TBCRC 039:术前服用或不服用紫杉醇治疗三阴性炎性乳腺癌的鲁索利替尼 II 期研究

IF 6.1 1区 医学 Q1 ONCOLOGY Breast Cancer Research Pub Date : 2024-01-31 DOI:10.1186/s13058-024-01774-0
Filipa Lynce, Laura E. Stevens, Zheqi Li, Jane E. Brock, Anushree Gulvady, Ying Huang, Faina Nakhlis, Ashka Patel, Jeremy M. Force, Tufia C. Haddad, Naoto Ueno, Vered Stearns, Antonio C. Wolff, Amy S. Clark, Jennifer R. Bellon, Edward T. Richardson, Justin M. Balko, Ian E. Krop, Eric P. Winer, Paulina Lange, E. Shelley Hwang, Tari A. King, Sara M. Tolaney, Alastair Thompson, Gaorav P. Gupta, Elizabeth A. Mittendorf, Meredith M. Regan, Beth Overmoyer, Kornelia Polyak
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引用次数: 0

摘要

炎性乳腺癌(IBC)患者的总体临床预后较差,其中三阴性 IBC(TN-IBC)患者的生存率最差,因此需要研究新型疗法。临床前研究表明,JAK1/2抑制剂鲁索利替尼(RUX)可能是治疗TN-IBC的有效疗法。我们开展了一项针对 TN-IBC 的嵌套机会窗随机 II 期研究。未经治疗的患者接受了单用 RUX 或 RUX 加紫杉醇 (PAC) 的 7 天磨合。磨合期结束后,单用 RUX 的患者接受为期 12 周的 RUX + PAC 或单用 PAC 新辅助治疗;接受 RUX + PAC 治疗的患者继续接受为期 12 周的治疗。随后,所有患者都在手术前接受了4个周期的多柔比星加环磷酰胺治疗。在基线(磨合前)和磨合期治疗后进行肿瘤活检研究。通过免疫染色法评估肿瘤的磷酸化STAT3(pSTAT3),并通过RNA-seq分析肿瘤子集。主要终点是pSTAT3阳性肿瘤中pSTAT3阴性肿瘤的百分比。次要终点包括病理完全反应(pCR)。共有 23 名患者入组,其中 21 人完成了术前治疗。在RUX治疗后的活检样本中,pSTAT3和IL-6/JAK/STAT3信号转导下降,而与单用RUX相比,RUX+PAC的持续治疗可上调IL-6/JAK/STAT3信号转导。两种治疗方法都会减少 GZMB+ T 细胞,这意味着免疫抑制。单独使用 RUX 可有效抑制 JAK/STAT3 信号传导,但与 PAC 联合使用则抑制不完全。RUX 单独或联合使用的免疫抑制作用可能会抵消其对癌细胞生长的抑制作用。总之,在 TN-IBC 中使用 RUX 与 pSTAT3 水平下降有关,尽管没有临床益处。要进一步评估作为癌症治疗靶点的JAK2/STAT3信号转导,可能需要针对癌细胞的JAK2/STAT3靶点或与免疫疗法相结合。www.clinicaltrials.gov ,NCT02876302。2016年8月23日注册。
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TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer
Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. www.clinicaltrials.gov , NCT02876302. Registered 23 August 2016.
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来源期刊
Breast Cancer Research
Breast Cancer Research 医学-肿瘤学
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期刊介绍: Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.
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