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.
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.


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



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


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.


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


* 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.


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?


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


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 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 (
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Karger Publishers
Ann N Y Acad Sci. 2006 Dec;1092:349-60.

Hormone replacement therapy in breast cancer survivors.


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


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.

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

HRT in difficult circumstances: are there any absolute contraindications?


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


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.

[PubMed – indexed for MEDLINE]

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.


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



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.


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.


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.


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.


Reproductive Endocrinologists, Augusta, GA 30910, USA.



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.


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


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.


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


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.

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

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


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



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


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.


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.


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.


Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Erratum in

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



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.


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.


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).


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.


Department of Oncology, Karolinska University Hospital & Institute, Stockholm, Sweden.


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.


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



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.


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.


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.


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.

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).


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.5,716We previously conducted an audit of women treated for breast cancer and their use of HRT.79 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.
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.
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.
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,79 as well as other observational studies of women with a history of breast cancer who took any HRT5,1012,14,16 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.1820

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.


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



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.


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.


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).


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.


Department of Obstetrics and Gynaecology, VU University Medical Centre, Amsterdam, Netherlands.



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.


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, number NCT00408863.


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.


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


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

  1. Just wish to say your article is as astounding. The clarity to your publish is just cool and i can think you are
    knowledgeable in this subject. Well together with your permission let me
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    Thanks one million and please continue the gratifying work.

  2. Valerie Assar

    Is hrt safe to take after a grade 1 tubular carcinoma which was very small,,,my doctor said its too risky ,,,

  3. Thankyou for your reply ,i thought that hrt after breast cancer appears to be less risky than for non users from all ive read above ,,,,,how risky is risky ,,i receive annual mammograms?

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