Chiaruttini Maria Vittoria, Proto Claudia, Lo Russo Giuseppe, Prelaj Arsela, Segale Miriam, Zanghì Anna, Galli Francesca, Greco Francesca G, Signorelli Diego, Brambilla Marta, Occhipinti Mario, De Braud Filippo, Garassino Marina C, Sozzi Gabriella, Rulli Eliana, Boeri Mattia
Laboratory of Methodology for Clinical Research, Clinical Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Unit of Biostatistics, Epidemiology and Public Health, University of Padua, Padua, Italy.
JCO Precis Oncol. 2025 May;9:e2400790. doi: 10.1200/PO-24-00790. Epub 2025 May 22.
Despite the significant improvement in outcomes for patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs), resistance, whether primary or secondary, remains a substantial challenge. Currently, reliable biomarkers to monitor ICI response are lacking, highlighting the need for minimally invasive tools like liquid biopsy to track treatment efficacy. This study aimed to identify circulating microRNAs (miRNAs) as potential biomarkers to track ICI response in patients with NSCLC.
The Apollo longitudinal study enrolled patients with advanced NSCLC receiving ICI in first or subsequent lines. Plasma samples were collected at baseline and follow-up to prospectively assess miRNA profiles until progressive disease (PD). Using a custom reverse transcription-quantitative polymerase chain reaction platform, 276 ratios among 24 lung cancer-related miRNAs were analyzed. The generalized estimating equation and joint models were applied to select the miRNA ratios most associated with PD over time. To control for multiple testing, the Benjamini-Yekutieli method was applied setting a 10% false discovery rate threshold.
From the 211 patients, a total of 454 plasma samples were analyzed. Clinical and biochemical variables had little effect on miRNAs' profile. The analysis identified nine miRNA ratios, all involving miR-145-5p, as significant biomarkers for monitoring treatment response, even after adjustment for the line of therapy. These ratios exhibited a longitudinal modulation pattern consistent with radiologic response, particularly in patients who initially benefited from ICI treatment. In addition, in an independent set of 32 plasma samples from 10 patients receiving ICI as maintenance therapy, the same trends were observed.
A focused panel of miRNA ratios, driven by miR-145-5p, effectively reflects response to ICI therapy in patients with advanced NSCLC, highlighting their potential as biomarkers for treatment monitoring.
尽管接受免疫检查点抑制剂（ICI）治疗的晚期非小细胞肺癌（NSCLC）患者的治疗结果有了显著改善，但耐药性，无论是原发性还是继发性，仍然是一个重大挑战。目前，缺乏可靠的生物标志物来监测ICI反应，这凸显了需要像液体活检这样的微创工具来跟踪治疗效果。本研究旨在鉴定循环微小RNA（miRNA）作为追踪NSCLC患者ICI反应的潜在生物标志物。
阿波罗纵向研究纳入了接受一线或后续线ICI治疗的晚期NSCLC患者。在基线和随访时采集血浆样本，以前瞻性评估miRNA谱，直至疾病进展（PD）。使用定制的逆转录定量聚合酶链反应平台，分析了24种肺癌相关miRNA之间的276个比率。应用广义估计方程和联合模型来选择随时间与PD最相关的miRNA比率。为了控制多重检验，应用Benjamini-Yekutieli方法设定10%的错误发现率阈值。
对211例患者共分析了454份血浆样本。临床和生化变量对miRNA谱影响很小。分析确定了9个miRNA比率，均涉及miR-145-5p，即使在调整治疗线后，也是监测治疗反应的重要生物标志物。这些比率呈现出与放射学反应一致的纵向调节模式，特别是在最初从ICI治疗中获益的患者中。此外，在一组来自10例接受ICI维持治疗患者的32份独立血浆样本中，也观察到了相同的趋势。
由miR-145-5p驱动的一组特定miRNA比率有效地反映了晚期NSCLC患者对ICI治疗的反应，突出了它们作为治疗监测生物标志物的潜力。
