BRAFV600E突变与甲状腺乳头状癌侵袭性及131I治疗疗效的相关性分析

Correlation analysis between BRAFV600E mutation and invasiveness of papillary thyroid carcinoma with efficacy of 131I therapy

  • 摘要:
    目的  探讨B-Raf原癌基因丝氨酸/苏氨酸蛋白激酶(BRAF)V600E基因突变与甲状腺乳头状癌(PTC)临床特征的相关性,并评估其对131I治疗疗效的预后预测价值。
    方法 回顾性分析2018年4月至2023年4月在天津医科大学总医院接受131I治疗的291例PTC患者的临床资料,其中男性100例、女性191例,年龄(43.4±12.8)岁,范围18~74岁。根据BRAFV600E基因检测结果将患者分为突变型组和野生型组。参照美国癌症联合会第八版肿瘤、淋巴结、转移分期系统对患者进行病理分期及年龄分组。参照《131I治疗分化型甲状腺癌指南(2021版)》,将疗效评估结果分为疗效满意(ER)、疗效不确切(IDR)、生化疗效不佳(BIR)、结构性疗效不佳(SIR),分别在治疗后半年至1年(短期)、3年(中期)、5年(长期)3个时间点进行疗效评价。计量资料的组间比较采用两独立样本t检验或Mann-Whitney U检验,多组间比较采用单因素方差分析或Kruskal-Wallis H检验。计数资料的组间比较采用χ2 检验。采用多因素Logistic回归模型分析BRAFV600E基因突变及PTC患者131I治疗疗效的影响因素。
    结果 突变型组225例(77.3%,225/291)、野生型组66例(22.7%,66/291)。突变型组较野生型组男性比例更高(38.2%对21.2%,χ2=6.55,P=0.007),脉管癌栓发生率更低(1.8%对10.6%,χ2=10.94,P=0.001)。野生型组N分期更高(68.2%对43.1%,χ2=15.41,P<0.001),远处转移率更高(9.1%对0.4%,χ2=16.25,P=0.001)。131I治疗后1年疗效评价结果显示,突变型组与野生型组达到ER、BIR、SIR、IDR比例的差异有统计学意义(71.1%对62.1%、8.9%对7.6%、3.1%对12.1%、16.9%对18.2%,χ2=8.79,P=0.032)。多因素Logistic回归模型分析结果显示,性别是BRAFV600E基因突变的独立影响因素,男性发生BRAFV600E基因突变的概率是女性的2.298倍(OR=2.298,95%CI:1.201~4.395,P=0.012)。半年疗效评价:131I治疗与手术的时间间隔每增加1个月,达到SIR(相较于ER)的风险增加8.1%(OR=1.081,95%CI:1.014~1.153;P=0.017)。3年疗效评价:年龄每增加1岁,达到BIR(相较于ER)的风险增加16.2% (OR=1.162,95%CI:1.001~1.349;P=0.048)。
    结论 BRAFV600E基因突变仅与性别相关(男性风险更高),是其独立危险因素,与PTC侵袭性增强及131I治疗疗效降低无明确相关性。年龄是影响中期(3年)疗效的关键因素。在手术伤口愈合良好的情况下,应缩短131I治疗与手术的时间间隔以优化短期(半年)疗效。

     

    Abstract:
    Objective To investigate the correlation between the B-Raf proto-oncogene, serine/threonine protein kinase (BRAF)V600E gene mutation and the clinical characteristics of papillary thyroid carcinoma (PTC) and evaluate its prognostic value in predicting the efficacy of 131I therapy.
    Methods A retrospective analysis was conducted on the clinical data of 291 patients with PTC who underwent 131I therapy at Tianjin Medical University General Hospital between April 2018 and April 2023. The patients included 100 males and 191 females, with an age of (43.4±12.8) years, ranging from 18 to 74 years. Patients were divided into mutation and wild-type groups on the basis of BRAFV600E gene test results. Pathological staging and age grouping were performed in accordance with the eighth edition of the tumor, node, metastasis staging system of the American Joint Committee on Cancer. According to the Guidelines for 131I Therapy of Differentiated Thyroid Cancer (2021 Edition), treatment response was categorized as excellent response (ER), indeterminate response (IDR), biochemical incomplete response (BIR), structural incomplete response (SIR), and assessed at three time points: half a year to one year (short term), three years (midterm), and five years (long term). Comparisons of measurement data between groups were performed by using the independent samples t-test or Mann-Whitney U test, whereas comparisons among multiple groups were conducted by utilizing one-way ANOVA or the Kruskal-Wallis H test. Count data were compared by applying the chi-squared test. A multivariate Logistic regression model was employed to analyze the influence of the BRAFV600E mutation and other factors on the efficacy of 131I therapy in patients with PTC.
    Results The mutation group comprised 225 patients (77.3%, 225/291), and the wild-type group comprised 66 patients (22.7%, 66/291). Compared with the wild-type group, the mutation group had a significantly higher proportion of males (38.2% vs. 21.2%, χ2=6.55, P=0.007) and a lower incidence of vascular tumor thrombus (1.8% vs. 10.6%, χ2=10.94, P=0.001). The wild-type group was associated with a higher N stage (68.2% vs. 43.1%, χ2=15.41, P<0.001) and a higher distant metastasis rate (9.1% vs. 0.4%, χ2=16.25, P=0.001) than the mutation group. In the one-year response assessment after 131I therapy, a comparison between the mutation and wild-type groups showed a statistically significant difference in ER, BIR, SIR, and IDR rates (71.1% vs. 62.1%, 8.9% vs. 7.6%, 3.1% vs. 12.1%, 16.9% vs. 18.2%; χ2=8.79, P=0.032). Multivariate Logistic regression model analysis revealed that gender is an independent influencing factor for the BRAFV600E gene mutation, the probability of harboring a BRAFV600E mutation was 2.298 times higher in males than in females (OR=2.298, 95%CI: 1.201–4.395, P=0.012). Half-year treatment response assessment: for each one-month increase in the time interval between surgery and 131I therapy, the risk of achieving SIR (compared with ER) increased by 8.1% (OR=1.081, 95%CI: 1.014–1.153; P=0.017). Three-year trestment response assessmengt: for each one-year increase in age, the risk of achieving BIR (compared with ER) increased by 16.2% (OR=1.162, 95%CI: 1.001–1.349; P=0.048).
    Conclusions The BRAFV600E gene mutation was correlated only with gender (higher risk in males) and was an independent risk factor for PTC. It lacked a significant correlation with enhanced PTC invasiveness or reduced 131I therapy efficacy. Age was a key determinant of midterm (three years) treatment response. The interval between surgery and 131I therapy should be shortened, provided that the surgical wound has healed adequately, to optimize short term (half a year) efficacy.

     

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