Rosenbaum Evan, Jonsson Philip, Seier Kenneth, Qin Li-Xuan, Chi Ping, Dickson Mark, Gounder Mrinal, Kelly Ciara, Keohan Mary L, Nacev Benjamin, Donoghue Mark T A, Chiang Sarah, Singer Samuel, Ladanyi Marc, Antonescu Cristina R, Hensley Martee L, Movva Sujana, D'Angelo Sandra P, Tap William D
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.
JCO Precis Oncol. 2020 Nov 6;4. doi: 10.1200/PO.20.00122. eCollection 2020.
To detect alterations in DNA damage repair (DDR) genes, measure homologous recombination deficiency (HRD), and correlate these findings with clinical outcome in patients with leiomyosarcoma (LMS).
Patients with LMS treated at Memorial Sloan Kettering (MSK) Cancer Center who consented to prospective targeted next-generation sequencing with MSK-IMPACT were screened for oncogenic somatic variants in one of 33 DDR genes; where feasible, an experimental HRD score was calculated from IMPACT data. Progression-free survival (PFS) and overall survival (OS) were estimated after stratifying patients by DDR gene alteration status and HRD score.
Of 211 patients with LMS, 20% had an oncogenic DDR gene alteration. Univariable analysis of PFS in 117 patients who received standard frontline chemotherapy in the metastatic setting found that an altered homologous recombination pathway gene was significantly associated with shorter PFS (hazard ratio [HR], 1.79; 95% CI, 1.04 to 3.07; = .035). Non- homologous recombination gene alteration was associated with shorter PFS (HR, 2.61; 95% CI, 1.35 to 5.04; = .004) compared with -altered and wild-type homologous recombination genes. Univariable analysis of OS from diagnosis in the entire cohort of 211 patients found that age, tumor size, number of metastatic sites, localized disease, and non- homologous recombination gene alteration were significantly associated with OS. On multivariable analysis, non- homologous recombination pathway gene alteration remained significant (HR, 4.91; 95% CI, 2.47 to 9.76; < .001). High HRD score was not associated with a different PFS or OS.
Patients with LMS with homologous recombination pathway gene alterations have poor clinical outcomes, particularly those with non- gene alterations. HRD score calculated from a targeted exome panel did not discern disparate clinical outcomes.
检测DNA损伤修复（DDR）基因的改变，测量同源重组缺陷（HRD），并将这些结果与平滑肌肉瘤（LMS）患者的临床结局相关联。
在纪念斯隆凯特琳（MSK）癌症中心接受治疗且同意使用MSK-IMPACT进行前瞻性靶向二代测序的LMS患者，被筛查33个DDR基因中一个基因的致癌体细胞变异；在可行的情况下，根据IMPACT数据计算实验性HRD评分。根据DDR基因改变状态和HRD评分对患者进行分层后，估计无进展生存期（PFS）和总生存期（OS）。
211例LMS患者中，20%存在致癌性DDR基因改变。对117例在转移性情况下接受标准一线化疗的患者进行PFS单变量分析发现，同源重组途径基因改变与较短的PFS显著相关（风险比[HR]，1.79；95%置信区间，1.04至3.07；P = 0.035）。与未改变和野生型同源重组基因相比，非同源重组基因改变与较短的PFS相关（HR，2.61；95%置信区间，1.35至5.04；P = 0.004）。对211例患者的整个队列从诊断开始进行OS单变量分析发现，年龄、肿瘤大小、转移部位数量、局限性疾病和非同源重组基因改变与OS显著相关。多变量分析显示，非同源重组途径基因改变仍然具有显著性（HR，4.91；95%置信区间，2.47至9.76；P < 0.001）。高HRD评分与不同的PFS或OS无关。
同源重组途径基因改变的LMS患者临床结局较差，尤其是那些存在非基因改变的患者。从靶向外显子组面板计算的HRD评分无法区分不同的临床结局。
