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Originally published as JCO Early Release 10.1200/JCO.2007.11.4132 on June 25 2007

Journal of Clinical Oncology, Vol 25, No 23 (August 10), 2007: pp. 3437-3439
© 2007 American Society of Clinical Oncology.

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Regional Changes in Hormone Therapy Use and Breast Cancer Incidence in California From 2001 to 2004

Anthony S. Robbins, Christina A. Clarke

From the California Cancer Registry, Public Health Institute, Sacramento; Northern California Cancer Center, Fremont; and the Stanford University School of Medicine, Stanford, CA

Address reprint requests to Anthony S. Robbins, MD, PhD, California Cancer Registry, Public Health Institute, 1700 Tribute Rd, Suite 100, Sacramento, CA 95815; e-mail: arobbins{at}ccr.ca.gov


    ABSTRACT
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 INTRODUCTION
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 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose: Recently, an unprecedented 1-year 7% decrease in the overall incidence of invasive female breast cancer in the United States was reported. It has been suggested that the decrease resulted from the mass cessation of estrogen-progestin hormone therapy (EPHT) in 2002. We took advantage of California's unique population-based cancer surveillance resources to assess whether regional changes in breast cancer incidence observed between 2001 and 2004 correlated with regional changes in EPHT use between 2001 and 2003.

Methods: We obtained statewide cancer registry and California Health Interview Survey (CHIS) EPHT data for almost 3 million non-Hispanic white women age 45 to 74 years, residing in California's 58 counties. We examined trends in the age-adjusted incidence of invasive female breast cancer and compared these with trends in the use of EPHT, after grouping all California counties into three groups based on EPHT use in 2001. We also examined CHIS data on trends in screening mammography.

Results: In 2001, there were large regional differences in EPHT use and breast cancer incidence. From 2001 to 2004, incidence declined by 8.8% in the counties with the smallest EPHT reductions, by 13.9% in those with intermediate reductions, and by 22.6% in counties with the largest EPHT reductions. Between 2001 and 2003, CHIS data did not show any significant change in the proportion of women who reported having a mammogram in the previous 2 years.

Conclusion: These data support the hypothesis that changes in EPHT use in 2002 may be responsible for significant declines in breast cancer incidence between 2002 and 2003 and sustained through 2004.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Recently, Ravdin et al1 reported an unprecedented 1-year 7% decrease in the overall incidence of invasive female breast cancer in the United States (2002 to 2003), and suggested that it resulted from the rapid decrease in use of estrogen-progestin hormone therapy (EPHT). A 66% decline in EPHT use occurred after the early termination of the EPHT arm of the Women's Health Initiative (WHI) in July 2002, and subsequent widespread media coverage.2 Clarke et al3 reported a strong temporal correlation between declines in EPHT use and breast cancer incidence in a clinical population of the San Francisco Bay area of California. California differs from most populations in that population-based cancer incidence and risk factor information are collected for individual counties. To understand better whether recent breast cancer declines were more pronounced where EPHT use was highest, we took advantage of the population-based cancer registry data available for all 58 California counties to determine whether regional changes in breast cancer incidence observed between 2001 and 2004 correlated with regional changes in EPHT use.


    METHODS
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 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
We obtained data on age-, race-, and county-specific rates of invasive female breast cancer (International Classification of Diseases for Oncology4 codes C50.0 through C50.9) from the population-based California Cancer Registry and population estimates from the National Center for Health Statistics. Data on EPHT use were obtained from the 2001 and 2003 California Health Interview Survey (CHIS).5 We used the Internet-based AskCHIS application to obtain age-, race-, and county-specific EPHT prevalence estimates. AskCHIS is an interactive, Web-based interface for accessing detailed CHIS estimates. To assess hormone therapy (HT) use, CHIS asked women age ≥ 40 years who were not pregnant, "Are you currently taking any hormone replacement supplements prescribed by a medical doctor to control the symptoms of menopause?" Given that this question referred to any kind of HT, to estimate more closely the population prevalence of women using EPRT, we only included in the numerator of our prevalence calculations women who reported HT use but also reported they had not had a hysterectomy, because women with intact uteri are not prescribed estrogen-only HT because of demonstrated risks of endometrial cancer. We limited the study to non-Hispanic white women age 45 to 74 years because breast cancer incidence varies strongly by race and this age group was the most likely to use EPHT.

We assessed the correlation of EPHT use and breast cancer incidence in two ways. First, we grouped all 58 California counties into three groups based on prevalence of EPHT use in 2001 (low, medium, high).6 Prevalence cut-points for the three groups were low, less than 14.0%; medium, 14.0% to 19.9%; and high, ≥ 20.0%. For each group, we obtained estimates of the prevalence of EPHT use in 2001 and 2003, and age-adjusted incidence in 2001 and 2004 (the most recent year for which data were available) per 100,000 women. Surveillance, Epidemiology, and End Results *Stat 6.2.3 (Information Management Systems, Silver Spring, MD) was used to obtain age-adjusted incidence rates. We used regression techniques to obtain point estimates and 95% CIs for changes in incidence and prevalence, and to test whether the changes were significantly different from zero. We assumed a Poisson distribution for incidence analyses and a binomial distribution for prevalence analyses. Second, to measure directly the correlation between change in breast cancer incidence ({Delta}I) and change in prevalence of EPHT use ({Delta}P), we used data from all California counties in an ordinary linear regression model, with weights proportional to the inverse of the variance of {Delta}I. All statistical analyses were performed using SAS version 9.1.3 (SAS Institute, Cary, NC) for Windows.

The purpose of the first method of analysis was to help place the findings in their public health context, given that correlation coefficients close to 1 could arise from small changes in incidence and prevalence that were highly correlated, or large changes in incidence and prevalence that were highly correlated. We used weighted regression methods to account for the 8,000-fold difference in population sizes across California's 58 counties, ranging from 1,200 (Alpine) to 9.6 million (Los Angeles). The weights reflect the fact that large fluctuations in incidence can occur by chance alone in small counties, whereas the year-to-year variation is much smaller in large counties.


    RESULTS
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 ABSTRACT
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 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Between 2001 and 2004, a total of 39,643 invasive breast cancers occurred among California white women age 45 to 74 years (a group totaling 2,967,912 women in 2004). Figure 1 shows that there were no significant year-to-year changes in age-adjusted breast cancer incidence in this population between 1996 and 2002, although rates peaked in 1999 and were generally stable, with a slight decline from 2001 to 2002. Between 2002 and 2003, there was a significant 9% decline that was sustained through 2004.


Figure 1
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Fig 1. Age-adjusted incidence of invasive breast cancer, non-Hispanic white women, age 45 to 74 years, California, 1996 to 2004. Rates are per 100,000 and age-adjusted to the 2000 US Standard Million (19 age groups) standard.

 
Table 1 shows that in 2001 (before the WHI announcement), there were large regional differences in breast cancer incidence and EPHT prevalence, and that there was a strong correlation between these incidence and prevalence measures. Regional differences in EPHT prevalence were eliminated substantially in 2003 (after the WHI announcement). Between 2001 and 2004, invasive breast cancer incidence declined by 29.5 cases per 100,000 women (–8.8%) in the counties with the smallest EPHT reductions, by 51.4 cases per 100,000 (–13.9%) in the counties with intermediate reductions, and by 89.2 cases per 100,000 (–22.6%) in counties with the largest EPHT reductions.


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Table 1. Regional Changes in Prevalence of EPHT Use and Incidence of Invasive Breast Cancer, Non-Hispanic White Women, Age 45 to 74 Years, California, 2001 to 2004

 
Linear regression results suggested that each 1% decrease in the prevalence of EPHT use was associated with an incidence decrease of 3.1 cases per 100,000 women (P < .001). The correlation coefficient between {Delta}P and {Delta}I was .75, and the model R2 indicated that 57% of the variation in {Delta}I was explained by variation in {Delta}P.

CHIS data from 2001 indicate that statewide, 83.2% (95% CI, 82.3% to 84.1%) of white women age 45 to 74 years had a mammogram in the prior 2 years, and in 2003, 82.6% (95% CI, 81.5% to 83.7%) of these women had a mammogram in the prior 2 years. Mammography trend data were similar in the three regions stratified by EPHT use.


    DISCUSSION
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
These data, based on analysis of nearly 40,000 occurrences of breast cancer diagnosed in a population of nearly 3,000,000 women, provide additional evidence that population-level changes in EPHT use between 2001 and 2003, when media attention surrounding the WHI results was widespread, may be responsible for substantial population-level declines in breast cancer incidence between 2001 and 2004, at least among non-Hispanic white women. In parts of the San Francisco Bay area, which had the highest prevalence of EPHT use in California, breast cancer incidence decreased by 22% during 3 years. Notably, regional variation in breast cancer incidence was mitigated substantially in 2004, even though it was observable in 2001. The observed breast cancer incidence trends—with rates peaking around 2000, followed by a slight decrease from 2001 to 2002 and a sharp decrease beginning in 2002—track closely with documented trends in HT prescriptions in the United States.2

The most notable limitation of this study is its ecologic design, which is necessitated by the lack in US cancer registry data of detailed information regarding EPHT and other cancer risk factors. Thus, it is possible that other, unmeasured changes in the population may explain the observed changes in breast cancer incidence. However, we found no evidence of a decline in reported use of screening mammography for the population studied. It also seems unlikely that the sharp declines seen after 2002 represent regression to the mean, given that no similar departures from the trend line were observed before 2002, and the declines were sustained through 2004 in all regions examined. The findings may be due to lead time bias (ie, merely a lengthening of the period before diagnosis without any decrease in the ultimate risk of developing breast cancer). Another limitation of the study is that CHIS data on EPHT use and mammography are self-reported, and may not be as accurate as medical records.

From a pathophysiologic standpoint, rapid declines in breast cancer after cessation of EPHT are consistent with epidemiologic data showing sharp decreases in risk within 1 year of stopping HT.7 The role of EPHT in breast carcinogenesis may be as a promoter, fueling the growth of small, subclinical tumors, particularly those that are hormone sensitive.8 If, in fact, EPHT cessation merely slows the growth of existing breast tumors, it is possible that breast cancer incidence rates may increase in future years. Therefore, continued, detailed surveillance of breast cancer incidence patterns, including temporal trends and geographic variation, is warranted in the years after mass cessation of HT among women in the United States.


    AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
 TOP
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 AUTHORS' DISCLOSURES OF...
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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Anthony S. Robbins, Public Health Institute; Christina A. Clarke, Northern California Cancer Center Testimony: Christina A. Clarke, Williams, Love, O'Leary, Craine & Powers, PC Other: N/A


    AUTHOR CONTRIBUTIONS
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Conception and design: Anthony S. Robbins, Christina A. Clarke

Collection and assembly of data: Anthony S. Robbins, Christina A. Clarke

Data analysis and interpretation: Anthony S. Robbins, Christina A. Clarke

Manuscript writing: Anthony S. Robbins, Christina A. Clarke

Final approval of manuscript: Anthony S. Robbins, Christina A. Clarke


    NOTES
 
Supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885 (for collection of cancer incidence data); the National Cancer Institute's Surveillance, Epidemiology and End Results Program under Contract No. N01-PC-35136 awarded to the Northern California Cancer Center, Contract No. N01-PC-35139 awarded to the University of Southern California, and Contract No. N02-PC-15105 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under Agreement No. U55/CCR921930-02 awarded to the Public Health Institute.

The ideas and opinions expressed herein are those of the authors and endorsement by the State of California, Department of Health Services, the National Cancer Institute, and the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

published online ahead of print at www.jco.org on June 25, 2007.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Ravdin PM, Cronin KA, Howlader N, et al: A sharp decrease in breast cancer incidence in the United States in 2003. Breast Cancer Res Treat 100:S6, 2006 (suppl 1)

2. Hersh AL, Stefanick ML, Stafford RS: National use of postmenopausal hormone therapy: Annual trends and response to recent evidence. JAMA 291:47-53, 2004[Abstract/Free Full Text]

3. Clarke CA, Glaser SL, Uratsu CS, et al: Recent declines in hormone therapy utilization and breast cancer incidence: Clinical and population-based evidence. J Clin Oncol 24:e49-e50, 2006[Free Full Text]

4. Fritz A, Percy C, Jack A, et al: International Classification of Diseases for Oncology (ed 3). Geneva, Switzerland, World Health Organization, 2000

5. UCLA Center for Health Policy Research: California Health Interview Survey. http://www.chis.ucla.edu/

6. Clarke CA, Purdie DM, Glaser SL: Population attributable risk of breast cancer in white women associated with immediately modifiable risk factors. BMC Cancer 6:170-180, 2006[CrossRef][Medline]

7. Beral V: Million Women Study Collaborators: Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419-427, 2003[CrossRef][Medline]

8. Dietel M, Lewis MA, Shapiro S: Hormone replacement therapy: Pathobiological aspects of hormone-sensitive cancers in women relevant to epidemiological studies on HRT—A mini-review. Hum Reprod 20:2052-2060, 2005[Abstract/Free Full Text]

Submitted February 21, 2007; accepted May 14, 2007.


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