人表皮生长因子受体2低表达乳腺癌的临床病理学特征及预后

Clinicopathological features and prognosis of breast cancer with human epidermal growth factor receptor 2 low expression

目的:新型抗人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)抗体偶联药物临床试验的成功,使HER2低表达乳腺癌是否将成为新的乳腺癌类型而受到关注。本研究分析比较HER2低表达与HER2零表达两组乳腺癌患者间的临床病理特征及生存数据,探讨其临床生物学上的差异性。方法:2014年1月至2017年12月北京大学第一医院乳腺疾病中心收治的1250例女性原发性非转移性乳腺癌中,969例HER2阴性(免疫组织化学染色评分为0、1+、2+,且荧光原位杂交未扩增),分析其中HER2低表达(1+或2+且荧光原位杂交未扩增)和HER2零表达(0分)两组患者间临床病理特征及预后情况。对两组患者进行无病生存期(disease free survival,DFS)和总生存期(overall survival,OS)预后评价,采用Kaplan-Meier曲线计算生存率,Log-rank检验比较生存差异,单因素和多因素Cox回归分析预后影响因素。采用双侧检验,P<0.05为差异有统计学意义。结果:969例HER2阴性乳腺癌中,HER2低表达者606例(62.54%)、HER2零表达者363例(37.46%)。与HER2零表达组相比,HER2低表达组的N分期(P=0.001)和TNM分期更高(P=0.044),非特殊型组织学类型占比(82.7%vs.79.1%,P=0.009)和组织学分级更高(P=0.048),激素受体阳性率偏高(83.2%vs.75.2%,P=0.003),Ki-67增殖指数>30%者的比例偏低(30.4%vs.36.6%,P=0.044)。两组间DFS及OS差异无统计学意义(P>0.05)。969例患者中,激素受体阳性777例,激素受体阴性(即三阴性乳腺癌)192例。激素受体阳性的777例中,HER2低表达504例(64.9%),HER2零表达273例(35.1%),两组比较,HER2低表达组的发病年龄小(P=0.016),未绝经者占比高(P=0.029),淋巴结受累更多(P=0.002),TNM分期更高(P=0.031),小叶癌和黏液癌组织学类型较少见(3.6%vs.7.3%,4.8%vs.10.6%,P<0.001),DFS和OS差异无统计学意义(P>0.05)。192例激素受体阴性(三阴性乳腺癌)中,HER2低表达102例(53.1%),HER2零表达90例(46.9%),两组比较,HER2低表达组的发病年龄大(P=0.001),未绝经所占比例低(P=0.029),组织学分级更低(P<0.001),Ki-67增殖指数更低(P<0.001),雄激素受体阳性率高(58.8%vs.34.4%,P<0.001),DFS比较好(P=0.038),OS差异无统计学意义(P>0.05)。结论:HER2低表达乳腺癌占所有乳腺癌约一半的比例,发病远高于HER2阳性乳腺癌,其临床病理特征存在异质性,激素受体表达状态对HER2低表达乳腺癌的临床生物学有影响。

Objective:There is an increasing interest in human epidermal growth factor receptor 2(HER2)low expression breast cancer with the result of novel anti-HER2 antibody-drug conjugates for breast cancer.HER2 low expression breast cancer is expected to become a new type of breast cancer.This study analyzed and compared the clinicopathological features and survival data of breast cancer with HER2 low expression group[immunohistochemistry(IHC)1+or IHC 2+,and fluorescence in situ hybridization(FISH)negative]and HER2 zero expression group(IHC 0),in order to explore the difference in clinical biology of HER2 low expression breast cancers.Methods:Among 1250 female patients with primary non-metastatic breast cancer admitted to the Breast Disease Center of Peking University First Hospital from January 2014 to December 2017,969 cases were HER2 negative(IHC 0,1+,2+,and FISH was not amplified).The clinicopathologic features and prognosis of the patients with HER2 low expression(IHC 1+or 2+,and unamplified by FISH)and HER2 zero expression(IHC 0)were analyzed.Disease free survival(DFS)and overall survival(OS)were evaluated,survival rates were calculated by Kaplan-Meier curve,and survival differences were compared by Log-rank test.Cox regression analysis of univariate and multivariate prognostic factors.Bilateral test was used,and P<0.05 was considered statistically significant.Results:In the 969 patients with HER2 negative breast cancer,606 had HER2 low expression(62.54%)and 363 had HER2 zero expression(37.46%).Compared with breast cancer with HER2 zero expression,those with HER2 low expression had higher N stage(P=0.001)and TNM stage(P=0.044),the proportion of non-specific histological types was higher(82.7%vs.79.1%,P=0.009),the histological grade was higher(P=0.048),and the positive rate of hormone receptor was higher(83.2%vs.75.2%,P=0.003).The percentage of Ki-67 value index>30%was lower(30.4%vs.36.6%,P=0.044).There was no significant difference in DFS and OS between the two groups(P>0.05).In the 969 cases,777 were hormone receptor positive and 192 were hormone receptor negative(triple negative cancer).Among the 777 cases with hormone receptor positive,504(64.9%)were HER2 low expression,and 273(35.1%)were HER2 zero expression.Compared with breast cancer with HER2 zero expression group,the HER2 low expression group had a younger age(P=0.016),a higher proportion of premenopausal patients(P=0.029),more lymph node involvement(P=0.002),and a higher total TNM stage(P=0.031),and less frequent histological types of lobular and mucinous carcinoma(3.6%vs.7.3%,4.8%vs.10.6%,P=0.001).There was no difference in DFS and OS between HER2 low expression and zero expression(P>0.05).Among 192 patients with hormone receptor negative,there were 102 cases(53.1%)with HER2 low expression and 90 cases(46.9%)with HER2 zero expression.Compared with the HER2 zero expression groups,HER2 low expression group was older(P=0.001),the proportion of premenopausal patients was low(P=0.029),the histological grade was lower(P<0.001),the Ki-67 value index was lower(P<0.001),and androgen receptor positive rate was higher(58.8%vs.34.4%,P<0.001).DFS was better than HER2 zero expression group(P=0.038),but there was no difference in OS between the two groups(P>0.05).Conclusion:HER2 low expression breast cancer accounts for about half of all breast cancers,and the incidence is much higher than that of HER2 positive breast cancer.Its clinicopathologic features are heterogeneous,and the status of hormone receptor expression has an impact on the clinical biology of this group.