Litton J K, Scoggins M, Ramirez D L, Murthy R K, Whitman G J, Hess K R, Adrada B E, Moulder S L, Barcenas C H, Valero V, Gomez J Schwartz, Mittendorf E A, Thompson A, Helgason T, Mills G B, Piwnica-Worms H, Arun B K
Department of Breast Medical Oncology, Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
NPJ Breast Cancer. 2017 Dec 6;3:49. doi: 10.1038/s41523-017-0052-4. eCollection 2017.
This study was undertaken to determine the feasibility of enrolling breast cancer patients on a single-agent-targeted therapy trial before neoadjuvant chemotherapy. Specifically, we evaluated talazoparib in patients harboring a deleterious BRCA mutation (BRCA+). Patients with a germline BRCA mutation and ≥1 cm, HER2-negative primary tumors were eligible. Study participants underwent a pretreatment biopsy, 2 months of talazoparib, off-study core biopsy, anthracycline, and taxane-based chemotherapy ± carboplatin, followed by surgery. Volumetric changes in tumor size were determined by ultrasound at 1 and 2 months of therapy. Success was defined as 20 patients accrued within 2 years and <33% experienced a grade 4 toxicity. The study was stopped early after 13 patients (1 + = 10; 2 + = 3) were accrued within 8 months with no grade 4 toxicities and only one patient requiring dose reduction due to grade 3 neutropenia. The median age was 40 years (range 25-55) and clinical stage included I ( = 2), II ( = 9), and III ( = 2). Most tumors ( = 9) were hormone receptor-negative, and one of these was metaplastic. Decreases in tumor volume occurred in all patients following 2 months of talazoparib; the median was 88% (range 30-98%). Common toxicities were neutropenia, anemia, thrombocytopenia, nausea, dizziness, and fatigue. Single-agent-targeted therapy trials are feasible in BRCA+ patients. Given the rapid rate of accrual, profound response and favorable toxicity profile, the feasibility study was modified into a phase II study to determine pathologic complete response rates after 4-6 months of single-agent talazoparib.
本研究旨在确定在新辅助化疗前让乳腺癌患者参加单药靶向治疗试验的可行性。具体而言，我们评估了他拉唑帕尼在携带有害BRCA突变（BRCA+）患者中的疗效。符合条件的患者为具有种系BRCA突变且原发肿瘤≥1 cm、HER2阴性。研究参与者接受了预处理活检、2个月的他拉唑帕尼治疗、非研究期核心活检、蒽环类和紫杉类化疗±卡铂，随后进行手术。在治疗1个月和2个月时通过超声确定肿瘤大小的体积变化。成功的定义为在2年内招募20名患者且<33%的患者发生4级毒性反应。在8个月内招募了13名患者（1+ = 10；2+ = 3），无4级毒性反应，仅有1名患者因3级中性粒细胞减少需要降低剂量后，该研究提前终止。中位年龄为40岁（范围25 - 55岁），临床分期包括I期（ = 2）、II期（ = 9）和III期（ = 2）。大多数肿瘤（ = 9）为激素受体阴性，其中1例为化生性癌。所有患者在接受2个月他拉唑帕尼治疗后肿瘤体积均减小；中位减小率为88%（范围30 - 98%）。常见的毒性反应为中性粒细胞减少、贫血、血小板减少、恶心、头晕和疲劳。单药靶向治疗试验在BRCA+患者中是可行的。鉴于入组速度快、反应深刻且毒性特征良好，该可行性研究被改为II期研究，以确定单药他拉唑帕尼治疗4 - 6个月后的病理完全缓解率。
