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

• Published in: Breast cancer research and treatment Vol. 92; no. 1; pp. 69 - 75
• Main Authors: ARPINO, G, CIOCCA, D. R, WEISS, H, ALLRED, D. C, DAGUERRE, P, VARGAS-ROIG, L, LEUZZI, M, GAGO, F, ELLEDGE, R, MOHSIN, S. K
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer 01.07.2005
• Subjects: Biological and medical sciences; Gynecology. Andrology. Obstetrics; Mammary gland diseases; Medical sciences; Tumors; Antineoplastic agent; Cell proliferation; aptosis; Enzyme; DNA topoisomerase; erbB2 Gene; Breast cancer; Malignant tumor; Neoadjuvant treatment; Human Epidermal growth factor Receptor 2; Mammary gland diseases; neoadjuvant chemotherapy; Chemotherapy; Isomerases; Cell death; C-Onc gene; Predictive value; Advanced stage; Anthracyclins; Protooncogene; Apoptosis
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-005-1721-9

Purpose.Laboratory evidence indicates that tumor growth depends on the balance between cell proliferation and cell death, and many anticancer agents may exert their therapeutic effect by decreasing proliferation and increasing apoptosis. Additionally, clinical observations indicate that overexpression of HER-2 or topoisomerase II alpha (topo II alpha ) may be predictors of better response to anthracyclines in breast cancer. The objective of this study was to determine if proliferation (Ki-67), apoptosis (TUNEL), and expression of HER-2 and topo II alpha are affected by anthracycline treatment, and if these molecular markers predict anthracycline responsiveness.Experimental design.Thirty-three women with primary breast tumors greater than or equal to 3 cm received either doxorubicin (75 mg/m super(2)) or epirubicin (120 mg/m super(2)) for 4 cycles before surgery. Clinical response was evaluated after 4 cycles of treatment. Changes in molecular markers were assessed from core needle taken before treatment (D0), at 24-48 h (Dl) and on day 7 (D7) while on treatment, and from the surgical specimen excised on day 84 (D84) after the fourth cycle of chemotherapy.Results.The overall response rate was 51% (17 of 33 patients), with a 12% complete clinical response rate (4 of 33 patients). There were trends for tumors with higher apoptosis and topo II alpha at baseline (D0) to be more responsive to anthracyclines, p = 0.1 and p = 0.08, respectively. Median apoptosis increased from D0 to Dl (p = 0.06) while median Ki-67 decreased (p = 0.07). Overall, expression of HER-2 remained stable throughout the chemotherapy administration. By Day 84, topo II alpha had significantly decreased from baseline in responders, while it increased in non-responders, p = 0.03.Conclusions.In human primary breast cancer, anthracycline treatment causes an early increase in apoptosis and a decrease in proliferation. In this pilot study, higher apoptosis and topo II alpha a levels in primary tumors were associated with greater responsiveness to anthracyclines, and topo II alpha levels declined in responsive tumors.