Arpino G, Ciocca D R, Weiss H, Allred D C, Daguerre P, Vargas-Roig L, Leuzzi M, Gago F, Elledge R, Mohsin S K
Breast Care Center, Baylor College of Medicine, 6550 Fannin Street, Houston, TX 77030, USA.
Breast Cancer Res Treat. 2005 Jul;92(1):69-75. doi: 10.1007/s10549-005-1721-9.
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 IIalpha (topo IIalpha) 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 IIalpha are affected by anthracycline treatment, and if these molecular markers predict anthracycline responsiveness.
Thirty-three women with primary breast tumors > or =3 cm received either doxorubicin (75 mg/m(2)) or epirubicin (120 mg/m(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.
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 IIalpha 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 IIalpha had significantly decreased from baseline in responders, while it increased in non-responders, p = 0.03.
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 IIalphaa levels in primary tumors were associated with greater responsiveness to anthracyclines, and topo IIalpha levels declined in responsive tumors.
实验室证据表明肿瘤生长取决于细胞增殖与细胞死亡之间的平衡，许多抗癌药物可能通过减少增殖和增加凋亡来发挥其治疗作用。此外，临床观察表明，HER-2或拓扑异构酶IIα（topo IIα）的过表达可能是乳腺癌患者对蒽环类药物反应较好的预测指标。本研究的目的是确定增殖（Ki-67）、凋亡（TUNEL）以及HER-2和topo IIα的表达是否受蒽环类药物治疗的影响，以及这些分子标志物是否能预测蒽环类药物的反应性。
33例原发性乳腺肿瘤直径≥3 cm的女性患者在手术前接受多柔比星（75 mg/m²）或表柔比星（120 mg/m²）治疗，共4个周期。治疗4个周期后评估临床反应。在治疗前（D0）、治疗24 - 48小时（D1）和治疗第7天（D7）时，通过粗针穿刺获取样本评估分子标志物的变化，在化疗第4周期后第84天（D84）通过手术切除标本评估分子标志物的变化。
总缓解率为51%（33例患者中有17例），完全临床缓解率为12%（33例患者中有4例）。基线时（D0）凋亡率和topo IIα水平较高的肿瘤对蒽环类药物反应更明显，趋势分别为p = 0.1和p = 0.08。凋亡中位数从D0到D1增加（p = 0.06），而Ki-67中位数下降（p = 0.07）。总体而言，在整个化疗过程中HER-2的表达保持稳定。到第84天时，反应者的topo IIα较基线显著下降，而无反应者则升高，p = 0.03。
在人类原发性乳腺癌中，蒽环类药物治疗可导致早期凋亡增加和增殖减少。在本初步研究中，原发性肿瘤中较高的凋亡率和topo IIα水平与对蒽环类药物的反应性更强相关，且反应性肿瘤中的topo IIα水平下降。
