ON: STUDY OF THE PREVALENCE OF AUTOIMMUNE THYROID DISEASE IN WOMEN WITH BREAST CANCER. Giovanni Sisti MD, Mariarosaria Di Tommaso MD

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. COMMENTARY EP CO ON: STUDY OF THE PREVALENCE OF AUTOIMMUNE THYROID DISEASE IN WOMEN WITH BREAST CANCER Giovanni Sisti MD, Mariarosaria Di Tommaso MD From: Department of Health Sciences, University of Florence, AOUCareggi, Italy Correspondence author: Prof. Giovanni Sisti Largo Brambilla, Firenze, Italy gsisti83@gmail.com

2 The article by Freitas et al. in this issue of Endocrine Practice, Study of the Prevalence of Autoimmune Thyroid Disease in Women with Breast Cancer [1], adds a new piece to the intricate puzzle of what, if any, is the association between autoimmune thyroid disease and breast cancer. This controversial topic has been explored by many authors in the world s literature during the past 50 years. The findings have not been consistent but there appears to be a relationship between these two entities. In the 1950s a pioneering study by Sommers noted histological evidence of thyroid atrophy in patients with carcinoma of the breast, proposing an association between thyroid hypofunction and breast cancer [2]. Subsequent primary studies did not confirm that there was a relationship between Hashimoto thyroiditis and breast cancer as this impression was supported, by a meta-analysis of 13 papers [3-14], that was published in 2002 [15]. In this meta-analysis Sarlis and coworkers applied broad criteria to the definition of Hashimoto thyroiditis, including patients with nodular goiter, the presence of antithyroid antibodies or simply reduced thyroid function [15]. More recent primary studies, however, supported a positive association. Eventually, in 2012, a new meta-analysis not only found a positive association between autoimmune thyroid disease and breast cancer, it also noted a positive association between goiter, anti-thyroid antibody and breast cancer [16]. The authors of this subsequent meta-analysis applied more specific inclusion criteria regarding the diagnosis of autoimmune thyroid disease, requiring the combination of two or more clinical parameters to confirm the diagnosis [16]. In addition they investigated the relationship between Graves disease and breast cancer as described in the literature, with only one study meeting the inclusion criteria [8]. This article by Giani and coworkers did not find a relationship between Graves disease and breast cancer [8]. Subsequently, in 2013, one Taiwanese study analyzed the risk of developing breast cancer in a population of 5025 patients with Graves disease, reporting an

3 adjusted Hazard Ratio (HR) of 1.58, based on a comparison with patients in the control group [17]. Only few studies have analyzed the level of thyrotropin receptor antibody (TRAK), characteristic of Grave s disease, as it relates to patients with breast cancer. In 2010 Ditsch and coworkers found higher concentrations of TRAK in patients with breast malignancy as compared to those with benign breast tumors and a healthy control group, however, the levels of TRAK never reached pathological values [18]. Recently, Prinzi and coworkers reported an increased prevalence of breast cancer in 139 patients with TRAK positivity as compared to the general population, however, after stratification by age, significant differences were noted only for those in the age range [19]. The most recent meta-analysis relating to anti-thyroid antibody titers and breast cancer, in 2014, concluded that thyroid peroxidase antibodies (TPOab) and thyroglobulin autoantibodies (TgAb) are higher in breast cancer patients than in women without breast cancer [20]. In addition, it was noted that FT3 and FT4 levels were significantly higher in breast cancer patients [20]. In the subgroup analyses, the authors noted area differences related to thyroid hormone levels but this observation was limited by lack of information regarding the mean age of patients in the articles analyzed; the authors noted this as a limitation of their study [20]. Studies have also tried to determine if there is a relationship between anti-thyroid antibody positivity/titers or thyroid hormones levels and the outcome of breast cancer patients. A retrospective analysis done by Smyth and coworkers found a better outcome in patients with breast cancer who had relatively high TPOab levels, using a cut-off of 0.3 U/mL [10]. Fiore and coworkers in 2007 replicated the study by Smyth and coworkers with a more accurate selection of patients in a prospective design; they found that the presence of anti-thyroid antibody, defined as

4 serum TgAb greater than 100 U/mL and/or TPOab values greater than 15 U/mL, was significantly related to a longer 5-year survival in breast cancer [21]. Other research groups noted a lower risk of metastasis in patients with breast cancer who had positive TPOab tests [22]. In apparent contrast, however, Cengiz and coworkers found that a subgroup of breast cancer patients with thyroid pathology, defined as any combination of a pathological result of thyroid function tests, high thyroid autoantibody levels or abnormal thyroid ultrasonography findings, had higher number of metastatic lymph nodes, bigger tumor volumes and more frequent vascular invasion [23]. Moreover, a prospective study of Jiskra et al. in 2007 did not find any difference in breast cancer survival in women with positive TgAb or TPOAb as compared to those with negative tests [24]. Serum thyroid hormone concentrations in breast cancer has not been extensively studied. Dulger and coworkers, in a 2004 report, did not find significant differences free triiodothyronine (FT3) or free thyroxine (FT4) in 16 patients with metastatic as compared to 34 patients with breast cancer but no metastases [25]. Fiore and coworkers in 2007 found median FT4 values of 8.6 pg/ml in the survivors group with breast cancer, not significantly different from 8.7 pg/ml in the group of patients with breast cancer who died [21]. The study by Jiskra and coworkers, also published in 2007, did not find any prognostic relationship between serum levels of FT4 on relapse-free and overall survival in patients with breast cancer [24]. To summarize, there has not been a consistent relationship between antithyroid antibody positivity or titer and the outcome of breast cancer nor is this related to serum thyroid hormone concentrations. Selection biases may have contributed to the inconsistency of the literature in this field. Most studies recruited patients in third level oncologic centers with the possible occurrence of referral bias. In addition, the inclusion criteria for the studies have been heterogeneous as has been the tests

5 used to evaluate thyroid status. Some studies evaluated only thyroid hormone levels while others focused on markers of thyroid autoimmunity. In a few papers the thyroid was assessed with neck ultrasound and fine needle aspiration (FNA). Moreover, in some studies the patients were selected before the surgery to avoid the influence of the stress on the endocrine system, or after the surgery but before beginning of any adjuvant anti-tumoral therapy to control the effect of chemotherapy on the immune response. Notably, however, most studies if not all studies have not been biased by studied subjects from regions that differed in iodine intake. In the majority of the studies the prevalence of benign thyroid disease has been assessed in a cohorts of patients with breast cancer, however few studies have looked at this issue from the opposite perspective, calculating the prevalence of breast cancer in a population with thyroid disease. In this regard Muller and coworkers in 2011 reported that the overall prevalence of breast cancer in patients with benign thyroid disease, defined with any type of thyroid antibody or with goiter, was significantly higher than that to be expected in the reference population [26]. Recently, Prinzi et al. found an increased risk of breast cancer when a large cohort of 3921 patients with any thyroid disease were compared to the general population, but a lower risk when comparing patients with thyroid disease and positive autoantibodies to patients with thyroid disease and negative autoantibodies [19]. Some biases in this field are difficult to overcome. The high prevalence of both thyroid diseases and breast cancer in the fourth and fifth decade of women s life may make it difficult to rule in or out an association between these entities. In this issue, the study by Freitas and coworkers, gives additional data in a well selected population and supports the hypothesis that there is little association between breast cancer and autoimmune thyroid disease [1]. This study defined autoimmune thyroid disease

6 patients as having any abnormality in a thyroid laboratory test (TSH, TPOab, TgAb) [1]. The patients included in the study group did not have any prior anti-tumor treatment and all the controls had a recent negative mammary ultrasound and/or mammography [1]. The only positive association found in the study was between a family history of thyroid disease and the presence of breast cancer, with the obvious limitation that the patient s family history was self-reported by the patients rather than from potentially more reliable sources [1]. Other limitations of the study are the absence of neck ultrasound and FNA for more definitive characterization of the thyroid [1]. The effort to find a relationship between the pathogenesis of thyroid disease and breast cancer is not without a rationale. The Na/I Symporter (NIS), which imports I - from the blood-stream to the thyroid colloid and is also present in cancerous breast cells [27]. The presence of this and other shared antigens raises the question of whether autoimmunity against the thyroid gland may also affect breast cells but, as a recent study demonstrated, anti-nis antibody staining in breast cancer tissue is weak [28]. It has also been reported that thyroid hormones mimic the effects of estrogen in breast cancer cells [29] but other studies have reported opposite findings [8]. In conclusion, studies like that of Freitas et al. help to clarify the relationship, if any, between autoimmune thyroid disease and breast cancer. To date any such relationship seems more likely to be related to shared risk factors rather than to a direct influence of one entity on the other. Despite this impression more studies of a basic nature are indicated to determine if there are common factors that predispose to thyroid autoimmunity and breast cancer or if there are interactions that influence their courses.

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