凋亡和增殖作为乳腺癌患者化疗反应的预测指标。

Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma.

作者信息

Chang J, Ormerod M, Powles T J, Allred D C, Ashley S E, Dowsett M

机构信息

Department of Biochemistry, Medicine and Computing, The Royal Marden Hospital, Sutton, Surrey, United Kingdom.

出版信息

Cancer. 2000 Dec 1;89(11):2145-52.

PMID:11147583

Abstract

BACKGROUND

Laboratory evidence suggests that many anticancer agents exert their effect by altering the ratio between apoptosis and cellular proliferation. The objective of this clinical study was to examine in vivo changes in apoptotic index (AI), Bcl-2 expression, proliferation (Ki-67 and S-phase fraction [SPF]), and ploidy as potential indicators of chemoresponsiveness.

METHODS

Twenty-eight women with primary operable breast carcinoma received 2M (mitoxantrone 11 mg/m2, methotrexate 35 mg/m2 every 3 weeks) for 4 cycles before surgery/radiotherapy, and an additional 2 cycles were given after surgery. Clinical response was assessed after four cycles of treatment according to World Health Organization criteria. Changes in molecular markers were assessed from biopsies obtained by fine-needle aspiration performed before treatment, repeated after 24 and/or 72 hours (T1), and on Days 7 and 21 after the first cycle of chemotherapy. Flow cytometric analysis was used to assess SPF, ploidy, and AI (in situ DNA nick end labeling assay) whereas Ki-67 and Bcl-2 were evaluated by immunocytochemical analysis.

RESULTS

The overall response rate was 61% (17 of 28 patients), with a 14% (4 of 28 patients) complete response rate. Patients with diploid carcinomas (P = 0.04) with high Ki-67 (P = 0.0001) and SPF (P = 0.09) were more likely to respond to treatment. Median AI increased by 3.4% with interquartile (IQ) range of 3.2 in responders, compared with only -0.1% (IQ range, 2.2) in nonresponders at T1 (P = 0.03). Median Ki-67 decreased by -12.0% (IQ range, 22.9) in responders and increased by 18.5% (IQ range, 15.1) in nonresponders on Day 21 (P = 0.003). Median Bcl-2 scores increased by 1.0 (IQ range, 4.0) in responders and were unchanged at 0.0 (IQ range, 0.5) in nonresponders (P = 0.08). Changes in SPF or ploidy were not significantly predictive of response.

CONCLUSIONS

The results of this preliminary study support evidence that chemotherapy may increase apoptosis, decrease Ki-67, and increase Bcl-2 expression in primary breast carcinomas that subsequently respond to therapy. Methodology allowing morphological confirmation of apoptosis would be advantageous.

摘要

背景

实验室证据表明，许多抗癌药物通过改变细胞凋亡与细胞增殖之间的比例发挥作用。本临床研究的目的是检测凋亡指数（AI）、Bcl-2表达、增殖（Ki-67和S期细胞比例[SPF]）及倍性的体内变化，作为化疗反应性的潜在指标。

方法

28例原发性可手术乳腺癌女性患者在手术/放疗前接受2M方案（米托蒽醌11 mg/m²，甲氨蝶呤35 mg/m²，每3周一次）共4个周期，术后再给予2个周期。根据世界卫生组织标准在4个周期治疗后评估临床反应。通过细针穿刺活检评估分子标志物的变化，在治疗前、24和/或72小时（T1）后以及化疗第一周期后的第7天和第21天重复进行。采用流式细胞术分析评估SPF、倍性和AI（原位DNA缺口末端标记法），而Ki-67和Bcl-2通过免疫细胞化学分析进行评估。

结果

总缓解率为61%（28例患者中的17例），完全缓解率为14%（28例患者中的4例）。二倍体癌患者（P = 0.04）以及Ki-67高表达（P = 0.0001）和SPF高表达（P = 0.09）的患者更可能对治疗有反应。在T1时，缓解者的AI中位数增加了3.4%，四分位间距（IQ）为3.2，而无反应者仅增加了-0.1%（IQ范围为2.2）（P = 0.03）。在第21天，缓解者的Ki-67中位数下降了-12.0%（IQ范围为22.9），无反应者增加了18.5%（IQ范围为15.1）（P = 0.003）。缓解者的Bcl-2评分中位数增加了1.0（IQ范围为4.0），无反应者无变化，为0.0（IQ范围为0.5）（P = 0.08）。SPF或倍性的变化对反应无显著预测价值。