David Cohen, M.D.·Published 19 March 2008·18 min read
Key points
What are the guidelines for screening in postmenopausal women?
Appropriate screening reduces breast cancer-related mortality among women aged 50 to 75 by 25% to 30%.
There is presently some controversy regarding the lifetime value of mammography as a screening tool.
Although most observational studies have failed to show a link between ERT/HRT and breast cancer, HRT has been associated with an increased relative risk in some studies.
What are the guidelines for screening in postmenopausal women? Are mammograms passe'? Who should be given chemopreventive agents? Does ERT/HRT increase breast cancer risk? Find answers to these and other important questions in this latest update.
The diagnosis, treatment, and follow-up of breast cancer in postmenopausal women is changing rapidly - cancers are being diagnosed earlier and prognoses are improving; hormone replacement therapy (HRT) is being considered for breast cancer survivors with debilitating menopausal symptoms; and new pharmacologic choices for cancer prevention are becoming available. One of these, tamoxifen, has been reported to reduce the risk of invasive breast cancer by 50%. In subgroups with atypical hyperplasia or lobular carcinoma in situ breast lesions, the relative risk reduction was even greater. Raloxifene, another selective estrogen receptor modulator (SERM), also reduces the risk of breast cancer to a similar degree in women taking it for treatment of osteoporosis. Increasingly, breast cancer risk assessment and chemoprevention counseling are becoming standard components of breast cancer screening and overall health maintenance.
Screening postmenopausal women
Appropriate screening reduces breast cancer-related mortality among women aged 50 to 75 by 25% to 30%. The American Cancer Society currently recommends that women begin monthly breast self-examination at age 20. Between ages 20 and 39, women should have a clinical breast examination every 3 years.
Guidelines on the appropriate interval between screening mammograms in asymptomatic low-risk women older than 40 differ among various organizations; some recommend yearly, others, every other year. Nearly everyone agrees that women over 50 should have yearly mammography. Vigilant screening remains important in women older than 65, as nearly 50% of new cases and nearly two thirds of the deaths from breast cancer occur among the 13% of the female population that is 65 years or older. Note that older black women experience higher rates of breast cancer mortality that are not explained by risk factor analysis nor by changes in breast cancer incidence rates. The unexplained increase of breast cancer mortality appears to occur in the postmenopausal period.
Key points
Appropriate screening reduces breast cancer-related mortality among women aged 50 to 75 by 25% to 30%.
Mammography remains the most effective screening tool for finding early breast lesions. Vigilantly screen women older than 65, as nearly 50% of new cases - and nearly two thirds of deaths from breast cancer - occur among this population.
The evidence fails to show that ERT/HRT users have an increased risk of breast cancer. The reported slight increase in numbers of diagnosed cancers after 10 to 15 years of use is a complex and unresolved issue.
Written and revised by
David Cohen, M.D.
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NCI recommends that only women at increased risk for breast cancer based on the Gail Model should consider taking tamoxifen.
Tamoxifen has been shown to reduce the risk of new breast cancers in either breast; how tamoxifen and raloxifene do so is still under investigation.
There is presently some controversy regarding the lifetime value of mammography as a screening tool. But the argument is so esoteric that it should not concern women at this time. No one is questioning the ability of mammograms to detect breast cancers; rather, the two reports of concern fault mammography since it finds early cancers for which treatment has not yet been defined. These reports are based on selective reviews of epidemiologic studies (meta-analyses) of all cause mortality in breast cancer patients who received screening mammograms, compared with those who did not. Since there were no data on the causes of death, most of these deaths were likely due to diseases other than breast cancer.
The first, a meta-analysis by Gotzsche and Olsen, has itself been controversial for its methods and possible bias. The authors do not actually address the value of mammography, just whether it affects all cause mortality among breast cancer subjects. Moreover, there is important internal inconsistency in their meta-analysis approach. When they used all studies that they deemed adequate, they showed a 20% protective effect; but their two "best" studies alone did not show protection against mortality. The authors' conclusions are driven by concern that early detection has led to overly aggressive treatment of early lesions. This justifies neither their methods or conclusions.
A second meta-analysis was done by a private consulting group, Physician Data Query (PDQ), a body affiliated with but independent of the NCI. Using similar data, that group also concluded that the use of all cause mortality was not sufficient to distinguish mammography as a screening tool. Since breast cancers are responsible for less than 5% of all deaths, the rise of all cause mortality as a measure of the value of mammography as a screening tool is clinically not relevant for individual women. The controversy over the value of screening mammography is not likely to be resolved in the near future and does not directly relate to diagnosis, just to outcomes of diagnosis. We prefer to continue to use mammography as a screening tool and await further information.
Mammography use by older women remains relatively low, however - fewer than 50% of women older than 65 have ever undergone mammography, and an even smaller proportion undergo mammography regularly. Scheduling a mammogram may become more difficult than it has been in many areas as several hospitals have scaled back their mammography programs. We suggest that a mammogram should be a "ticket" for the annual exam, and that patient pressure should be applied to any log jams and under reimbursement by insurers. {pagebreak}
Better prognosis in ERT/HRT users diagnosed with breast Cancer
Although most observational studies have failed to show a link between ERT/HRT and breast cancer, HRT has been associated with an increased relative risk in some studies. There is some evidence that risk increases at 10 to 15 years of ERT/HRT, but this is neither consistent, nor does it correct for increased lifespan due to ERT/HRT. Regardless of risk, the prognosis of diagnosed cases is better in women taking ERT/HRT.
Other studies show that HRT may even lower the risk of breast cancer. Overall, while investigators may differ in their view, there is no convincing evidence that contemporary doses of ERT/HRT increase the rate of breast cancers in women, and this is without correction for level of risk.
The lower cell-proliferation rate and smaller tumor size found in estrogen receptor (ER)-positive tumors from current HRT users suggest a direct ER-mediated growth inhibitory effect of HRT on established breast tumors. This may at least partly explain why breast cancer in women taking HRT has a more favorable clinical course than it does in nonusers. Although some literature indicates that tumors in HRT users are biologically less aggressive, it is less clear whether HRT alters the tumor features early during carcinogenesis or modulates growth and dissemination in established malignant tumors.
Several other explanations have been presented for the less advanced clinical stage and increased survival time reported in breast cancer patients who take HRT. The association between HRT and tumor size may partly reflect earlier diagnosis due to better medical surveillance and awareness of breast cancer in general. Also, tumors in HRT users were more often detected during screening. Women taking HRT have more frequent mammographic or other examinations for breast cancer. It is a well-established fact that slow-growing tumors are detected at a smaller size. Thus, the relationship of HRT to tumor size may be secondary to the effect on proliferation rate.
When progestin is combined with estrogen
Although estrogen was long the focus of attention regarding increased breast cancer risk, studies have also questioned whether the addition of a progestin - but generally not progesterone - increases breast cancer risk. Although there has been such concern, it is not borne out by the data.
To be sure, this global view of the data does not represent specific positive studies. For example, in the case of ERT or HRT, there are some studies that go against the grain of the majority: A recent reanalysis of data from the landmark Nurses' Health Study showed that more than 5 years' use of estrogen plus progestin increased the relative risk of breast cancer by 9% per year, but estrogen alone increased the risk by 3.5%. A second study found that the relative risk of breast cancer rose 24% for every 5 years women took estrogen plus progestin. In contrast, women taking an estrogen-only regimen had a considerably smaller additional risk of 6%. Another similar, more recent study based on data from 46,000 women in the Breast Cancer Detection Demonstration Project also showed that estrogen plus progestin increased breast cancer risk beyond that for estrogen use alone. When the researchers categorized women by weight, however, any difference between estrogen-only and estrogen plus progestin disappeared among heavier women. The increased risk was in lean women (body mass index < 23) or in women who used progestin cyclically, which may increase risk by inducing mitotic changes.
The American College of Obstetricians and Gynecologists does not recommend a change in clinical practice based on recent estrogen-progestin studies. Most often, says ACOG, the benefits of adding a progestin to the HRT regimen will outweigh the risks for women with a uterus. Finally, there is an important generally agreed upon result of observational studies: Women in whom breast cancer develops while taking ERT or HRT will as a group have a better prognosis and less aggressive lesions. At the very least, this indicates that many factors are at play in the ductal epithelium of women on ERT/HRT. Some of these effects may be healthful in the face of endogenous influences on breast cancer development. {pagebreak}
HRT for breast cancer survivors
Commonly accepted dogma says that HRT is not recommended for survivors of breast cancer. This is partly because of the possibility that it will exacerbate the illness and partly because any potential benefits are diminished by the risk of death from breast cancer in these women. These ideas have not withstood the test of time, however, and consideration of HRT seems reasonable in some survivors of breast cancer. This may include women who have severe, debilitating symptoms due to estrogen deprivation; who have menopause-related illnesses such as osteoporosis; who initially had tumors with a favorable prognosis and remained disease-free for extended periods; and those with other indications for HRT. For these women, who should be fully informed about the risk and benefits, low-dose estrogen (0.625 mg/d or less of conjugated estrogens, with or without progestin) may relieve symptoms and is apparently safe.
Hot flashes can be the most bothersome of menopausal symptoms among survivors of breast cancer. A variety of nonestrogenic agents may have mild to moderate effects on hot flashes in some women. Patients with hot flashes or vasomotor symptoms who are taking tamoxifen may also obtain relief with concurrent HRT. Although this combination of therapies is sometimes used, the overall effect is unknown. In some European studies in which concomitant therapy was used, tamoxifen was shown to have no preventive benefit against breast cancer, although patients in a specific study did show a reduced risk of subsequent breast cancer.
Possible chemopreventive agents
The development of SERMS to prevent breast cancer is complex because of the myriad physiologic functions affected by estrogen. The ideal agent for postmenopausal women would take advantage of the short- and long-term beneficial effects of HRT (especially in treating symptoms such as hot flashes while preventing osteoporosis and cardiovascular disease) and minimize adverse effects on the breast and uterus. SERMs offer the possibility of selectively targeting various estrogen responses to prevent the sequelae of estrogen deficiency and menopause. Two major classes of synthetic SERMs are the nonsteroidal triphenylethylenes (tamoxifen and toremifene) and the benzothiophenes (raloxifene). The next generation of SERMs will likely be increasingly tissue- and disease-selective as a much greater understanding is gained of the estrogen response mechanism. Aromatase inhibitors currently being investigated may provide another chemopreventive option in the future.
Who should receive tamoxifen?
For the past 20 years, tamoxifen has been used in the treatment of breast cancer. In 1998, it received FDA approval for reducing the threat of breast cancer in women at high risk for the disease based on the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, which had the largest sample size, greatest statistical power, and greatest number of new breast cancer cases of any similar study conducted to date. But as others had reported, long-term effects of tamoxifen were observed in this study. Endometrial cancers were more common in the tamoxifen group, with a tamoxifen-to-placebo risk ratio of 2.53; risk was greatest in women 50 years of age or older. Moreover, the rates of stroke, pulmonary embolism, and deep vein thrombosis (DVT) were as great in the tamoxifen group as among HRT users, particularly among those aged 50 or older.
Although tamoxifen has a favorable effect on lipids, evidence for favorable effects on cardiac events has not been consistent. New data were obtained recently on this issue by a large study, the Breast Cancer Prevention Trial (BCPT), conducted by the National Cancer Institute. Researchers found that when used for breast cancer prevention in 13,388 women with and without heart disease, tamoxifen did not reduce the threat of cardiovascular disease, but neither did it increase the risk. Interestingly, tamoxifen is also associated with several beneficial effects, including a reduction in hip, radius, and spine fractures, probably due to maintenance of bone mineral density.
At present, ACOG recommends that the decision to use tamoxifen for reducing the risk of breast cancer be made on an individual basis after taking into consideration the patient's medical history, risk assessment, and preferences. The American Society of Clinical Oncology defines appropriate risk as comparable to women in the BCPT - at least a 1.67% 5-year risk as calculated by the Gail model.
Although the NCI estimates that 29 million women in the United States are at great enough risk for breast cancer to be candidates for prophylactic therapy with tamoxifen, 20 mg/d, for 5 years, the means of calculating risk are not determined and there are risks of tamoxifen that are not accounted for by the Gail model. But, according to the NCI, those at high risk are women whose risk is equal to or greater than that of the average 60-year-old woman based on the Gail Model, a statistical model of breast cancer risk. The relative benefits of tamoxifen in women taking HRT and in those with specific breast cancer genotypes remains unclear.
We still have no definitive answer about the prophylactic use of tamoxifen for one group of women: cancer-free breast cancer survivors who were diagnosed 5 or more years ago, but who were not then treated with adjuvant tamoxifen. Data from several NSABP protocols examined the subsequent risk of breast cancer in women who survived disease-free for 5 years following an initial diagnosis of invasive breast cancer and who had not received adjuvant tamoxifen. The subsequent 5-year cumulative risk of contralateral invasive breast cancer was 3.4%, which is close to the 3.3% risk for invasive breast cancer in the placebo arm of the P-1 trial; the cumulative risk of all invasive breast cancer in such women was 14.4%. The decision to use tamoxifen for risk reduction in these patients must be based on an assessment of the duration and quality of life remaining, the risks as well as potential benefits of tamoxifen, and the presence of competing morbidity that may weigh against the use of tamoxifen. For example, tamoxifen may be appropriate in a 50-year-old woman who is otherwise healthy, but less suitable for a 68-year-old woman with a history of cataracts and DVT. {pagebreak}
Alternatives to tamoxifen
Several other pharmacologic agents that affect reproductive hormones or their actions are being examined to reduce the risk of breast cancer. While raloxifene's only approved indication is for the treatment of osteoporosis, secondary data analysis from the Multiple Outcomes of Raloxifene Evaluation (MORE) clinical trial showed a 76% reduction in the frequency of breast cancer in the raloxifene group. The analysis was criticized because the study was never designed as a breast cancer prevention study. Participants were not randomized based on their breast cancer risk, so it is unknown if the placebo and raloxifene groups had the same average risk. Also, the study population was at high risk for osteoporosis, and some research shows that such women have a lower overall risk of breast cancer. Since the follow-up period is now only 4 years, the question of suppression of growth versus true prophylaxis awaits resolution. The data are powerful evidence, however, of an anti-breast cancer effect of raloxifene.
The Study of Tamoxifen and Raloxifene (STAR) trial, currently enrolling participants, is aimed at clarifying the benefits of raloxifene. This will be the first breast cancer prevention trial to incorporate an active agent (tamoxifen instead of placebo) as the standard of care. Two additional ongoing trials that will add more raloxifene data are Raloxifene Use for The Heart (RUTH) and Continuing Outcomes Relevant to Evista (CORE). Now 4 years into the trials, researchers have preliminarily reported a lack of cognitive decline.
Another agent being examined for risk reduction is a chlorinated derivative of tamoxifen, toremifene. This agent is approved for the treatment of breast cancer in postmenopausal women with ER-positive or receptor-unknown status tumors. Clinical experience with toremifene is limited. This agent has bone antiresorptive effects comparable to those of tamoxifen, but its effect on the uterus and endometrium has not been clearly defined in clinical trials. The risk of DVT is probably comparable to that for tamoxifen. Trials are under way in postmenopausal women comparing the efficacy of tamoxifen with toremifene for the adjuvant treatment of early-stage breast cancer.
Finally, some researchers see aromatase inhibitors as the wave of the future. Early but valid studies indicate that these agents, which block estrogen formation throughout the body, are approximately one third more effective at shrinking breast lesions than SERMs like tamoxifen. This evidence, plus the other data mentioned earlier in this article, indicate a role for endogenous estrogen in breast cancer development that is much more profound than that due to conventional doses of ERT/HRT.
Conclusions
Many unsettling questions remain to be answered. But evidence is still lacking that ERT or HRT contribute to breast cancer. Rather, there may be a marginal increase in diagnoses after a decade or more of ERT/HRT use that actually represents a very small number of cases per 1,000 women at risk. It remains to be seen whether the additional cases are a result of the increased longevity of women who receive ERT/HRT. On the other hand, there is considerable evidence that estrogen formed in the breast may play a key role in the development of breast cancer and that this local estrogen plays a dominant role in the disease's cause.
Patients who are diagnosed with breast cancer and are on ERT/HRT have a better prognosis stage for stage, and large series appear to show no change in recurrence rates in women receiving ERT/HRT after apparently successful primary treatment for breast cancer. Mammography is the most successful tool in early diagnosis of breast cancer and the current controversy over mammography deals with the possibility that early diagnosis may lead to unnecessary treatment of early lesions whose propensity to metastasize is not yet defined. Tamoxifen, raloxifene, toremifene, and aromatase inhibitors are all very promising agents that obviate locally formed and circulating estrogens at the level of the breast. They have been shown effective in preventing and treating breast cancer.
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By Frederick Naftolin, MD, DPhil, Dahlia Mishell Sataloff, MD, and Trudy L. Bush, PhD, MHS
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