CEBP Infection and Cancer: Biology, Therapeutics, and Prevention Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
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Cancer Epidemiology Biomarkers & Prevention Vol. 11, 1574-1578, December 2002
© 2002 American Association for Cancer Research

Do Thyroid Disorders Increase the Risk of Breast Cancer?1

Michael S. Simon2, Mei-Tzu C. Tang, Leslie Bernstein, Sandra A. Norman, Linda Weiss3, Ronald T. Burkman, Janet R. Daling, Dennis Deapen, Suzanne G. Folger, Kathi Malone, Polly A. Marchbanks, Jill A. McDonald, Brian L. Strom, Hoyt G. Wilson and Robert Spirtas

Divisions of Hematology and Oncology [M. S. S.] and Epidemiology [L. W.], Karmanos Cancer Institute at Wayne State University, Detroit, Michigan; Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington [M-T. C. T., J. R. D., K. M.]; Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California [L. B., D. D.]; Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania [S. A. N., B. L. S.]; Department of Obstetrics and Gynecology, Baystate Medical Center, Springfield, Massachusetts [R. T. B.]; University of Washington, School of Public Health and Community Medicine, Department of Epidemiology, Seattle, Washington [J. R. D., K. M.]; Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia [S. G. F., P. A. M., J. A. M., H. G. W.]; and Contraception and Reproductive Health Branch, Center for Population Research, National Institute of Child Health and Human Development, Bethesda, Maryland [R. S.]


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The objective of this study was to determine whether thyroid disorders or treatment of such disorders affects the risk of breast cancer. Subjects aged 35–64 years were participants in the National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences Study, a population-based, case-control study of invasive breast cancer that was carried out at five sites in the United States. In-person interviews were completed for 4575 women (cases) with breast cancer (2953 white and 1622 black) and 4682 control women (3021 white and 1661 black). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multiple logistic regression methods. Models included adjustment for age (5-year age groups), race (white or black), and site. A history of any thyroid disorder (OR = 1.1, 95% CI = 0.9–1.2) was not associated with breast cancer risk. Only women with a history of thyroid cancer had an increased risk, but this was restricted to parous women (parous OR = 3.4, 95% CI = 1.5–8.1; nulliparous OR = 0.5, 95% CI = 0.04–5.1). Breast cancer risk was not associated with treatment for thyroid disorders. There was no statistical interaction between thyroid disorders, thyroid treatments, and race, menopausal status, or parity. We found no association between thyroid disorders or their associated treatments and the risk of breast cancer.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A relationship between thyroid disease and risk of breast cancer is supported by experiments suggesting a role for thyroid hormones (1) , insulin, and insulin-like growth factor-1 (2) on the regulation of breast epithelial cell growth. Even so, evidence regarding a relationship between diseases of the thyroid and breast cancer risk is, on the whole, not compelling (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13) . Several epidemiological studies have found no significant relationship between either thyroid disorders (3) or treatment for thyroid disorders (12) and breast cancer risk, but others have found modest effects for hyperthyroidism (13) , thyroid hormone treatment (4) , and radioactive iodine treatment (13) . In addition, a protective effect was found for untreated goiters (4) . Limitations in the literature investigating relationships between breast cancer and thyroid disorders include small samples (4) and a lack of information of the specific types of thyroid disorder (6) or treatment (3) .

We examined whether thyroid disorders and/or treatment of these disorders affect the risk of breast cancer. We used data from a large case-control study of invasive breast cancer in which participants were asked about their history of several medical conditions potentially related to use of female hormones. That study ascertained data on specific thyroid conditions and treatments, as well as the timing of disease onset and duration of treatment.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Participants were enrolled in the National Institute of Child Health and Human Development Women’s CARE4 Study, a population-based, case-control study that was carried out at five sites in the United States. Four of the sites were affiliated with cancer registries funded through the National Cancer Institute’s SEER Program (Atlanta, Detroit, Los Angeles, and Seattle/Puget Sound); the fifth site had no SEER affiliation (Philadelphia; Ref. 14 ).

As described previously in detail, United States-born white and black women aged 35–64 years who were newly diagnosed with invasive breast cancer in July 1994 to April 1998 were eligible to serve as cases in the Women’s CARE Study (14) . Cases were identified through rapid ascertainment systems at the SEER-affiliated sites and by field staff in Philadelphia. Controls were chosen from the same counties as the cases, selected by random-digit dialing, and were frequency matched to cases based on 5-year age groups, race, and geographic site. Younger cases, and black cases and controls were oversampled to approximate a uniform distribution across age and race groups with the goal of efficiently assessing effect modification.

Exposure information was obtained during in-person interviews conducted by trained interviewers. Completed interviews were obtained for 4575 of the 5982 eligible cases (76.5%) and 4682 of the 5956 randomly selected controls (78.6%). The interview instrument included detailed questions on the previous use of oral contraceptive pills, HRT, fertility drugs, and other hormones. It also included questions on many other potential risk factors for breast cancer, including: (a) reproductive; (b) exercise; (c) health and family histories; (d) smoking and alcohol exposures; (e) demographics; and (f) medical history. Exposure information was collected for the time period preceding a set reference date, which was the date of diagnosis for cases and of initial household screening for controls.

All respondents were asked, "Before (reference date), did a doctor or other health professional ever tell you that you had a thyroid problem or any condition requiring thyroid medication or treatment?" Those who answered "yes" were shown a list of thyroid-associated conditions, including: (a) Graves’ disease; (b) Hashimoto’s disease (chronic thyroiditis); (c) overactive (hyperactive) thyroid; (d) under active (hypoactive); (e) goiter; (f) nodules; (g) cancer; and (h) other conditions. They were then asked, "What type of problem or condition was this?" Subsequently, respondents were asked, "Before (reference date), have you been hospitalized, had surgery, been prescribed medications, or been treated for any thyroid problem or condition?" Those who answered "yes" were shown a list of thyroid-associated medications, including: (a) thyroid USP or equivalent; (b) Synthroid or equivalent; (c) thyroid gland inhibitors; and (d) other medications. They were also shown a list of thyroid-associated procedures, including: (a) thyroid surgery; (b) radioactive iodine treatment; (c) X-ray or radiation treatment; and (d) other treatments. We evaluated whether a history of a thyroid disorder was associated with breast cancer risk and whether risk varied by time since first diagnosis, type of thyroid disorder, or treatments and duration of treatments.

ORs and 95% CIs were calculated using unconditional multivariate logistic regression methods (15) . Models included adjustment for age (5-year groups), race (white or black), and study site. We examined other variables as potential confounding factors. None of the factors we considered changed the ORs by >=10%, including: (a) first-degree family history of breast cancer (except in the analysis of thyroid cancer); (b) BMI at reference date minus 5 years; (c) number of full-term pregnancies (>26 weeks); (d) age at first full-term pregnancy; (e) education; (f) income; (g) age at menarche; (h) menopausal status; (i) mammogram screening history in the past 2 years; (j) alcohol consumption; (k) smoking history; (l) duration of oral contraceptive use; and (m) duration of HRT. In analyzing the association between preexisting thyroid cancer and risk of breast cancer, we adjusted for family history of breast cancer because the adjusted and unadjusted effect estimates as noted differed by >=10%. Stratified analyses were conducted using likelihood tests for heterogeneity to the regression models to assess effect modification by menopausal status, race, and parity (16) .


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Demographic and risk factor characteristics of 4575 cases and 4682 controls in the Women’s CARE Study, which have been described elsewhere (14) , are presented in Table 1Citation . The study population was approximately one-third black, and just over half was premenopausal. On average, controls in our study had more full-term pregnancies than did the cases and were less likely than the cases to have had a first-degree family history of breast cancer.


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  		Table 1 Demographic and risk factor characteristics of 4575 cases and 4682 controls in the Women’s CARE Study

 
The relationship between a history of thyroid disorders and risk of breast cancer is shown in Table 2Citation . A history of any thyroid disorder was not associated with breast cancer (OR = 1.1, 95% CI = 0.9–1.2). There were no significant associations by time since first diagnosis of any of the thyroid disorders. An increased risk of breast cancer was detected among women with a history of thyroid cancer (OR = 2.7, 95% CI = 1.2–5.9), although this risk was restricted to parous women (OR = 3.4, 95% CI = 1.5–8.1). On the basis of the small number of women (one case and two controls), thyroid cancer was not found to be associated with risk of breast cancer for nulliparous women. We observed no association between breast cancer risk and type of thyroid medication, duration of thyroid medication use, or exposure to other thyroid procedures or treatments (Table 3)Citation . Finally, no statistical interaction was seen by race, menopausal status, or parity (data not shown).


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  		Table 2 Relationship between history of thyroid disorders and breast cancer risk

 

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  		Table 3 Relationship between use of thyroid medications and procedures and breast cancer riska

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The largely negative results of this study support the majority of reports in the literature and provide additional reassurance that neither disorders of the thyroid nor treatment for these conditions substantially alters the risk for breast cancer among women aged 35–64 years. This study was large and population based, providing an advantage over studies that are hospital based (8 , 10) . Although two other studies included some data on minority populations (12 , 13) , no other investigations had a sample large enough to evaluate differences in risk by race. In addition, we tried to evaluate issues not completely addressed in previous publications, such as the potential elevation in risk associated with specific thyroid disorders and treatments and the recency of diagnoses and duration of treatments. This is potentially important because these conditions probably operate via different mechanisms, and group analysis could mask true findings. Limitations inherent in the design of a case-control study, such as selection bias, have been discussed previously, although our high-response rates argue against much selection bias (14) . Other limitations that are specific to our analysis include the lack of provisions to confirm diagnoses of medical conditions other than breast cancer and the fact that subject recall was the only basis for data on previous medications or treatments.

Even though there is in vitro evidence for an effect of thyroid hormones on breast epithelial proliferation (1 , 17 , 18) , the epidemiological literature provides little support for an association between thyroid disorders and breast cancer risk (3 , 6 , 12) . In one large population-based, case-control study, there was a protective effect associated with untreated goiters (OR = 0.34, 95% CI = 0.1–0.8; Ref. 4 ), but this finding was based on small numbers. Other researchers have not identified associations for a history of goiters or untreated goiters (8) , and analysis of our data supports these earlier findings (data not shown; Ref. 13 ). Data from another hospital-based, case-control study showed a small protective effect for thyroid adenomas diagnosed among premenopausal women (OR = 0.4, 95% CI = 0.1–0.7) or among women aged <35 (OR = 0.4, 95% CI = 0.2–0.8; Ref. 8 ). Our study was not able to evaluate the risk of breast cancer for women aged <35 years. However, we found no association for thyroid adenomas (nodules) among premenopausal women (OR = 1.1, 95% CI = 0.6–2.1). Others who have evaluated time since diagnosis of thyroid disease found no significant effects (3 , 12 , 13) . One other report found a relationship between hyperthyroidism and breast cancer risk, but it was based on only 17 cases and 19 controls (OR = 2.2, 95% CI = 1.1–4.4; Ref. 13 ), and this finding has not been replicated by us or by others (3 , 4 , 8) . Thus, although some studies suggest a protective effect of goiters or adenomas, our results, as well as much of the published literature on this issue, do not substantiate these findings.

Epidemiological support is also scant for an association between treatments for thyroid disorders and breast cancer risk (3 , 6 , 8 , 10) . One study showed a decrease in risk for women with untreated goiters and an increase in risk after 5–9 years of thyroid medication use, but no time trends were seen, and no significant effects were observed for euthyroid women who used thyroid medications for other reasons (4) . Our results are consistent with those from other large studies in which no significant effects have been found for specific thyroid treatments, particularly I131 and X-ray treatment, on breast cancer risk (9 , 11 , 13) .

Our finding of a significant association between a history of thyroid cancer and breast cancer risk has been reported by others (19 , 20) . In our study, the direction and strength of this association varied by parity, although the interaction was not found to be statistically significant and could very well have been attributable to chance. The relationship between thyroid cancer and breast cancer may reflect the influence of shared hormonal or genetic factors and should be studied further.

In conclusion, although there is laboratory evidence that thyroid hormones, insulin, and other growth factors can influence the growth and regulation of breast epithelial cells in vivo, we found no evidence of a positive association between risk of breast cancer and thyroid disease or its treatment, among women aged 35–64 years, except for thyroid cancer.


   Acknowledgments
 
We thank all past and present members of the Women’s CARE Study team for their important contributions to this project.

Investigators in the National Institute of Child Health and Human Development Women’s CARE Study include: Project Officer Dr. Robert Spirtas; Principal Investigators Drs. Leslie Bernstein, Janet R. Daling, Jonathan M. Liff, Polly A. Marchbanks, Brian L. Strom, and Linda K. Weiss; Coprincipal Investigators Drs. Dennis M. Deapen, Elaine W. Flagg, Jill A. McDonald, Sandra A. Norman, Michael F. Press, Hoyt G. Wilson; Coinvestigators Drs. Jesse A. Berlin, Ronald T. Burkman, Ralph J. Coates, Suzanne G. Folger, Kathleen E. Malone, Michael S. Simon, Giske Ursin, and Phyllis Wingo. Members of the Scientific Advisory Committee include Drs. Barbara S. Hulka, Carrie Hunter, Dennis Lezotte, and James Schlesselman.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by the National Institute of Child Health and Human Development, with additional support from the National Cancer Institute, through contracts with Emory University (N01-HD-3-3168), Fred Hutchinson Cancer Research Center (N01-HD-2-3166), Karmanos Cancer Institute at Wayne State University (N01-HD-3-3174), University of Pennsylvania (N01-HD-3-3176), and University of Southern California (N01-HD-3-3175) and through an intra-agency agreement with the Centers for Disease Control and Prevention (Y01-HD-7022). The Centers for Disease Control and Prevention contributed additional staff and computer support. Back

2 To whom requests for reprints should be addressed, at Harper Hospital–514 Hudson, 3990 John R. Street, Detroit, MI 48201. Phone: (313) 745-9155; Fax: (313) 993-0559; E-mail: Simonm{at}karmanos.org Back

3 Present address: National Cancer Institute, Bethesda, Maryland 20892. Back

4 The abbreviations used are: CARE, Contraceptive and Reproductive Experiences; SEER, Surveillance, Epidemiology, and End Results; OR, odds ratio; BMI, body mass index; HRT, hormone replacement therapy; CI, confidence interval. Back

Received 2/22/02; revised 8/ 6/02; accepted 10/ 4/02.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation