The principle that women who have been treated for breast cancer should avoid exogenous estrogen has been an area of general agreement and standard practice for many years; it is based on both theoretical considerations and experimental data. However, this proscription has been challenged recently because both the population characteristics and the health needs of women with a prior diagnosis of breast cancer have been changing. The emerging skepticism about our current practice regarding HRT in breast cancer survivors is reflected in many recent editorials and commentaries. Many investigators have emphasized the need for clinical trials specifically designed to evaluate the use of HRT in breast cancer survivors.
A consensus statement regarding treatment of estrogen deficiency symptoms in women survivors of breast cancer was released after a conference of scientists and survivors (Sellers et al., 1997). The consensus statement discourages use of HRT and encourages appropriate studies to explore alternatives.
In any discussion with a breast cancer survivor considering HRT, the health professional must carefully examine the woman’s views and opinions regarding HRT, because the woman needs to be a thoughtful partner in all health-care decisions. Opinion pieces, editorials, scientific studies, and philosophical analyses of menopause and its “management” have occupied a prominent position in both the medical and popular literature in recent years. New titles are published regularly, adding information and points of view. In addition, women receive advice about HRT from their health-care providers, their relatives, and their friends.
Opinions about HRT shift in response to new studies, personal experiences, and anecdotes, and well-intended but frequently contradictory advice is quite common. The shifting opinions about HRT in the medical and lay literature underscore the complexity of decision-making regarding HRT after breast cancer. The long-standing “standard” position of regulatory agencies and medical practice that HRT is contraindicated in breast cancer survivors places significant constraints on health professionals.
In addition, many patients with a history of breast cancer are reluctant to receive HRT; this reluctance leads them to avoid estrogen despite considerable climacteric discomfort. It is important, however, to recognize that a number of women resolve that the potential benefits of HRT outweigh the potential risks and make a personal decision to begin taking estrogen (Vassilopoulou-Sellin and Zolinski, 1992; Utian and Schiff, 1994; Grodstein et al., 1997).
Many investigators have discussed the importance of developing appropriate guidelines for use of HRT in women with a history of breast cancer and have emphasized the need for clinical trials of HRT specifically designed for this population. We recently conducted a 5-year randomized clinical trial to assess the safety and efficacy of prolonged estrogen replacement therapy in a group of menopausal women with localized (stage I or II) breast carcinoma and a minimum disease-free interval of 2 years (if estrogen receptor status was negative) or 10 years (if estrogen receptor status was unknown) (Vassilopoulou-Sellin et al., 2002). In total, our analysis included 56 women receiving estrogen and 243 women not receiving estrogen; patient and disease characteristics were similar in the two groups. Two (3.6%) of the 56 women receiving estrogen developed a contralateral, new breast carcinoma, and 33 (13.5%) of the 243 women not receiving estrogen developed a new or recurrent breast carcinoma.
We concluded that estrogen replacement therapy did not compromise disease-free survival in selected patients previously treated for localized breast carcinoma.
Two randomized trials based in Scandinavia were designed to address the safety of HRT use in patients with a history of breast cancer: the Hormonal Replacement Therapy after Breast Cancer: Is It Safe? (HABITS) trial and a similar study from Stockholm (Holmberg et al., 2004). In the HABITS trial, 434 women with a history of breast cancer were randomly assigned to either HRT or placebo.
After a median follow-up of 2.1 years, 26 women in the HRT group and 7 in the non-HRT group had had a new breast cancer event, prompting the HABITS steering committee to terminate the trial. Because of slow recruitment for the Stockholm study, data from that study were pooled with data from the HABITS trial, and a joint data monitoring committee was formed. Interim analyses showed a relative hazard of a new breast cancer of 3.29 in the HABITS trial but 0.82 in the Stockholm study.
The difference between the two studies was statistically significant (P = .02), but in spite of the lower relative hazard, the Stockholm study was also terminated because the pooled analysis of all data showed a significantly increased risk with HRT. The reason for these divergent findings is unclear.
We are aware of no other randomized clinical trials addressing the safety of HRT in women with a history of breast cancer. However, additional information about this topic can be obtained from prior retrospective and prospective single-arm and pilot studies, some of which are outlined in Table 18-2. In general, these studies tended to include women with localized disease with different combinations of hormone receptor and lymph node status. It is difficult to reach meaningful conclusions about the safety of HRT from such limited reports. Still, the recurrence rates reported in these studies are fairly low and similar to what might generally be expected among HRT nonusers.
From such reports and the aforementioned prospective studies, one can reasonably infer that HRT does not have a pronounced adverse effect on cancer recurrence in patients with a history of breast cancer who were rendered disease free after treatment for localized disease.
Nevertheless, in routine clinical practice, it is not appropriate to deviate from the widely held, established standards of care unless appropriate safety data become available. In the absence of definitive safety data, we continue to counsel our patients that a history of breast cancer remains a relative contraindication to HRT. We do, however, take into account the menopausal health of individual patients and occasionally agree together with a patient that HRT is the preferred choice.
Rather than attempt to construct arbitrary criteria for such a decision, we weigh the anticipated benefits against the potential risks and frankly discuss the inherent uncertainties with the patient. We particularly discourage patients with recently treated, extensive, or hormonally responsive disease from using HRT.
Gilbert G. Fareau and Rena Vassilopoulou-Sellin
Estrogen replacement therapy in breast cancer patients: a time for change? Proc Am Soc Clin Oncol 1996;15:121.