Studies aimed at defining the association between BC and benign TD, in particular AITD, have produced conflicting results causing a long-lasting debate
[82][83][84][85][86][87][88][89][90][91][92][93]. In 2002, Sarlis and colleagues performed a meta-analysis of 13 articles published over the previous 50 years including 14,226 women
[82]. The authors failed to demonstrate any association between Hashimoto thyroiditis (HT) and BC
[82]. Ten years later, Hardefeldt and colleagues accomplished a meta-analysis comprising 28 studies and showed the presence of a higher risk of BC in patients with AITD
[7]. In addition, their results testified an increased BC risk associated with the presence of anti-thyroid antibodies and goiter, with Odds Ratios (OR) of 2.92, and 2.26, respectively
[7]. The latter data were confirmed in 2020 by Pan and colleagues by means of a meta-analysis on 11 different studies
[8]. The authors could establish that patients with BC had higher titers of anti-thyroid peroxidase antibodies (TPOAb) and anti-thyroglobulin antibodies (TgAb) compared to a non-breast disease control group
[8]. Similarly, in a very recent meta-analysis involving 21 studies, Chen and colleagues identified TgAb and TPOAb as significantly associated with an increased risk of BC
[6]. In
theour Institute
of the group, it was, we analyzed the prevalence of EM in 6386 female patients affected by different TD and
it waswe found that a number of EM were associated with TD
[83][94]. The EM most frequently recorded was BC (OR 3.94), followed by colorectal (OR 2.18), melanoma (OR 6.71), hematological (OR 8.57), uterus (OR 2.52), kidney (OR 3.40), and ovary (OR 2.62) neoplasms. By age-matched analysis,
it w
ase observed that the risk of EM was maximal in the age group 0–44 years (OR 11.28), remaining lower but significantly higher than that observed in the general population in the 45–59 and 60–74-years groups
[83].
It wasWe also show
ned that when TD patients were dichotomized based on the presence or the absence of TgAb and/or TPOAb, both groups had a higher risk of BC compared to the general population, but the risk was significantly lower in autoantibody-positive patients
[83][94]. This finding suggests that amongst TD patients, the presence of thyroid autoantibodies may have a partial protective effect against BC. The latter hypothesis is in agreement with an earlier observation by Smyth and colleagues on TPOAb-positive BC patients, who had a significantly better disease-free and overall survival compared to patients who were TPOAb-negative
[84]. In this
bac
kgroundontext, the study by Weijl and colleagues reporting the occurrence of hypothyroidism and anti-thyroid antibodies in patients affected by different types of cancer and undergoing immunotherapy with interleukin-2 is of some interest
[85]. They found that the preexistence or development of thyroid autoantibodies-related hypothyroidism was associated with a favorable response to immunotherapy
[85]. Similar observations were reported by Franzke and colleagues, who observed that autoimmunity caused by IL-2 and IFN-α2 treatment predicted long-term survival in patients affected by metastatic renal cell cancer
[86]. To explain the protective role of thyroid autoantibodies, it has been proposed that cell-mediated cytotoxicity elicited by these antibodies against shared antigens may affect the thyroid gland as well as the tumor
[87][88]. This hypothesis is consistent with the expression of natrium iodide symporter (NIS) and TPO noticed in breast tissues
[87][89]. Despite this evidence, however, further prospective large case studies should be undertaken to definitely prove the protective role of thyroid antibodies in BC cancer progression.
4. Conclusions
The impact of thyroid axis dysfunctions on BC progression has been a matter of debate for more than a century, and still today many controversies exist. The available information strongly suggests that TD may affect BC progression in several ways, through (i) altered plasma levels of deregulated thyrotropin (TSH), and THs or production of specific thyroid autoantibodies; (ii) dysregulation of PRL secretion due to hypothyroidism; (iii) alterations in THs responsiveness of BC cells. Thus, different hormonal and molecular players should be taken into consideration in every single patient, when analyzing the association between TD and BC. This knowledge will likely shed light on the potential pathogenic links between TD and BC, possibly allowing a more personalized clinical management of these patients.