Jee Justin, Lebow Emily S, Yeh Randy, Das Jeeban P, Namakydoust Azadeh, Paik Paul K, Chaft Jamie E, Jayakumaran Gowtham, Rose Brannon A, Benayed Ryma, Zehir Ahmet, Donoghue Mark, Schultz Nikolaus, Chakravarty Debyani, Kundra Ritika, Madupuri Ramyasree, Murciano-Goroff Yonina R, Tu Hai-Yan, Xu Chong-Rui, Martinez Andrés, Wilhelm Clare, Galle Jesse, Daly Bobby, Yu Helena A, Offin Michael, Hellmann Matthew D, Lito Piro, Arbour Kathryn C, Zauderer Marjorie G, Kris Mark G, Ng Kenneth K, Eng Juliana, Preeshagul Isabel, Victoria Lai W, Fiore John J, Iqbal Afsheen, Molena Daniela, Rocco Gaetano, Park Bernard J, Lim Lee P, Li Mark, Tong-Li Candace, De Silva Madhawa, Chan David L, Diakos Connie I, Itchins Malinda, Clarke Stephen, Pavlakis Nick, Lee Adrian, Rekhtman Natasha, Chang Jason, Travis William D, Riely Gregory J, Solit David B, Gonen Mithat, Rusch Valerie W, Rimner Andreas, Gomez Daniel, Drilon Alexander, Scher Howard I, Shah Sohrab P, Berger Michael F, Arcila Maria E, Ladanyi Marc, Levine Ross L, Shen Ronglai, Razavi Pedram, Reis-Filho Jorge S, Jones David R, Rudin Charles M, Isbell James M, Li Bob T
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Weill Cornell Medicine, Cornell University, New York, NY, USA.
Nat Med. 2022 Nov;28(11):2353-2363. doi: 10.1038/s41591-022-02047-z. Epub 2022 Nov 10.
Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.
循环肿瘤DNA（ctDNA）测序可指导治疗决策，但大多是在小队列中进行研究，缺乏足够的随访来确定其对总生存期的影响。我们前瞻性地跟踪了一个由1127例非小细胞肺癌患者组成的国际队列，并采用了ctDNA指导的治疗方法。ctDNA检测与较短的生存期相关（风险比[HR]，2.05；95%置信区间[CI]，1.74 - 2.42；P < 0.001），且独立于临床病理特征和代谢肿瘤体积。在722例（64%）可检测到ctDNA的患者中，255例（23%）通过ctDNA测序匹配到靶向治疗的患者比未接受靶向治疗的患者生存期更长（HR，0.63；95% CI，0.52 - 0.76；P < 0.001）。在25%的患者中发现了时间匹配的组织测序未检测到的ctDNA基因组改变。这些仅在ctDNA中出现的改变不成比例地以耐药的亚克隆驱动因素为特征，包括RICTOR和PIK3CA改变，并与生存期短相关。微创ctDNA分析可以识别组织测序未捕获的异质性驱动因素，并扩大社区获得延长生命治疗的机会。
