The good news is that since 1990, incidence of breast cancer has plateaued, increasing only in women older than age 50 years at a rate of about 0.4% per year, and has been limited to localized disease. Mortality rates also began to decline in the 1990s. The 5-year survival rate for localized breast cancer (about 60% of cases) has risen from 72% in the 1940s to 97%.1 This trend, which is expected to continue, is attributable to earlier diagnosis as a result of greater utilization of screening mammography and increased use of chemotherapy. For clinicians who care for postmenopausal women, breast cancer is a major focus because it is increasingly frequent with age. About 94% of all breast cancers occur in women older than age 40 years, versus 15% in those younger than age 50 years, and only 6.5% in women younger than age 40 years.

The study was terminated early because the results of an interim safety analysis indicated an unacceptable risk of breast cancer recurrence in women randomized to HT, compared to those randomized to “best symptomatic treatment without hormones.” After a median of 2.1 years, 26 women (14%) in the HT group and seven (4%) in the non-HT group had a new breast cancer event (local or distant recurrence or disease in the contralateral breast). These findings disagree with the results of previous studies that have found either a decreased or no increased risk of recurrence associated with HT use in breast cancer survivors.2-6 The HABITS investigators indicated that the hazard ratio of 3.5 (95% CI, 1.5-8.1) also differed significantly (p=0.02) from the unpublished, interim results of a similar trial among breast cancer survivors in Stockholm, Sweden, which found no increased risk of recurrence among HT users (RH=0.82, 95% CI 0.35-1.9)

As one of relatively few prospective randomized trials investigating the safety of HT use among breast cancer survivors, the early cessation of the HABITS study is important to note. Equally important to consider, however, are a number of limitations in the trial’s design. Primarily, the study is not double blinded or placebo controlled. Randomization occurred centrally, but the only categories used for data stratification were the participating research center, current use of tamoxifen, and history of HT use before cancer diagnosis (patients could have a history of HT use, but must not have been on HT for 3 months prior to randomization). In addition, while patients were randomized to either HT or “best symptomatic treatment without hormones,” the protocol was highly flexible, and decisions about the specific type of treatment were made by local practitioners. As a result, women in the HT group received varying types and doses of estrogen and progestin, and we do not know the impact of differing dose or preparation on the study results. The protocol recommends administration of “medium potency estrogen replacement (with or without progestins) therapy as it is commonly given in the environment where the patient lives and the clinician works” for those in the HT arm, although the term “medium potency”is not defined. Local vaginal hormone treatment was allowed in the control arm. Furthermore, it is difficult to assess the degree of adherence to other aspects of the study protocol; for example, some patients in the HT group received tibolone even though the investigators noted in their research letter that this therapy was not allowed. Similarly, the protocol recommended recent mammograms (within 3 months) for all patients before inclusion in the study, although no documentation is provided to confirm that this was done.

The brevity of the published report from the safety analyses on which termination of the trial was based leaves many additional questions unanswered:

Patients with a history of previously treated in situ, stage 1 or stage 2 breast cancer were eligible for the trial, but we are not provided with the numbers of patients in each stage in either HT or non-HT arms of the study. Patients whose tumors were estrogen receptor positive, receptor negative, or receptor status unknown were enrolled in the trial, although we do not know how many women in each of these groups were included in the HT and non-HT arms. An individual patient could also be included if she had four or fewer positive nodes, if nodal status was known. There is no documentation regarding the number of patients in whom nodal involvement was investigated, or the percentage of patients in whom data concerning the presence of positive nodes was lacking. At baseline, the HT population included 5% more patients with positive nodes than those randomized to the non-HT group. From this incomplete information, we cannot accurately assess if the arms of the study are equivalent for comparison, as there is no correction for the most important risk factors, stage and node status. Clearly, the patient with four positive nodes carries a worse prognosis than the patient with only one positive node.

The purpose of the trial was to investigate whether treatment of menopausal symptoms with HT was safe in women with a previously treated breast cancer, but the degree to which patients were symptomatic is not specified. We do not know the number of patients who were menopausal versus postmenopausal, or the length of time that elapsed since last menses. The study includes women up to 75 years of age-how many of these older women had menopausal symptoms?

It was anticipated that analysis would require enrollment of 250 to 300 patients per year, for a total population of 1300 participants. Only 381 patients were enrolled in the trial from its initiation in May 1997 until May 2002. The HABITS protocol was then amended to include collaboration with the Stockholm trial to pool data for safety and final analyses. Only 434 patients were enrolled by September 2003, and the study was discontinued in December 2003. Interestingly, only 79% of enrolled patients were included in the data analysis, as the other 21% did not have at least one follow-up examination. Information regarding compliance with follow-up is not given. The investigators recommended clinical mammograms every 12 to 24 months or participation in screening, although no information about adherence to these guidelines is provided. Thus, we cannot tell if there is a difference in compliance with imaging follow-up between the two arms.

The impact of duration of treatment and compliance with assigned therapy is unknown as well. The authors indicate that 18% of the patients assigned to the non-HT group received HT. In addition, we do not know the duration of therapy in those randomized to the HT group. Although the authors state that all participants diagnosed with recurrences in the HT group took hormones, 19% were not currently receiving HT when the cancer was discovered. It is also unknown if the patients treated with tamoxifen were compliant with its use, and if tamoxifen use affected the recurrence rate.

The follow-up period of 2.1 years is very short and information regarding the timing of breast cancer recurrence is not provided. Certainly, we know that when breast cancer is diagnosed it has been in the breast for up to 10 years or longer; thus, it is likely that the study patients with cancer recurrence or contralateral breast cancer had unrecognized disease at the time of initial randomization. Long-term follow-up of recurrence incidence in the non-HT group will be required before conclusions can be made regarding the potential role of HT as a promoter.

Additionally, observational studies reported by DiSaia, O’Meara, and Peters have supported this same conclusion. O’Meara assembled data from 2,755 women ages 35 to 74 years who were diagnosed with incident invasive breast cancer while they were enrolled in a large health maintenance organization from 1977 to 1994. Pharmacy data identified 174 users of hormone replacement therapy (HRT) after diagnosis. Each HRT user was matched to four randomly selected non-users of HRT with similar age, disease stage, and year of diagnosis. The rate of breast cancer recurrence was 17 per 1,000 person-years in women who used HRT after diagnosis and 30 per 1,000 person-years in non-users (adjusted relative risk for users, compared with non-users was equivalent to 0.50; 95% confidence interval was 0.30-0.85). Total mortality rates were 16 per 1,000 person-years in the HRT users and 30 per 1,000 person-years in the non-users.

DiSaia et al reported on 125 women who were breast cancer survivors with and without positive nodes, both ER positive and ER negative, who elected to take ERT or HRT. These patients were matched to 362 control patients from the same population base with the approximate ratio of four controls to one patient taking ERT or HRT. The risk of death was lower among the HRT survivors; odds ratio 0.28 (95% Cl 0.11-0.71). This analysis also did not suggest an adverse outcome with HRT use.

Peters interviewed 607 breast cancer survivors concerning ERT usage. Sixty-four patients indicated they had received some form of ERT after their breast cancer diagnosis. Eight patients were excluded because they had used only vaginal cream ERT. The remaining 56 received ERT as conjugated estrogens, an estradiol patch, or birth control pills. The median follow-up from diagnosis was 12.8 years and the median time on ERT since diagnosis was 6.4 years. One local recurrence and one contralateral breast cancer occurred during the follow-up period at 13.5 and 9.6 years respectively. There were no breast cancer deaths. The author also concluded that the use of ERT in a cohort of breast cancer survivors with tumors of generally good prognosis was not associated with increased breast cancer events compared with non-ERT users, even after a long follow-up period.

The question then remains as to whether all patients who have had breast cancer should be denied the benefits of estrogen replacement therapy. This is particularly relevant in the patient who has serious quality of life issues before her. At present, therapy with ERT/HRT is indicated in the management of quality of life issues, using lowest possible dose of hormone for shortest duration of time possible. Is it appropriate to deny a woman the option of taking replacement therapy for relief of her symptoms when there is no clinical evidence that it adversely affects outcome?

The excess risk of breast cancer with long-term use (10 years) of 19/1000 EPT and 5/1000 for ET alone can be compared with the excess risk of endometrial cancer after 10 years use of ET alone of 10/1000. Ten years of EPT is estimated to result in no increased risk of endometrial cancer.

Since the Million Women study shows a greater risk of breast cancer with combined EPT, women and their physicians will need to weigh the possibility that the increased risk of breast cancer caused by the addition of a progestogen is greater than the risk of endometrial cancer with estrogen only. If this is correct, the logical conclusion may be that women should be advised to take estrogen alone for hormonal therapy, even if they have a uterus and that screening be instituted for endometrial cancer. This possibility would need extensive discussion before making a general recommendation. Other options include using progestogen delivery systems that allow a local progestogen effect at the uterus.

Because this is an observational study, it has potential for error. According to Utian and colleagues6, the major weakness is that the study took only a snapshot of hormone therapy use at the time of entry into the study, when women had their every third year mammogram. No further information was obtained about changes in hormones, route, dose, or discontinuation.

In conclusion, the Million Women Study serves as a large observational study that confirms the WHI findings of a small increase in absolute risk of breast cancer with EPT therapy, and confirms prior observational studies of a smaller increase in absolute risk of breast cancer with ET. These findings are important to convey to women making decisions about initiation or continuation of hormone therapy. The findings do not change current recommendations to use hormones primarily for menopausal symptom relief, vulvovaginal atrophy, and quality of life issues in symptomatic menopausal women with natural, premature, or surgically induced menopause.

They support current recommendations from the North American Menopause Society (NAMS)7, American College of Obstetrics and Gynecology (ACOG),8 and the Food and Drug Administration (FDA)9,10 to use the lowest, most effective dose for the shortest period of time.

This large cohort study1 confirms the findings from the Women’s Health Initiative (WHI) (2,3) that current users of estrogen plus progestogen (EPT) are at an increased risk of invasive breast cancer (RR 2.0). This study also confirms prior observational studies4 that estrogen therapy alone (ET) increases the risk of breast cancer (RR1.30).

Over one million women (1,084,110) ages 50 to 64 years (average age 55.9 years) who were initially cancer-free were followed from 1996 to 2001 in a national screening program. Mean follow-up was 2.6 years for breast cancer incidence and 4.1 years for mortality. Primary endpoints of the study were diagnosis of breast cancer and deaths from breast cancer. Overall, current use of ET/EPT (Estrogen therapy/Estrogen and Progesterone therapy) was associated with a statistically significant increased risk of breast cancer incidence (RR 1.66; 95% CI 1.58-1.75) and breast cancer mortality (RR 1.22; 95% CI 1.00-1.48) compared to nonusers. Past use did not increase the risk of incidence or mortality and the risk of breast cancer decreased with time since last use. Current users of estrogen plus progestogen were at the highest increased risk (RR 2.0; 95% CI 1.88-2.12) of invasive breast cancer, compared to current ET users (RR1.30; 95%CI 1.21-1.40). In current users of each type of HRT, the risk of breast cancer increased with duration of HRT use. This risk appeared to be linear over time and was less in heavier women. In women with a BMI > 25, the relative risk of breast cancer for all users of HRT was 1.46 versus 1.97 for those with a BMI < 25. Of note, vaginal or other local EPT formulations did not increase the risk (RR 0.67; 95% CI 0.30-1.49). No significant differences in risk were found between specific types or doses or regimens of systemic ET or EPT. However, breast cancer risk increased as duration of use increased.

Although this study is observational, the results are very similar to those of the WHI and the results predicted by the Collaborative Group on Hormonal Factors in Breast Cancer Study4, which lends credence to these findings. Prior observational studies have suggested that ET alone increases the risk of breast cancer (RR 1.3). Ten years of HRT with ET alone is estimated to result in five (95% CI 3-7) additional breast cancers per 1000 women, and EPT combination to result in 19 (95% CI 15-23) additional cancers per 1000 women.

Evaluating a broader range of hormone therapy products than the WHI (which examined just one specific type of estrogen and progestogen, conjugated equine estrogen plus medroxyprogesterone acetate), the Million Women Study found very little variation between specific estrogen and progestogen products, their doses, their routes of administration, or whether the regimen was continuous or sequential. For estrogen-only users, increased risk was seen with oral, transdermal, or implanted formulations. No increased risk was seen with vaginal or local estrogen preparations. Progestogen only preparations were associated with an increased risk, but based on only nine incident breast cancers. Tibolone was also found to increase breast cancer risk, but less than combined EPT.

On an absolute basis, the breast cancer risk from ET is not very high. Many physicians are awaiting the results of the estrogen alone arm of the WHI to determine if estrogens in the absence of a progestin also increase the risk of breast cancer. However, a calculation of expected breast cancer incidence rates in the ongoing WHI ET arm estimates that there would be 70 new breast cancer cases in the women taking placebo and 78 in those taking estrogen alone. Thus, the WHI trial may not have sufficient statistical power (i.e., enough women in the study) to detect the slightly increased relative risk seen in the Million Women Study.

In this study, the follow-up was 2.6 years for cancer incidence and 4.1 for mortality. The increased risk in breast cancer became apparent within 1 to 2 years of starting treatment, irrespective of type of hormone therapy used. Once hormone therapy was stopped, the risk began to decline, and by 5 years reached the same level as never users. Increased mortality was seen, but it was of borderline statistical significance. Longer follow-up is needed from this study and the WHI to determine any effects on mortality from breast cancer.

Once a large-scale trial has been set up it has its own momentum. A positive correlation of smoking with incidence of Alzheimer’s has recently been observed. As for estrogen, it is said to have an effect on human cognitive function. But the only evidence is from short-term administration of estrogen to small mammals in the laboratory, animals not normally noted for intricacy of brain function.

Sex steroids can hardly be expected to be neutral in their effect on behavior, mood, cognitive function and so forth, especially if we consider that the pharmacologic versions of sex steroids are administered at much higher levels than those occurring naturally. We are also beginning to realize that there are reciprocal interactions between steroids and behavior. In other words, as hormones influence behavior, so behavior influences hormones. The more expert the endocrinologist, the more respect she/he has for the synergistic interactions of body chemicals; unfortunately most health practitioners have only an elementary understanding of endocrinology and are far too ready to believe in quick-fix remedies for perceived malfunction.

What is claimed for Alzheimer’s is also claimed for cancers, except those of the endometrium and breast, which are considered estrogen-dependent. The data are difficult to interpret. Women on replacement estrogen are three times as likely to develop endometrial cancer as women who are not, but opposing the estrogen with progestogens is thought to control the risk factor. British doctors believe that after stopping HRT women should continue to take progestogens for two years but American doctors have yet to be convinced of the usefulness of opposing estrogen at all. Women on HRT have twice the rate of breast cancer after nine years, and women on combined regimes are four times as likely to have breast cancer after six years. HRT used to be denied to women who have had a brush with the disease, but now HRT users may also take tamoxifen if the risk of breast cancer is considered significant. The constant crying up of HRT has the effect of making women who are denied the therapy feel hard done by, when the truth is that most women who could use replacement estrogen don’t. The latest cross-national study of HRT users in Europe calculated current users as only one-third of women actually going through menopause and no more than 13 per cent of post-menopausal women. About a quarter of post-menopausal women reported use at some time.

Still fortunes are to be made and professional clout to be accumulated by setting up large-scale cohort trials to track the incidence of the diseases of ageing in a post-menopausal population that faithfully persists in dosing itself with estrogen. The difficulty will be to find that population, because if current trends persist women will use HRT during the period of menopausal discomfort as a symptomatic treatment and then abandon it. The drug houses, who anticipated easy pickings as women remained on their product for the term of their unnatural lives, are perplexed. They want explanations of this poor compliance. They blame voices like my own crying in the wilderness, effortlessly overcoming the booming sound of their endless promotion of their product in the medical press, and the equally energetic distribution of free samples to GPs. The truth is that selling estrogen as a panacea was a miscalculation. Nobody knows better than women that biology offers no free lunches. In women with wombs and ovaries estrogen has got to be opposed by progestogens if uterine hyperplasia is not to result. This results in administration regimes that are onerous, especially when the adverse effects of exogenous progestogens, bloating, headaches, mood swings, etc., are taken into account. Then there is the question of monthly bleeding. Every year the drug houses present new methods of administration, tacitly admitting that they have not got the mixture right. There will be no definitive large-scale cohort trial of the prophylactic effects of post-menopausal estrogen because there are insufficient examples of long-term use of any single method.