We investigated trends in incidence of invasive breast cancer and DCIS in relation to changes in HT use in a population of women undergoing regular screening mammography. Concomitant with a rapid decline in HT use beginning in 2002, we observed significant decreases in invasive breast cancer incidence in 2002 to 2006 among women age 50 to 69 and 70 to 79 years undergoing regular mammography, but not in women age 40 to 49 years. Rates of DCIS were observed to decline significantly after 2002 in women age 50 to 69 years, but not in the other age groups.
Our invasive breast cancer results corroborate previous findings by our group and others indicating an association between declining HT use and decreasing breast cancer incidence.6–13,15
Recently, Coombs et al19
modeled the direct impact of HT cessation on breast cancer in the United States. They reported that the 52% decline in HT use between 2000 and 2005 resulted in a 2% to 8% reduction in breast cancer incidence in women age 40 to 79 years, suggesting that changes in HT could provide partial to full explanation of the decreasing trend in breast cancer.19
As expected, the decline in invasive cancer in our study was more prominent in women age 50 to 69 and 70 to 79 years, the age groups with higher prevalence of HT use and steeper cessation rate.
To our knowledge, this is the first study to report a significant decline in DCIS rates in relation to the decrease in HT use in a population undergoing regular mammography screening. HT use has been associated with higher DCIS risk in two prospective studies. The Million Women Study reported a 56% increased risk for DCIS in HT users,20
and the BCSC reported a 39% increased risk among women who used E+P for 5 years or more.21
Studies that looked at recent trends in DCIS have mostly reported no change in rates.6,15
In one study using national data from state population-based cancer registries, the incidence of DCIS was found to increase between 1999 and 2004, with the rates being 8% higher in 2004 than in 1999. Despite the overall increase, the report indicated a decline in DCIS rates in 2002 and 2003.22
Given our longer follow-up, we may have been more able to observe the declining trend than the previous studies. Our DCIS findings are in line with a recent report from the BCSC that observed declines in rates of atypical ductal hyperplasia in parallel to the decrease in HT use.23
The effect of HT on breast cancer risk is thought to vary by tumor histologic type. In a meta-analysis of observational studies, the risk of HT was found to be greater for ILC and IDLC than IDC.20
However, the WHI randomized trial indicated a similar distribution of tumor histologic types in the E+P treatment and placebo groups, although statistical power was limited to detect differences.24
A recent report looking at trends in ILC and IDC showed a decline in both rates in 1999 to 2004, albeit of stronger magnitude for ILC (annual percent change for ILC, −4.6%; annual percent change for IDC, −3.3%).22
Our study results are in line with these findings in that we observed a decreased incidence of IDC in women age 50 to 69 and 70 to 79 years only, consistent with a large, absolute decline in HT use in these women. We also observed a significantly decreasing trend in ILC rates in women age 50 to 69 years in 2002 to 2005; however, this trend was nonsignificant when examining the 4-year period from 2002 to 2006. The low rate of ILC makes it difficult to characterize the incidence pattern for this histologic type.
The decreasing trend in ER-positive tumor rates, but not ER-negative tumor rates, in the older age groups is expected and confirms previous reports.2,6,15,25
We observed that the rates of ER-unknown cancers have decreased significantly across all age groups in the latter years. This is consistent with the fact that testing tumors for ER status has increasingly become standard of care in clinical oncology over the past years.26
Saturation in screening mammography27
and the decrease in mammography rates in 2003,14
particularly in women age 50 to 69 years, were proposed to contribute to the decline in breast cancer incidence. Given that our study population was restricted to women undergoing mammography and our analyses were adjusted for time between screening examinations, the effect of changes in mammography use is unlikely to explain our findings. However, this does not preclude a contribution of screening mammography to the decline in overall incidence in the broader population, although several studies offer evidence against a screening mammography effect.8,13,28
One of the main questions in establishing a causal relationship between HT cessation and breast cancer incidence relates to whether the rapid decline in incidence is biologically plausible. An immediate effect of HT cessation is in fact compatible with the role of estrogen as promoter rather than initiator of breast tumorigenesis.29
Thus, withdrawal of HT may halt the progression of pre-existing tumors or even cause them to regress completely. The rapid decline is also consistent with epidemiologic evidence that the elevated risk of breast cancer with current HT use decreases after cessation and is almost completely eliminated by 5 years after treatment discontinuation.20,30
In the Million Women Study, the relative risks associated with past HT use were reduced proportionally to time since cessation.20
More recent evidence from the WHI study indicated marked reductions in breast cancer risk within 1 year of discontinuing combined HT (E+P clinical trial: 28% reduction in rates from the last year of the trial to the first year after intervention; observational study: 43% reduction from 2002 to 2003).13
Another unanswered question is whether the decline in breast cancer continues as the rates of HT use stabilize. Notably, we observed that the incidence rates for the majority of outcomes in women age 50 to 69 years tended to increase in 2006, compared with the prior year, as the decline in HT use started to level off. This could be explained by the fact that HT cessation may have slowed down the growth of tumors but did not cause them to regress completely, resulting in subsequent detection. Studies investigating recent trends in breast cancer rates have reported conflicting results.8,31,32
One study reported a nonsignificantly increasing trend in 2005 to 2007,31
another observed a stabilization in rates in 2005 to 2006,8
whereas another observed a steady decline from 2003 to 2006.32
Thus, ongoing monitoring of rates beyond 2006 is needed to verify whether the trend has indeed started to stabilize.
The main limitation of our study was the lack of information on HT formulations; therefore, we could not separate the effects of E+P and estrogen-alone therapy. Results from the WHI HT trials indicated that although E+P increased breast cancer risk,24
estrogen alone was likely to have no effect or possibly decrease the risk.33
Another limitation is that we assessed current HT status only, and no data were available on prior HT use, including duration and recency. Furthermore, the rarity of ILC and IDLC hindered our drawing stronger conclusions regarding trends in incidence for these histologic types.
In conclusion, our study provides further support for the role of HT discontinuation in the decreasing incidence of invasive breast cancer, as well as DCIS. Our results also hint to the possibility that the decrease in breast cancer may not persist; however, this finding certainly requires confirmation using longer monitoring of incidence rates. It is reassuring that the effect of HT on breast cancer risk is reversed soon after discontinuation of therapy. However, given that the effect may not be long term for all tumors influenced by HT, the use of HT for the management of menopausal symptoms should be limited to the shortest duration possible.