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MET Alterations are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer.

MET 改变是 ALK 阳性肺癌中反复发作且可操作的耐药机制。

  • 影响因子:8.32
  • DOI:10.1158/1078-0432.CCR-19-3906
  • 作者列表:"Dagogo-Jack I","Yoda S","Lennerz JK","Langenbucher A","Lin JJ","Rooney MM","Prutisto-Chang K","Oh A","Adams NA","Yeap BY","Chin E","Do A","Marble HD","Stevens SE","Digumarthy SR","Saxena A","Nagy RJ","Benes CH","Azzoli CG","Lawrence MS","Gainor JF","Shaw AT","Hata AN
  • 发表时间:2020-02-21
Abstract

BACKGROUND:Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. METHODS:We performed fluorescence in-situ hybridization and/or next-generation sequencing on 207 post-treatment tissue (n=101) or plasma (n=106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed activity of ALK/MET blockade in ALK-positive cell lines and two patients with MET-driven resistance. RESULTS:MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation inhibitor in the first-line setting were more likely to develop MET amplification than those who received next-generation ALK inhibitors after crizotinib (p=0.019). Two tumor specimens harbored an ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition re-sensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved responses to ALK/MET combination therapy. CONCLUSIONS:Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may select for MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.

摘要

背景: 大多数 ALK 阳性肺癌在接受 ALK 抑制剂治疗后会出现 ALK 非依赖性耐药。已在使用 ALK 抑制剂进展的患者中描述了 MET 扩增,但尚未全面评估该事件的频率。 方法: 我们对 207 例治疗后组织 (n = 101) 或血浆 (n = 106) 进行荧光原位杂交和/或新一代测序 ALK 阳性肺癌患者标本检测 MET 基因改变。我们在 MET 改变的细胞系中评价了 ALK 抑制剂的敏感性,并在 ALK 阳性细胞系和 2 例 MET 驱动耐药的患者中评估了 ALK/MET 阻断的活性。 结果: 在 15% 接受新一代 ALK 抑制剂复发患者的肿瘤活检中检测到 MET 扩增,其中分别有 12% 和 22% 接受第二代抑制剂或洛拉替尼进展患者的活检。与克唑替尼后接受下一代 ALK 抑制剂的患者相比,在一线环境中接受第二代抑制剂治疗的患者更容易发生 MET 扩增 (p = 0.019)。两个肿瘤标本携带 ST7-MET 重排,其中一个同时有 MET 扩增。在敏感的 H3122 ALK 阳性细胞系中表达 ST7-MET 诱导了对 ALK 抑制剂的抗性,这与双重 ALK/MET 抑制一起被逆转。MET 抑制重新致敏了一种同时携带 ST7-MET 和 MET 扩增的患者来源细胞系 ALK 抑制剂。2 例 ALK 阳性肺癌并获得 MET 改变的患者达到了 ALK/MET 联合治疗的反应。 结论: 使用下一代 ALK 抑制剂治疗,特别是在一线情况下,可能会选择 MET 驱动的耐药性。获得性 MET 改变的患者可能从同时靶向 ALK 和 MET 的治疗中获得临床获益。

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发表时间:2020-01-01
DOI:10.1016/j.asjsur.2019.03.008
作者列表:["Esme H","Can A","Şehitogullari A"]

METHODS:BACKGROUND:The objectives of this study are to assess the chest drainage volumes of patients undergoing anatomic resection of non-small cell lung carcinoma and to determine the safety and effectiveness of administering enoxaparin for thromboprophylaxis. METHODS:A total of 77 patients were included in the study. A study was conducted on the first group of 42 patients in which enoxaparin prophylaxis (enoxaparin, 40 mg) was subcutaneously injected once a day for a period of three days after the patients underwent anatomic pulmonary resection between March 2016 and March 2018. An enoxaparin-free group was identified and included 35 patients who received no enoxaparin prophylaxis after undergoing anatomic pulmonary resection between February 2013 and February 2016. We compared the changes in hemoglobin (Hb) levels, postoperative 3-day drainage volume, transfusion volume, pulmonary complications and length of stay between the two groups. RESULTS:No differences in postoperative Hb levels, chest drainage volume, transfusion volume, postoperative complications, and length of stay were observed between the two groups. Deep-vein thrombosis was noted in a patient in the enoxaparin-free group. No major bleeding was noted in either group. CONCLUSION:We found that for patients undergoing anatomic resection of primary lung cancer, the blood transfusion and chest drainage volumes did not differ, regardless of whether the patients were given enoxaparin. To the best of our knowledge, the impact of low-molecular-weight heparin on chest tube drainage volume for patients undergoing anatomic resection of non-small cell lung carcinoma has not been investigated before.

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影响因子:1.84
发表时间:2020-01-01
来源期刊:Oncology letters
DOI:10.3892/ol.2019.11149
作者列表:["Das SK","Huang YY","Li B","Yu XX","Xiao RH","Yang HF"]

METHODS::The aim of the present study was to compare the safety and efficacy of cryoablation (CA) and microwave ablation (MWA) as treatments for non-small cell lung cancer (NSCLC). Patients with stage IIIB or IV NSCLC treated with CA (n=45) or MWA (n=56) were enrolled in the present study. The primary endpoint was progression-free survival (PFS); the secondary endpoints included overall survival (OS) time and adverse events (AEs). The median PFS times between the two groups were not significantly different (P=0.36): CA, 10 months [95% confidence interval (CI), 7.5-12.4] vs. MWA, 11 months (95% CI, 9.5-12.4). The OS times between the two groups were also not significantly different (P=0.07): CA, 27.5 months (95% CI, 22.8-31.2 months) vs. MWA, 18 months (95% CI, 12.5-23.5). For larger tumors (>3 cm), patients treated with MWA had significantly longer median PFS (P=0.04; MWA, 10.5 months vs. CA, 7.0 months) and OS times (P=0.04; MWA, 24.5 months vs. CA, 14.5 months) compared patients treated with CA. However, for smaller tumors (≤3 cm), median PFS (P=0.79; MWA, 11.0 months vs. CA, 13.0 months) and OS times (P=0.39; MWA, 30.0 months vs. CA, 26.5 months) between the two groups did not differ significantly. The incidence rates of AEs were similar in the two groups (P>0.05). The number of applicators, tumor size and length of the lung traversed by applicators were associated with a higher risk of pneumothorax and intra-pulmonary hemorrhage in the two groups. Treatment with CA resulted in significantly less intraprocedural pain compared with treatment with MWA (P=0.001). Overall, the present study demonstrated that CA and MWA were comparably safe and effective procedures for the treatment of small tumors. However, treatment with MWA was superior compared with CA for the treatment of large tumors.

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影响因子:8.44
发表时间:2020-02-01
DOI:10.1016/j.annonc.2019.10.022
作者列表:["Mazieres J","Cropet C","Montané L","Barlesi F","Souquet PJ","Quantin X","Dubos-Arvis C","Otto J","Favier L","Avrillon V","Cadranel J","Moro-Sibilot D","Monnet I","Westeel V","Le Treut J","Brain E","Trédaniel J","Jaffro M","Collot S","Ferretti GR","Tiffon C","Mahier-Ait Oukhatar C","Blay JY"]

METHODS:BACKGROUND:BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. PATIENTS AND METHODS:Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). RESULTS:Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications. CONCLUSION:Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02304809.

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