Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.
Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.
复制标题
DOI：
10.1038/s41523-022-00493-z
复制
发表时间：
2022-12-01
影响因子：
5.9
通讯作者：
Esserman, Laura J.
中科院分区：
文献类型：
--
作者：
Lang, Julie E.;Forero-Torres, Andres;Yee, Douglas;Yau, Christina;Wolf, Denise;Park, John;Parker, Barbara A.;Chien, A. Jo;Wallace, Anne M.;Murthy, Rashmi;Albain, Kathy S.;Ellis, Erin D.;Beckwith, Heather;Haley, Barbara B.;Elias, Anthony D.;Boughey, Judy C.;Yung, Rachel L.;Isaacs, Claudine;Clark, Amy S.;Han, Hyo S.;Nanda, Rita;Khan, Qamar J.;Edmiston, Kristen K.;Stringer-Reasor, Erica;Price, Elissa;Joe, Bonnie;Liu, Minetta C.;Brown-Swigart, Lamorna;Petricoin, Emanuel F.;Wulfkuhle, Julia D.;Buxton, Meredith;Clennell, Julia L.;Sanil, Ashish;Berry, Scott;Asare, Smita M.;Wilson, Amy;Hirst, Gillian L.;Singhrao, Ruby;Asare, Adam L.;Matthews, Jeffrey B.;Melisko, Michelle;Perlmutter, Jane;Rugo, Hope S.;Symmans, W. Fraser;van't Veer, Laura J.;Hylton, Nola M.;DeMichele, Angela M.;Berry, Donald A.;Esserman, Laura J.
HSP90 抑制剂会破坏与细胞周期、血管生成、RAS-MAPK 活性、组蛋白修饰、激酶和生长因子相关的癌蛋白的稳定性。我们评估了 HSP90 抑制剂 ganetespib 与标准化疗联合治疗高危早期乳腺癌患者的情况。 I-SPY2 是一项多中心、II 期适应性随机新辅助 (NAC) 临床试验，根据激素受体 (HR)、HER2 和 Mammaprint 状态招募肿瘤直径为 2.5 厘米或更大的 II-III 期乳腺癌患者。并行评估多种新型研究药物加标准化疗的病理完全缓解（pCR）的主要终点。 2014 年 10 月至 2015 年 10 月期间，HER2 阴性乳腺癌患者符合随机分配至 ganetespib 的条件。在最终分析中纳入的 233 名女性中，140 名被随机分配至标准 NAC 对照； 93 名受试者被随机分配每 3 周接受 150 mg/m2 ganetespib 治疗，并在 12 周内每周接受紫杉醇治疗，随后接受 AC 治疗。双臂的激素受体状态保持平衡（51-52% HR 阳性）。在达到最大入学人数之前，Ganetespib 没有完成所研究的任何生物标志物特征。与对照相比，ganetespib 的最终估计 pCR 率分别为 26% 与 18% HER2 阴性、38% 与 22% HR 阴性/HER2 阴性以及 15% 与 14% HR 阳性/HER2 阴性。 3 期测试的预测成功概率为 47% HER2 阴性、72% HR 阴性/HER2 阴性和 19% HR 阳性/HER2 阴性。与标准 NAC 相比，在标准疗法中添加 Ganetespib 不太可能在 HER2 阴性乳腺癌中产生显着更高的 pCR 率，并且 HSP90 通路和复制应激表达标记物都无法预测缓解。 HSP90 抑制剂在乳腺癌方面的临床兴趣仍然有限，但可能在其他临床环境中，例如 HER2 阳性疾病或与三阴性乳腺癌中的抗 PD1 新辅助化疗联合使用。试验注册：www.clinicaltrials.gov/ct2/show/NCT01042379
HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51–52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer. Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379
登录
查看更多内容
影响因子：
9
作者：
Eyermann CE;Haley JD;Alexandrova EM
通讯作者：
Alexandrova EM
DOI：
10.1186/s13058-017-0879-5
发表时间：
2017-08-02
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jhaveri K;Wang R;Teplinsky E;Chandarlapaty S;Solit D;Cadoo K;Speyer J;D'Andrea G;Adams S;Patil S;Haque S;O'Neill T;Friedman K;Esteva FJ;Hudis C;Modi S
通讯作者：
Modi S
影响因子：
64.5
作者：
Dai, Chengkai;Whitesell, Luke;Lindquist, Susan
通讯作者：
Lindquist, Susan
影响因子：
6.4
作者：
McCleese, Jennifer K.;Bear, Misty D.;London, Cheryl A.
通讯作者：
London, Cheryl A.
影响因子：
158.5
作者：
Cardoso, F.;van't Veer, L. J.;Piccart, M.
通讯作者：
Piccart, M.