In our study, the thyroid irAE group showed better prognosis than the no thyroid irAE group, regardless of age, sex, ICI, or type of underlying malignancy. In particular, the newly developed hypothyroidism group showed a significantly better prognosis.
In our study, 33.7% of patients developed thyroid irAEs. Although the occurrence rate was slightly different from those in other studies [24, 26, 28], the occurrence rate in our study was similar to that in the existing literature. The actual prevalence of thyroid dysfunction could be higher because we only included patients who underwent thyroid function tests at ICI treatment initiation. Because most practice was performed by oncologists and not endocrinologists, thyroid function tests were often omitted.
The patients in the thyroid dysfunction group, especially those with newly developed overt hypothyroidism, showed better prognosis than patients in the no thyroid irAE group. Even after adjusting for sex, age, and cancer type, this same result was consistently obtained. Similar results have been reported extensively [26, 27, 29, 30]. However, these studies either included relatively small numbers of patients or included those with only a specific cancer type or treated with a particular ICI regimen. Kotwal et al. showed improved survival in the thyroid dysfunction group, although they only included patients treated with a PD-L1 inhibitor . Lima Ferreira et al. recently reported improved survival in patients with thyroid dysfunction due to several cancer types and ICI types . However, none of them showed a difference in the thyroid dysfunction type. Moreover, data from Korean patients have rarely been reported.
Newly developed overt hypothyroidism patients showed significantly lower hazard ratio mortality, whereas the thyrotoxicosis group showed a high hazards ratio. In fact, previous studies shown ICI induced thyrotoxicosis would eventually develop hypothyroidism[28, 31, 32]. In our study, period from ICI initiation to diagnosis of thyrotoxicosis was shorter than period to diagnosis of hypothyroidism. In addition, among 40 hypothyroidism patients, 13 experienced thyrotoxicosis period. However, 6 thyrotoxicosis patients did not show development of hypothyroidism. Because almost their malignancy showed progression, thyroid problem was not concerned.
On the other hand, many studies have suggested that hyperthyroidism was linked to poorer cancer prognosis . However, considering that patients who had already taken a thyroid hormone for hypothyroidism showed better prognosis, the TSH stimulation pathway might be associated with prognosis. The underlying mechanisms involved in thyroid irAE and ICI treatment are not yet fully understood . Thyroid irAEs often manifest as asymptomatic thyrotoxicosis, followed by a rapid transition to hypothyroidism . Intrathyroidal predominance of specific T lymphocytes is thought to be associated with ICI-induced thyroiditis . However, how ICI efficacy and thyroid irAEs are connected remains unknown. Previous studies have suggested that some immune pathways involving T cells or NK cells influenced thyroiditis with an anti-cancer effect [21, 22, 35]. However, the underlying mechanisms remain unknown. Moreover, the link between irAEs and anti-tumor effects remains unclear .
There is no reliable marker for predicting the prognosis, response, or adverse events after ICI treatment . Recently, in one study in a single center in Korea, a positivity for thyroid autoantibodies could predict the progression to overt hypothyroidism . In a small group study, a low frequency of thyroid autoantibody was observed, suggesting that there might be a different pathogenesis between ICI-induced thyroiditis and classical autoimmune thyroiditis . In our results, thyroid autoantibody positivity was not significantly different between the thyroid irAE group and the no thyroid irAE group. However, in the subgroup comparison, there was a significant difference among the groups. Positive TPO-Ab was associated with levothyroxine dose elevation, and positive Tg-Ab was associated with thyrotoxicosis development. This is similar to the results from a previous study [26, 28]. This suggests that thyroid autoantibodies could predict the course after ICI treatment. Another factor that has drawn our attention was the BMI. Many studies have reported that a higher BMI was associated with better cancer prognosis in a variety of cancer types [38–40]. Wang et al. have shown that although obesity causes were increased immune aging and tumor growth; it also causes PD-1 mediated T cell dysfunction, which led to stronger responses to ICI treatment . Leptin is thought to be involved in this process . Rena et al. reported an association between higher BMI and ICI-induced thyroiditis . However, this was a single-center study that did not analyze the relationship with prognosis. In our study, BMI did not show a significant difference among patients with thyroid dysfunction. In a study by Pollack Rena et al. , 20% of patients had a BMI > 30. However, only 2.6% of the patients had a BMI than higher than 30 in our study.
This study has some limitations. First, the study population was heterogeneous due to the retrospective nature of the study. ICI treatment was performed by various oncologists; therefore, thyroid function test was not routinely performed in all cases. A well-designed prospective analysis will overcome these limitations. Second, the median follow-up period was relatively short because the use of ICIs was recently started in our center. We could include duvalumab, another PD-L1 inhibitor, because this agent was stated to be used in our hospital in 2020 with a follow-up duration of too short.
In conclusion, it was verified that ICI treatment-induced thyroid dysfunction was associated with better survival in the real-world practice of Korean patients. The overall prognosis was the best when newly developed hypothyroidism occurred, and since TPO-Ab was significantly observed in the occurrence of overt hypothyroidism, the presence or absence of TPO-Ab could be used as a marker to predict patient prognosis in real practice.