Unmet Clinical Needs in the Treatment of Patients with Thyroid Cancer

Abstract

The increased incidence of thyroid cancer is a worldwide phenomenon; however, the issue of overdiagnosis has been most prominent in South Korea. The age-standardized mortality rate of thyroid cancer in Korea steeply increased from 1985 to 2004 (from 0.17 per 100,000 to 0.85 per 100,000), and then decreased until 2015 to 0.42 per 100,000, suggesting that early detection reduced mortality. However, early detection of thyroid cancer may be cost-ineffective, considering its very high prevalence and indolent course. Therefore, risk stratification and tailored management are vitally important, but many prognostic markers can only be evaluated postoperatively. Discovery of preoperative marker(s), especially for small cancers, is the most important unmet clinical need for thyroid cancer. Herein, we discuss some such factors that we recently discovered. Another unmet clinical need is better treatment of radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) and undifferentiated cancers. Although sorafenib and lenvatinib are available, better drugs are needed. We found that phosphoglycerate dehydrogenase, a critical enzyme for serine biosynthesis, could be a novel therapeutic target, and that the lymphocyte-to-monocyte ratio is a prognostic marker of survival in patients with anaplastic thyroid carcinoma or RAIR DTC. Deeper insights are needed into tumor-host interactions in thyroid cancer to improve treatment.

Keywords: Prognosis; Therapeutics; Thyroid neoplasms.

Fig. 1. Age-standardized thyroid cancer mortality rates based on the World Health Organization standard population are illustrated from 1985 to 2015 in Korea among (A) men and (B) women and among patients (C) younger than <55 years and (D) aged 55 years and older. Adapted from Choi et al. [26], with permission from John Wiley and Sons (Licence No. 4751250684699).

Fig. 2. Recurrence-free survival according to B type Raf kinase (BRAF) V600E mutational status (A) and BRAF V600E mutational status and X-linked inhibitor of apoptosis protein (XIAP) expression (B) in patients with papillary thyroid carcinoma. The Kaplan-Meier method was used to establish survival curves, and log-rank testing was used to compare recurrence-free survival between groups. Adapted from Yim et al. [36], with permission from Mary Ann Liebert Inc. (publisher does not require authors of the content being used to obtain a license for their personal reuse of full article, charts/graphs/tables or text excerpt).

Fig. 3. Recurrence-free survival according to cleavage and polyadenylation specific factor 2 (CPSF2) protein expression status. The Kaplan-Meier method was used to establish survival curves, and log-rank testing was used to compare recurrence-free survival between groups. Adapted from Sung et al. [37], with permission from Mary Ann Liebert Inc. (publisher does not require authors of the content being used to obtain a license for their personal reuse of full article, charts/graphs/tables or text excerpt).

Fig. 4. Recurrence-free survival (RFS) of patients with papillary thyroid carcinoma (PTC) according to expression of Slit2. PTC patients negative for Slit2 expression had poorer RFS than those positive for Slit2 expression. Adapted from Jeon et al. [38], with permission from Elsevier (License No. 4753570662104).

Fig. 5. Summary of changes in the metabolic characteristics of cancer cells. Red arrows indicate increased activity of various metabolic pathways in cancer. HK, hexokinase; Gluc-6-phosphate, glucose-6-phosphate; PPP, pentose phosphate pathway; 3PG, 3-phosphoglycerate; AcCoA, acetyl coenzyme A; TCA, tricarboxylic acid; αKG, alpha-ketoglutarate; Gln, glutamate; Glu, glutamine.

Fig. 6. Overall survival (OS) based on the lymphocyte-to-monocyte ratio (LMR) in patients with anaplastic thyroid carcinoma. The solid line represents the OS rate of the high LMR group (≥4) (n=12, 34%), while the dotted line represents the OS rate of the low LMR group (<4) (n= 23, 66%). A significant difference was found in the OS between the two groups (P=0.004). Adapted from Ahn et al. [58], with permission from Mary Ann Liebert Inc. (publisher does not require authors of the content being used to obtain a license for their personal reuse of full article, charts/graphs/tables or text excerpt).

Fig. 7. Overall survival based on the lymphocyte-to-monocyte ratio (LMR) in patients with progressive radioiodine-refractory differentiated thyroid carcinoma treated with sorafenib. Adapted from Ahn et al. [59], with permission from John Wiley and Sons (License No. 4757610873680).