血清TTF-1、PAX-8与乳腺癌术后放疗后甲状腺功能异常的相关性队列研究

doi:10.19401/j.cnki.1007-3639.2024.12.004

摘要/Abstract

摘要：

背景与目的：甲状腺功能异常在乳腺癌术后放疗患者的长期随访中较为常见。本研究旨在结合血清学甲状腺功能指标的检查结果，比较乳腺癌术后患者在放疗前后甲状腺转录因子-1（thyroid transcription factor-1，TTF-1）和配对盒转录因子8（paired box 8，PAX-8）血清水平的变化，分析两种甲状腺转录因子血清水平的变化与乳腺癌术后放疗后出现甲状腺功能异常的相关性。方法：前瞻性选取上海交通大学医学院附属第九人民医院黄浦分院放疗科2022年1月—2022年6月收治的无甲状腺疾病史且在乳腺癌术后接受放疗的女性患者，按照有无锁骨上区放疗野分成两组。所有患者入组前均被完整告知研究内容，并签署知情同意书。本研究设计通过了上海交通大学医学院附属第九人民医院黄浦分院伦理委员会的伦理审查（审批号：伦审2021-KY-2）。分别记录入组患者放疗前、放疗结束时、放疗结束后6、12和24个月两种甲状腺转录因子（TTF-1、PAX-8）的血清水平、血清甲状腺功能指标的检查结果，包括三碘甲状腺原氨酸（triiodothyronine，T3）、四碘甲状腺原氨酸（tetraiodothyronine，T4）、游离三碘甲状腺原氨酸（free triiodothyronine，FT3）、游离四碘甲状腺原氨酸（free tetraiodothyronine，FT4）、促甲状腺激素（thyroid stimulating hormone，TSH）、甲状腺过氧化物酶抗体（thyroid peroxidase antibody，TPO-Ab）。本研究严格遵循《加强流行病学中观察性研究报告质量》指南中的各项条目。结果：共80例患者入组（每组各40例）。两组患者中有19例发生甲状腺功能减退，其中锁骨上区野放疗组15例，无锁骨上区野放疗组4例（P=0.004）。两组患者放疗前血清TTF-1[5.70（5.11，7.13） vs 6.68（5.15，7.57），P=0.296]、PAX-8（5.26±1.01 vs 5.66±1.37，P=0.149）水平差异无统计学意义。其中锁骨上区野放疗组患者TTF-1、PAX-8的血清检测值在放疗结束后的12个月内逐渐升高;而无锁骨上区野放疗组TTF-1、PAX-8的血清水平在放疗结束后的24个月内无明显变化。两组患者的TTF-1的血清检测值在放疗结束后6个月[6.99（4.73，13.94） vs 5.79（5.01，6.28），P=0.049]、12个月[7.65（5.02，17.85） vs 5.43（4.52，6.22），P=0.005]的差异均有统计学意义;PAX-8的血清检测值在放疗后12个月[6.79（4.86，14.30） vs 5.81（4.70，7.25），P=0.042]的差异有统计学意义。以锁骨上区野放疗组TTF-1以及PAX-8均明显升高的放疗结束后12个月的检测值中位数作为参考数值，将检测值超过平均值的患者定义为甲状腺转录因子升高亚组，低于平均值定义为甲状腺转录因子正常亚组，比较两个亚组中甲状腺功能减退发生情况的差异，并分析锁骨上区野放疗组患者TTF-1/PAX-8升高与甲状腺功能减退发生的相关性，结果显示升高亚组的甲状腺功能减退发生率明显高于正常亚组（分别为65.0% vs 10.0%、60.0% vs 15%，P=0.001、P=0.008）。多因素分析结果显示乳腺癌术后锁骨上区野放疗结束后12个月的TTF-1/PAX-8升高与甲状腺功能减退的发生呈正相关（OR=9.702、OR=3.930，P=0.020、P=0.046）。结论：乳腺癌术后放疗引起的甲状腺功能异常主要表现为甲状腺功能减退;乳腺癌术后锁骨上区野放疗显著增加患者甲状腺功能减退的发生率;而在乳腺癌术后锁骨上区野放疗后甲状腺功能减退的患者中，甲状腺转录因子TTF-1和PAX-8的血清水平显著增高。

关键词: 乳腺癌, 放疗, 锁骨上区放疗野, 甲状腺转录因子, 甲状腺功能异常

Abstract:

Background and purpose: Thyroid dysfunction can frequently be discovered in breast cancer patients during long-term follow-up after receiving post-operative radiation therapy (PORT). This study aimed to compare serum levels of thyroid transcription factors (TTFs) TTF-1 and paired box 8 (PAX-8) before and after PORT in breast cancer patients, combined with the results of serological thyroid indicators tests, and to analyze the relationship between the changes in serum levels of these two kinds of TTFs and thyroid dysfunction after breast cancer PORT. Methods: Female breast cancer patients without thyroid disease records who received PORT in Department of Radiation Oncology, Shanghai Ninth People’s Hospital Huangpu Branch, Shanghai Jiao Tong University School of Medicine from Jan. 2022 to Jun. 2022 were prospectively selected, and were divided into two groups according to being with or without supraclavicular radiation field. All the patients had given informed consent before joining the study. The study design was approved by the ethic committee of our hospital (Ethic Approval No. 2021-KY-2). Serum levels of TTF-1 and PAX-8, serological thyroid indicators [triiodothyronine (T3), tetraiodothyronine (T4), free triiodothyronine (FT3), free tetraiodothyronine (FT4), thyroid stimulating hormone (TSH) and thyroid peroxidase antibody (TPO-Ab)] were recorded before PORT, at the end of PORT, 6, 12 and 24 months after the end of PORT, respectively. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist was followed for this study. Results: Eighty patients were enrolled in this study (40 in each group). A total of 19 patients who had hypothyroidism were divided in two groups, 15 in supraclavicular field group (SC group) and 4 in non-supraclavicular field group (NSC group), respectively (P=0.004). Levels of TTF-1 [5.70 (5.11, 7.13) vs 6.68 (5.15, 7.57), P=0.296] and PAX-8 (5.26±1.01 vs 5.66±1.37, P=0.149) did not show statistically significant deference between two groups before PORT. In SC group, levels of TTF-1 and PAX-8 gradually rose in 12 months after the end of PORT. In NCS group, levels of TTF-1 and PAX-8 did not change significantly during 24 months after the end of PORT. Test results of serum TTF-1 between two groups were statistically different at 6 months [6.99 (4.73, 13.94) vs 5.79 (5.01, 6.28), P=0.049], 12 months [7.65 (5.02, 17.85) vs 5.43 (4.52, 6.22), P=0.005] after the end of PORT, while test results of serum PAX-8 between two groups were statistically different at 12 months [6.79 (4.86, 14.30) vs 5.81 (4.70,7.25), P=0.042] after the end of PORT. The median values of TTF-1 and PAX-8 test results at 12 months after the end of PORT in SC group which were both significantly higher compared with NSC group were selected as the referent thresholds. Patients in SC group whose test results were higher than referent thresholds were defined as TTF-1/PAX-8 elevating subgroups, and patients whose test results under the threshold defined as TTF-1/PAX-8 normal subgroups. The incidences of hypothyroidism were higher in elevation subgroups than in normal subgroups (65.0% vs 10.0%, 60.0% vs 15.0%, respectively, P=0.001, P=0.008, respectively). Positive correlations were observed between the elevation of TTF-1/PAX-8 at 12 months after the end of PORT and hypothyroidism after breast cancer supraclavicular field radiation (OR=9.702, 3.930, and P=0.020, 0.046, respectively) according to multivariate analysis. Conclusion: Thyroid dysfunction after breast cancer PORT was mainly manifested with hypothyroidism; supraclavicular field radiation may significantly increase the incidence of hypothyroidism; serum levels of TTF-1 and PAX-8 elevated obviously in breast cancer PORT patients who had hypothyroidism after receiving supraclavicular field radiation.

Key words: Breast cancer, Radiation therapy, Supraclavicular field, Thyroid transcription factor, Thyroid dysfunction

陈刚, 张顺康, 郭绍文, 卢月, 孙丽云, 沈磊, 汪成. 血清TTF-1、PAX-8与乳腺癌术后放疗后甲状腺功能异常的相关性队列研究[J]. 中国癌症杂志, 2024, 34(12): 1100-1107.

CHEN Gang, ZHANG Shunkang, GUO Shaowen, LU Yue, SUN Liyun, SHEN Lei, WANG Cheng. Cohort study on correlation between serum TTF-1, PAX-8 and thyroid dysfunction after breast cancer post-operative radiation therapy[J]. China Oncology, 2024, 34(12): 1100-1107.

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参考文献 17

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Applications and reagents	Manufacturer (brand)	Model number (lot number)
PAX-8 reagent	Proteintech	10336-1-AP
TTF-1 reagent	Proteintech	21777-1-AP
Microplate reader	Biotek	H1M
HRP color reagent kit	PERFEMIKER	PM11239
HRP seondary antibodies	Proteintech	PR30011
ELISA plate	YEASEN	83650ES03

Item	SC group (n=40)	NSC group (n=40)
T3 decreased	3	1
T4 decreased	4	2
FT3 decreased	2	0
FT4 decreased	8	1
TSH increased	15	4
TPO-Ab increased	13	2

Item	TTF-1 (unit: pg/10 μL)			PAX-8 (unit: pg/10 μL)
Item	SC group	NSC group	P value^*	SC group	NSC group	P value^*
Before PORT	5.70(5.11, 7.13)	6.68(5.15, 7.57)	0.296	5.26±1.01	5.66±1.37	0.149^#
At the end of PORT	6.37(5.26, 8.64)	6.01(5.26, 6.60)	0.181	5.28±1.24	5.76±1.40	0.105^△
6 months after the end of PORT	6.99(4.73, 13.94)	5.79(5.01, 6.28)	0.049	5.45(4.69, 8.37)	6.52(4.45, 7.74)	0.665^*
12 months after the end of PORT	7.65(5.02, 17.85)	5.43(4.52, 6.22)	0.005	6.79(4.86, 14.30)	5.81(4.70, 7.25)	0.042^*
24 months after the end of PORT	6.22(4.84, 9.00)	5.34(4.88, 5.86)	0.108	5.22(4.78, 6.40)	5.77(4.36, 6.84)	0.900^*

Item	Hypothyroidism		P value
Item	Yes	No	P value
Age/year			0.673^#
≤54	5	10
>54	10	15
Operation style			0.715*
BCS	3	7
MRM	12	18
TTF-1			0.001^*
Increased	13	7
Normal	2	18
PAX-8			0.008^*
Increased	12	8
Normal	3	17