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Synchronous Oligometastasis and Oligoprogression as a Prognostic Marker in Patients With Extensive-Stage SCLC Treated With a Combination of Immune-Checkpoint Inhibitor and Chemotherapy (HOT2301) 免疫检查点抑制剂与化疗联合疗法(HOT2301)作为广泛期SCLC患者预后标志的同步寡转移和寡进展
IF 3 Q2 ONCOLOGY Pub Date : 2024-09-07 DOI: 10.1016/j.jtocrr.2024.100715
Kana Hashimoto MD , Daisuke Morinaga MD , Hajime Asahina MD, PhD , Mina Ishidoya MD , Hajime Kikuchi MD, PhD , Hiroshi Yokouchi MD, PhD , Toshiyuki Harada MD, PhD , Osamu Honjo MD , Ryota Shigaki MD , Taichi Takashina MD, PhD , Yuka Fujita MD, PhD , Mamoru Takahashi MD, PhD , Yasutaka Kawai MD , Ryotaro Kida MD , Kenichiro Ito MD , Noriaki Sukoh MD, PhD , Ayumu Takahashi MD, PhD , Fumihiro Hommura MD, PhD , Yoshihito Ohhara MD, PhD , Megumi Furuta MD, PhD , Satoshi Oizumi MD, PhD

Introduction

Oligometastasis and oligoprogression (OP) has not been adequately defined in extensive-stage SCLC (ES-SCLC) and may be a good indication for adding local treatment. Therefore, this multicenter study aimed to investigate the prognostic impact of oligometastasis and OP in ES-SCLC.

Methods

We enrolled patients who received chemoimmunotherapy between September 2019 and June 2022. Patients were classified into oligometastasis and non-oligometastasis groups by determining the number of original tumor lesions and distant metastases (worsening or newly appearing lesions) at the time of initial diagnosis and disease progression after first-line treatment.

Results

We retrospectively analyzed 265 consecutive patients with ES-SCLC. Synchronous oligometastasis (SOM) and OP was defined as less than or equal to five lesions in less than or equal to two organs, including lungs; 21.0% and 53.2% of patients had SOM and OP, respectively. Median progression-free survival was 5.8 months and 4.9 months in patients with and without SOM, respectively (hazard ratio [HR] = 0.72, 95% confidence interval [CI]: 0.51–1.02, p = 0.065). Median overall survival was 20.5 months and 15.0 months in patients with and without SOM (HR = 0.58, 95% CI: 0.37–0.95, p = 0.027) from the initiation of first-line treatment. The OP group revealed a better progression-free survival of 5.2 months (versus 3.2 mo, HR = 0.69, 95% CI: 0.50–0.96, p = 0.026) and overall survival of 15.1 months (versus 7.5 mo, HR = 0.44, 95% CI: 0.29–0.66, p = 0.027) from the initiation of second-line treatment compared with the non-OP group. The Lung Immune Prognostic Index score was significantly lower in the SOM and OP group.

Conclusions

ES-SCLC in patients with SOM and OP may be more indolent than that of the nonoligometastasis group, therefore, new treatment strategies, including the addition of local treatment, should be explored.

Clinical trial registration

This study was registered at UMIN-CTR (UMIN000053402).
导言寡转移和寡进展(OP)在广泛期SCLC(ES-SCLC)中尚未得到充分定义,可能是增加局部治疗的良好指征。因此,这项多中心研究旨在探讨ES-SCLC中寡转移和OP对预后的影响。方法我们纳入了2019年9月至2022年6月期间接受化疗免疫治疗的患者。结果我们回顾性分析了265例连续的ES-SCLC患者。同步少转移(SOM)和远处转移(OP)被定义为在少于或等于两个器官(包括肺部)出现少于或等于五个病灶;分别有21.0%和53.2%的患者出现SOM和OP。有SOM和无SOM患者的中位无进展生存期分别为5.8个月和4.9个月(危险比[HR] = 0.72,95%置信区间[CI]:0.51-1.02,P<0.05):0.51-1.02, p = 0.065).从一线治疗开始,SOM患者和非SOM患者的中位总生存期分别为20.5个月和15.0个月(HR = 0.58,95% CI:0.37-0.95,p = 0.027)。与非OP组相比,OP组的无进展生存期为5.2个月(相对于3.2个月,HR=0.69,95% CI:0.50-0.96,p=0.026),总生存期为15.1个月(相对于7.5个月,HR=0.44,95% CI:0.29-0.66,p=0.027)。结论SOM和OP组患者的ES-SCLC可能比非寡转移组患者更不活跃,因此应探索新的治疗策略,包括增加局部治疗。
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引用次数: 0
The Whole Picture of First-Line Osimertinib for EGFR Mutation-Positive Advanced NSCLC: Real-World Efficacy, Safety, Progression Pattern, and Posttreatment Therapy (Reiwa Study) 一线奥希替尼治疗表皮生长因子受体突变阳性晚期 NSCLC 的全貌:真实世界的疗效、安全性、进展模式和治疗后疗法(Reiwa 研究)
IF 3 Q2 ONCOLOGY Pub Date : 2024-09-07 DOI: 10.1016/j.jtocrr.2024.100720
Kageaki Watanabe MD , Yukio Hosomi MD, PhD , Katsuhiko Naoki MD, PhD , Yoshiro Nakahara MD, PhD , Yoko Tsukita MD, PhD , Hirotaka Matsumoto MD, PhD , Kiyotaka Yoh MD , Yasuhito Fujisaka MD, PhD , Satoshi Takahashi MD, PhD , Saori Takata MD, PhD , Kazuhiro Usui MD, PhD , Kazuma Kishi MD, PhD , Go Naka MD, PhD , Shu Tamano MSS , Kohei Uemura PhD , Hideo Kunitoh MD, PhD

Introduction

Osimertinib is used as the first-line treatment for EGFR mutation-positive NSCLC. Nevertheless, its efficacy and safety in clinical practice remain to be fully elucidated and the pattern of progression and the optimal subsequent treatment after osimertinib remains unclear.

Methods

This was a multicenter prospective observational study. EGFR mutation-positive patients with NSCLC who started first-line osimertinib from September 2018 to August 2020 were enrolled and followed up until August 2022.

Results

A total of 583 patients received osimertinib. The median progression-free and overall survival were 20.0 (95% confidence interval [CI]: 17.6–21.7) months and 41.0 (95% CI: 37.1–44.1) months, respectively. Grade 3 or worse adverse events were observed in 136 patients (23.3%). Progression patterns were categorized as central nervous system only, oligo-progression, and multiple organs on the basis of the Response Evaluation Criteria in Solid Tumors—progressive disease and occurred in 37 (10.8%), 156 (45.4%), and 151 patients (43.9%). The patient’s condition on progression was asymptomatic in 195 patients (56.7%). Osimertinib was continued in 163 patients (47.4%) after confirming progression. In clinically stable population with progressive disease (n = 247), survival after progression was 13.3 (95% CI: 10.9–16.4) months for those who continued osimertinib beyond progressive disease (n = 124), and 24.1 (95% CI: 17.7–34.0) months for those who discontinued osimertinib (n = 123) (hazard ratio = 2.01, 95% CI: 1.38–2.91, p = 0.0002). Platinum plus pemetrexed had the best overall survival benefits after osimertinib.

Conclusions

First-line osimertinib was found to have good effectiveness comparable to that reported in pivotal studies. Nevertheless, osimertinib should be discontinued among those who develop progression.

Trial registration number

UMIN000038683
导言奥希替尼是表皮生长因子受体突变阳性NSCLC的一线治疗药物。然而,其在临床实践中的疗效和安全性仍有待充分阐明,奥希替尼治疗后的进展模式和最佳后续治疗方法仍不明确。入组2018年9月至2020年8月开始一线奥希替尼治疗的EGFR突变阳性NSCLC患者,并随访至2022年8月。结果共有583名患者接受了奥希替尼治疗。中位无进展生存期和总生存期分别为20.0个月(95%置信区间[CI]:17.6-21.7)和41.0个月(95% CI:37.1-44.1)。136名患者(23.3%)出现了3级或更严重的不良反应。根据实体瘤进展性疾病的反应评估标准,进展模式分为仅中枢神经系统、少部分进展和多器官进展,分别有37名患者(10.8%)、156名患者(45.4%)和151名患者(43.9%)出现进展。195名患者(56.7%)在病情进展时无症状。163名患者(47.4%)在确认病情进展后继续服用奥希替尼。在病情进展的临床稳定人群(n = 247)中,病情进展后继续使用奥希替尼者(n = 124)的生存期为13.3个月(95% CI:10.9-16.4),停用奥希替尼者(n = 123)的生存期为24.1个月(95% CI:17.7-34.0)(危险比 = 2.01,95% CI:1.38-2.91,p = 0.0002)。在奥希替尼治疗后,铂类加培美曲塞的总生存率最高。尽管如此,奥希替尼仍应停用。
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引用次数: 0
ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor Resistance ALKTERNATE:一项针对ALK抑制剂耐药的ALK+非小细胞肺癌患者交替使用lorlatinib和crizotinib的试验研究。
IF 3 Q2 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jtocrr.2024.100703
Malinda Itchins BMedSci, M.B.B.S., FRACP, PhD , Shirley Liang BSc , Chris Brown MBiostats, BSc , Tristan Barnes BSc (Med), M.B.B.S., FRACP , Gavin Marx BSc, M.B.B.S., FRACP , Venessa Chin M.B.B.S., FRACP, PhD , Steven Kao BHB, MBChB, PhD, FRACP , Po Yee Yip MBChB, FRACP, PhD , Antony J. Mersiades BMedSc, M.B.B.S., FRACP, MMed (Clin. Epi) , Adnan Nagrial M.B.B.S., FRACP, PhD , Victoria Bray M.B.B.S., FRACP, PhD , Geoffrey Peters BPharm, M.B.B.S., FRACP , Sagun Parakh BSc, MBChB, FRACP, PhD , Kavita Garg PhD , Bob T. Li MD, PhD, MPH , Matthew McKay PhD , Kenneth O'Byrne M.B.B.S., FRACP, FRCPA, MD , Thomas John M.B.B.S., FRACP, PhD , Anthony J. Gill MD, FRCPA , Mark P. Molloy PhD , Nick Pavlakis BSc, M.B.B.S., MMed (Clin. Epi), PhD, FRACP

Introduction

ALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring.

Methods

The single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma.

Results

A total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants.

Conclusions

ALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.

导言 ALK 阳性肺癌是一种分子多样的疾病。随着药物暴露、驱动选择压力和耐药途径的增加,疾病会出现复发。方法ALKTERNATE单臂试验研究调查了对第二代ALK抑制剂耐药的患者使用氯唑替尼与洛拉替尼固定交替循环的情况。动态ctDNA探讨了与疾病反应和疾病复发的相关性,并定义了疾病耐药性。主要结果是治疗失败时间,这是耐受性、可行性和疗效的综合结果。次要结果包括标准生存指标、毒性、药代动力学分析和患者报告结果。三级结果为组织和血浆的蛋白质基因组学分析。有12人接受了交替治疗,这种方法显示了安全性、可行性和有效性。患者报告的结果在治疗中得到了维持或改善,毒性与之前的报告一致。药代动力学指标与单臂用药经验相似。中位治疗失败时间为10个月;总生存期为23个月。ctDNA图谱显示,在试验诱导时存在TP53突变和ctDNA不明确或未清除的患者生存率较低。结论 ALKTERNATE揭示了新型交替ALK抑制剂策略在ALK阳性NSCLC中的可行性。研究结果支持对这种方法进行深入研究,并提出了一种灵活的设计方案,即根据实时血浆分析结果选择药物并交替使用。将这一概念应用于天真无邪的治疗也可优化疗效。
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引用次数: 0
Effect of FDG PET-CT for Staging and Radiotherapy Planning – A Comparison of Cohorts From Two Randomized Trials of Thoracic Radiotherapy in Limited-Stage SCLC FDG PET-CT 对分期和放疗计划的影响--两项胸腔放疗随机试验中局限期 SCLC 队列的比较
IF 3 Q2 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jtocrr.2024.100688

Introduction

18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) is recommended for staging and defining target volume in limited-stage SCLC, though the impact on outcomes compared with CT staging and elective nodal irradiation (ENI) is not well documented. We analyzed patients receiving 45 Gy/30 fractions in two randomized trials of thoracic radiotherapy (TRT) in limited-stage SCLC (HAST and THORA trials) to evaluate whether PET-CT for staging and radiotherapy planning reduces radiotoxicity and improves survival.

Methods

Patients in HAST were staged with CT of the thorax and upper abdomen and brain magnetic resonance imaging of the brain. Patients in THORA were staged with PET-CT in addition. All patients were to receive four courses of platinum/etoposide chemotherapy and concurrent TRT starting three to four weeks after the first chemotherapy course. In HAST, target volumes included pathological lesions on CT plus ENI of lymph node stations 4–7 (bilateral). In THORA, target volumes were limited to PET-CT-positive lesions (selective nodal irradiation [SNI]).

Results

A total of 149 patients were included (PET-CT/SNI: n = 76, CT/ENI: n=73); the median age was 64 years, 56% were women, 85% had PS 0 to 1, and 81% had stage III disease. The PET-CT/SNI group experienced less grade 3-4 esophagitis (18% versus 33%, p = 0.043), less grade >=1 pneumonitis (5% versus 16%, p = 0.028), and less dysphagia after TRT (mean scores on European Organisation for Research and Treatment of Cancer 13-item lung cancer module: 45 versus 72). There was no difference in median overall survival (24 versus 25 mo, p = 0.59) or progression-free survival (11 versus 11 mo, p = 0.23).

Conclusions

Using PET-CT for staging and target volume definition of TRT reduces acute radiotoxicity but does not improve overall or progression-free survival in limited-stage SCLC.

导言18F-氟脱氧葡萄糖正电子发射断层扫描-计算机断层扫描(PET-CT)被推荐用于局限期SCLC的分期和靶体积的确定,但与CT分期和选择性结节照射(ENI)相比,PET-CT对疗效的影响尚无充分的文献记载。我们分析了两项胸腔放疗(TRT)随机试验(HAST 试验和 THORA 试验)中接受 45 Gy/30 分次放疗的局限期 SCLC 患者,以评估 PET-CT 用于分期和放疗计划是否能降低放射性毒性并提高生存率。THORA的患者还需进行PET-CT分期。所有患者都将接受四个疗程的铂/依托泊苷化疗,并在第一个化疗疗程后三到四周开始同时接受TRT治疗。在HAST中,目标体积包括CT上的病理病灶和4-7淋巴结站(双侧)的ENI。结果 共纳入 149 例患者(PET-CT/SNI:n = 76,CT/ENI:n = 73);中位年龄为 64 岁,56% 为女性,85% 为 PS 0 至 1,81% 为 III 期疾病。PET-CT/SNI 组的 3-4 级食管炎较少(18% 对 33%,P = 0.043),1 级肺炎较少(5% 对 16%,P = 0.028),TRT 后吞咽困难较少(欧洲癌症研究和治疗组织 13 项肺癌模块平均得分:45 对 72):45对72)。中位总生存期(24 个月对 25 个月,p = 0.59)或无进展生存期(11 个月对 11 个月,p = 0.23)均无差异。结论使用 PET-CT 对 TRT 进行分期和靶体积定义可降低急性放射性毒性,但不会改善局限期 SCLC 的总生存期或无进展生存期。
{"title":"Effect of FDG PET-CT for Staging and Radiotherapy Planning – A Comparison of Cohorts From Two Randomized Trials of Thoracic Radiotherapy in Limited-Stage SCLC","authors":"","doi":"10.1016/j.jtocrr.2024.100688","DOIUrl":"10.1016/j.jtocrr.2024.100688","url":null,"abstract":"<div><h3>Introduction</h3><p><sup>18</sup>F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) is recommended for staging and defining target volume in limited-stage SCLC, though the impact on outcomes compared with CT staging and elective nodal irradiation (ENI) is not well documented. We analyzed patients receiving 45 Gy/30 fractions in two randomized trials of thoracic radiotherapy (TRT) in limited-stage SCLC (HAST and THORA trials) to evaluate whether PET-CT for staging and radiotherapy planning reduces radiotoxicity and improves survival.</p></div><div><h3>Methods</h3><p>Patients in HAST were staged with CT of the thorax and upper abdomen and brain magnetic resonance imaging of the brain. Patients in THORA were staged with PET-CT in addition. All patients were to receive four courses of platinum/etoposide chemotherapy and concurrent TRT starting three to four weeks after the first chemotherapy course. In HAST, target volumes included pathological lesions on CT plus ENI of lymph node stations 4–7 (bilateral). In THORA, target volumes were limited to PET-CT-positive lesions (selective nodal irradiation [SNI]).</p></div><div><h3>Results</h3><p>A total of 149 patients were included (PET-CT/SNI: n = 76, CT/ENI: n=73); the median age was 64 years, 56% were women, 85% had PS 0 to 1, and 81% had stage III disease. The PET-CT/SNI group experienced less grade 3-4 esophagitis (18% versus 33%, <em>p</em> = 0.043), less grade &gt;=1 pneumonitis (5% versus 16%, <em>p</em> = 0.028), and less dysphagia after TRT (mean scores on European Organisation for Research and Treatment of Cancer 13-item lung cancer module: 45 versus 72). There was no difference in median overall survival (24 versus 25 mo, <em>p</em> = 0.59) or progression-free survival (11 versus 11 mo, <em>p</em> = 0.23).</p></div><div><h3>Conclusions</h3><p>Using PET-CT for staging and target volume definition of TRT reduces acute radiotoxicity but does not improve overall or progression-free survival in limited-stage SCLC.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"5 9","pages":"Article 100688"},"PeriodicalIF":3.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000584/pdfft?md5=bf75f29edc6b92975d18460f22eafb5e&pid=1-s2.0-S2666364324000584-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141047048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Brief Report of Lung Cancer Screening Utilization Before, During, and in the Later Stages of the COVID-19 Pandemic in the United States 关于美国 COVID-19 大流行之前、期间和后期肺癌筛查利用情况的简要报告
IF 3 Q2 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jtocrr.2024.100705
Hermine Poghosyan PhD, MPH, FAAN , Sayantani Sarkar PhD , Ilana Richman MD, MHS , Robert H. Pietrzak PhD, MPH , Lisa Carter-Bawa PhD, MPH, APRN, ANP-C, FAAN , Mary E. Cooley PhD, RN, FAAN

Introduction

Although COVID-19 has affected health care and screening utilization, its impact on lung cancer screening (LCS) uptake remains unclear. Our study investigated LCS utilization and associated predictors among adults eligible for LCS before (2019), during (2020–2021), and at a later stage (2022) of COVID-19.

Methods

We used cross-sectional, nationally representative, population-based data from the Behavioral Risk Factor Surveillance System over 4 consecutive years: 2019 (n = 4484; weighted n = 1,559,37), 2020 (n = 1239; weighted n = 200,301), 2021 (n = 1673; weighted n = 668,359), and 2022 (n = 20,804; weighted n = 9,458,907). The outcome was self-reported LCS uptake (0 = did not have LCS in the past 12 mo and 1 = underwent LCS in the past 12 mo). We conducted weighted statistics and multivariable logistic regression.

Results

Overall, of 11,886,704 million individuals eligible for LCS, 2,129,900 received LCS in 4 years (2019–2022). National rates of LCS among individuals eligible for screening were 16.3% (95% confidence interval [CI]:14.4–18.5), 19.4% (95% CI:15.3–24.3), 18.3% (95% CI:15.6–21.3), and 18.1% (95% CI:17.1–19.2) in 2019, 2020, 2021, and 2022, respectively. Respondents reporting lung disease and cancer (other than lung cancer) history were more likely to receive LCS across all 4 years. During the pandemic (2020), Hispanic (versus White), and rural (versus urban) residents had lower odds of LCS utilization. In 2022, men had increased odds of reporting LCS use relative to women. No sex differences in LCS use were observed in previous years.

Conclusions

Our findings indicate consistently low LCS utilization (<20%) over 4 years. Nationwide efforts to boost LCS awareness and utilization are essential for mitigating the lung cancer burden in the United States.

导言尽管 COVID-19 对医疗保健和筛查利用率产生了影响,但其对肺癌筛查(LCS)接受率的影响仍不明确。我们的研究调查了 COVID-19 实施前(2019 年)、实施期间(2020-2021 年)和实施后期(2022 年)符合肺癌筛查条件的成年人的肺癌筛查利用率和相关预测因素。方法我们使用了行为风险因素监测系统中连续 4 年具有全国代表性的横截面人群数据:2019 年(n = 4484;加权 n = 1,559,37)、2020 年(n = 1239;加权 n = 200,301)、2021 年(n = 1673;加权 n = 668,359)和 2022 年(n = 20,804;加权 n = 9,458,907)。结果是自我报告的接受 LCS 的情况(0 = 在过去 12 个月中没有接受 LCS,1 = 在过去 12 个月中接受了 LCS)。我们进行了加权统计和多变量逻辑回归。结果总体而言,在符合 LCS 条件的 1188.6704 万人中,有 212.99 万人在 4 年内(2019-2022 年)接受了 LCS。2019 年、2020 年、2021 年和 2022 年,全国符合筛查条件者的 LCS 患病率分别为 16.3%(95% 置信区间 [CI]:14.4-18.5)、19.4%(95% CI:15.3-24.3)、18.3%(95% CI:15.6-21.3)和 18.1%(95% CI:17.1-19.2)。报告有肺部疾病和癌症(肺癌除外)病史的受访者在所有 4 年中都更有可能接受 LCS。在大流行期间(2020 年),西班牙裔(相对于白人)和农村(相对于城市)居民使用 LCS 的几率较低。2022 年,男性报告使用 LCS 的几率高于女性。我们的研究结果表明,4 年来,LCS 的使用率一直很低(20%)。在全国范围内努力提高人们对 LCS 的认识和使用率,对于减轻美国的肺癌负担至关重要。
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引用次数: 0
Three-Year Overall Survival Outcomes and Correlative Analyses in Patients With NSCLC and High (50%–89%) Versus Very High (≥90%) Programmed Death-Ligand 1 Expression Treated With First-Line Pembrolizumab or Cemiplimab PD-L1高表达(50-89%)与极高表达(≥90%)非小细胞肺癌患者接受pembrolizumab或cemiplimab一线治疗后的三年总生存期结果及相关分析
IF 3 Q2 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jtocrr.2024.100675

Introduction

Responses to first-line programmed cell death protein 1 inhibition vary among patients with metastatic NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. We previously reported improved clinical outcomes to first-line programmed cell death protein 1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of greater than or equal to 90% versus 50% to 89% in a pilot study. Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS greater than or equal to 90% versus 50% to 89% and characterize genomic and immunophenotypic differences between these PD-L1 expression groups, which were largely unknown.

Methods

We analyzed three-year outcomes of the following two independent cohorts: (1) a multicenter cohort of patients from four academic centers in the United States treated with pembrolizumab and (2) EMPOWER-Lung 1, randomized, phase III trial comparing first-line cemiplimab with chemotherapy. Tumor genomic profiling and multiplexed immunofluorescence were performed to evaluate genomic and immunophenotypic correlates of very high PD-L1 expression.

Results

At three years of follow-up, progression-free survival (hazard ratio [HR], 0.69; p < 0.001) and overall survival (HR, 0.70; p < 0.01) to first-line commercial pembrolizumab were significantly improved in patients with a PD-L1 TPS greater than or equal to 90% versus 50% to 89%. In the EMPOWER-Lung 1, patients assigned to the cemiplimab arm with a PD-L1 TPS greater than or equal to 90% also had significant improvements in progression-free survival (HR, 0.53; p < 0.0001) and overall survival (HR, 0.63; p = 0.007) compared with those with a PD-L1 of 50% to 89%. Tumor genomic profiling of 553 NSCLC samples revealed that mutations in STK11 and SMARCA4 were significantly more frequent in tumors with a PD-L1 TPS of 50% to 89% compared with those with a PD-L1 TPS greater than or equal to 90% (Q < 0.15), whereas BRCA2 was enriched in NSCLC samples with a PD-L1 TPS greater than or equal to 90% (Q < 0.15). Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8+PD1+ T cells (p = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%.

Conclusion

Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%.
导言:转移性 NSCLC 患者的程序性细胞死亡配体 1(PD-L1)肿瘤比例评分(TPS)大于或等于 50%,不同患者对一线程序性细胞死亡蛋白 1 抑制剂的反应各不相同。我们曾在一项试验性研究中报道,PD-L1 TPS大于或等于90%的转移性NSCLC患者一线使用程序性细胞死亡蛋白1抑制剂的临床疗效比PD-L1 TPS大于或等于50%至89%的患者有所改善。在此,我们报告了两个大型独立队列中PD-L1 TPS大于或等于90%与50%至89%的患者使用pembrolizumab和cemiplimab一线治疗的三年生存率,并描述了这些PD-L1表达组之间的基因组和免疫表型差异,这些差异在很大程度上是未知的:我们分析了以下两个独立队列的三年疗效:(1) 来自美国四个学术中心、接受过 pembrolizumab 治疗的患者组成的多中心队列;(2) EMPOWER-Lung 1 随机 III 期试验,比较了一线 cemiplimab 和化疗。结果随访三年后,PD-L1 TPS大于或等于90%的患者的无进展生存期(危险比[HR],0.69;p <;0.001)和一线商用pembrolizumab的总生存期(HR,0.70;p <;0.01)明显改善,PD-L1 TPS大于或等于90%的患者的无进展生存期(危险比[HR],0.69;p <;0.001)和总生存期(HR,0.70;p <;0.01)明显改善,PD-L1 TPS大于或等于50%至89%的患者的总生存期(HR,0.70;p <;0.01)明显改善。在EMPOWER-Lung 1研究中,与PD-L1为50%至89%的患者相比,PD-L1 TPS大于或等于90%的患者在无进展生存期(HR,0.53;p <;0.0001)和总生存期(HR,0.63;p = 0.007)方面也有显著改善。553份NSCLC样本的肿瘤基因组图谱显示,与PD-L1 TPS大于或等于90%的肿瘤相比,STK11和SMARCA4的突变在PD-L1 TPS为50%至89%的肿瘤中明显更频繁(Q <0.15),而BRCA2在PD-L1 TPS大于或等于90%的NSCLC样本中富集(Q <0.15)。对93份NSCLC样本进行多重免疫荧光检测发现,PD-L1 TPS大于或等于90%的肿瘤中CD8+PD1+ T细胞比TPS为50%至89%的肿瘤中CD8+PD1+ T细胞多(p = 0.02)。结论与TPS为50%至89%的晚期NSCLC患者相比,Pembrolizumab和cemiplimab对PD-L1 TPS大于或等于90%的晚期NSCLC患者具有长期生存益处和良好的基因组和免疫表型特征。
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引用次数: 0
Eftilagimod Alpha (a Soluble LAG-3 Protein) Combined With Pembrolizumab in Second-Line Metastatic NSCLC Refractory to Anti–Programmed Cell Death Protein 1/Programmed Death-Ligand 1-Based Therapy: Final Results from a Phase 2 Study Eftilagimod Alpha(一种可溶性 LAG-3 蛋白)与 Pembrolizumab 联合用于抗程序性细胞死亡蛋白 1/程序性死亡配体 1 治疗难治的二线转移性 NSCLC:2 期研究的最终结果
IF 3 Q2 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.1016/j.jtocrr.2024.100725
Matthew G. Krebs MD , Martin Forster MD, PhD , Margarita Majem MD, PhD , Julio Peguero MD , Wade Iams MD , Tim Clay MD , Patricia Roxburgh MD, PhD , Bernard Doger MD, PhD , Pawan Bajaj MD , Andres Barba MD , Suvini Perera MS , Christian Mueller MS , Frédéric Triebel MD, PhD

Introduction

Eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4+ and CD8+) activation and helps overcome resistance to programmed cell death protein 1 or programmed cell death-ligand 1 (PD-(L)1) inhibitors. We assessed efti plus pembrolizumab in second-line anti–PD-(L)1-refractory metastatic patients with NSCLC.

Methods

After confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary endpoint was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary endpoints included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory endpoints included tumor growth kinetics and predefined subgroup analyses. Programmed cell death-ligand 1 tumor proportion score was assessed centrally.

Results

Thirty-six patients were enrolled from April 2019 to August 2021 using Simon’s two-stage design. Most patients (81.8%) had low or negative (<50%) PD-(L)1 tumor proportion score. First-line therapy was anti–PD-(L)1-based for all patients, combined with chemotherapy for 66.7%. The confirmed objective response and disease control rates were 8.3% and 33.3%. The median progression-free survival was 2.1 months and the median OS was 9.9 months. Patients exhibiting high PD-(L)1 expression or acquired resistance to PD-(L)1 inhibitors revealed superior response and survival outcomes, and OS was closely correlated with disease control. No treatment-emergent adverse event led to permanent discontinuation of study treatment.

Conclusions

Efti plus pembrolizumab was well-tolerated and revealed signs of antitumor activity in patients with NSCLC resistant to PD-(L)1 inhibitors, warranting further investigation. Trial registration number: NCT03625323.
导读:Eftilagimod alpha(efti)是一种可溶性淋巴细胞活化基因-3蛋白,可触发抗原递呈细胞和T细胞(CD4+和CD8+)活化,有助于克服程序性细胞死亡蛋白1或程序性细胞死亡配体1(PD-(L)1)抑制剂的耐药性。方法在抗PD-(L)1一线治疗确诊进展后,患者接受依夫替(30 毫克,每2 周皮下注射一次,8 个3 周周期,然后每3 周注射一次,最多54 周)和pembrolizumab(200 毫克,每3 周静脉注射一次,最多105 周)治疗。主要终点是根据修订后的实体瘤免疫疗法反应评估标准1.1版得出的客观反应率。次要终点包括疾病控制率、无进展生存期、总生存期(OS)和耐受性。探索性终点包括肿瘤生长动力学和预定义亚组分析。对程序性细胞死亡配体1肿瘤比例评分进行集中评估。结果从2019年4月到2021年8月,采用西蒙两阶段设计入组了36名患者。大多数患者(81.8%)的PD-(L)1肿瘤比例评分较低或为阴性(<50%)。所有患者的一线治疗均以抗PD-(L)1为基础,66.7%的患者联合化疗。确诊客观反应率和疾病控制率分别为8.3%和33.3%。中位无进展生存期为2.1个月,中位OS为9.9个月。PD-(L)1高表达或对PD-(L)1抑制剂获得性耐药的患者显示出更优越的反应和生存结果,而OS与疾病控制密切相关。结论Efti加pembrolizumab对PD-(L)1抑制剂耐药的NSCLC患者耐受性良好,并显示出抗肿瘤活性迹象,值得进一步研究。试验注册号:NCT03625323:NCT03625323。
{"title":"Eftilagimod Alpha (a Soluble LAG-3 Protein) Combined With Pembrolizumab in Second-Line Metastatic NSCLC Refractory to Anti–Programmed Cell Death Protein 1/Programmed Death-Ligand 1-Based Therapy: Final Results from a Phase 2 Study","authors":"Matthew G. Krebs MD ,&nbsp;Martin Forster MD, PhD ,&nbsp;Margarita Majem MD, PhD ,&nbsp;Julio Peguero MD ,&nbsp;Wade Iams MD ,&nbsp;Tim Clay MD ,&nbsp;Patricia Roxburgh MD, PhD ,&nbsp;Bernard Doger MD, PhD ,&nbsp;Pawan Bajaj MD ,&nbsp;Andres Barba MD ,&nbsp;Suvini Perera MS ,&nbsp;Christian Mueller MS ,&nbsp;Frédéric Triebel MD, PhD","doi":"10.1016/j.jtocrr.2024.100725","DOIUrl":"10.1016/j.jtocrr.2024.100725","url":null,"abstract":"<div><h3>Introduction</h3><div>Eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4<sup>+</sup> and CD8<sup>+</sup>) activation and helps overcome resistance to programmed cell death protein 1 or programmed cell death-ligand 1 (PD-(L)1) inhibitors. We assessed efti plus pembrolizumab in second-line anti–PD-(L)1-refractory metastatic patients with NSCLC.</div></div><div><h3>Methods</h3><div>After confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary endpoint was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary endpoints included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory endpoints included tumor growth kinetics and predefined subgroup analyses. Programmed cell death-ligand 1 tumor proportion score was assessed centrally.</div></div><div><h3>Results</h3><div>Thirty-six patients were enrolled from April 2019 to August 2021 using Simon’s two-stage design. Most patients (81.8%) had low or negative (&lt;50%) PD-(L)1 tumor proportion score. First-line therapy was anti–PD-(L)1-based for all patients, combined with chemotherapy for 66.7%. The confirmed objective response and disease control rates were 8.3% and 33.3%. The median progression-free survival was 2.1 months and the median OS was 9.9 months. Patients exhibiting high PD-(L)1 expression or acquired resistance to PD-(L)1 inhibitors revealed superior response and survival outcomes, and OS was closely correlated with disease control. No treatment-emergent adverse event led to permanent discontinuation of study treatment.</div></div><div><h3>Conclusions</h3><div>Efti plus pembrolizumab was well-tolerated and revealed signs of antitumor activity in patients with NSCLC resistant to PD-(L)1 inhibitors, warranting further investigation. Trial registration number: NCT03625323.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"5 11","pages":"Article 100725"},"PeriodicalIF":3.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Rearranged During Transfection Rearrangement Detection by Fluorescence In Situ Hybridization Compared With Other Techniques in NSCLC 与其他技术相比,荧光原位杂交法检测 NSCLC 转染过程中的基因重组情况
IF 3 Q2 ONCOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.jtocrr.2024.100714
Anne Mc Leer PhD , Julie Mondet PharmD, PhD , Nelly Magnat MSc , Mailys Mersch MSc , Diane Giovannini MD , Camille Emprou MD , Anne-Claire Toffart MD, PhD , Nathalie Sturm MD, PhD , Sylvie Lantuéjoul MD, PhD , David Benito PhD

Introduction

RET rearrangements occur in 1% to 2% NSCLCs. Since no clinically validated RET antibody is currently available, fluorescence in situ hybridization (FISH) is often used as a screening tool to identify patients likely to benefit from RET-targeted therapy. In this study, we performed a comprehensive review of publications in which RET-rearrangement testing was performed by FISH and compared the methods and results with our data.

Methods

The findings of an electronic search for publications using RET-FISH in lung cancer were compared with the results obtained at the Grenoble University Hospital where 784 EGFR-, KRAS-, ALK-, and ROS1-negative NSCLCs were tested by RET break-apart FISH and confirmed by RNA-sequencing (RNA-seq).

Results

Out of the 85 publications using RET-FISH analysis, 52 pertained to patients with lung cancer. The most often used positivity threshold was 15%. Six publications compared RET-FISH with at least one other molecular technique on at least eight samples, and the concordance was variable, from 5.9% to 66.7% for FISH-positive cases. Regarding our data, out of the 784 analyzed samples, 32 (4%) were positive by RET-FISH. The concordance between RET-FISH and RNA-seq in RET-FISH positive samples was 69%.

Conclusions

Overall, both existing literature and our data suggest that RET-FISH testing can be used for rapid screening of RET rearrangements in NSCLC. Nevertheless, using an orthogonal technique such as RNA-seq to confirm RET-FISH-positive cases is essential for ensuring that only patients likely to benefit from RET-target therapy receive the treatment.
1%至2%的NSCLC会出现RET重排。由于目前还没有经过临床验证的 RET 抗体,荧光原位杂交(FISH)通常被用作筛选工具,以确定可能从 RET 靶向治疗中获益的患者。在本研究中,我们对通过 FISH 进行 RET 重排检测的文献进行了全面回顾,并将其方法和结果与我们的数据进行了比较。在格勒诺布尔大学医院,784 例 EGFR、KRAS、ALK 和 ROS1 阴性 NSCLC 接受了 RET 重排 FISH 检测,并通过 RNA 序列(RNA-seq)进行了确认。结果在 85 篇使用 RET-FISH 分析的文献中,52 篇与肺癌患者有关。最常用的阳性阈值为 15%。有 6 篇文献对至少 8 个样本的 RET-FISH 与至少一种其他分子技术进行了比较,两者的一致性不尽相同,FISH 阳性病例的一致性从 5.9% 到 66.7% 不等。就我们的数据而言,在 784 份分析样本中,有 32 份(4%)RET-FISH 阳性。在RET-FISH阳性样本中,RET-FISH与RNA-seq的一致性为69%。结论总的来说,现有文献和我们的数据都表明,RET-FISH检测可用于快速筛查NSCLC中的RET重排。然而,使用 RNA-seq 等正交技术确认 RET-FISH 阳性病例对于确保只有可能从 RET 靶向治疗中获益的患者接受治疗至关重要。
{"title":"Rearranged During Transfection Rearrangement Detection by Fluorescence In Situ Hybridization Compared With Other Techniques in NSCLC","authors":"Anne Mc Leer PhD ,&nbsp;Julie Mondet PharmD, PhD ,&nbsp;Nelly Magnat MSc ,&nbsp;Mailys Mersch MSc ,&nbsp;Diane Giovannini MD ,&nbsp;Camille Emprou MD ,&nbsp;Anne-Claire Toffart MD, PhD ,&nbsp;Nathalie Sturm MD, PhD ,&nbsp;Sylvie Lantuéjoul MD, PhD ,&nbsp;David Benito PhD","doi":"10.1016/j.jtocrr.2024.100714","DOIUrl":"10.1016/j.jtocrr.2024.100714","url":null,"abstract":"<div><h3>Introduction</h3><div><em>RET</em> rearrangements occur in 1% to 2% NSCLCs. Since no clinically validated RET antibody is currently available, fluorescence in situ hybridization (FISH) is often used as a screening tool to identify patients likely to benefit from RET-targeted therapy. In this study, we performed a comprehensive review of publications in which <em>RET</em>-rearrangement testing was performed by FISH and compared the methods and results with our data.</div></div><div><h3>Methods</h3><div>The findings of an electronic search for publications using <em>RET</em>-FISH in lung cancer were compared with the results obtained at the Grenoble University Hospital where 784 <em>EGFR</em><em>-</em>, <em>KRAS</em><em>-</em>, <em>ALK</em>-, and <em>ROS1</em>-negative NSCLCs were tested by <em>RET</em> break-apart FISH and confirmed by RNA-sequencing (RNA-seq).</div></div><div><h3>Results</h3><div>Out of the 85 publications using <em>RET</em>-FISH analysis, 52 pertained to patients with lung cancer. The most often used positivity threshold was 15%. Six publications compared <em>RET</em>-FISH with at least one other molecular technique on at least eight samples, and the concordance was variable, from 5.9% to 66.7% for FISH-positive cases. Regarding our data, out of the 784 analyzed samples, 32 (4%) were positive by <em>RET</em>-FISH. The concordance between <em>RET</em>-FISH and RNA-seq in <em>RET</em>-FISH positive samples was 69%.</div></div><div><h3>Conclusions</h3><div>Overall, both existing literature and our data suggest that <em>RET</em>-FISH testing can be used for rapid screening of <em>RET</em> rearrangements in NSCLC. Nevertheless, using an orthogonal technique such as RNA-seq to confirm <em>RET</em>-FISH-positive cases is essential for ensuring that only patients likely to benefit from <em>RET</em>-target therapy receive the treatment.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"5 12","pages":"Article 100714"},"PeriodicalIF":3.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142534274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Combined RET and MEK Inhibition as a Treatment for RET Fusion-Positive NSCLC With Acquired BRAF Fusion: A Case Report RET和MEK联合抑制治疗RET融合阳性且伴有获得性BRAF融合的NSCLC:病例报告
IF 3 Q2 ONCOLOGY Pub Date : 2024-08-28 DOI: 10.1016/j.jtocrr.2024.100724
Jacobi B. Hines MD , Benjamin C. Bowar PharmD , Margaret Colleton MMS , Lydia Chelala MD , Peng Wang MD , Angad A. Chadha MD , Jeremy Segal MD , Christine M. Bestvina MD
RET fusions are present in 1% to 2% of NSCLCs. Although RET inhibitors like selpercatinib are effective, resistance inevitably develops. We present the case of a 28-year-old female with recurrent NSCLC and a CCDC6::RET fusion treated with selpercatinib. Testing at the time of progression revealed a new SKAP2::BRAF fusion. She was then treated with a combination of selpercatinib and trametinib, which led to a likely partial response, despite the combination demonstrating side effects. This case report details the first known instance of NSCLC with a RET fusion developing resistance by means of a BRAF fusion, treated with combined RET and MEK inhibition.
1%至2%的NSCLC存在RET融合。尽管像色瑞帕替尼这样的RET抑制剂很有效,但不可避免地会产生耐药性。我们报告了一例28岁女性患者的病例,该患者患有复发性NSCLC,并伴有CCDC6::RET融合,曾接受过舍培卡尼治疗。病情恶化时的检测发现了新的 SKAP2::BRAF 融合。随后,她接受了塞培卡替尼和曲美替尼的联合治疗,尽管联合治疗出现了副作用,但她很可能获得了部分应答。本病例报告详细介绍了第一例已知的RET融合的NSCLC患者通过BRAF融合产生耐药性,并接受RET和MEK联合抑制治疗的病例。
{"title":"Combined RET and MEK Inhibition as a Treatment for RET Fusion-Positive NSCLC With Acquired BRAF Fusion: A Case Report","authors":"Jacobi B. Hines MD ,&nbsp;Benjamin C. Bowar PharmD ,&nbsp;Margaret Colleton MMS ,&nbsp;Lydia Chelala MD ,&nbsp;Peng Wang MD ,&nbsp;Angad A. Chadha MD ,&nbsp;Jeremy Segal MD ,&nbsp;Christine M. Bestvina MD","doi":"10.1016/j.jtocrr.2024.100724","DOIUrl":"10.1016/j.jtocrr.2024.100724","url":null,"abstract":"<div><div><em>RET</em> fusions are present in 1% to 2% of NSCLCs. Although RET inhibitors like selpercatinib are effective, resistance inevitably develops. We present the case of a 28-year-old female with recurrent NSCLC and a <em>CCDC6::RET</em> fusion treated with selpercatinib. Testing at the time of progression revealed a new <em>SKAP2</em><em>:</em>:BRAF fusion. She was then treated with a combination of selpercatinib and trametinib, which led to a likely partial response, despite the combination demonstrating side effects. This case report details the first known instance of NSCLC with a <em>RET</em> fusion developing resistance by means of a <em>BRAF</em> fusion, treated with combined RET and MEK inhibition.</div></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"5 11","pages":"Article 100724"},"PeriodicalIF":3.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142426752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unveiling the Molecular Features of SCLC With a Clinical RNA Expression Panel 用临床 RNA 表达面板揭示 SCLC 的分子特征
IF 3 Q2 ONCOLOGY Pub Date : 2024-08-28 DOI: 10.1016/j.jtocrr.2024.100723
Hilal Ozakinci MD , Aileen Y. Alontaga PhD , Pedro Cano MD , John M. Koomen PhD , Bradford A. Perez MD , Amer A. Beg PhD , Alberto A. Chiappori MD , Eric B. Haura MD , Theresa A. Boyle MD, PhD

Introduction

The translation of gene expression profiles of SCLC to clinical testing remains relatively unexplored. In this study, gene expression variations in SCLC were evaluated to identify potential biomarkers.

Methods

RNA expression profiling was performed on 44 tumor samples from 35 patients diagnosed with SCLC using the clinically validated RNA Salah Targeted Expression Panel (RNA STEP). RNA sequencing (RNA-Seq) and immunohistochemistry were performed on two different SCLC cohorts, and correlation analyses were performed for the ASCL1, NEUROD1, POU2F3, and YAP1 genes and their corresponding proteins. RNA STEP and RNA-Seq results were evaluated for gene expression profiles and heterogeneity between SCLC primary and metastatic sites. RNA STEP gene expression profiles of independent SCLC samples (n = 35) were compared with lung adenocarcinoma (n = 160) and squamous cell carcinoma results (n = 25).

Results

The RNA STEP results were highly correlated with RNA-Seq and immunohistochemistry results. The dominant transcription regulator by RNA STEP was ASCL1 in 74.2% of the samples, NEUROD1 in 20%, and POU2F3 in 2.9%. The ASCL1, NEUROD1, and POU2F3 gene expression profiles were heterogeneous between primary and metastatic sites. SCLCs displayed markedly high expression for targetable genes DLL3, EZH2, TERT, and RET. SCLCs were found to have relatively colder immune profiles than lung adenocarcinomas and squamous cell carcinomas, characterized by lower expression of HLA genes, immune cell, and immune checkpoint genes, except the LAG3 gene.

Conclusions

Clinical-grade SCLC RNA expression profiling has value for SCLC subtyping, design of clinical trials, and identification of patients for trials and potential targeted therapy.
导言:SCLC 的基因表达谱在临床检测中的应用相对来说仍有待探索。本研究评估了SCLC中的基因表达变异,以确定潜在的生物标记物。方法使用经临床验证的RNA Salah靶向表达面板(RNA STEP)对35名确诊为SCLC患者的44个肿瘤样本进行了RNA表达谱分析。对两个不同的SCLC队列进行了RNA测序(RNA-Seq)和免疫组化,并对ASCL1、NEUROD1、POU2F3和YAP1基因及其相应蛋白进行了相关性分析。对 RNA STEP 和 RNA-Seq 结果进行了评估,以了解 SCLC 原发部位和转移部位之间的基因表达谱和异质性。将独立 SCLC 样本(n = 35)的 RNA STEP 基因表达谱与肺腺癌(n = 160)和鳞状细胞癌(n = 25)的结果进行了比较。74.2% 的样本中,RNA STEP 的主导转录调节因子是 ASCL1,20% 是 NEUROD1,2.9% 是 POU2F3。ASCL1、NEUROD1和POU2F3基因的表达谱在原发部位和转移部位之间存在差异。SCLCs的靶向基因DLL3、EZH2、TERT和RET的表达明显较高。与肺腺癌和鳞状细胞癌相比,SCLC 的免疫特征相对较低,HLA 基因、免疫细胞和免疫检查点基因(LAG3 基因除外)的表达较低。
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引用次数: 0
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JTO Clinical and Research Reports
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