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

BACKGROUND. Laboratory evidence suggests that many anticancer agents exert their effect by altering the ratio between apoptosis and cellular prolifera tion. The objective of this clinical study was to examine in vivo changes i n 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/m(2), methotrexate 35 mg/m(2) every 3 weeks) for 4 cycles before surgery/radiotherapy, and an additional 2 cycles were given a fter surgery. Clinical response was assessed after four cycles of treatment according to World Health Organization criteria. Changes in molecular mark ers were assessed from biopsies obtained by fine-needle aspiration performe d before treatment, repealed after 24 and/or 72 hours (T1), and on Days 7 a nd 21 after the first cycle of chemotherapy. Flow cytometric analysis was u sed to assess SPF, ploidy, and Al (in situ DNA nick end labeling assay) whe reas 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 likel y 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 nonrespond ers 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 nonresponde rs (P = 0.08). Changes in SPF or ploidy were not significantly predictive o f response. CONCLUSIONS. The results of this preliminary study support evidence that ch emotherapy may increase apoptosis, decrease Ki-67, and increase Bcl-2 expre ssion in primary breast carcinomas that subsequently respond to therapy. Me thodology allowing morphological confirmation of apoptosis would be advanta geous. Cancer 2000;89:2145-52. (C) 2000 American Cancer Society.