Sparano Joseph A, Moulder Stacy, Kazi Aslamuzzaman, Vahdat Linda, Li Tianhong, Pellegrino Christine, Munster Pam, Malafa Mokenge, Lee David, Hoschander Shira, Hopkins Una, Hershman Dawn, Wright John J, Sebti Said M
New York Phase II Consortium, Albert Einstein Cancer Center, Montefiore Medical Center-Weiler Division, Department of Oncology, 2 S, Room 47-48, 1825 Eastchester Rd, Bronx, NY 10461, USA.
J Clin Oncol. 2006 Jul 1;24(19):3013-8. doi: 10.1200/JCO.2005.04.9114. Epub 2006 Jun 12.
To determine the recommended phase II dose (RPTD) of the farnesyltransferase (FTase) inhibitor tipifarnib when combined with doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer, the pathologic complete response (pCR) rate after preoperative treatment with four cycles of the combination in locally advanced breast cancer (LABC), and the effect of tipifarnib on primary tumor FTase enzyme activity in vivo.
Thirty-two patients with metastatic breast cancer (n = 11) or LABC (n = 21) received AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously on day 1 plus tipifarnib (100, 200, or 300 mg bid for 6 to 14 days) without (n = 2) or with (n = 30) granulocyte colony-stimulating factor (G-CSF) for up to four cycles. Patients with LABC underwent surgery after up to four cycles of the combination.
When combined with AC every 2 weeks plus G-CSF, the RPTD of tipifarnib was 200 mg bid administered on days 2 to 7. Seven (33%) of 21 patients (95% CI, 15% to 55%) with LABC treated with up to four cycles of the combination at the RPTD had a pCR in the breast at surgery. The five patients had serial biopsies that demonstrated at least 50% FTase enzyme inhibition in the primary tumor (median, 100%; range, 55% to 100%) after tipifarnib.
Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.
确定法尼基转移酶（FTase）抑制剂替匹法尼与多柔比星及环磷酰胺（AC）联合应用于晚期乳腺癌患者时的推荐II期剂量（RPTD），接受四个周期该联合方案术前治疗的局部晚期乳腺癌（LABC）患者的病理完全缓解（pCR）率，以及替匹法尼对体内原发性肿瘤FTase酶活性的影响。
32例转移性乳腺癌患者（n = 11）或LABC患者（n = 21）接受AC（多柔比星60 mg/m²和环磷酰胺600 mg/m²）静脉注射，于第1天给药，加用替匹法尼（100、200或300 mg，每日两次，共6至14天），其中2例未使用（n = 2）或30例使用（n = 30）粒细胞集落刺激因子（G-CSF），共进行四个周期治疗。LABC患者在接受最多四个周期联合治疗后接受手术。
当每2周联合AC并加用G-CSF时，替匹法尼的RPTD为200 mg，每日两次，于第2至7天给药。21例接受最多四个周期该联合方案RPTD治疗的LABC患者中，7例（33%）（95% CI，15%至55%）在手术时乳腺达到pCR。5例患者进行了系列活检，结果显示在使用替匹法尼后，原发性肿瘤中FTase酶抑制至少达50%（中位数，100%；范围，55%至100%）。
替匹法尼可安全地与剂量密集型AC联合使用，采用的剂量和方案可在体内显著抑制人乳腺癌中的FTase酶活性，并可能提高四个周期术前剂量密集型AC后的pCR率。
