TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.
TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.
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TBCRC 039：术前鲁索替尼联合或不联合紫杉醇治疗三阴性炎症性乳腺癌的 II 期研究。
DOI：
10.1186/s13058-024-01774-0
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发表时间：
2024-01-31
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影响因子：
--
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中科院分区：
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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. The online version contains supplementary material available at 10.1186/s13058-024-01774-0.
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影响因子：
11.2
作者：
通讯作者：
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影响因子：
50.5
作者：
Masuda, H.;Brewer, T. M.;Ueno, N. T.
通讯作者：
Ueno, N. T.
DOI：
10.1158/1078-0432.ccr-09-1532
发表时间：
2010-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Park SY;Lee HE;Li H;Shipitsin M;Gelman R;Polyak K
通讯作者：
Polyak K
影响因子：
45.3
作者：
Rueth, Natasha M.;Lin, Heather Y.;Babiera, Gildy
通讯作者：
Babiera, Gildy
影响因子：
9.6
作者：
Kupstas, A. R.;Hoskin, T. L.;Hieken, T. J.
通讯作者：
Hieken, T. J.