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
University of Southern California, Los Angeles, USA.
University of Alabama at Birmingham, Birmingham, USA.
NPJ Breast Cancer. 2022 Dec 1;8(1):128. doi: 10.1038/s41523-022-00493-z.
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/m 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.
热休克蛋白90（HSP90）抑制剂可使与细胞周期、血管生成、RAS - MAPK活性、组蛋白修饰、激酶及生长因子相关的癌蛋白失稳。我们评估了HSP90抑制剂ganetespib联合标准化疗用于高危早期乳腺癌患者的疗效。I - SPY2是一项多中心、II期适应性随机新辅助化疗（NAC）临床试验，纳入II - III期乳腺癌患者，肿瘤大小基于激素受体（HR）、HER2及Mammaprint状态为2.5 cm或更大。平行评估多种新型研究药物加标准化疗的病理完全缓解（pCR）主要终点。2014年10月至2015年10月，HER2阴性乳腺癌患者符合随机分配至ganetespib组的条件。最终分析纳入的233名女性中，140名随机分配至标准化疗对照组；93名随机接受每3周150 mg/m² ganetespib联合每周紫杉醇共12周，随后进行AC化疗。两组激素受体状态均衡（HR阳性率51 - 52%）。在达到最大入组人数之前，ganetespib在任何研究的生物标志物特征中均未达到标准。最终估计的pCR率，ganetespib组与对照组相比，HER2阴性分别为26%对18%，HR阴性/HER2阴性分别为38%对22%，HR阳性/HER2阴性分别为15%对14%。在3期试验中成功的预测概率，HER2阴性为47%，HR阴性/HER2阴性为72%，HR阳性/HER2阴性为19%。与标准化疗相比，在HER2阴性乳腺癌中，ganetespib加至标准化疗不太可能显著提高pCR率，且HSP90通路及复制应激表达标志物均不能预测疗效。HSP90抑制剂在乳腺癌中的临床应用价值有限，可能在其他临床环境中如HER2阳性疾病或三阴乳腺癌中与抗PD1新辅助化疗联合使用。试验注册号：www.clinicaltrials.gov/ct2/show/NCT01042379 。
