聚(ADP-核糖)聚合酶抑制剂(PARPis)被美国食品和药物管理局(FDA)批准用于治疗BRCA突变的转移性乳腺癌。此外，BROCADE研究证明了添加口服PARPI的益处，维利帕里布,卡铂和紫杉醇在携带BRCA突变的转移性乳腺癌患者中的应用。鉴于多种可能的给药方案以及该方案对BRCA以外的DNA修复缺陷患者的潜在益处，我们试图找到晚期乳腺癌患者的推荐II期剂量（RP2D）和维利帕里布联合卡铂的时间表，无论是三阴性（TNBC）或激素受体（HR）阳性，基于Fanconi贫血（FA）DNA修复途径缺陷的人表皮生长受体2（HER2）阴性，基于FA三重染色免疫荧光分析。
患者在7-，14-,或21天的时间表与卡铂每3周。患者接受[18]氟-3'-脱氧胸苷（18FLT）正电子发射断层扫描（PET）成像。
44例患者（39例TNBC，5个HR阳性/HER2阴性，FA途径缺陷）的中位数为5个周期（范围1-36）。观察到的剂量限制性毒性为（G）4级血小板减少症（n=4），G4中性粒细胞减少症（n=1），和G3静坐不能（n=1）。常见的3-4级毒性包括血小板减少症，淋巴细胞减少,中性粒细胞减少症,贫血,和疲劳。在可评估反应的43名患者中，18.6％的患者获得部分缓解，48.8％的患者病情稳定。中位无进展生存期为18.3周。在第1-21天,将维利帕里布的RP2D与卡铂一起在曲线5下面积建立为250mg,每天两次。基于18FLT-PET(第7-21天;ptrend=.006),部分反应的患者在基线和第1周期早期之间靶病变的最大标准摄取值(SUVmax)显著下降。
连续给药维利帕里布和每3周卡铂的组合显示出活性和可接受的毒性特征。在该疗法的第一个周期期间，在18FLT-PET扫描上SUVmax的降低可以识别可能有反应的患者。
BROCADE研究表明，具有BRCA突变的乳腺癌患者在卡铂加紫杉醇的基础上加入维利帕利布。该研究表明,较高剂量的维利帕里布与卡铂单独组合是可耐受和有活性的。随着人们对基于成像的早期反应评估的兴趣日益浓厚，作者证明[18]氟-3'-脱氧胸苷正电子发射断层扫描(FLT-PET)SUVmax在治疗第1周期期间的降低与缓解相关.总的来说，这项研究确立了维利帕利布和卡铂在晚期乳腺癌中的安全性,同时还提供了关于FLT-PET成像模式在监测治疗反应方面的潜力的额外数据.
Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Furthermore, the BROCADE studies demonstrated benefit of adding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay.
Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3\'-deoxythymidine (18 FLT) positron emission tomography (PET) imaging.
Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n = 1), and G3 akathisia (n = 1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUVmax ) of target lesions between baseline and early in cycle 1 based on 18 FLT-PET (day 7-21; ptrend = .006).
The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18 FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response.
The BROCADE studies suggest that breast cancer patients with BRCA mutation benefit from addition of veliparib to carboplatin plus paclitaxel. This
study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, the authors demonstrate that decrease in [18]fluoro-3\'-deoxythymidine positron emission tomography (FLT-PET) SUVmax during cycle 1 of therapy is associated with response. Collectively, this
study established a safety profile of veliparib and carboplatin in advanced breast cancer while also providing additional data on the potential for FLT-PET imaging modality in monitoring therapy response.
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