Tanioka M, Sakai K, Sudo T, Sakuma T, Kajimoto K, Hirokaga K, Takao S, Negoro S, Minami H, Nakagawa K, Nishio K
Department of Medical Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi, Hyogo, 673-8558, Japan,
Breast Cancer Res Treat. 2014 Oct;147(3):513-25. doi: 10.1007/s10549-014-3121-5. Epub 2014 Sep 9.
Several trials have confirmed that the pathological complete response (pCR) rates after neoadjuvant chemotherapy (NAC) are significantly lower in HER2-positive/ER-positive patients than in HER2-positive/ER-negative patients. To understand this phenomenon, we investigated the association between NAC resistance and CCND1, which is frequently overexpressed in ER-positive tumors. Pretreatment formalin-fixed tumor tissues were collected from 75 HER2-positive patients receiving NAC comprised anthracyclines, taxanes, and trastuzumab. Seventeen gene transcripts along with PIK3CA mutations were detected using MassARRAY (Sequenom, San Diego, CA). The gene expression levels were dichotomized according to the median values. The immunohistochemical expression of ER, PTEN, BCL-2, and cyclin D1 was scored. The relationship between the variables was assessed using the Spearman correlation. A logistic regression analysis was performed to detect predictors of pCR, which was defined as no invasive tumor in the breast or axilla. Forty-seven percent of the cases were ER-positive and 52 % (40/63 % in ER-positive/ER-negative) achieved a pCR. Among the ER-positive patients, the CCND1 gene expression level was 2.1 times higher than that in ER-negative patients and was significantly correlated with the expression of cyclin D1 protein. In a univariate analysis, a pCR was associated with high mRNA levels of ESR1, PGR, LMTK3, HER2, IGF1R, INPP4B, PDL-1, BCL-2, and CCND1 (P ≤ 0.05). In contrast, none of these genes were significantly correlated with a pCR among the ER-negative tumors and only EGFR was significantly correlated with a pCR. PIK3CA mutations or PTEN loss were not associated with a pCR in either group. After excluding ESR1 (r = 0.58), PGR (r = 0.64), and IGF1R (r = 0.59), the expressions of which were correlated with CCND1, a multivariate analysis revealed that CCND1 [P = 0.043; OR, 0.16] and HER2 [P = 0.012; OR, 11.2] retained its predictive value for pCR among ER-positive patients, but not among ER-negative patients. A High Level of CCND1 gene expression is a poor predictor of a pCR and provides a rationale for evaluating CDK4/6 inhibitors in HER2-positive/ER-positive breast cancer patients.
多项试验证实，新辅助化疗（NAC）后，HER2阳性/ER阳性患者的病理完全缓解（pCR）率显著低于HER2阳性/ER阴性患者。为了解这一现象，我们研究了NAC耐药性与CCND1之间的关联，CCND1在ER阳性肿瘤中经常过表达。从75例接受包含蒽环类、紫杉类和曲妥珠单抗的NAC的HER2阳性患者中收集治疗前福尔马林固定的肿瘤组织。使用MassARRAY（Sequenom，加利福尼亚州圣地亚哥）检测17种基因转录本以及PIK3CA突变。根据中位数将基因表达水平二分法分类。对ER、PTEN、BCL-2和细胞周期蛋白D1的免疫组化表达进行评分。使用Spearman相关性评估变量之间的关系。进行逻辑回归分析以检测pCR的预测因素，pCR定义为乳腺或腋窝无浸润性肿瘤。47%的病例为ER阳性，52%（ER阳性/ER阴性患者中的40/63%）达到pCR。在ER阳性患者中，CCND1基因表达水平比ER阴性患者高2.1倍，并且与细胞周期蛋白D1蛋白的表达显著相关。在单因素分析中，pCR与ESR1、PGR、LMTK3、HER2、IGF1R、INPP4B、PDL-1、BCL-2和CCND1的高mRNA水平相关（P≤0.05）。相比之下，在ER阴性肿瘤中，这些基因均与pCR无显著相关性，只有EGFR与pCR显著相关。PIK3CA突变或PTEN缺失在两组中均与pCR无关。在排除ESR1（r = 0.58）、PGR（r = 0.64）和IGF1R（r = 0.59）（其表达与CCND有关）后，多因素分析显示，CCND1[P = 0.043；OR，0.16]和HER2[P = 0.012；OR，11.2]在ER阳性患者中对pCR仍具有预测价值，但在ER阴性患者中则不然。CCND1基因的高水平表达是pCR的不良预测指标，并为评估HER2阳性/ER阳性乳腺癌患者中的CDK4/6抑制剂提供了理论依据。
