局部进展期乳腺癌雌、孕激素受体和HER2的表达与双周ET新辅助化疗疗效的相关性

Association of the expression of ER, PR, and HER2 in locally advanced breast cancer patients with the efficacy of epirubicin and paclitaxel(ET) biweekly neoadjuvant chemotherapy

背景与目的：新辅助化疗（neo-adjuvant chemotherapy,NAC）在局部进展期乳腺癌（locally advanced breast cancer,LABC）中的作用已经很明确,达到病理完全缓解者可提高生存率,因而,临床上能否找到可以预测新辅助化疗效果的指标显得日益重要。对于雌、孕激素受体（ER,PR）和人类表皮生长因子受体（HER2）表达与新辅助化疗疗效之间的相关性一直存在争论,至今尚未统一。近年研究提示缩短化疗间期实施密集化疗将有希望进一步提高疗效,因此,本研究中采用表柔比星（EPI）加紫杉醇（PTX）双周ET联合方案新辅助化疗治疗LABC,同时比较ER/PR、HER2表达与疗效的相关性。方法：将82例未经治疗的Ⅱb~Ⅲb期LABC患者入组双周ET联合新辅助化疗,其方案为EPI50mg/m^2,第1天,静脉注射;PTX175mg/m^2,第2天,静脉滴注3h,每2周重复1次,均接受3个周期化疗后评估,观察其疗效、不良反应以及比较ER/PR和HER2表达与疗效和预后的相关性。结果：肿瘤原发灶总有效率（RR）为85.4%,临床完全缓解（cCR）19.5%,部分缓解（PR）65.9%,病理完全缓解（pCR）12.2%。36.5%发生白细胞减少症（3-4级）,3.7%出现白细胞减少性发热,心脏毒性较轻微,有4例（4.9%）发生心脏毒性（1级）,1例发生心脏毒性（2级）,末梢周围神经损害44.9%,主要为1～2级,所有患者完成了3个周期化疗后接受手术。ER、PR表达分别与pCR呈明显相关性（P=0.017,P=0.004）,ER、PR阴性表达者pCR的概率明显大于阳性表达者。ER和PR双阴性者pCR的概率较ER和（或）PR阳性表达者有显著性增高（P=0.001）。HER2过表达者pCR率为27.3%,明显高于低表达者的6.7%（P=0.020）。结合分子亚型比较,三阴性组和HER2过表达组pCR明显高于LuminalA和LuminalB。获得pCR患者中,HER2过表达和无表达者的5年无病生存率（DFS）和总生存率（OS）差异无统计学意义,相反,在非pCR患者中,HER2过表达者DFS、OS却明显低于HER2无表达者。结论：双周ET联合方案在LABC的新辅助化疗中疗效显著,耐受性良好,ER、PR和HER状态能较好预测pCR,HER2过表达者提高了获得pCR患者的生存率,而未获得pCR的患者预后更差。

Background and purpose： The effectiveness of neoadjuvant chemotherapy （NAC） in locally advanced breast cancer （LABC） has been proved and that pathologic complete response （pCR） after NAC can improve survival, therefore, it is increasingly important to find relative factors to predict the effect of NAC. There has been much debate about the correlation between estrogen receptor （ER）, progestogen receptor （PR）, and human epidermal growth factor receptor （HER2） expression and the effect of NAC. Some studies suggested that shortening the interval of the chemotherapy would hopefully increase its effectiveness. Therefore, we used the biweekly regimen of epirubicin （EPI） and paclitaxel （PTX） for LABC and compared the relationship of EIUPR, HER2 expression and the effectiveness. Methods： Eighty-two untreated patients with Ⅱ b to Ⅲb stage LABC were enrolled into the study from Feb 2002 to Dec 2007. They received biweekly NAC described as below： EPI, 50 mg/m^2, dl, iv; PTX, 175 mg/m^2, d2, iv for three hours. Each patient was treated with three cycles of NAC. Results： Overall response rate （RR） was 85.4% including 19.5% clinical complete response （cCR）, and pathological complete response （pCR） was found in 10（12.2%） patients. The incidence rate of 3-4 grade leucopenia was 36.5%, including febrile neutropenia （3.7%）. The heart toxicity was slight, 4 （4.9%） patients had grade 1 heart toxicity, only 1 patient got grade 2 heart toxicity, peripheral nerve toxicity （44.9%） was common and most of them with grade 1-2. （The average tumor sizes before and after NAC were 5.4 and 1.8 cm, respectively. 9（20.5%） of 44 ER negative patients, 10（21.3%） of 47 PR negative and 6（27.3%） of 22 HER2 overexpression patients achieved pCR, which were higher than ER positive, PR positive, and HER2 low expression patients, respectively）. If pCR was achieved, patients with and without HER2 overexpression had similar survival. In contrast, patients without pCR had worse disease-free survival （DFS） and overall survival（OS） if they had HER2 overexpression, compared with low expression of HER2. Conclusion： The biweekly regimen of EPI and PTX was effective and well tolerated and high pCR rates were achieved in ER, PR negative, and HER2-overexpression patients. HER2 overexpression patients with pCR had excellent DFS and OS, compared with no pCR patients.