摘要
目的:探索雄激素受体(androgen receptor,AR)、S期激酶相关蛋白2(S-phase kinase-associated protein 2,SKP2)、性别决定区Y相关的HMG盒含因子10(sry-related HMG box-containing factor 10,SOX10)、程序性死亡配体1(programmed death-ligand 1,PD-L1)及肿瘤浸润性淋巴细胞(tumor infiltrating lymphocyte,TIL)在三阴性乳腺癌(triple negative breast cancer,TNBC)表达与临床病理特征和预后的关系。方法:根据苏木精-伊红染色(hematoxylineosin, HE)染色切片评判109例TNBC瘤巢内TIL的比例,采用Leica Bond-Max全自动免疫组化仪检测TNBC组织中AR、SKP2、SOX10、PD-L1的表达。分析以上各生物指标与临床病理特征间的关系,并采用kaplan-Meier、Log-rank进行生存分析。结果:95例患者获得随访,中位随访时间为48个月,中位无病生存时间(disease-free survival, DFS)为42个月,中位总生存时间(overall survival, OS)48个月。在TNBC中,AR阳性表达与淋巴结转移阴性(P=0.009)、肿瘤最大径<2 cm(P=0.008)相关,TIL高表达与低级别TNBC相关(P=0.007),SKP2阳性表达与神经/脉管侵犯阳性(P=0.011)、高级别TNBC相关(P=0.002),SOX10阳性表达与淋巴结转移阳性(P=0.022)、高级别TNBC(P=0.005)相关,PD-L1阳性表达与淋巴结转移阳性(P=0.020)、神经/脉管侵犯阳性(P=0.006)、高级别TNBC(P=0.042)相关。生存分析显示,SKP2、SOX10阳性表达与更差的DFS(P=0.007、P<0.001)和OS(P=0.013、P<0.001)相关,TIL高表达与更好的DFS(P=0.016)及OS(P=0.004)相关。在生物表志物的联合表达中,AR+/SKP2-、AR+/SOX10-与更好的DFS(P=0.004、P<0.001)及OS(P=0.007、P=0.001)相关,SOX10+/低TIL、PD-L1+/低TIL与更差的DFS(P<0.001、P=0.008)及OS(P=0.001、P=0.002)相关,AR-/低TIL者具有更差的OS(P=0.014)。SKP2(HR=4.143,95%CI为1.578~10.875)、SOX10(HR=7.578,95%CI为2.067~27.782)的阳性表达是影响TNBC患者DFS的独立预后因子,SKP2(HR=3.758,95%CI为1.400~10.084)、SOX10(HR=5.131,95%CI为1.316~20.000)及TIL(HR=0.375,95%CI为0.154~0.917)的阳性表达是TNBC患者OS的独立预后因子(P均<0.05)。结论:在TNBC中,AR阳性、TIL高表达与具有更好预后的临床病理特征相关,SKP2、SOX10和PD-L1与具侵袭性的临床病理特征相关。SKP2、SOX10及TIL表达与TNBC预后相关,提示这些生物指标可能成为TNBC新的预后因子,同时它们也有可能成为潜在的治疗靶点。
Objective To explore the expression of androgen receptor(AR),S-phase kinase associated protein 2(SKP2),Sry-related HMG box-containing factor 10(SOX10),programmed death-ligand 1(PD-L1)and tumor infiltrating lym-phocytes(TILs)in triple-negative breast cancer(TNBC)and their relationships with clinical prognosis.Methods The pro-portion of TILs in 109 TNBCs was assessed on Hematoxylin-eosin stained sections,and Leica Bond-Max automatic immu-nohistochemistry apparatus was used to detect the expressions of AR,SKP2,SOX10 and PD-L1 in TNBC tissue.The rela-tionship between the above indicators and clinicopathological charactersitics was analyzed.Univariate survival analysis was performed by Kaplan-Meier,and survival by Log rank test.Multivariate survival analysis was performed by cox regres-sion model.Results A total of 95 patients were followed-up with a median follow-up time of 48 months.For 95patients,the median disease-free survival(DFS)time was 42 months,and median overall survival(OS)time were 48 months.In TNBC,the expression of AR was associated with negative lymph node metastasis,maximum tumor diameter<2 cm.High expres-sion of TILs was associated with low grade TNBC.The expression of SKP2 was associated with positive nerve/vasculature invasion and high grade TNBC.The expression of SOX10 was associated with high grade TNBC and positive lymph node metastasis.The expression of PD-L1 was associated with positive lymph node metastasis,positive nerve/vascular invasion,and high grade TNBC(all the P<0.05 as above).Survival analysis demonstrated that the positive expression of SKP2 or AR SOX10 was correlated with worse DFS(P=0.007、P<0.001)and OS(P=0.013、P<0.001),and patients with high expression of TILs showed better DFS(P=0.016)and OS(P=0.004).TNBC patients with AR+/SKP2-or AR+/SOX10-had better DFS(P=0.004、P<0.001)and OS(P=0.007、P<0.001),while those with SOX10+/low TILs or PD-L1+/low TILs had worse DFS(P=0.000、P=0.008)and OS(P=0.001、P=0.002),and AR-/low TILs had worse OS(P=0.014).Multivariate survival analy-sis showed positive expression SKP2(HR=4.143,95%CI 1.578-10.875),or SOX10(HR=7.578,95%CI 2.067-27.782)were independent prognostic factors for worse DFS,postive expression SKP2(HR=3.758,95%CI 1.400-10.084),or SOX10(HR=5.131,95%CI 1.316-20.000),were independent prognostic factors for worse OS(all the P<0.05 as above)and higher TILs(HR=0.375,95%CI 0.154-0.917)was independent prognostic factors for better OS(all the P<0.05 as above).Conclu-sions High expression of AR and TILs in TNBC indicate better prognosis,while SKP2,SOX10 and PD-L1 expression dem-onstrate more aggressive clinicopathological features in TNBC.The expression of SKP2,SOX10 and TILs in TNBC are asso-ciated with prognosis,suggesting that these indicators may serve as new prognostic factors and potential therapeutic targets in TNBC.
作者
刘娟
殷丽娟
范德生
LIU Juan;YIN Lijuan;FAN Desheng(Department of Pathology,Baoshan Branch of Shuguang Hospital,Shanghai University of Traditional Chinese Medicine,Hospital of Traditional Chinese and Western Medicine of Baoshan,Shanghai 201900,China;Department of Pathology,First affiliated hospital,The Navy Military Medical University,Shanghai 200433,China)
出处
《诊断学理论与实践》
2024年第2期162-172,共11页
Journal of Diagnostics Concepts & Practice
基金
上海市宝山区医学重点专科项目(BSZK-2023-BP06)
上海市宝山区卫生健康系统优秀学科带头人培养计划(BSWSYX-2024-4)。
