Front Endocrinol: the relationship between benign thyroid disease and breast cancer risk

Background: In 2020, the latest data from the World Health Organization's International Agency for Research on Cancer (IARC) showed that the number of breast cancer (BC) patients had increased to 2.
26 million, making it the most common cancer
in the world.
Therefore, it is important
to identify possible risk factors, prevent them in time, and reduce the incidence of BC.
Many risk factors, such as age, sex, estrogen, family history, genetic mutations, and unhealthy lifestyle habits, have been shown to increase the probability
of BC.
Since both the thyroid and breast glands are regulated by the hypothalamic-pituitary-glandular axis, there may be some intrinsic connection and interaction
between BC and benign thyroid disease (BTD).
The first to propose a link between BTD and BC was Schottenfeld et al
.
While it failed to prove the relationship between the two, it provided new insights
for later researchers.
However, the results of the available studies are inconsistent
.
Some studies have shown that BTD increases the risk of BC, while some studies suggest that BTD reduces the risk of
BC.
In addition, some studies have found no link
between BTD and BC risk.
Therefore, whether BTD increases the risk of BC requires further research
.

A meta-analysis published in 2012 by Hardefeldt et al.
confirmed a positive association
between autoimmune thyroiditis (AITD), goiter, and antithyroid antibodies and the risk of BC.
However, the effects of Graves disease (GD), hypothyroidism, and hyperthyroidism on the risk of BC have not been elucidated, and the relationship between BTD and BC aggressiveness is unclear
.
In addition, recently published high-quality clinical studies were not included in previous meta-analyses, adding justification
to the performance of current studies.

Purpose: Therefore, our meta-analysis aimed to systematically review and assess the impact of different types of BTD on the risk of BC, including the latest research findings, and subgroup analyses
based on different regions.
Compared with existing studies, we further identify the potential relationship between BTD and BC aggressiveness based on different markers of BC aggressiveness, which is of great significance
in clinical practice.

Methods: A systematic literature search (PubMed, Web of Science, MEDLINE, and Embase databases) identified studies
assessing the association between BTD and BC risk.
Data were analyzed using version 16.
0 of the STATA software, including odds ratios (OR) and their corresponding 95% confidence intervals (ci).

Included studies were assessed
for publication bias and quality.

Results: A total of 18 studies involving 422,384 patients with
BTD were included.
The results showed autoimmune thyroiditis (OR: 2.
56, 95%CI: 1.
95 ~ 3).

I2 = 0.
0%, p = 0.
460), goiter (OR: 2.
13, 95% ci: 1.
19 3
.
I2 = 80.
6%, p=0.
000), Graves disease (OR: 5.
01, 95% CI: 1.
49-16).

I2 = 0.
0%, p=0.
358) was associated with
a higher risk of BC.
Hypothyroidism (OR: 0.
82, 95% CI: 0.
64 to 1.
04, I2 = 85.
0%, p=0.
000) and hyperthyroidism (OR: 1.
07, 95% CI: 0.
93-1).

I2 = 24.
9%, p=0.
206) was not significantly associated
with BC risk.
In addition, pooled analysis showed no significant correlation
between BTD and BC aggressiveness.
However, subgroup analysis showed that BTD in the European subgroup was positively correlated with BC aggressiveness (HR: 2.
05, 95% CI: 1.
32-3
.
I2 = 86.
4%， p=0.
000)
。

Figure 1 (A) Forest plot
used to assess the relationship between BTD and breast cancer.
(B) Forest plot
used to assess the relationship between GD and breast cancer.
(C) Subgroup analysis
of BTD and BC risk in different regions.

Figure 2 Sensitivity analysis
of BTD and BC risks.

Fig.
3 (A) BTD and aggressiveness
of breast cancer.
(B) Subpopulation analysis
of BC and aggressiveness by different types of BTD.
(C) Analysis
of invasive subpopulations of BC in different regions.
a = grade II, b = grade III, c = tumor> 20 mm, d = lymph node metastases, e = estrogen receptor negative, f = progesterone receptor negative
.

Figure 4 Assessment of publication bias
.
No publication bias
was found in the subgroups of (A) autoimmune thyroiditis; (B) goiter; (C) hypothyroidism; (D) hyperthyroidism (autoimmune thyroiditis (p=0.
857), hypothyroidism (p=0.
287), and hyperthyroidism (p=0.
754).
The goiter subgroup had publication bias, with a p-value of 0.
019).

Conclusions: Autoimmune thyroiditis, goiter and Graves disease are associated with
an increased risk of BC.
In addition, subgroup analysis showed that BTD geographically increased the aggressiveness
of BC in the European population.
However, further research is needed to prove these findings
.

Han M, Wang Y, Jin Y, et al.
Benign thyroid disease and the risk of breast cancer: An updated systematic review and meta-analysis Front Endocrinol (Lausanne) 2022; 13