% zoledronic acid).

Cheung et al. recently reviewed the relationship between breast cancer and osteoporosis (35). Most patients with ER+ breast cancer benefit from an endocrine treatment and for most menopausal patients, they will be offered an AI. These can accelerate bone loss and cause fractures. Interestingly, bisphosphonates used in the standard (low doses) used for osteoporosis treatment, not only prevented bone loss and fracture but seemed to be associated with improved disease-free survival and a decreased risk of death in postmenopausal women (35, 36, 37, 38). Tamoxifen and other SERMs (e.g. raloxifene) appear to decrease menopausal bone loss, in contrast to the AIs (35, 36). Of course, tamoxifen can cause other side effects such as endometrial polyps and cancer as well as eye complications such as cataracts.

All women with a diagnosis of breast cancer should be offered the same prevention and monitoring of bone loss as other menopausal women. Supplements containing calcium and vitamin D are helpful. The combination of vitamin D deficiency and an AI can induce marked bone loss. Those with osteoporosis (low-T scores; fragility fractures; FRAX score consistent with high risk of fracture) especially those on AIs, should be offered standard doses of bisphosphonates or denosumab.

Conclusions

Over the last 40 years, there has been a steady improvement in survival rates after a diagnosis of breast cancer. Earlier diagnosis and better therapies have meant that many more women are surviving breast cancer. However, many have poor quality of life due to persistent severe hot flushes, insomnia and vulvovaginal dryness. Over the last fifteen years, or so there has been much research aimed at controlling menopausal symptoms (and side effects of endocrine therapies).

When planning therapy, consideration should be given to co-morbidies and other medical conditions. For example, the hypertensive patient with hot flushes might be offered clonidine and a first-line therapy. The migranous flushing patient could be offered gabapentin or clonidine. Many would like to try a herbal therapy first and Remifemin should be considered. If mood swings, anxiety and/or depression are present as well as hot flushes, a low-dose SSRI is likely to be helpful.

It is important to ask menopausal women who have had breast cancer about genito-urinary health. Most women want to talk to a health profession about these problems. Most women suffering from vulvovaginal atrophy will respond to simple measures. Some will need referral to a pelvic floor physiotherapist or a gynaecologist. In a few cases, the only treatment that seems to work is a topical oestrogen. Obviously, the theoretical risks need to be discussed on an individual basis.

All menopausal breast cancer patients should be offered bone density screening. It seems clear that Tamoxifen has a positive bone effect, unlike the AIs which can accelerate bone loss. Fortunately, standard doses of bisphosphonates or denosumab are effective and safe in this setting.

In general, HRT and tibolone should be avoided in this setting. Trials using these therapies after a diagnosis of breast cancer suggest a higher risk of recurrence of cancer. In a very small number of cases, a patient having severe intractable hot flushes who has failed to respond to all other treatments may choose to use HRT and accept the small increased risk of recurrence.

As the medical profession is curing more and more patients who have had breast cancer, it is hoped that we can also offer them safe and effective therapies to manage unpleasant menopausal symptoms.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

  • Received 10 August 2015
  • Revised version received 8 October 2015
  • Accepted 14 October 2015
  • Made available online as an Accepted Preprint 14 October 2015

References

  1. ↵
    1. Hickey M,
    2. Saunders CM &
    3. Stuckey BG

    . Management of menopausal symptoms in patients with breast cancer: an evidence-based approach. Lancet. Oncology 2005 6 687–695. (doi:10.1016/S1470-2045(05)70316-8).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  2. ↵
    1. Yamaguchi N,
    2. Okajima Y,
    3. Fujii T,
    4. Natori A &
    5. Kobayashi D

    . The efficacy of nonestrogenic therapy to hot flushes in cancer patients under hormonal manipulation therapy: a systematic review and meta-analysis. Journal of Cancer Research and Clinical Oncology 2013 139 1701–1707. (doi:10.1007/s00432-013-1491-4).

    MedlineGoogle Scholar
  3. ↵
    1. Nelson HD,
    2. Vesco KK,
    3. Haney E,
    4. Fu R,
    5. Nedrow A,
    6. Miller J,
    7. Nicolaidis C,
    8. Walker M &
    9. Humphrey L

    . Nonhormonal therapies for menopausal hot flushes. Journal of the American Medical Association 2006 295 2057–2071. (doi:10.1001/jama.295.17.2057).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  4. ↵
    1. Einbond LS,
    2. Wen-Cai Y,
    3. He K,
    4. Wu H,
    5. Cruz E,
    6. Roller M &
    7. Kronenberg F

    . Growth inhibitory activity of extracts and compounds from Cimicifuga species on human breast cancer cells. Phytomedicine 2008 15 504–511. (doi:10.1016/j.phymed.2007.09.017).

    CrossRefMedlineGoogle Scholar
  5. ↵
    1. Obi N,
    2. Chang-Claude J,
    3. Berger J,
    4. Braendle W,
    5. Slanger T,
    6. Schmidt M,
    7. Steindorf K,
    8. Ahrens W &
    9. Flesch-Janys D

    . The use of herbals preparations to alleviate climacteric disorders and risk of postmenopausal breast cancer in a German case–control study. Cancer Epidemiology, Biomarkers & Prevention 2009 18 2207–2213. (doi:10.1158/1055-9965.EPI-09-0298).

    Abstract/FREE Full Text
  6. ↵
    1. Hirschberg AL,
    2. Edlund M,
    3. Svane G,
    4. Azavedo E,
    5. Skoog L &
    6. von Schoultz B

    . An isopropanolic axtract of black cohosh does not increase breast density or breast cell proliferation in postmenopasal women. Menopause 2007 14 1–8. (doi:10.1097/01.gme.0000230346.20992.34).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  7. ↵
    1. Palacio C,
    2. Masri G &
    3. Mooradian AD

    . Black cohosh for the management of menopausal symptoms. Drugs & Aging 2009 26 23–36. (doi:10.2165/0002512-200926010-00002).

    CrossRefMedlineGoogle Scholar
  8. ↵
    1. Uebelhack R,
    2. Blohmer JU,
    3. Graubaum HJ,
    4. Busch R,
    5. Gruenhack J &
    6. Wernecke KD

    . Black cohosh and St John’s Wort for climacteric complaints. Obstetrics and Gynecology 2006 107 247–255. (doi:10.1097/01.AOG.0000196504.49378.83).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  9. ↵
    1. Osmers R,
    2. Friede M,
    3. Liske E,
    4. Schnitker J,
    5. Freudenstein J,
    6. Henneicke HH &
    7. Zeplin H

    . Effiicacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstetrics and Gynecology 2005 105 1074–1083. (doi:10.1097/01.AOG.0000158865.98070.89).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  10. ↵
    1. Nappi R,
    2. Malavasi B,
    3. Brundu B &
    4. Facchinetti F

    . Efficacy of Cimicifuga racemose on climacteric complaints: a randomized study versus low-dose transdermal estradiol. Gynecological Endocrinology 2005 20 30–35. (doi:10.1080/09513590400020922).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  11. ↵
    1. Frei-Kleiner S,
    2. Schaffner W,
    3. Rahlfs VW,
    4. Bodmer Ch &
    5. Birkhauser M

    . Cimicifuga racemose dried ethanolic extract in menopausal disorders: a double blind placebo controlled trial. Maturitas 2005 51 397–404. (doi:10.1016/j.maturitas.2004.10.003).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  12. ↵
    1. Teschke R

    . Black cohosh and suspected hepatotoxicity: inconsistencies, confounding variables and prospective use of a diagnostic causality algorithm. A critical review. Menopause 2010 17 426–440. (doi:10.1097/gme.0b013e3181c5159c).

    CrossRefMedlineGoogle Scholar
  13. ↵
    1. Shams T,
    2. Firwana B,
    3. Habib F,
    4. Aishahrani A,
    5. Alnouh B,
    6. Murad MH &
    7. Ferwana M

    . SSRIs for hot flashes: a systematic review and meta-analysis of randomized trials. Journal of General Internal Medicine 2013 29 204–213. (doi:10.1007/s11606-013-2535-9).

    MedlineGoogle Scholar
  14. ↵
    1. Stearns V,
    2. Johnson MD,
    3. Rae JM,
    4. Morocho A,
    5. Novielli A,
    6. Bhargava P,
    7. Hayes DF,
    8. Desta Z &
    9. Flackhart DA

    . Active tamoxifen metabolite plasma concentrations after co-administration of tamoxifen and the selective reuptake inhibitor paroxetine. Journal of the National Cancer Institute 2003 95 1758–1764. (doi:10.1093/jnci/djg108).

    Abstract/FREE Full Text
  15. ↵
    1. Nurnberg HG,
    2. Hensley PL,
    3. Heiman JR,
    4. Croft HA,
    5. Debattista C &
    6. Paine S

    . Sildenafil treatment of women with antidepressant-associated sexual dysfunction. Journal of the American Medical Association 2008 300 395–404. (doi:10.1001/jama.300.4.395).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  16. ↵
    1. Buijs C,
    2. Mom CH,
    3. Willemse PH,
    4. Boezen HM,
    5. Maurer JM,
    6. Wymenga AN,
    7. Jong RS,
    8. Nieboer P,
    9. de Vries EG &
    10. Mourits MJ

    . Venlafaxine versus clonidine for the treatment of hot flashes in breast cancer patients: a double-blind randomized cross-over study. Breast Cancer Research and Treatment 2009 115 573–580. (doi:10.1007/s10549-008-0138-7).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  17. ↵
    1. Loibi S,
    2. Schwedler K,
    3. von Minckwitz G,
    4. Strohmeier R,
    5. Mehta KM &
    6. Kaufmann M

    . Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients – a double-blind, randomized study. Annals of Oncology 2007 18 689–693.

    Abstract/FREE Full Text
  18. ↵
    1. Boekhout AH,
    2. Vincent AD,
    3. Dalaasio OB,
    4. van den Bosch J,
    5. Foekema-Tons JH,
    6. Adriaansz S,
    7. Sprangers S,
    8. Huijen B,
    9. Beijnen JH &
    10. Schellens JH

    . Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology 2001 29 3962–3968.

    Google Scholar
  19. ↵
    1. Toulis KA,
    2. Tzellos T,
    3. Louvelas D &
    4. Goulis DG

    . Gabapentin for the treatment of hot flashes in women with natural or tamoxifen-induced menopause: a systematic review and meta-analysis. Clinical Therapeutics 2009 31 221–235. (doi:10.1016/j.clinthera.2009.02.006).

    CrossRefMedlineGoogle Scholar
  20. ↵
    1. Yadav M &
    2. Volkar J

    . Potential role of gabapentin and extended-release gabapentin in the management of menopausal hot flashes. International Journal of General Medicine 2013 6 657–664. (doi:10.2147/IJGM.S45880).

    MedlineGoogle Scholar
  21. ↵
    1. Muss HB

    . Endocrine therapy for advanced breast cancer. Breast Cancer Research and Treatment 1992 21 15–26. (doi:10.1007/BF01811960).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  22. ↵
    1. Bertelli GB,
    2. Venturini M,
    3. Del Mastro L,
    4. Bergaglio M,
    5. Sismondi P,
    6. Biglia Venturini S,
    7. Porcile G,
    8. Pronzato P,
    9. Costantini M &
    10. Rosso R

    . Intramusculer medroxyprogesterone acetate versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study. Annals of Oncology 2002 13 883–888. (doi:10.1093/annonc/mdf151).

    Abstract/FREE Full Text
  23. ↵
    1. Durna EM,
    2. Wren BG,
    3. Heller GZ,
    4. Leader LR,
    5. Sjoblom P &
    6. Eden JA

    . Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality. Medical Journal of Australia 2002 177 347–351.

    MedlineWeb of ScienceGoogle Scholar
  24. ↵
    Writing Group for the Women’s Health Initiative InvestigatorsRisks and benefits of estrogen plus progestin in healthy postmenopausal women. Journal of the American Medical Association 2002 288 321–333. (doi:10.1001/jama.288.3.321).
    CrossRefMedlineWeb of ScienceGoogle Scholar
  25. ↵
    1. Sutherland RL,
    2. Prall OW,
    3. Watts CK &
    4. Musgrove EA

    . Estrogen and progestin regulation of cell cycle progression. Journal of Mammary Gland Biology and Neoplasia 1998 3 63–72. (doi:10.1023/A:1018774302092).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  26. ↵
    1. Eden J

    . Progestins and breast cancer. American Journal of Obstetrics and Gynecology 2003 188 1123–1131. (doi:10.1067/mob.2003.201).

    CrossRefMedlineGoogle Scholar
  27. ↵
    1. Fahlen M,
    2. Fornander T,
    3. Johansson H,
    4. Johansson U,
    5. Rutqvist LE,
    6. Wlking N &
    7. von Schoultz E

    . Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomized trial. European Journal of Cancer 2013 49 52–59. (doi:10.1016/j.ejca.2012.07.003).

    MedlineGoogle Scholar
  28. ↵
    1. Holmberg L,
    2. Iversen OE,
    3. Rudenstam CM,
    4. Hammar M,
    5. Kumpulainen E,
    6. Jaskiewicz J,
    7. Jassem J,
    8. Dobaczewska D,
    9. Fjosne HE,
    10. Peralta O
    11. et al

    . Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. Journal of the National Cancer Institute 2008 100 475–482. (doi:10.1093/jnci/djn058).

    Abstract/FREE Full Text
  29. ↵
    1. Kenemans P,
    2. Bundred NJ,
    3. Foidart JM,
    4. von Schultz B,
    5. Sisondi P,
    6. Vassilopoulou-Sellin R,
    7. Yip CH,
    8. Egberts J,
    9. Mol-Arts M,
    10. Mulder R
    11. et al

    . Safety and efficacy of tibolone in breast cancer patients with vasomotor symptoms: a double blind, randomized, non-inferiority trial. Lancet. Oncology 2009 10 135–146. (doi:10.1016/S1470-2045(08)70341-3).

    CrossRefMedlineWeb of ScienceGoogle Scholar
    1. Sinha A &
    2. Ewies AA

    . Non-hormonal and topical treatment of vulvovaginal atrophy: an up-to-date overview. Climacteric 2013 16 305–312. (doi:10.3109/13697137.2012.756466).

    CrossRefMedlineGoogle Scholar
  31. ↵
    1. Dew JE,
    2. Wren BG &
    3. Eden JA

    . A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer. Climacteric 2003 6 45–52. (doi:10.1080/cmt.6.1.45.52).

    CrossRefMedlineWeb of ScienceGoogle Scholar
  32. ↵
    1. Salvatore S,
    2. Nappi RE,
    3. Chionna R,
    4. Zerbinati N,
    5. Ferrero S,
    6. Origoni M,
    7. Candiani M,
    8. Leone U &
    9. Maggiore R

    . Sexual function after fractional microablative CO2 lser in women with vulvovaginal atrophy. Climacteric 2015 18 219–225. (doi:10.3109/13697137.2014.975197).

    MedlineGoogle Scholar
  33. ↵
    1. Drooger JC,
    2. van der Padt A,
    3. Sleijfer S &
    4. Jager A

    . Denosumab in breast cancer treatment. European Journal of Pharmacology 2013 717 12–19. (doi:10.1016/j.ejphar.2013.03.034).

    MedlineGoogle Scholar
  34. ↵
    1. Stopeck AT,
    2. Body JJ,
    3. Steger GG,
    4. Tonkin K,
    5. de Boer RH,
    6. Lichinitser M,
    7. Fujiwara Y,
    8. Yardley DA,
    9. Viniegra M,
    10. Fan M
    11. et al

    . Denosumab compared with Zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. Journal of Clinical Oncology 2010 28 5132–5139. (doi:10.1200/JCO.2010.29.7101).

    Abstract/FREE Full Text
  35. ↵
    1. Cheung AM,
    2. Heisey R &
    3. Srighanthan J

    . Breast Cancer and Osteoporosis. Current Opinion in Endocrinology, Diabetes and Obesity 2013 20 532–538. (doi:10.1097/01.med.0000436195.10599.dd).

    Google Scholar
  36. ↵
    1. Agrawal NK,
    2. Prakash V &
    3. Singh K

    . Saving the bones in breast cancer: aromatase inhibitor-induced osteoporosis. Expert Review of Endocrinology & Metabolism 2013 8 311–313. (doi:10.1586/17446651.2013.811892).

    Google Scholar
  37. ↵
    1. Hadji P,
    2. Kauka A,
    3. Birkholz K,
    4. Baier M,
    5. Muth M &
    6. Bauer M

    . Effects of zoledronic acid on bone density in premenopausal women receiving neoadjuvant or adjuvant therapies of HR+ breast cancer: the ProBONE II study. Osteoporosis International 2014 25 1369–1378. (doi:10.1007/s00198-013-2615-z).

    MedlineGoogle Scholar
  38. ↵
    1. Greenspan SL,
    2. Vujevich KT,
    3. Brufsky A,
    4. Lembersky BC,
    5. van Londen GJ,
    6. Jankowitz RC,
    7. Puhalla SL,
    8. Rastogi P &
    9. Perera S

    . Prevention of bone loss with risedronate in breast cancer survivors: a randomized, controlled trial. Osteoporosis International 2015 26 1857–1864. (doi:10.1007/s00198-015-3100-7).

    MedlineGoogle Scholar
CMAJ. 2002 Apr 16;166(8):1017-22.

Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer.

Source

Toronto Sunnybrook Regional Cancer and Department of Medicine, University of Toronto, Ont.

Abstract

OBJECTIVE:

To provide information and recommendations to women with a previous diagnosis of breast cancer and their physicians regarding hormone replacement therapy (HRT).

OUTCOMES:

Control of menopausal symptoms, quality of life, prevention of osteoporosis, prevention of cardiovascular disease, risk of recurrence of breast cancer, risk of death from breast cancer.

EVIDENCE:

Systematic review of English-language literature published from January 1990 to July 2001 retrieved from MEDLINE and CANCERLIT.

RECOMMENDATIONS:

* Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer. Randomized controlled trials are required to guide recommendations for this group of women. Women who have had breast cancer are at risk of recurrence and contralateral breast cancer. The potential effect of HRT on these outcomes in women with breast cancer has not been determined in methodologically sound studies. However, in animal and in vitro studies, the development and growth of breast cancer is known to be estrogen dependent. Given the demonstrated increased risk of breast cancer associated with HRT in women without a diagnosis of breast cancer, it is possible that the risk of recurrence and contralateral breast cancer associated with HRT in women with breast cancer could be of a similar magnitude. * Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT. If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized.

VALIDATION:

Internal validation within the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer; no external validation.

=============================================================
Breast Care (Basel). 2008;3(3):204-209. Epub 2008 Jun 20.

Climacteric Complaints after Breast Cancer – Is HRT an Option?

Source

Division of Special Gynecology, Department of OB/GYN, Medical University of Vienna, Austria.

Abstract

Systemic estrogen depletion is the mechanism of action of most endocrine treatment strategies, and a common side effect of most chemotherapy regimens that are currently used to treat invasive breast cancer. The ensuing immediate and profound decline in estrogen levels is, however, often associated with considerable climacteric complaints. While oral estrogen add-back therapy is effective in alleviating menopausal symptoms, it is feared that it might also promote tumor cell growth. This concern is largely based on circumstantial evidence from large trials in healthy women, in which hormone replacement therapy (HRT) resulted in a slight, albeit significant, increase in incident breast cancer. In breast cancer survivors, however, evidence from studies remains controversial. Despite these caveats, the severity of symptoms and the lack of effective alternatives still cause many women to opt for HRT.

Nevertheless, HRT cannot generally be recommended as first-line therapy for climacteric complaints in women with a history of breast cancer. It may, however, be a valid option for selected women with climacteric symptoms refractory to previous non-hormonal treatments. In these cases, an individualized risk-benefit analysis is imperative before treatment initiation, and a treatment duration of less than 5 years with intermittent withdrawal attempts should be aimed for.

While systemic treatment for early breast cancer has become very effective in preventing recurrence and in improving survival, it is still burdened by severe, in some cases almost unacceptable, side effects. Chemotherapy and endocrine treatment strategies can both lead to estrogen deprivation which results in severe and prolonged menopausal complaints [1]. These include hot flashes, vasomotor symptoms, palpitations, vaginal dryness, joint pain, depression, and a variety of other symptoms that can have profound effects on the quality of life of breast cancer survivors [2]. Estrogen-containing hormone replacement therapy (HRT) is effective in alleviating menopausal symptoms, but low-dose estrogens have been shown to promote tumor cell growth in vitro and in animal experiments [3]. It is therefore feared that HRT might exert a proliferative stimulus on remaining tumor cells, and ultimately result in increased recurrence rates. In addition, the concern of an increase in breast cancer risk in healthy postmenopausal HRT users has conventionally led to a general contraindication for HRT in women with a history of breast cancer.
Unfortunately, despite being widely used, many alternative, non-hormonal treatments have not been shown to be superior to placebo [4]. In addition, little is usually known regarding side effect profile and potential drug interactions with adjuvant endocrine therapy. While selective serotonin reuptake inhibitors (SSRIs) have shown some effects on menopausal symptoms, some may also inhibit the hepatic cytochrome P450 oxidase Cyp2D6, and are thus believed to have a profound negative effect on the metabolization of tamoxifen to its active metabolite endoxifen [5, 6]. It can thus not be excluded that, while patients experience symptom relief by taking SSRIs, they might at the same time jeopardize the therapeutic benefit of their antineoplastic endocrine therapy. The lack of safe and effective alternatives for the treatment of climacteric complaints in breast cancer survivors has led to a dissension between patients who experience severe impairment of their quality of life and who are thus more willing to accept potentially deleterious HRT treatment, and physicians who, because of potential medical and medico-legal implications, are considerably more restrictive [7]. In this publication, we will review epidemiological and trial-based evidence regarding breast safety in women who use HRT for the treatment of menopausal symptoms.
==============================================================

Hormone Therapy in Women with a History of Breast Cancer

In a meta-analysis of 11 clinical trials investigating the safety and efficacy of HRT use in breast cancer survivors that was conducted in 2001, only 4 studies could be identified that had been designed with a control group. Together, these 4 trials monitored 214 HRT users over a mean follow-up of 30 months [15]. While in the HRT group 4.2 recurrences were observed per year, the 623 control patients experienced a similar relapse rate (5.4% per year; RR = 0.64, 95% CI 0.36–1.15). When the analysis was extended to all 11 studies, now comprising 669 HRT users, the combined relative risk compared to an estimated control group remained essentially unchanged (RR 0.82; 95% CI 0.58–1.15).
The authors therefore suggested that HRT had no significant effect on breast cancer recurrence, although they cautioned that these findings were based on observational data and thus subject to a variety of biases.
With most individual observational studies on HRT use in breast cancer survivors being reassuring, 2 prospectively randomized clinical trials were initiated in 1997 which were designed to investigate the effects of menopausal hormone therapy in women after they had been diagnosed with early-stage breast cancer: The relatively small HABITS (Hormonal replacement therapy After Breast cancer—Is iT Safe?) trial with 434 randomized women, was stopped prematurely in December after a median follow-up of 2.1 years because the risk of recurrence was found to be significantly higher in women receiving HRT than in women who did not receive therapy (relative HR 3.3; 95% CI 1.5–7.4) [16]. The increased risk of developing a new breast cancer event in survivors who took HRT even persisted after an extended follow-up period [17].
The Stockholm trial, another prospectively designed open label trial that evaluated HRT in women with a history of breast cancer, however, found no evidence of an increased risk of recurrence in women treated with HRT compared to women who did not receive HRT (relative HR 0.82; 95% CI 0.35–1.9). Unfortunately, the trial, which had recruited 378 women and was terminated after a median follow-up of 4.1 years, was hampered by slow recruitment and poor compliance following population-wide awareness of the WHI results. The reason for the somewhat contradictory results are not entirely clear, but differing patient characteristics, a higher prevalence of tamoxifen comedication, and the deliberate attempt to minimize the use of progestin in combination HRTs in the Stockolm trial population have been proposed as possible explanations [18].
Tibolone
Tibolone is a synthetic steroid with a distinct clinical profile that distinguishes it from both conventional HRT and selective ER modulators (SERMs). Because of its unique tissueselective metabolization and its tissue-specific action, it has been classified as a selective tissue estrogenic activity regulator (STEAR) [19]. The efficacy of tibolone in reducing climacteric symptoms in healthy women has been confirmed in a number of trials [20, 21]. In addition, available clinical data suggest that it results in less breast tenderness than conventional HRT, and that it does not increase mammographic breast density [22].
A few small studies have even explored the feasibility of tibolone therapy in breast cancer patients: in a prospectively randomized, double-blind, placebo-controlled study in 70 postmenopausal women receiving tamoxifen for early breast cancer, tibolone was significantly more effective than placebo in reducing hot flashes. No breast cancer recurrences were reported during the 12 month therapy, however, the trial duration was too short to draw any conclusions regarding breast safety [23]. Results from the ADAGIO trial suggest that an add-back therapy using tibolone is also helpful in alleviating menopausal symptoms in premenopausal breast cancer patients who receive a combined gonadotropin-releasing hormone (GnRH) and aromatase inhibitor regimen [24]. More recently, a 2-week application of tibolone in women with ER-positive early breast cancer in the preoperative setting has not been shown to be associated with a significant effect on tumor cell proliferation when compared to placebo [25]. These data, in combination with the favorable therapeutic profile of tibolone have resulted in its preferential prescription to women with a history of breast cancer who continue to complain about severe vasomotor symptoms after non-hormonal therapies have failed.
Although the results from small randomized pilot trials and from observational studies are promising, they are insufficient to conclude that tibolone is safe in breast cancer patients. In addition, results from the Million Women Study have recently indicated a somewhat worrying increase in the relative risk of developing breast cancer (RR 1.45; 95% CI 1.25–1.68) in women who at some point in their life had used tibolone. It should, however, be noted that the number of tibolone users in the cohort study was comparably small, and that until the publication of the report, tibolone had preferentially been prescribed to women with increased breast cancer risk, thus suggesting that the data might be somewhat biased [26].
The LIBERATE (Livial Intervention following Breast cancer: Efficacy, Recurrence And Tolerability Endpoints), a prospective, randomized, double-blind, multicenter trial has been designed to investigate safety and efficacy of 2.5 mg/day oral tibolone in women with vasomotor symptoms and a history of invasive breast cancer in the previous 5 years. The primary research objective was breast cancer recurrence, secondary objectives are effects on vasomotor symptoms as well as overall survival, bone mineral density, and health-related quality of life [27]. After successful recruitment starting in 2003, LIBERATE was halted in late 2007 because the primary endpoint, non-inferiority compared to placebo regarding the risk of breast cancer relapse, could not be reached [Kenemans P, personal communication].
Conclusions and Recommendations
The treatment of climacteric complaints poses a veritable dilemma for the treating physician: On the one hand, women who experience bothersome, sometimes barely supportable episodes of profuse sweating that limit them in their professional, social, and sexual life, demand treatment modalities that have proven to be effective. On the other hand, there is now little doubt that estrogen-progestagen combinations increase the chances of developing incident, and in breast cancer survivors also recurrent breast cancer. It is exceedingly difficult to postulate guidelines for breast cancer survivors in the absence of convincing data, yet it is unlikely that following the premature halt of the LIBERATE trial, new evidence will come from prospective clinical trials anytime soon. Many physicians have nevertheless found the following suggestions helpful:
HRT offered to hysterectomized women should not contain a progestagenic component. From what we now know through circumstantial evidence from healthy women, estrogen monotherapy is only associated with a small increase in breast cancer risk, and has little to no effect on CHD [28]. In women with an intact uterus, it appears prudent to initiate HRT at the lowest possible effective dose. Approximately 1 month of HRT treatment is currently considered sufficient to determine the effectiveness in alleviating vasomotor symptoms. If ineffective, the dosage should be increased until the women experience symptom improvement. While the optimal duration of HRT remains unclear, both WHI and the HERS trial have identified a relative increase in breast cancer risk after only 2 years [29]. Since vasomotor symptoms usually resolve within an average of 4 years, it appears prudent to limit HRT use to a maximum of 5 years. Intermittent, gradual HRT withdrawal should be attempted to identify those women in whom symptoms have ceased, and who do therefore not require further treatment.
Finally, the benefits and risks of HRT should be discussed in detail with each patient, and an written informed consent should be obtained before initiating therapy in order to ensure that women are fully aware of the potential health implications of their therapy. Further advice on symptomatic treatment of postmenopausal symptoms may also be drawn from the current AGO recommendations (www.ago-online.de).
References
1. Schover LR. Premature ovarian failure and its consequences: vasomotor symptoms, sexuality, and fertility. J Clin Oncol. 2008;26:753–8. [PubMed]
2. Bachmann GA. Menopausal vasomotor symptoms: a review of causes, effects and evidence-based treatment options. J Reprod Med. 2005;50:155–65. [PubMed]
3. Gompel A, Soma S, Chaouat M, Kazem A, Kloosterboer HJ, Beusman I, Forgez P, Mimoun M, Rostène W. Hormonal regulation of apoptosis in breast cells and tissues. Steroids. 2000;65:593–8. [PubMed]
4. Hickey M, Saunders CM, Stuckey BGA. Management of menopausal symptoms in patients with breast cancer: an evidence-based approach. Lancet Oncol. 2005;6:687–95. [PubMed]
5. Speroff L, Gass M, Constantine G, Olivier S, Study 315 Investigators Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol. 2008;111:77–87. [PubMed]
6. Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther. 2008;83:160–6. review. [PMC free article] [PubMed]
7. Newton KM, Lacroix AZ, Leveille SG, Rutter C, Keenan NL, Anderson LA. The physician’s role in women’s decision making about hormone replacement therapy. Obstet Gynecol. 1998;92:580–4. [PubMed]
8. Writing Group for the Women’s Health Initiative Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA. 2002;288:321–33. [PubMed]
9. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–77. [PubMed]
10. Million Women Study Collaborators Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–27. [PubMed]
11. Fournier A, Fabre A, Mesrine S, Boutron-Ruault MC, Berrino F, Clavel-Chapelon F. Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol. 2008;26:1260–8. [PMC free article] [PubMed]
12. Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, Edwards BK, Berry DA. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670–4. [PubMed]
13. Porter PL, El-Bastawissi AY, Mandelson MT, et al. Breast tumor characteristics as predictors of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst. 1999;91:2020–8. [PubMed]
14. Robbins AS, Clarke CA. Regional changes in hormone therapy use and breast cancer incidence in califormia from 2001 to 2004. J Clin Oncol. 2007;25:5038–9. author reply 5039–40. [PubMed]
15. Col NF, Hirota LK, Orr RK, et al. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol. 2001;19:2357–63. [PubMed]
16. Holmberg L, Anderson H. The HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer – is it safe?), a randomised comparison: trial stopped. Lancet. 2004;363:453–5. [PubMed]
17. Holmberg L, Iversen OE, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, Jassem J, Dobaczewska D, Fjosne HE, Peralta O, Arriagada R, Holmqvist M, Maenpaa J, HABITS Study Group Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst. 2008;100:451–2. [PubMed]
18. Von Schoultz E, Rutqvist LE, Stockholm Breast Cancer Study Group Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst. 2005;97:533–5. [PubMed]
19. Reed MJ, Kloosterboer HJ. Tibolone: a selective tissue estrogenic activity regulator (STEAR) Maturitas. 2004;48(suppl 1):S4–6. [PubMed]
20. Landgren MB, Coelingh Bennink HJT, Engelen S. Dose-response analysis of effects of tibolone on climacteric symptoms. Br J Obstet Gynaecol. 2002;109:1109–14.
21. Modelska K. Cummings S Tibolone for postmenopausal women: systematic review of randomized trials. J Clin Endocrinol Metab. 2002;87:6–23.
22. Valdivia I, Campodónico I, Tapia A, Capetillo M, Espinoza A, Lavín P. Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women. Fertil Steril. 2004;81:617–23. [PubMed]
23. Kroiss R, Fentiman IS, Helmond FA, et al. The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, double-blind, placebo-controlled trial. Br J Obstet Gynaecol. 2005;112:228–33.
24. Pollow K, Schaffrath M, Kölbl A, et al. Phase II study of goserelin adjuvant therapy combined with exemestane with or without tibolone in premenopausal women with receptor positive, node negative mammary carcinoma: ADAGIO Study. Geburtsh Frauenheilk. 2005;65:612–9.
25. Kubista E, Planellas Gomez JV, Dowsett M, Foidart JM, Pohlodek K, Serreyn R, Nechushkin M, Manikhas AG, Semiglazov VF, Hageluken CC, Singer CF. Effect of tibolone on breast cancer cell proliferation in postmenopausal ER+ patients: results from STEM trial. Clin Cancer Res. 2007;13:4185–90. [PubMed]
26. Velthuis-Te Wierik EJ, Hendricks PT, Martinez C. Preferential prescribing of tibolone and combined estrogen plus progestogen therapy in postmenopausal women. Menopause. 2007;14:518–27. [PubMed]
27. Kubista E, Kenemans P, Foidart JM, Yip CH, von Schoultz B, Sismondi P, Vassilopoulou-Sellin R, Beckmann MW, Bundred NJ. Safety of tibolone in the treatment of vasomotor symptoms in breast cancer patients-design and baseline data ‘LIBERATE’ trial. Breast. 2007;16(suppl 2):S182–9. [PubMed]
28. U.S. Preventive Services Task Force Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med. 2005;142:855–60. [PubMed]
29. Neves-e-Castro M, Samsioe G, Dören M, Skouby OS, European Menopause & Andropause Society Results from WHI and HERS II-implications for women and the prescriber of HRT. Maturitas. 2002;42:255–8. [PubMed]
Articles from Breast Care are provided here courtesy of
Karger Publishers
PMID:
20824041
[PubMed]
PMCID:
PMC2931119
===============================================================================
Ann N Y Acad Sci. 2006 Dec;1092:349-60.

Hormone replacement therapy in breast cancer survivors.

Source

Second Department of Obstetrics and Gynicology, Aretaieion Hospital, Medical School, University of Athens, Athens, Greece.

Abstract

It is well known that women with breast cancer who undergo therapies beyond the surgical intervention (adjuvant chemotherapy, hormone therapy, or both) often suffer from the lack of estrogen, manifesting as climacteric symptoms in either treated premenopausal or postmenopausal women. Although HRT (hormone replacement therapy) is traditionally viewed as a contraindication in women with a history of breast cancer, more women are willing to receive HRT for symptom relief. No observational or retrospective study in breast cancer survivors (whether in pre- or postmenopausal women) has shown an increased risk of tumor recurrence or increased mortality associated with HRT use. Nevertheless, because these studies are retrospective and different in terms of lymph node status, estrogen receptor (ER) status, and type of HRT used, firm conclusions on potential HRT use cannot be safely drawn. The few prospective studies appear controversial possibly due to differences in the studies’ design. A potential scheme for possible HRT use in selected breast cancer survivors with severe climacteric symptoms is suggested. The duration of HRT use is debatable because there is insufficient evidence at present.

However, the available data suggest that 3-year and possibly 5-year HRT use may be safe. In summary, while HRT cannot currently be recommended as first-line therapy, it may still be of benefit in the management of selected early stage breast cancer survivors with refractory climacteric symptoms after a well-informed decision and an individualized risk benefit discussion.

PMID:
17308160
[PubMed – indexed for MEDLINE]
===================================================================================================
Climacteric. 2011 Aug;14(4):409-17. Epub 2011 Feb 28.

HRT in difficult circumstances: are there any absolute contraindications?

Source

The Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Medicine, The University of Adelaide, South Australia, Australia.

Abstract

Many traditional contraindications to hormone replacement therapy (HRT) are based on the theoretical potential for these hormones to worsen a disease process and are rarely based on supporting data. This review addresses the available data and lack of data that make the prescription of HRT difficult in a variety of common morbidities. In each circumstance, it is assumed that conservative evidence-based therapies have been tried and that menopausal symptoms remain debilitating and are reducing quality of life. Tailoring of the product, dose, route and regimen may avoid some of the theoretical risks of HRT in particular women or conditions and guidelines are given for each co-morbidity. Specifically, it is discussed that tailored HRT may be used without strong evidence of a deleterious effect after ovarian cancer, endometrial cancer, most other gynecological cancers, bowel cancer, melanoma, a family history of breast cancer, benign breast disease, in carriers of BRACA mutations, after breast cancer if adjuvant therapy is not being used, past thromboembolism, varicose veins, fibroids and past endometriosis. Relative contraindications are existing cardiovascular and cerebrovascular disease and breast cancer being treated with adjuvant therapies.

Consultation with other carers and written consent are recommended in all these difficult circumstances, but no condition is an absolute contraindication to HRT if potential risk is understood, if HRT is effective in symptom control and if quality of remaining life is paramount.

PMID:
21355685
[PubMed – indexed for MEDLINE]

 

Maturitas. 2017 Jan;95:11-23. doi: 10.1016/j.maturitas.2016.10.010. Epub 2016 Oct 18.

The use of high–dose estrogens for the treatment of breast cancer.

Coelingh Bennink HJ1, Verhoeven C2, Dutman AE1, Thijssen J3.

Author information

1
Pantarhei Oncology BV, Zeist, The Netherlands.
2
Pantarhei Oncology BV, Zeist, The Netherlands. Electronic address: cv@pantarheibio.com.
3
Department of Endocrinology, University Medical Center Utrecht, The Netherlands.

Abstract

Estrogens are known to stimulate the growth of breast cancer but they are also an effective treatment for this disease (this has been termed the ‘estrogen paradox’). The fact that estrogens can be an effective treatment for breast cancer is something that has almost been forgotten, whereas the fear for estrogens remains. This paper reviews the use of estrogens for the treatment of breast cancer and identifies possible applications. The data summarised in this review demonstrate that high–dose estrogens are effective for the treatment of advanced breast cancer, both as first-line treatment as well as for treatment after occurrence of endocrine resistance to TAM and AIs. Essential for efficacy is an extended period of estrogen deprivation before the tumour is subject to estrogen treatment (the gap hypothesis). Research on the mechanism of action has shown that apoptosis induced by estrogens is regulated via the estrogen receptor and growth factor signalling pathways. High–dose estrogens have a negative safety image, especially in terms of side-effects and increased rates of cardiovascular disease, but the safety data reviewed in this paper do not give rise to major concerns. Taking into account their side-effect profile together with their observed clinical efficacy, high–dose estrogens should be considered a valuable alternative to chemotherapy in selected patients.

Cureus. 2017 Jul 6;9(7):e1434. doi: 10.7759/cureus.1434.

Estradiol as a Targeted, Late-Line Therapy in Metastatic Breast Cancer with Estrogen Receptor Amplification.

Kota K1, Brufsky A2, Oesterreich S3, Lee A3.

Author information

1
Internal Medicine, UPMC Presbyterian.
2
Division of Hematology/Oncology, Magee Women’s Hospital of UPMC.
3
Pharmacology and Chemical Biology, University Of Pittsburgh.

Abstract

Estradiol is a major regulator of growth for the subset of breast cancers that express the estrogen receptor (ER, ESR1). Strategies to block ER action, via reduction of estradiol or direct inhibition of ER, have shown major success in the prevention and treatment of breast cancer. However, most ER-positive (ER+) metastatic breast cancers (MBC) eventually become resistant to these interventions. Interestingly, high dose estrogen can induce apoptosis in breast cancer cell lines, and high-dose estrogen has been used for over 50 years as therapy for ER+ breast cancer. The mechanism for growth control of MBC by high dose estrogen is unclear. We present a patient with metastatic breast cancer whose tumor was found to have amplification of ESR1 by tumor genome sequencing. This patient was treated with high dose estradiol and subsequently experienced a sustained partial response, which was predicted by prior experiments with patient-derived xenograft animal models containing breast cancers with ER amplification.

===========================================================================

See 1 citation found using an alternative search:

Cancer. 2002 Nov 1;95(9):1817-26.

Estrogen replacement therapy for menopausal women with a history of breast carcinoma: results of a 5-year, prospective study.

Source

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. rsellin@manderson.org

Abstract

BACKGROUND:

Women with a history of breast carcinoma generally have been advised to avoid estrogen replacement therapy (ERT). The validity of this approach has been scrutinized and debated in recent years, and reassessment through appropriate clinical trials has been suggested.

METHODS:

The authors conducted a prospective clinical trial to assess the safety and efficacy of prolonged ERT in a group of menopausal women with localized (Stage I or Stage II) breast carcinoma and a minimum disease free interval of 2 years if estrogen receptor (ER) was negative or 10 years if ER status was unknown. For 5 years, the authors followed 77 trial participants and 222 other women with clinical and prognostic characteristics comparable to those of the trial participants. Overall, 56 women were on ERT, and 243 women were not on ERT. The association of ERT with skeletal and lipid changes was assessed in the randomized trial participants. The effect of ERT on the development of recurrent or new breast carcinoma and other carcinomas was analyzed both in the trial participants and in the overall group.

RESULTS:

Patient and disease characteristics, such as tumor size, number of lymph nodes involved, ER status, menopausal status, and disease free interval were comparable for women who were on ERT and women who were not on ERT. These same parameters also were comparable for women who joined the trial and women who did not. ERT use was associated with modest lipid and skeletal benefits. The introduction of ERT did not compromise disease free survival. Two of 56 women on ERT (3.6%) developed a contralateral, new breast carcinoma. In the group that was not on ERT, 33 of 243 women (13.5%) developed new or recurrent breast carcinoma. There were no differences in the development of other carcinomas with respect to ERT.

CONCLUSIONS:

ERT did not compromise disease free survival in select patients who were treated previously for localized breast carcinoma. Larger scale randomized trials are needed to confirm these findings.

Copyright 2002 American Cancer Society.

—————————————————————————————————————————————————————————————

Am J Obstet Gynecol. 2002 Aug;187(2):289-94; discussion 294-5.

Estrogen replacement therapy in patients with early breast cancer.

Source

Reproductive Endocrinologists, Augusta, GA 30910, USA.

Abstract

CONCLUSION:

Estrogen replacement therapy apparently does not increase either the risk of recurrence or of death in patients with early breast cancer. These patients may be offered estrogen replacement therapy after a full explanation of the benefits, risks, and controversies.

———————————————————————————————————————————————————————————-

Climacteric. 2001 Sep;4(3):181-93.

Controversial issues in climacteric medicine II. Hormone replacement therapy and cancer. International Menopause Society Expert Workshop. 9-12 June 2001, Opera del Duomo, Pisa, Italy.

Source

Department of Gynecology and Obstetrics, University of Pisa, Via Roma 35, 56126 Italy.

Abstract

Sex steroids are not known to damage DNA directly. They can stimulate or inhibit cell proliferation, and thus can modulate tumor developmental progression. Sex steroid-related tumors in women are represented by breast cancer and endometrial cancer, and a possible relationship exists between sex steroids and both ovarian and colon cancer. Among current ERT users or those who stopped use 1-4 years previously, the relative risk of having breast cancer diagnosed increases by a factor of 1.023 for each year of hormone use. This increase is comparable with the effect on breast cancer of delaying menopause, and seems to be largely limited to lean women. The breast cancers diagnosed during ERT are more likely to contain ER and are less aggressive. Some reports indicate no increase in breast cancer mortality in HRT users. Recent data suggest that an estrogen-progestin regimen may increase breast cancer risk beyond that associated with estrogen alone. However, the effect of progestogens on the breast awaits further clarification.

ERT/HRT is generally considered to be contraindicated in breast cancer patients, as no firm data are yet available from randomized clinical trials. Despite the potential risks, ERT/HRT could be considered for breast cancer patients suffering from menopausal symptoms resistant to alternative treatments, after completely informed consent is given, particularly in women with ER–(hormone-resistant) cancers.

 Unopposed estrogen therapy is known to increase endometrial cancer risk, and is appropriate only for hysterectomized women. To negate the excess risk of endometrial hyperstimulation, an adequate progestin dose must be given in a continuous combined regimen or for an appropriate number of days in sequential regimens (10 days or more for some progestogens or 12 days or more for other progestogens). An appropriate combination of estrogen and progestin does not appear to increase, and may even decrease, the risk of endometrial cancer. HRT is generally considered to be contraindicated in endometrial cancer patients. Despite the potential risks, HRT could be considered for patients suffering from menopausal symptoms resistant to alternative treatments, after completely informed consent is given. Available data suggest a reduced risk of colorectal adenoma and colon cancer in current users of HRT, but definitive studies are still needed. There is no contraindication to HRT prescription in colon cancer survivors. Consistent epidemiological data describe a decreased incidence of ovarian cancer with oral contraceptive use during the reproductive years. Studies on HRT and risk of epithelial ovarian cancer have produced conflicting results but most data seem to exclude a strong association. While no data contraindicate HRT use in epithelial ovarian cancer survivors, current studies do not allow us to exclude the possibility that estrogens alone could stimulate ovarian cancer growth in a small fraction of patients. Additional studies are required. It is important to consider that not all estrogens and progestins are used with the same dosage, route of administration (oral, transdermal and for estradiol intranasal) and, mostly, different estrogens do not show the same bioavailability and tissue effects. The available data do not allow to discriminate for all these variables and therefore it is inappropriate to consider jointly all forms of hormonal therapy. This issue is considered as an important area for future evaluation and research. The International Menopause Society is in the process of drawing up specific recommendations for further research in the field of HRT and cancer.

Comment in

===========================================================================

Drug Saf. 2005;28(12):1085-100.

Therapy for menopausal symptoms during and after treatment for breast cancer : safety considerations.

Source

Division of Women’s and Children’s Health, Royal North Shore Hospital of Sydney, Sydney, New South Wales, Australia.

Abstract

Breast cancer is the most common newly diagnosed cancer in women. Life-time risk in the US is 1 in 8 (13.2%), in the UK it is 1 in 9 and in Australia it affects 1 in 11 women, of whom approximately 27% will be premenopausal at the time of their diagnosis. Many of these women will experience a sudden menopause as a result of chemotherapy, endocrine therapy or surgical interventions. For these women, the onset of menopausal symptoms is often sudden and severe. The management of such symptoms remains controversial. Women experiencing menopausal symptoms after breast cancer should be encouraged to avoid identifiable triggers for their symptoms and to consider lifestyle modification as a means of controlling those symptoms. When such measures fail, non-hormonal treatments may also be considered. These include clonidine, gabapentin and some antidepressants. Randomised trials have shown a significant difference in the symptom relief associated with various selective serotonin reuptake inhibitors and selective serotonin and noradrenaline (norepinephrine) reuptake inhibitors compared with placebo. Many women elect to use non-prescription complementary therapies to alleviate their menopausal symptoms. Systematic reviews of phytoestrogens have, however, failed to demonstrate significant relief of menopausal symptoms.

More than 20 clinical trials have been conducted examining the relationship between postmenopausal hormone replacement therapy and breast cancer recurrence. The majority of these have been observational and have shown no increased risk of recurrence.

However, the largest randomised trial that has thus far been conducted was recently halted because of a reported increase in the risk of recurrence amongst users of hormone replacement therapy. Tibolone, a selective tissue estrogen activity regulator, is a compound that exerts clinical effects both by receptor-mediated actions and tissue selective enzyme inhibition, and has been shown in preclinical studies to have different effects to estrogen on the breast. Although tibolone may prove safer than estrogen for long-term use in breast cancer survivors, the results of a large randomised trial are awaited to confirm this.The decision on how best to manage menopausal symptoms must thus be made on an individual basis and after thorough discussion and evaluation of the risks and benefits of each potential intervention.

PMID:
16329712
[PubMed – indexed for MEDLINE]
======================================================================
Maturitas. 2006 Jan 20;53(2):123-32.

Menopausal hormone therapy (HT) in patients with breast cancer.

Source

Department of Internal Medicine, Section of Women’s Health Cleveland Clinic Foundation, Crown Centre II, Independence, OH 44131, USA. baturp@ccf.org

Abstract

OBJECTIVES:

To assess the effect of menopausal hormone therapy (HT) on reoccurrence, cancer-related mortality, and overall mortality after a diagnosis of breast cancer.

METHODS:

We performed a quantitative review of all studies reporting experience with menopausal HT for symptomatic use after a diagnosis of breast cancer. Rates of reoccurrence, cancer-related mortality, and overall mortality were calculated in this entire group. A subgroup analysis was performed in studies using a control population to assess the odds ratio of cancer reoccurrence and mortality in hormone users versus non-users.

RESULTS:

Fifteen studies encompassing 1416 breast cancer survivors using HT were identified. Seven studies included a control group comprised of 1998 patients. Among the 1416 HT users, reoccurrence was noted in 10.0% (95% CI: 8.4-11.6%). Cancer-related mortality occurred at a rate of 2.6% (95% CI: 1.8-3.7%), while overall mortality was 4.5% (95% CI: 3.4-5.8%). Compared to non-users, patients using HT had a decreased chance of reoccurrence and cancer-related mortality with combined odds ratio of 0.5 (95% CI: 0.2-0.7) and 0.3 (95% CI: 0.0-0.6), respectively.

CONCLUSIONS:

In our review, menopausal HT use in breast cancer survivors was not associated with increased cancer re-occurrence  cancer-related mortality or total mortality. Despite conflicting opinions on this issue, it is important for primary care physicians to feel comfortable medically managing the increasing number of breast cancer survivors. In the subset of women with severe menopausal symptoms, HT options should be reviewed if non-hormonal methods are ineffective. Future trials should focus on better ways to identify breast cancer survivors who may safely benefit from HT versus those who have a substantial risk of re-occurrence with HT use.

======================================================================

J Natl Cancer Inst. 2008 Apr 2;100(7):475-82. Epub 2008 Mar 25.

Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.

Source

Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. lars.holmberg@kcl.ac.uk

Erratum in

  • J Natl Cancer Inst. 2008 May 7;100(9):685. Maenpa, Johanna [corrected to Maenpaa, Johanna].

Abstract

BACKGROUND:

Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. The randomized HABITS study, which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer, was stopped early due to suspicions of an increased risk of new breast cancer events following HT. We present results after extended follow-up.

METHODS:

HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT. Cox models were used to estimate relative risks of a breast cancer event, the maximum likelihood method was used to calculate 95% confidence intervals (CIs), and chi(2) tests were used to assess statistical significance, with all P values based on two-sided tests. The absolute risk of a new breast cancer event was estimated with the cumulative incidence function. Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone.

RESULTS:

Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm. By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test).

CONCLUSION:

After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

======================================================================
J Natl Cancer Inst. 2005 Apr 6;97(7):533-5.

Menopausal hormone therapy after breast cancer: the Stockholm randomized trial.

Source

Department of Oncology, Karolinska University Hospital & Institute, Stockholm, Sweden. eva.vonschoultz@karolinska.se

Abstract

In 1997 two independent randomized clinical trials, Hormonal Replacement Therapy After Breast Cancer–Is It Safe? (HABITS; 434 patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hormone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was similar; however, a goal of the Stockholm protocol, not shared with the HABITS trial, was to minimize the use of progestogen combined with estrogen. The HABITS trial was prematurely stopped in December 2003, because, at a median follow-up of 2.1 years, the risk for recurrence of breast cancer among patients receiving menopausal hormone therapy was statistically significantly higher (relative hazard [RH] = 3.3, 95% confidence interval [CI] = 1.5 to 7.4) than among those receiving no treatment. In the Stockholm trial, however, at a median follow-up of 4.1 years, the risk of breast cancer recurrence was not associated with menopausal hormone therapy (RH = 0.82, 95% CI = 0.35 to 1.9). Statistically significant heterogeneity in the rate of recurrence was observed (P = .02; two-sided likelihood-ratio test) between the two studies, indicating that chance may not be the only explanation.

Doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer.

=========================================———————————————-

Climacteric. 2002 Sep;5(3):266-76.

Quality of life of breast cancer survivors: the impact of hormonal replacement therapy.

Source

The Barbara Gross Research Unit, Sydney Menopause Centre, Royal Hospital for Women, Sydney, Australia.

Abstract

OBJECTIVES:

The aims of this non-randomized qualitative study were to compare the quality of life (QOL) of breast cancer survivors who received hormone replacement therapy (HRT) and those who did not, and to describe the impact of breast cancer on their social, physical, psychological and spiritual domains. A QOL self-evaluation questionnaire was used to determine the most important concerns and changes described by women that affected, or were likely to affect, their QOL as a result of breast cancer.

METHODS:

In total, 220 patients who had finished treatment for breast cancer were contacted; 190 agreed to participate, of whom 123 (64.8%) completed and returned their questionnaires, which comprised demographic data, Quality of Life Breast Cancer Version Questionnaire and Quality of Life Self Evaluation Questionnaire. The results for women taking HRT were compared with results for those who were not.

RESULTS:

There were no significant differences in time between surgery for breast cancer and the survey, age at last birthday, number of pregnancies and live births, employment, breast cancer surgery and adjuvant therapy between HRT and non-HRT groups. No differences were found in the social, physical, psychological and spiritual domains between the two groups; however, significant differences were found between survival time and quality of life in some domains. During the study, none of the 123 women developed a recurrence of their breast cancer.

CONCLUSION:

There were no significant differences in any demographic variables between the users of HRT and the non-users. The same level of QOL was observed between HRT and non-HRT groups in the four domains of well-being. The majority of women with breast cancer recovered to a near normal level of QOL after a 4-year adjustment period, and lead fulfilling lives. This adjustment period cannot be quantified, as individual factors such as emotional, social and financial concerns will differ for each individual.

============================================—————————————–

Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality

Eva M Durna, Leo R Leader, Peter Sjoblom, John A Eden, Barry G Wren and Gillian Z Heller
Med J Aust 2002; 177 (7): 347-351.
Abstract

Objective: To determine whether hormone replacement therapy (HRT) after treatment for breast cancer is associated with increased risk of recurrence and mortality.

Design: Retrospective observational study.

Participants and setting: Postmenopausal women diagnosed with breast cancer and treated by five Sydney doctors between 1964 and 1999.

Outcome measures: Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes and to death from primary tumour were compared between women who used HRT for menopausal symptoms after diagnosis and those who did not. Relative risks (RRs) were determined from Cox regression analyses, adjusted for patient and tumour characteristics.Results: 1122 women were followed up for 0–36 years (median, 6.08 years); 154 were lost to follow-up. 286 women used HRT for menopausal symptoms for up to 26 years (median, 1.75 years). Compared with non-users, HRT users had reduced risk of cancer recurrence (adjusted relative risk [RR], 0.62; 95% CI, 0.43–0.87), all-cause mortality (RR, 0.34; 95% CI, 0.19–0.59) and death from primary tumour (RR, 0.40; 95% CI, 0.22–0.72). Continuous combined HRT was associated with a reduced risk of death from primary tumour (RR, 0.32; 95% CI, 0.12–0.88) and all-cause mortality (RR, 0.27; 95% CI, 0.10–0.73).

Conclusion:

HRT use for menopausal symptoms by women treated for primary invasive breast cancer is not associated with an increased risk of breast cancer recurrence or shortened life expectancy.

Around 11 000 women are diagnosed with breast cancer in Australia each year.1 About three-quarters are aged over 50 years, and many have menopausal symptoms. In addition, most chemotherapies for breast cancer can cause ovarian dysfunction or premature menopause. For example, tamoxifen promotes vasomotor symptoms, despite oestrogen-like effects on the uterus and vagina.2 Indeed, 60% of premenopausal women who receive adjuvant therapy for breast cancer subsequently have oestrogen deficiency.3,4A significant reduction in menopausal symptoms and improvement in bone mineral density have been reported in women taking hormone replacement therapy (HRT) after breast cancer diagnosis.5 However, few women use HRT after treatment for this disease,6 possibly because of concern about the effect on disease progression. Nevertheless, none of the previous studies of breast cancer survivors prescribed HRT have found an increased risk of tumour recurrence or death from progressive disease.5,7–16We previously conducted an audit of women treated for breast cancer and their use of HRT.7–9 The current study extends this audit to 1999 and further analyses the data, focusing on postmenopausal women. It examines the association between HRT taken after diagnosis and breast cancer recurrence and death.
Methods

This was a retrospective observational study of breast cancer recurrence and mortality among postmenopausal women with histopathologically confirmed breast cancer. As the study was a retropective audit, approval from a human research ethics committee was not deemed necessary.

Study populationWe analysed records of women who were diagnosed with breast cancer between 1964 and 1999 and were patients of three surgeons and two gynaecologists at three tertiary hospitals in Sydney, New South Wales. Women attended either public hospital clinics or the doctors’ private rooms. The entry criterion for the study was histopathologically confirmed primary invasive breast cancer diagnosed after menopause. All women were reviewed clinically at six- to 12-monthly intervals and had annual mammograms.
Data collection
Information was collected from the medical records of both the treating doctors and the hospitals and entered into a database. Ages at diagnosis of breast cancer, menarche and menopause were entered as completed years. If age at menopause was missing, it was deemed to be 50 years. Other characteristics entered were parity, gravidity, menstrual status at diagnosis, tumour size (< 2 cm, 2–5 cm or > 5 cm), number of positive axillary lymph nodes, and stage of disease. Tumour grade was not recorded. Oestrogen-receptor status was obtained from records of the treating doctors, or, if not available, from the pathology laboratory. We also recorded HRT type and duration of use before and after diagnosis, and any changes in HRT use at annual follow-up visits.Women were followed up to the end of 1999 for cancer recurrence or new breast cancer, death from primary tumour or other cause. Observations were censored for cancer recurrence or new breast cancer at the time of death or last specialist visit, for death from primary tumour at the time of death from another cause or last visit, and for death from all causes at the last visit.If case notes were lost, a letter was sent to the patient’s general practitioner asking for the information. If no response had been received from the GP by the end of 1999, the patient was contacted by letter or telephone with the same questions.
Statistical analysis
Characteristics were compared between patients who used HRT after diagnosis and those who did not by one-way analysis of variance (for normally distributed continuous variables), Mann–Whitney U test (for non-normally distributed continuous variables), χ2 test for independence (categorical variables) and the log-rank test (time-to-event variables).The effect on risk of HRT use after diagnosis was determined by Cox regression analysis. Analyses were carried out for the outcomes time from diagnosis to cancer recurrence or new breast cancer, time to death from primary tumour, and time to death from all causes. The analyses were stratified by stage of breast cancer disease and adjusted for the covariates tumour size; number of positive axillary nodes; HRT use before diagnosis; ages at diagnosis, menarche and menopause; parity; gravidity; and calendar year of diagnosis. The latter was considered a covariate because of the long time-span of the study and was classified as 1964–1979, 1980–1989 or 1990–1999. Non-significant covariates were progressively eliminated from the regression models, leaving only covariates significant at the 5% level in the final models.HRT use after diagnosis was included as a factor to enable comparison of women who used HRT with non-users. Comparisons were also made between those who used different HRT types (continuous combined oestrogen and progestins, oral or transdermal oestrogen alone, progestin alone, vaginal oestrogen alone, and vaginal oestrogen plus oral progestin) and non-users. The final models were reanalysed with stage of disease as a covariate rather than stratification variables to assess the prognostic effect of HRT use over the stages of disease.All analyses were performed at a 5% level of significance.
Result
sA total of 1122 women met the entry criteria and were followed up for a median of 6.08 years (range, 0 to 36 years). One hundred and fifty-four of the 1122 women were lost to follow-up; their observations were censored at the date of the last specialist visit.Of the 1122 women in the study, 286 used HRT after breast cancer diagnosis to treat menopausal symptoms. A further 60 women with advanced breast cancer disease took oral progestins to control tumour recurrence and were classified as not having used HRT.The women in the study were aged 35 to 96 years at diagnosis. Their characteristics are shown in Box 1by HRT use. Those who used HRT after diagnosis were significantly younger when diagnosed with breast cancer than non-users (P < 0.001). They were also significantly more likely to have used HRT before diagnosis (P < 0.001), had smaller tumours (P < 0.001) and fewer positive axillary lymph nodes (P = 0.006) and were followed up for longer (P < 0.001). There were no significant differences between the two groups in ages at menarche and menopause, parity and gravidity. Oestrogen-receptor status of the tumour was known in only 282 patients and was not included in the analysis. Most women in both groups took tamoxifen (58% and 60%, respectively).Women who used HRT after diagnosis comprised 180 of 650 with Stage I disease (28%) and 64 of 255 with Stage II disease (25%), compared with 22 of 142 with Stage III or IV disease (15%; P = 0.01). (Stage was unknown for 75 women.)
Types of HRT used
Types of HRT used after breast cancer diagnosis were continuous combined oestrogen plus progestin (138; 48%), oral progestin alone (78; 27%), vaginal oestrogen alone (32; 11%), vaginal oestrogen plus oral progestin (21; 7%), and oral or transdermal oestrogen alone (17; 6%).Median daily dose of oestrogen used by women taking continuous combined HRT was 0.625 mg conjugated equine oestrogen (range, 0.3–0.625 mg) or equivalent (1.25 mg oestrone sulfate, 2 mg oestradiol valerate or 50 μg transdermal oestradiol). Median daily dose of progestin in combined HRT was 50 mg medroxyprogesterone acetate (range, 10–500 mg) or 5 mg norethisterone (range, 1–5 mg). Similar doses of oestrogen and progestin, respectively, were used by women who took oestrogen or progestin alone. Vaginal oestrogens included oestriol cream (0.5 g) and oestradiol vaginal tablets (25 μg) used twice weekly, either alone or combined with oral progestins in similar doses to those in combined HRT.
Variables included in final modelsCovariates found to be significantly associated with outcomes are shown in Box 2with their relative risks [RRs]. Tumour size was significant to all outcomes, with larger tumours associated with higher risk of recurrence and death. For example, a woman with a tumour 2–5 cm in diameter had a risk of recurrence or new breast cancer 1.90 times that of a woman with a tumour < 2 cm when analysed by the model that included any HRT use as a covariate. RR rose to 1.93 for the model that included individual HRT types as covariates. We note the anomaly that women with 2–5-cm tumours had significantly lower risk of death from primary tumour than those with smaller tumours when analysed using the latter model.Age at diagnosis was significant only for death from all causes. Year of surgery was significant for death both from all causes and from the primary tumour, with surgery between 1964 and 1979 being associated with longer survival times than later surgery. HRT use before diagnosis, ages at diagnosis, menarche and menopause, parity and gravidity and number of positive axillary nodes were not significant determinants of recurrence or survival, and therefore not included in the final regression models.
HRT versus no HRT
Adjusted RRs of each outcome in HRT users versus non-users are shown in Box 3. After adjustment for significant covariates, the group that used HRT after diagnosis had a significantly lower risk of recurrence or new breast cancer compared with the no-HRT group (adjusted relative risk [RR], 0.62; 95% CI, 0.43–0.87). The HRT group also had significantly lower risks of death from all causes (adjusted RR, 0.34; 95% CI, 0.19–0.59) and from the primary tumour (adjusted RR, 0.40; 95% CI, 0.22–0.72).When the analysis was performed according to type of HRT used, women who used continuous combined HRT had significantly lower risks of death from all causes (adjusted RR, 0.27; 95% CI, 0.10–0.73) and from the primary tumour (adjusted RR, 0.32; 95% CI, 0.12–0.88) compared with the no-HRT group. Women who used progestin alone also had significantly lower risks of death from all causes (adjusted RR, 0.34; 95% CI, 0.12–0.93) and from the primary tumour (adjusted RR, 0.33; 95% CI, 0.12–0.91), while those who used vaginal oestrogen alone had a significantly lower risk of recurrence or new breast cancer (adjusted RR, 0.18; 95% CI, 0.04–0.75).When stage of disease was included in the regression models as a covariate rather than a stratification variable, adjusted RRs were little changed. As expected, the earlier the stage of disease, the less the chance of cancer recurrence or new breast cancer (P < 0.001), and the longer the disease-free interval (P < 0.001) and survival time (P < 0.001). In all regression analyses, the stage–HRT interaction term was non-significant, implying that the observed prognostic effect associated with HRT use is seen over all stages of disease.
Discussion
We found that women who used HRT after diagnosis of breast cancer had a significantly lower risk of cancer recurrence or new breast cancer than women who did not use HRT (RR, 0.62). Women who used HRT also had significantly lower risks of death from all causes (RR, 0.34) and from the primary tumour (RR, 0.40). These risks were determined after adjustment for other variables found to be significantly associated with outcome — tumour size (all outcomes), age at diagnosis (death from all causes only), year of operation (death from primary tumour and death from all causes) — and after stratification for stage of disease (all outcomes).All HRT regimens were associated with smaller risks of recurrence and death than no HRT use, with the exception of unopposed oestrogen for risk of death from primary tumour. However, not all the differences reached statistical significance. Similar results were obtained from previous analyses of early data from our study,7–9 as well as other observational studies of women with a history of breast cancer who took any HRT5,10–12,14,16 or continuous oestrogen–progestin regimens.13 A recent systematic review and quantitative assessment of breast cancer recurrence also concluded that HRT taken after diagnosis has no significant effect on recurrence.15There are potential sources of bias in our study.
We observed that women with Stage I and II breast cancer were more likely to use HRT than women with Stage III or IV disease, and that, as expected, the earlier the stage of disease, the lower the risk of recurrence or new breast cancer and death. This is a potential source of bias leading to more favourable outcomes for HRT users. However, the regression analyses were stratified by stage of disease to adjust for this effect. Similarly, although women who used HRT were younger at breast cancer diagnosis than non-users, also potentially leading to bias, the regression analysis for death from all causes was adjusted for age at diagnosis.Length bias may also have favoured outcome for HRT users, as women with longer times to recurrence or longer survival have more opportunity to use HRT. However, as HRT is usually administered around the time of menopause, longer survival does not imply longer exposure to HRT. Therefore, we consider the length bias unlikely to be clinically significant. In addition, the exclusion of some women from the analyses because of missing data also led to potential bias. However, as analyses included 84%–89% of women, we consider any potential bias to be of no clinical importance.It is surprising that women diagnosed between 1964 and 1979 seemed to have longer survival times than those diagnosed later, as surveillance and treatment have supposedly improved with time. We are unable to explain this result.As our study was not a randomised controlled trial, the observed association between HRT use and risks of breast cancer recurrence and death cannot be inferred to be causal.

HRT was used to treat menopausal symptoms, thereby confounding the two factors. A possible explanation of the results is that women with oestrogen deficiency tend to have better outcomes after breast cancer. Nevertheless, we conclude that women who use HRT after diagnosis of breast cancer do not have an increased risk of recurrence or death. In particular, we found that use of continuous combined HRT had no adverse effect.HRT is usually not recommended for breast cancer patients because of reports of an increased risk of breast cancer in normal postmenopausal women. A 1997 meta-analysis of 51 studies from 21 countries reported a per annum increased risk of breast cancer of 1.7% with use of oestrogen alone, 1.8% with oestrogen plus continuous progestins, and 7.6% with oestrogen plus cyclic progestins.17 Other recent observational studies also suggest that the use of sequential or cyclic progestins in HRT may increase the risk of breast cancer.18–20

In contrast, our results suggest that HRT is a safe treatment for women with a history of breast cancer. These results need to be confirmed in a randomised trial before HRT can be advocated for all women who have had breast cancer. However, we believe that the current practice of withholding HRT from women with breast cancer who suffer menopausal symptoms may need review.

==========================================———————————————

J Clin Oncol. 2001 Apr 15;19(8):2357-63.

Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk.

Source

Division of General Medicine and Decision Systems Group, Brigham and Women’s Hospital and Harvard Medical School, Chestnut Hill, MA 02467, USA. ncol@Dsg.harvard.edu

Abstract

PURPOSE:

Hormone replacement therapy (HRT) is typically withheld from women with breast cancer because of concern that it might increase the risk of recurrence. The purpose of this study was to quantify the risk of recurrent breast cancer associated with HRT among breast cancer survivors.

METHODS:

We performed a systematic literature review through May 1999, calculating the relative risk (RR) of breast cancer recurrence in each study by comparing the number of recurrences in the HRT group to those in the control group. In studies that did not contain a control group, we constructed one by estimating the expected number of recurrences based on data from the Early Breast Cancer Trialists’ Collaborative Group, adjusting for nodal status and disease-free interval. RRs across all studies were combined using random-effects models.

RESULTS:

Of the 11 eligible studies, four had control groups and included 214 breast cancer survivors who began HRT after a mean disease-free interval of 52 months. Over a mean follow-up of 30 months, 17 of 214 HRT users experienced recurrence (4.2% per year), compared with 66 of 623 controls (5.4% per year). HRT did not seem to affect breast cancer recurrence risk (RR = 0.64, 95% confidence interval [CI], 0.36 to 1.15). Including all 11 studies in the analyses (669 HRT users), using estimated control groups for the seven uncontrolled trials, the combined RR was 0.82 (95% CI, 0.58 to 1.15).

CONCLUSION:

Although our analyses suggest that HRT has no significant effect on breast cancer recurrence, these findings were based on observational data subject to a variety of biases

_____________________________________________________________________________________________________________

Lancet Oncol. 2009 Feb;10(2):135-46. doi: 10.1016/S1470-2045(08)70341-3. Epub 2009 Jan 23.

Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial.

Source

Department of Obstetrics and Gynaecology, VU University Medical Centre, Amsterdam, Netherlands. kenemans@vumc.nl

Abstract

BACKGROUND:

Vasomotor symptoms and bone loss are complications frequently induced by adjuvant treatment for breast cancer. Tibolone prevents both side-effects, but its effect on cancer recurrence is unknown. The aim of this study was to show non-inferiority of tibolone to placebo regarding risk of recurrence in breast-cancer patients with climacteric complaints.

METHODS:

Between July 11, 2002, and Dec 20, 2004, women surgically treated for a histologically confirmed breast cancer (T(1-3)N(0-2)M(0)) with vasomotor symptoms were randomly assigned to either tibolone 2.5 mg daily or placebo at 245 centres in 31 countries. Randomisation was done by use of a centralised interactive voice response system, stratified by centre, with a block size of four. The primary endpoint was breast-cancer recurrence, including contralateral breast cancer, and was analysed in the intention-to-treat (ITT) and per-protocol populations; the margin for non-inferiority was set as a hazard ratio of 1.278. This study is registered with ClinicalTrials.gov, number NCT00408863.

FINDINGS:

Of the 3148 women randomised, 3098 were included in the ITT analysis (1556 in the tibolone group and 1542 in the placebo group). Mean age at randomisation was 52.7 years (SD 7.3) and mean time since surgery was 2.1 years (SD 1.3). 1792 of 3098 (58%) women were node positive and 2185 of 3098 (71%) were oestrogen-receptor positive. At study entry, 2068 of 3098 (67%) women used tamoxifen and 202 of 3098 (6.5%) women used aromatase inhibitors. The mean daily number of hot flushes was 6.4 (SD 5.1). After a median follow-up of 3.1 years (range 0.01-4.99), 237 of 1556 (15.2%) women on tibolone had a cancer recurrence, compared with 165 of 1542 (10.7%) on placebo (HR 1.40 [95% CI 1.14-1.70]; p=0.001). Results in the per-protocol population were similar (209 of 1254 [16.7%] women in the tibolone group had a recurrence vs 138 of 1213 [11.4%] women in the placebo group; HR 1.44 [95% CI 1.16-1.79]; p=0.0009). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality (72 patients vs 63 patients, respectively), cardiovascular events (14 vs 10, respectively), or gynaecological cancers (10 vs 10, respectively). Vasomotor symptoms and bone-mineral density improved significantly with tibolone, compared with placebo.

INTERPRETATION:

Tibolone increases the risk of recurrence in breast cancer patients, while relieving vasomotor symptoms and preventing bone loss.

FUNDING:

Schering-Plough (formerly NV Organon, Oss, Netherlands).

Leave a Reply

Please log in using one of these methods to post your comment:

Gravatar
WordPress.com Logo

You are commenting using your WordPress.com account. ( Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. ( Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. ( Log Out /  Change )

Cancel

Connecting to %s

%d bloggers like this: