218例女性乳腺癌患者行新辅助化疗及伴随分子标志物改变的临床价值

Significance of neoadjuvant chemotherapy and molecular marker changes in 218 women with breast cancer

目的探讨乳腺癌新辅助化疗(NAC)的临床价值及可能适用人群,以及NAC对雌激素受体(ER)、孕激素受体(PR)、表皮生长因子受体2(Her-2)及增殖细胞核抗原Ki-67分子标志物表达状态的影响及表达变化的预后价值。方法选取2009年1月至2017年12月就诊于山东大学齐鲁医院的女性乳腺癌患者2 928例,经纳入标准与排除标准筛选,最终纳入患者1 817例,使用COX回归分析NAC组与辅助化疗组年龄、初诊时肿瘤大小、初诊时淋巴结状态、是否绝经、淋巴结转移个数、分子分型的临床病理学指标对患者预后的影响;根据NAC对ER、PR、Her-2、Ki-67表达的影响,分析分子标志物改变的预后价值。结果与行辅助化疗相比,肿瘤≤5 cm、转移淋巴结个数≥4个及三阴性乳腺癌的患者行NAC生存获益最高;50~80岁、初诊时淋巴结为阴性、已绝经者及Her-2阳性型乳腺癌患者行NAC生存获益最低;20~49岁、肿瘤>5 cm、初诊时淋巴结为阳性、未绝经者、淋巴结转移个数<4个及Luminal型患者行NAC有高复发风险;NAC前后ER、PR、Ki-67的改变差异有统计学意义(P<0.05),Her-2的变化无统计学意义的关联(P=0.754)。NAC前后ER、PR、Her-2的改变与乳腺癌患者的OS及DFS无统计学意义的关联(P>0.05),Ki-67由低表达变为高表达患者与Ki-67表达稳定及降低患者相比,OS与DFS较差,差异有统计学意义(P<0.05)。结论可手术的乳腺癌患者并不一定均适合行NAC治疗,需根据患者年龄、肿瘤大小、淋巴结转移状态、分子分型等临床病理指标及保乳意愿综合判断生存获益。NAC可改变乳腺癌ER、PR及Ki-67的表达状态,Ki-67的表达变化可作为NAC疗效的有效预测因子。

Objective To explore the significance of neoadjuvant chemotherapy(NAC) in the treatment of breast cancer and to identify the possible applicable population, to investigate the effects of NAC on the expressions of estrogen receptor(ER), progesterone receptor(PR), human epidermal growth factor receptor 2(Her-2) and Ki-67, and to evaluate the prognostic value of such expression changes. Methods Clinical data of 2,928 female breast cancer patients treated in our hospital during Jan. 2009 and Dec. 2017 were retrospectively analyzed. After screening with inclusion and exclusion criteria, 1,817 cases were included. COX regression was used to analyze the effects of clinicopathological indicators on the prognosis of patients in NAC group and adjuvant chemotherapy group, including age, tumor size and lymph node status at initial diagnosis, menopause, number of lymph node metastasis, and molecular classification. According to the effects of NAC on the expressions of ER, PR, Her-2 and Ki-67, the prognostic value of the changes in these molecular markers was explored. Results In the NAC group, patients with tumor size ≤5 cm, metastatic lymph nodes ≥4 and triple negative breast cancer had the highest survival benefits, while patients aged 50-80 years, with negative lymph node at initial diagnosis, menopausal and Her-2 positive had the lowest survival benefits. Patients aged 20-49 years, with tumor size >5 cm, lymph node positive at initial diagnosis, premenopausal, metastatic lymph nodes <4, and Luminal type breast cancer were associated with high recurrence risk. There were significant differences in ER, PR and Ki-67 expressions before and after NAC(P<0.05), while there was no significant difference in Her-2(P=0.754). There was no significant correlation between the changes of ER, PR and Her-2 before and after NAC with overall survival(OS) and disease-free survival(DFS)(P>0.05). Compared with patients with stable and decreased expression of Ki-67, patients with low to high expression of Ki-67 had poorer survival benefits(P<0.05). Conclusion NAC is not suitable for all patients with operable breast cancer. Survival benefits should be evaluated comprehensively based on patients’ age, tumor size, lymph node metastasis status, molecular typing and other pathological indicators as well as breast preservation willingness. NAC can change the expressions of ER, PR and Ki-67 in breast cancer, and the expression of Ki-67 can be considered as a predictive marker of the effects of NAC.