Mezquita Laura, Swalduz Aurélie, Jovelet Cécile, Ortiz-Cuaran Sandra, Howarth Karen, Planchard David, Avrillon Virginie, Recondo Gonzalo, Marteau Solène, Benitez Jose Carlos, De Kievit Frank, Plagnol Vincent, Lacroix Ludovic, Odier Luc, Rouleau Etienne, Fournel Pierre, Caramella Caroline, Tissot Claire, Adam Julien, Woodhouse Samuel, Nicotra Claudio, Auclin Edouard, Remon Jordi, Morris Clive, Green Emma, Massard Christophe, Pérol Maurice, Friboulet Luc, Besse Benjamin, Saintigny Pierre
Cancer Medicine Department, Gustave Roussy, Villejuif, France.
Department of Medical Oncology, Centre Léon Bérard Lyon, France.
JCO Precis Oncol. 2020 Apr 2;4. doi: 10.1200/PO.19.00281. eCollection 2020.
Liquid biopsy specimen genomic profiling is integrated in non-small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with -positive NSCLC and its impact on outcomes.
Patients with advanced -positive NSCLC were prospectively enrolled in the study by researchers at eight French institutions. Plasma samples were analyzed using InVisionFirst-Lung and correlated with clinical outcomes.
Of the 128 patients included in the study, 101 were positive for and 27 for alterations. Blood samples (N = 405) were collected from 29 patients naïve for treatment with tyrosine kinase inhibitors (TKI) or from 375 patients under treatment, including 105 samples collected at disease progression (PD). Sensitivity was 67% (n = 18 of 27) for fusion detection. Higher detection was observed for fusions at TKI failure (n = 33 of 74; 46%) versus in patients with therapeutic response (n = 12 of 109; 11%). -resistance mutations were detected in 22% patients (n = 16 of 74) overall; 43% of the total -resistance mutations identified occurred after next-generation TKI therapy. was the most common mutation detected (n = 7 of 16). Heterogeneity of resistance was observed. resistance was detected in 30% (n = 3 of 10). The absence of circulating tumor DNA mutations at TKI failure was associated with prolonged median overall survival (105.7 months). Complex -resistance mutations correlated with poor overall survival (median, 26.9 months NR for single mutation; = .003) and progression-free survival to subsequent therapy (median 1.7 6.3 months; = .003).
Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy.
液体活检样本基因组分析已纳入非小细胞肺癌（NSCLC）指南；然而，关于基因改变临床相关性的数据却很匮乏。我们在一个大型前瞻性队列的EGFR阳性NSCLC患者中评估了基于靶向扩增子检测的临床效用及其对预后的影响。
法国8家机构的研究人员前瞻性招募了晚期EGFR阳性NSCLC患者。使用InVisionFirst-Lung分析血浆样本并与临床预后相关联。
该研究纳入的128例患者中，101例EGFR阳性，27例有EGFR改变。从29例未接受过酪氨酸激酶抑制剂（TKI）治疗的患者或375例接受治疗的患者中采集血样（N = 405），其中105份样本在疾病进展（PD）时采集。EGFR融合检测的灵敏度为67%（27例中的18例）。在TKI治疗失败时EGFR融合的检测率更高（74例中的33例；46%），而治疗有反应的患者中为（109例中的12例；11%）。总体上，22%的患者（74例中的16例）检测到EGFR耐药突变；鉴定出的所有EGFR耐药突变中，43%发生在新一代TKI治疗后。T790M是检测到的最常见突变（16例中的7例）。观察到耐药的异质性。10%的患者（10例中的3例）检测到C797S耐药。TKI治疗失败时循环肿瘤DNA无突变与总生存期延长相关（中位生存期105.7个月）。复杂的EGFR耐药突变与总生存期差相关（中位生存期，单突变时为26.9个月，无进展生存期为1.7至6.3个月；P = 0.003）。
用于液体活检样本分析的新一代靶向扩增子测序可在未接受TKI治疗的患者中实现对EGFR融合的临床相关检测，并能鉴定接受TKI治疗患者的耐药突变。接受TKI治疗患者的液体活检样本可能影响临床预后并捕捉TKI耐药的异质性，支持其在选择序贯治疗中的作用。
