Rocca Andrea, Cortesi Pietro, Cortesi Laura, Gianni Lorenzo, Matteucci Federica, Fantini Lorenzo, Maestri Antonio, Giunchi Donata Casadei, Cavanna Luigi, Ciani Rosa, Falcini Fabio, Bagni Antonella, Meldoli Elena, Dall'Agata Monia, Volpi Roberta, Andreis Daniele, Nanni Oriana, Curcio Annalisa, Lucchi Leonardo, Amadori Dino, Fedeli Anna
Department of Clinical and Experimental Oncology and Hematology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, Meldola 47014, Italy.
Department of Clinical and Experimental Oncology and Hematology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
Ther Adv Med Oncol. 2021 Feb 9;13:1758835920985632. doi: 10.1177/1758835920985632. eCollection 2021.
The aim of this study was to improve activity over single human epidermal growth factor receptor 2 (HER2)-blockade sequential neaodjuvant regimens for HER2-positive breast cancer, by exploiting the concomitant administration of trastuzumab, taxane and anthracycline, while restraining cardiac toxicity with use of liposomal doxorubicin, and by adding metformin, based on preliminary evidence of antitumor activity.
This multi-center, single-arm, two-stage phase II trial, assessed the safety and the activity of a new treatment regimen for HER2-positive, early or locally advanced breast cancer. Patients received six 21-day cycles of non-pegylated liposomal doxorubicin, 50 mg/m intravenously (i.v.) on day 1, docetaxel, 30 mg/m i.v. on days 2 and 9, trastuzumab, 2 mg/kg/week i.v. on days 2, 9, and 16 (with 4 mg/kg loading dose), in association with metformin 1000 mg orally twice daily. The primary endpoint was the rate of pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). A subgroup of patients performed a 3-deoxy-3-18F-fluorothymidine positron emission tomography (FLT-PET) at baseline and after one cycle.
Among 47 evaluable patients, there were 18 pCR [38.3%, 95% confidence interval (CI) 24.5-53.6%]. A negative estrogen-receptor status, high Ki67, and histological grade 3 were related with pCR, although only grade reached statistical significance. FLT-PET maximum standardized uptake value after one cycle was inversely related to pCR in the breast (odds ratio 0.29, 95% CI 0.06-1.30, = 0.11). Toxicity included grade 3-4 neutropenia in 70% and febrile neutropenia in 4% of patients, grade 1-2 nausea/vomiting in 60%/38%, and grade 3 in 4%/2%, respectively, grade 1-2 diarrhea in 72%, and grade 3 in 6%. There were two cases of reversible grade 2 left-ventricular ejection-fraction decrease, and one case of sharp troponin-T increase.
The concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and metformin is safe and shows good activity, but does not appear to improve activity over conventional sequential regimens.
本研究的目的是通过同时给予曲妥珠单抗、紫杉烷和蒽环类药物来改善针对人表皮生长因子受体2（HER2）阳性乳腺癌的单药HER2阻断序贯新辅助治疗方案，同时使用脂质体阿霉素抑制心脏毒性，并基于抗肿瘤活性的初步证据添加二甲双胍。
这项多中心、单臂、两阶段的II期试验评估了一种针对HER2阳性早期或局部晚期乳腺癌的新治疗方案的安全性和活性。患者接受六个21天周期的治疗，其中非聚乙二醇化脂质体阿霉素在第1天静脉注射50mg/m²，多西他赛在第2天和第9天静脉注射30mg/m²，曲妥珠单抗在第2天、第9天和第16天静脉注射2mg/kg/周（负荷剂量为4mg/kg），同时口服二甲双胍1000mg，每日两次。主要终点是乳腺和腋窝的病理完全缓解（pCR）率（ypT0/is ypN0）。一组患者在基线和一个周期后进行了3-脱氧-3-¹⁸F-氟胸腺嘧啶正电子发射断层扫描（FLT-PET）。
在47例可评估患者中，有18例达到pCR[38.3%，95%置信区间（CI）24.5-53.6%]。雌激素受体阴性、Ki67高表达和组织学3级与pCR相关，尽管只有分级达到统计学意义。一个周期后的FLT-PET最大标准化摄取值与乳腺pCR呈负相关（优势比0.29，95%CI 0.06-1.30，P = 0.11）。毒性包括70%的患者出现3-4级中性粒细胞减少，4%的患者出现发热性中性粒细胞减少，60%/38%的患者出现1-2级恶心/呕吐，4%/2%的患者出现3级，72%的患者出现1-2级腹泻，6%的患者出现3级。有2例出现2级左心室射血分数可逆性下降，1例肌钙蛋白-T急剧升高。
同时给予曲妥珠单抗、脂质体阿霉素、多西他赛和二甲双胍是安全的，且显示出良好的活性，但似乎并未比传统序贯方案提高活性。
