Hypothyroidism as a Predictive Biomarker for Survival Benefits in Advanced Colorectal Cancer Patients Treated with Apatinib-Based Therapy

Yi Zhong¹Jingyi Wu¹Fang Guo²Shuang Dong¹Xiaoyu Li¹Xianmin Zhu¹Yuze Zhu¹Kun Wang³Yuanxiang Li¹Sheng Hu^1*

• ¹Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, wuhan, China
• ²Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology., Wuhan, China
• ³Department of Clinical Laboratory, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Huazhong University of Science and Technology, Wuhan, China

Background: Apatinib, a novel oral small-molecule tyrosine kinase inhibitor (TKI), has been widely used to improve clinical outcomes in advanced gastrointestinal and liver cancers; however, it lacks well-defined predictive and prognostic biomarkers. This study investigated whether hypothyroidism, a common side effect of apatinib, predicts enhanced survival outcomes in patients with advanced colorectal cancer (CRC). Methods: Patients with advanced CRC who were treated with apatinib and chemotherapy were classified into three thyroid function groups: euthyroid, subclinical hypothyroidism (SCH), and clinical hypothyroidism (CH). Progression-free survival (PFS) and overall survival (OS) were compared among these groups. Additionally, in a mouse CRC model, we assessed apatinib targets such as CD31 and the immune context, including thyroid inflammatory cell infiltration and peripheral blood cytokine levels. Results: In general, the degree of thyroid dysfunction significantly correlated with prolonged survival, although there was some inconsistency in terms of OS and PFS (mPFS: CH 8.2 m vs SCH 4.8 m, p=0.023, HR 0.627 (0.292-1.346); CH 8.2 m vs euthyroid 3.7 m, p=0.002, HR 0.301 (0.138-0.657); SCH 4.8 m vs euthyroid 3.7 m, p=0.101, HR 0.585 (0.294-1.126); mOS: CH 12.6 m vs SCH 9.3 m p=0.296, HR 0.612 (0.240-1.557); CH 12.6 m vs euthyroid 7.4 m, p=0.001, HR 0.274 (0.119-0.630); SCH 9.3 m vs euthyroid 7.4 m, p=0.024, HR 0.413 (0.187-0.909), respectively)) in 59 patients with advanced CRC. Thyroid dysfunction significantly correlated with prolonged survival in patients with CRC, with early onset hypothyroidism (<3.1 months) providing the most pronounced benefits. In animal models, apatinib treatment led to stronger inflammatory cell infiltration in the thyroid gland and increased CD8+ T-cell infiltration, although CD31 expression and cytokine levels remained unchanged. Conclusions: Early onset hypothyroidism may serve as a predictive biomarker for improved survival in patients with advanced CRC undergoing apatinib-based therapy. Larger studies are needed to confirm these findings and explore the underlying mechanisms linking the immunogenic toxicity of the thyroid to treatment efficacy.