Kurebayashi Junichi, Kanomata Naoki, Yamashita Tetsumasa, Shimo Toshiro, Mizutoh Akiko, Moriya Takuya, Sonoo Hiroshi
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan,
Breast Cancer. 2015 May;22(3):292-9. doi: 10.1007/s12282-013-0478-y. Epub 2013 Jun 8.
Adjuvant trastuzumab has been routinely used in HER2-positive operable breast cancer patients. Prognostic factors remain to be well characterized in these patients and might correlate with primary and/or acquired resistance to trastuzumab.
The study subjects were 78 HER2-positive operable breast cancer patients treated with adjuvant chemotherapy followed by 1-year trastuzumab between 2005 and 2010 in our institute. All breast tumors showed a HercepTest score of 3+ or that of 2+ and positive fluorescence in situ hybridization. Expression levels of HER1, phosphorylated HER2 (pY1248), HER3, HER4, and p53 were assessed by immunohistochemistry. Prognostic factors were investigated with univariate and multivariate analyses using the Kaplan-Meier/log-rank test and Cox proportional hazards model, respectively.
The median age and follow-up period of the patients were 54 years and 39 months, respectively. The mean tumor size was 2.1 cm and the node-positive rate was 42 %. Eight patients had recurrent diseases but no patient died of cancer. Univariate analysis revealed that pHER2 positivity was only a significantly worse prognostic factor for relapse-free survival (RFS) (P = 0.049). A HercepTest score of 2+ and high expression level of p53 showed a trend. Multivariate analysis revealed three biological markers: pHER2 positivity [hazard ratio (HR) = 11.6, 95 % confidence interval (CI) 1.3-111.1, P = 0.031], p53 positivity (HR = 6.4, 95 % CI 1.0-40.0, P = 0.047) and a HercepTest score of 2+ (HR = 8.6, 95 % CI 1.6-45.2, P = 0.011) to be worse prognostic factors for RFS. Notably, three out of five patients with breast tumors expressing HER2 at a score of 2+ and pHER2 had recurrent diseases. Interestingly, the expression level of pHER2 significantly correlated with the expression levels of HER2 and HER3 in HER2-positive breast tumors.
This retrospective cohort study suggests that a lower expression level of HER2 and high expression levels of pHER2 and p53 may indicate a worse prognosis in HER2-positive breast cancer patients treated with trastuzumab and chemotherapy. Further studies are needed to evaluate pHER2 expression in HER2-positive breast cancer as a prognostic and/or predictive marker.
辅助性曲妥珠单抗已常规用于HER2阳性的可手术乳腺癌患者。这些患者的预后因素仍有待充分明确，并且可能与对曲妥珠单抗的原发性和/或获得性耐药相关。
研究对象为2005年至2010年期间在我院接受辅助化疗后再接受1年曲妥珠单抗治疗的78例HER2阳性可手术乳腺癌患者。所有乳腺肿瘤的HercepTest评分为3+或2+且荧光原位杂交呈阳性。通过免疫组织化学评估HER1、磷酸化HER2（pY1248）、HER3、HER4和p53的表达水平。分别使用Kaplan-Meier/对数秩检验和Cox比例风险模型通过单因素和多因素分析来研究预后因素。
患者的中位年龄和随访时间分别为54岁和39个月。平均肿瘤大小为2.1cm，淋巴结阳性率为42%。8例患者出现疾病复发，但无患者死于癌症。单因素分析显示，pHER2阳性仅是无复发生存期（RFS）的一个显著更差的预后因素（P = 0.049）。HercepTest评分为2+和p53高表达呈一种趋势。多因素分析显示三个生物学标志物：pHER2阳性[风险比（HR）= 11.6，95%置信区间（CI）1.3 - 111.1，P = 0.031]、p53阳性（HR = 6.4，95% CI 1.0 - 40.0，P = 0.047）和HercepTest评分为2+（HR = 8.6，95% CI 1.6 - 45.2，P = 0.011）是RFS更差的预后因素。值得注意的是，五分之三的HER2评分为2+且pHER2表达的乳腺肿瘤患者出现了疾病复发。有趣的是，在HER2阳性乳腺肿瘤中，pHER2的表达水平与HER2和HER3的表达水平显著相关。
这项回顾性队列研究表明，HER2低表达以及pHER2和p53高表达可能提示接受曲妥珠单抗和化疗的HER2阳性乳腺癌患者预后更差。需要进一步研究来评估HER2阳性乳腺癌中pHER2的表达作为一种预后和/或预测标志物的情况。
