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Vol. 12 Issue 3, Summer 2007

The Recent Decline in Breast Cancer Incidence: What is its Relationship to Hormone Therapy Use?
The Ribbon 

Article available in Spanish (Español) (PDF)

By Barbour S. Warren, Ph.D., Research Associate, BCERF, and
Carol M. Devine, Ph.D., R.D., Associate Professor, BCERF and Division of Nutritional Sciences

A report presented at the last San Antonio Breast Cancer Symposium in December 2006 (1) received a great deal of coverage in the popular press. Investigators utilizing the National Cancer Institute’s SEER cancer registry reported a steep decline in the overall rate of breast cancer incidence between 2001 and 2003. Over this two-year period a decline of 7% was reported for women of all ages and tumor types. A decrease of this size was unprecedented. Of further surprise, an even greater decrease, 12%, was reported for the subgroup of women ages 50 to 69 with estrogen receptor positive tumors. The validity of this report has been confirmed by both earlier (2, 3) and subsequent reports (4-7) utilizing US cancer registries as well as those from other countries. These results reverse an 18-year trend from 1980 to 1998, over which breast cancer incidence increased by almost 40% (6). Although these changes have not been fully explained, this article reviews the potential explanations. Please see the box below for a description and definition of breast cancer incidence.

Breast cancer incidence.

Most simply, breast cancer incidence is a measure of the level of occurrence of new cases of breast cancer during a given year. Formally defined, it is the number of cases of breast cancer that occur in a certain group of people during a specific year. Since incidence reflects an occurrence over a period of time, it can be considered a rate and is frequently called the incidence rate. To allow for comparison between different groups of people, incidence values are typically mathematically adjusted for size (per 100,000 people) and for differences in the numbers of people of different ages within the groups (age adjustment). The values used typically come from state and federally run registries that track the occurrence of different types of cancer. For example, the Centers for Disease Control, using data from the National Cancer Institute’s SEER cancer registry, recently reported that for women age 50 to 59 living in the areas covered by this registry, there was 7.4% decrease in the incidence of invasive breast cancer between 2002 and 2003 (8). The invasive breast cancer incidence rate in 2002 for women age 50 to 59 (269.1 new cases of invasive breast cancer per 100,000 people) declined in 2003 to 249.1 new cases of invasive breast cancer per 100,000 people. Both these values were adjusted to the age distribution, or fractions of the population in different age groups, seen in 2000 for the US population.

Breast cancer incidence decrease related to decrease in hormone therapy use: the evidence

Over almost the same time period that the breast cancer incidence decrease occurred, the number of annual prescriptions for hormone therapy after menopause (also known as hormone replacement therapy) dropped by 30% to 40% (9, 10). Most investigators agree that this large cessation of the use of hormone therapy plays the major role in the decreased breast cancer incidence. There is a substantial body of evidence supporting this conclusion.

First, long term use of hormone therapy containing estrogen and progestin has been well documented to cause breast cancer. In 2005, following review of existing evidence, the International Agency for Research on Cancer classified estrogen/progestin hormone therapy as “carcinogenic to humans” (11). This classification has been described as equivalent to a “case closed” determination for estrogen/progestin hormone therapy having a causative effect on breast cancer (12).

Second, as stated above, use of hormone therapy after menopause declined over a similar period as breast cancer incidence. This decline occurred following the failure of the first clinical trials examining hormone therapy for beneficial effects on coronary heart disease and osteoporosis. One trial was the Heart and Estrogen/progestin Replacement Study (HERS) which evaluated the effect of estrogen and progestin hormone therapy on women with existing heart disease (13, 14). No benefit was found, as benefits seen later in use were overridden by risk occurring during the first year of use. A second trial was the Women’s Health Initiative (WHI) which examined both estrogen/progestin and estrogen alone hormone therapy for long-term prevention of coronary heart disease and osteoporosis (15, 16). Both the estrogen/progestin and estrogen alone arms of the WHI trial were terminated early when it became apparent that risks of the treatments exceeded their benefits.

The US national trends for the number of prescriptions written for hormone therapy (estrogen/progestin and estrogen alone therapy) increased by 54% from 1995 to 1999, but from 1999 (one year following the HERS report) to 2002 they remained stable (9). However, between 2001 and 2003, following the WHI termination, they plummeted to 63% of their starting value. The decline in use of estrogen/progestin therapy was even greater, ending in 2003 at a number 28% of the 2001 annual rate.

As the above discussion indicates, there was little to no lag between the decreases in hormone prescription and the decline in breast cancer incidence. Such a change was not without precedence. A similar change in incidence was seen in the late 1970s following a large decrease in prescription of estrogen-only hormone therapy after it was associated with a very strong increase in the risk of uterine cancer (17). As will be discussed below, the rapid decline in breast cancer incidence is also biologically credible.

Third, the key role played by hormone therapy in the recent decrease in breast cancer incidence is also supported by a substantial body of observational evidence showing an association between hormone therapy and increased breast cancer risk. Almost 20 case control and cohort studies have examined the association of hormone therapy and breast cancer risk. In the vast majority of the studies estrogen/progestin therapy was found to moderately increase breast cancer risk (18). The majority of the studies also reported similar findings for estrogen-alone hormone therapy which, because of its very strong association with uterine cancer, was only prescribed to women without a uterus (18). As discussed above, the WHI trial provided a causative link between estrogen/progestin therapy and breast cancer risk. However, unlike the epidemiological studies, the WHI trial did not find a causative link between estrogen-alone therapy and breast cancer risk. This difference is currently unresolved.

Fourth, the level of decrease in breast cancer incidence has been demonstrated to vary in populations with different levels of hormone therapy use. A well-conceived study in California examined the incidence of breast cancer and survey-reported use of estrogen/progestin hormone therapy between 2001 and 2004 for 58 counties in California (19). They found that: 1) those counties with the least reduction in use of hormone therapy had an 9% decrease in breast cancer incidence; 2) those counties with an intermediate decrease in hormone therapy had a 14% decrease in breast cancer incidence; and 3) those counties with the largest decrease in hormone therapy had a 23% decrease in breast cancer incidence. This study indicates not only a link between hormone therapy and breast cancer incidence but, more significantly, a quantified link.

Fifth, the biological plausibility for a connection between the recent decline of hormone therapy use and breast cancer incidence is also good. Estrogen and progestin function as tumor promoters for breast cancer formation (20). A key characteristic of carcinogenic promoters is the requirement of repeated exposure. Some scientists describe this as promoters “fueling” tumor growth. In the absence of these “fuels,” tumors stop growing and can potentially regress. Studies of cancer incidence found that tumors which expressed estrogen receptors were affected to a much larger degree by the use of hormone therapy. Such an outcome would be expected in an environment where breast tumor growth was “fueled” by estrogen- and progestin-containing hormone therapy. These results provide additional support for a role of decreased use of hormone therapy in this decline in breast cancer incidence.

Epidemiological studies have also provided supporting evidence from cohort and case control studies which evaluated changes in breast cancer risk after hormone therapy is stopped. These studies have found that the risk of breast cancer is greatest during hormone therapy use and following termination of use risk decreases to control levels over a five-year period (21, 22).

Other possible contributors to decline in breast cancer incidence

While reduction in the use of hormone therapy is likely to have played the major role in the decline in breast cancer incidence, other contributors have also been mentioned. These include inaccuracy in the cancer registry data, a decrease in the number of women getting mammograms, changes in the use of tamoxifen or roloxifen, and changes in risk factors associated with breast cancer risk.

Inaccuracy of cancer registry data is highly unlikely to have contributed to the breast cancer incidence decrease. Beyond the fact that cancer registries in the US are considered very accurate, the effect of hormone therapy on breast cancer incidence has been reported in data from a number of different cancer registries in both the US and other countries (2-7). It is not likely that similar inaccuracies would be found in multiple registries.

Changes in the number of women getting mammograms may have contributed to the decline in breast cancer incidence, as cancer incidence rises and falls with the number of women examined. However, the contribution of changes in mammography to this phenomenon is likely to have been very small. The rate of mammography in the US during 2002 to 2003, when the decreases in breast cancer incidence occurred, fell only of a few percentage points (23). Small decreases such as these would be expected to have little effect on breast cancer incidence.

The use of tamoxifen and roloxifen did not change over this time period (4). Thus, population-wide changes in the use of these estrogen antagonists cannot be linked to the drop in breast cancer incidence.

Clearly, these alternative factors could at best act as minor contributors for the recent decline in breast cancer incidence. Accordingly, the decreases in the use of hormone therapy in response to the negative results from the HERS and WHI clinical trials are almost certainly responsible for the decline in breast cancer incidence. The story does not end here; there are a number of important questions that remain.

Remaining questions regarding breast cancer risk and mortality, and hormone therapy

First, how is breast cancer incidence expected to change from this point forward? This is unclear. Some have proposed a continued decrease in breast cancer incidence to a new and lower level. Others have predicted that established tumors will grow at a slower rate in the absence of hormone therapy and that incidence levels will rise again albeit less dramatically. These changes will, no doubt, be closely monitored in the future.

Second, it will be important to evaluate how and if these changes will affect overall death rate from breast cancer. This effect is also unclear. Since decreases were seen in the both the tumors which respond well and poorly to therapy, there is potential for future decreases in the breast cancer death rate. A change in breast cancer prognosis is also possible as the decrease in cancer incidence was greatest for estrogen receptor positive tumors. These tumors have much better treatment outcomes and their decrease may lead to change in the overall percentage of tumors responding well to therapy.

Finally, it is important to examine the size of the impact of hormone therapy on public health. This is best done using an epidemiological calculation known as the population attributable fraction or PAR. The PAR is best understood as the fraction or percentage of breast cancer cases that would be theoretically eliminated if a certain risk factor (hormone therapy) was eliminated. The PAF, in this case, would be calculated from the prevalence of hormone therapy use and the risk of breast cancer linked to this use. A PAF between 8% and 15% has been determined for estrogen /progestin hormone therapy (12, 20, 24). These values agree well with the changes in incidence reported to date. These values also indicate that over the 7.5-year period that a combined estrogen /progestin pill (1995) was approved to the WHI cessation (mid-year 2002) more than a 100,000 breast cancer cases could be related to estrogen/progestin hormone therapy (12).

When the WHI was being planned, so strong was the belief in the benefit of hormone therapy that some investigators protested that the trial would be unethical as the control group would be receiving a placebo drug (25). In hindsight, we can be ever so thankful that that this idea was overridden.

References

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    26. Last Update 02.26.08