Higher baseline TSH levels predict early hypothyroidism during cancer immunotherapy

Abstract

Background and purpose Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that enhance the immune response against cancer cells. ICIs are generally well tolerated, although endocrine immune-related adverse events (irAEs) are common. We investigated the risk factors for thyroid irAEs in patients treated with ICIs. Moreover, we evaluated the clinical outcome of subjects who became hypothyroid compared to euthyroid patients. Patients and methods We retrospectively analyzed a series of 195 consecutively subjects treated with ICIs for metastatic tumors at the University of Naples “Federico II” between January 2014 and March 2020. Only subjects tested for thyroid function before and during the treatment with ICIs were included. Results In the 96 patients treated with ICIs who were included [66 males, median age: 62 years (27–87)], thyroid irAEs occurred in 36 (37.5%), 16 (16.7%) a transient thyrotoxicosis, and 20 (20.8%) an hypothyroidism (in nine subjects hypothyroidism was preceded by a transient thyrotoxicosis). Only baseline TSH levels above 1.67 mIU/L and positive anti-thyroid antibodies (Ab-T) were associated with a higher risk of hypothyroidism. Patients with hypothyroidism during ICI treatment showed an improved 2-year PFS (HR = 0.82 CI 0.47–1.43; p = 0.0132) and OS (HR = 0.38 CI 95% 0.17–0.80; p = 0.011) compared to euthyroid patients. Conclusions Baseline TSH levels above 1.67 mIU/L and presence of Ab-T are risk factors for the development of thyroid irAEs. Patients affected by thyroid irAEs showed a longer survival than patients who remained euthyroid.

Survival benefit of endocrine dysfunction following immune checkpoint inhibitors for nonthyroidal cancers

“…However, the number of patients presenting with overt hypothyroidism was smaller and no analyses were done for pooled hypothyroidism, i.e., those following thyrotoxic phase as well as those with overt hypothyroidism. On the other hand, another study [21] demonstrated the opposite pattern, showing an improved survival in patients with hypothyroidism but not in those with thyrotoxicosis as compared to euthyroid patients. Inaba et al [22] further demonstrated that patients who developed permanent thyroid dysfunction (required levothyroxine supplemental therapy for hypothyroidism for >3 months) had a better OS than those with only transient thyroid dysfunction (required no therapy or therapy discontinued within 1 month).…”

Correlation between immune-related adverse events and long-terms outcome in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: a retrospective study

“…Typically, thyroid dysfunction caused by ICIs triggers transient hyperthyroidism, followed by permanent hypothyroidism in a median of 6-12 weeks [21,22] . Previous studies have found that the better median PFS and OS in patients with thyroid irAEs [23,24] , and it could be related to a different immunological background that exposes them to a higher risk of thyroid irAEs but at the same time that makes them more sensitive to the ICI treatment [25] . In our study, univariate and multivariate Cox proportional regression analysis had shown that patients with hypothyroidism had a longer OS.…”

Changes in TgAb and TPOAb titers are greater in thyrotoxicosis than isolated hypothyroidism induced by PD-1 blockade

“…In addition to the difference in ATA titer changes, this study showed that TgAb titers, but not TPOAb titers, were higher at baseline and at the time of thyroid-irAEs onset in patients with thyrotoxicosis than patients with isolated hypothyroidism. Because it has been reported that CD4 + T cells specific to thyroglobulin are essential in the development of thyrotoxicosis induced by PD-1-Ab in a mouse model [16], the immune response to Several studies have reported that elevated TSH levels are a risk factor for thyroid-irAEs induced by ICIs [17][18][19]. It has also been shown that TSH levels at baseline are significantly higher in patients who developed overt hypothyroidism induced by PD-1-Ab or antiprogrammed cell death ligand 1 antibody (PD-L1-Ab) than patients who developed subclinical hypothyroidism or patients who did not develop thyroid dysfunction [20], suggesting that higher TSH levels at baseline, even within the normal range, become a risk factor for overt thyroid-irAEs.…”