Predictive value of apoptosis, proliferation, and HER-2 for anthracycline chemotherapy in locally advanced breast cancer

ARPINO, G.; CIOCCA, D.R.; WEISS, H.; DAGUERRE, P.; VARGAS-ROIG, L.M.; LEUZZI, M.; GAGO, F.E.; ELLEDGE, R.; MOSHIN, S.

Toronto

Congreso; 94th Annual Meeting of the American Association for Cancer Research; 2003

Background: Laboratory evidence indicates that tumor volume depends on the relative balance between cell proliferation and cell death, and many anticancer agents may exert their therapeutic effect by decreasing proliferation and increasing apoptosis. From clinical observations, overexpression of HER-2 may be a predictor of response to anthracyclines. Therefore, the objective of this study was to determine if apoptotic index (AI), proliferation (Ki67), and HER-2 were affected by anthracycline treatment, and if these molecular events predicted tumor responsiveness in human breast cancer. Methods: Thirty-three women with primary breast tumors >3cm in size received either doxorubicin (75mg/m2) or epirubicin (120mg/m2) for 4 cycles before surgery. The median tumor size at diagnosis was 6.0 cm (range 3-9 cm). Clinical response was evaluated after four cycles of treatment according to World Health Organization Criteria. Changes in molecular markers were assessed from biopsies obtained by 14-gauge core needle biopsy performed before treatment (T0), at 24 to 48 hrs (T1), on day 7 (T7), and on day 84 (T84) after the first cycle of chemotherapy. Ki67 and HER-2 were evaluated by immunohistochemical analysis and apoptosis by TUNEL assay. Results: The overall response rate was 51% (17 of 33 patients), with a 12% (4 of 33 patients) complete response rate. The median increase of AI from TO to Ti was +0.60 (p=0.06) and median overall decrease of Ki67 was -1.0 (p=0.07). At T7, AI median increase was +0.1 (p=0.53) and Ki67 median decrease was ­­-­­­7 (p=0.45). At T84, AI median increase was +0.2 (p=0.05) and Ki67 median decrease was ­­-6.5 (p=0.23). Median overall expression of HER-2 remained stable throughout the chemotherapy administration. In responders, proliferation decreased (median = -6.5), AI increased (median = +0.1), and HER-2 was stable (median =0) at T84, but none of these changes were significantly different from non-responders (>>0.05). Patients with high AI (p=0.08) at T0 and high HER-2 expression at T84 (p=0.05) were more likely to respond to treatment. Ki67 level at T0 was also higher in responders but this difference was not significantly different from non-responders. Conclusions: Anthracycline treatment caused an increase in apoptosis and decrease in proliferation in human primary breast cancer. Apoptosis in the primary tumors was associated with higher tumor responsiveness and may indicate a lower threshold for chemotherapy induced cell death.