乳腺癌原发灶与肝转移灶受体表达差异研究

Receptor discordance between primary breast cancer and liver metastases

背景与目的:雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)的表达情况是决定乳腺癌全身系统治疗方案的重要依据。有研究发现一定比例的乳腺癌患者原发灶与远处转移之间存在ER、PR和HER2的表达差异。肝脏是乳腺癌转移主要的靶器官之一,目前有关乳腺癌肝转移受体转变的研究数据较少。本研究旨在探讨乳腺癌原发灶与肝转移灶之间受体状态变化的发生率、影响因素及对患者预后的影响。方法:回顾性收集2013年1月—2020年5月在复旦大学附属肿瘤医院经病理学检查确诊为乳腺癌肝转移的患者资料,最终纳入353例原发灶和配对肝转移灶均完整记录ER、PR和HER2表达情况的患者。根据美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)/美国病理学家协会(College of American Pathologists,CAP)指南对受体状态进行分析。用桑基图说明受体状态和分子分型在乳腺癌原发灶和肝转移灶之间的转变;采用Kappa一致性检验和配对χ2检验分析原发灶和转移灶受体表达情况的一致性。绘制Kaplan-Meier生存曲线,采用log-rank检验比较组间差异。基于COX比例风险回归模型进行多因素生存分析。结果:在所有患者中,ER、PR和HER2在原发灶与肝转移灶间的不一致率分别为19.5%、39.4%和4.8%,对应的Kappa值分别为0.569、0.258和0.876。在初治Ⅳ期患者中,ER、PR和HER2的不一致率分别为15.2%、28.3%和2.2%。多因素分析结果表明,仅有PR状态改变受到内分泌治疗的影响。在感兴趣的变量中未发现与ER、HER2不一致相关的因素。原发灶HER2零表达的患者有37.9%在肝转移灶中呈现为HER2低表达。肝转移灶更多呈现为三阴性型,更少表现为激素受体(hormone receptor,HR)+/HER2-型。对于预后来说,在原发灶为HR+/HER2-的患者中,肝转移灶转变为三阴性型的患者比维持原分型的患者总生存期(overall survival,OS)显著更短。当肝转移灶分子分型相同时,无论原发灶状态如何,OS不受影响。结论:乳腺癌原发灶与肝转移灶之间存在ER、PR、HER2表达的异质性,患者的远期预后主要受肝转移灶的分子分型影响,而非原发灶。伴有肝转移的初治Ⅳ期患者同样有必要联合肝脏病灶穿刺活检;超过1/3的HER2零表达患者在肝转移中转变为HER2低表达,这部分患者有必要再次穿刺活检以获得新型抗体药物偶联物(antibody-drug conjugate,ADC)类药物治疗的机会。

Background and purpose:Systematic treatment for breast cancer largely depends on the status of estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor 2(HER2).Discordance in ER,PR and HER2 status between primary breast cancer and distant metastases has been observed in a proportion of patients in previous studies.Liver is one of the frequent metastatic sites of breast cancer.Currently,limited data are available on the receptor conversion between primary breast cancer and matched liver metastases.This study aimed to investigate the prevalence,risk factors and prognostic impact of receptor conversion between primary breast cancer and paired liver metastases.Methods:The data of breast cancer patients who had pathologically confirmed liver metastases from January 2013 to May 2020 at Fudan University Shanghai Cancer Center were retrospectively collected.A total of 353 patients with ER,PR and HER2 status available on both primary breast cancer and matched liver metastases were finally included in this study.ER,PR and HER2 status were interpreted according to the most updated American Society of Clinical Oncology(ASCO)/College of American Pathologists(CAP)guidelines.The evolution of receptor status and phenotype from primary to metastatic breast cancer was illustrated using Sankey diagrams.Kappa coefficient and McNemar’s test were used to assess the agreement on receptor status between primary breast cancer and liver metastases.The Kaplan-Meier curves were plotted and survival differences across each group were assessed by log-rank test.Multivariate analyses were performed based on the COX proportional hazard regression model.Results:The total discordance rate of ER,PR and HER2 was 19.5%,39.4%and 4.8%,respectively(Kappa coefficient:0.569,0.2580.876).In de novo stageⅣpatients,the discordance rate of ER,PR and HER2 was 15.2%,28.3%and 2.2%,respectively.Multivariate analysis showed that previous endocrine therapy before liver re-biopsy was an independent risk factor of PR discordance.None of the variables of interest was found to be associated with discordance in ER or HER2 status.Additionally,37.9%of the HER2-0 tumors converted to HER2-low.A trend of increase in triple-negative and decrease in hormone receptor(HR)+/HER2-cases were observed in liver metastases.Patients with HR+/HER2-primary breast cancer who converted to triple-negative in liver metastases had a significantly shorter overall survival(OS)than those with consistent HR+/HER2-subtype.Patients with the same subtype in liver metastases shared similar OS.Conclusion:This study confirmed discordance in ER,PR and HER2 status between primary breast cancer and liver metastases.The prognosis of breast cancer patients was determined mainly by the subtype in metastases rather than that in primary disease.Our study underlined the necessity of liver re-biopsy in de novo stageⅣpatients with liver metastases.Over one-third of HER2-0 patients converted to HER2-low in liver metastases after reassessment,which enabled them to be treated with new antibody-drug conjugate(ADC).