Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
Target Oncol. 2018 Aug;13(4):495-500. doi: 10.1007/s11523-018-0576-z.
Tumor profiling by targeted next-generation sequencing (tNGS) and personalized treatment based on these results is becoming increasingly common in patients with metastatic solid tumors, but it remains unclear whether this strategy results in benefit to patients with metastatic prostate cancer (mPCa).
To assess the clinical utility of tNGS in treatment decision-making for patients with mPCa.
Patients with available genomic profiling using tumor tissue (FoundationOne, F1) or cell-free DNA (FoundationACT, Guardant360) were included. Targetable genomic alterations (tGA) included a change in the copy number or mutations in DNA repair genes, mismatch repair genes, PTEN, cyclin-dependent kinases, ERBB2, BRAF, TSC, and the PIK3/mTOR pathway.
The study included 66 patients, 86% of which had metastatic castration-resistant prostate cancer (mCRPC), and who had received a median of 3 (range 0-7) treatments prior to tNGS. The most frequent alterations were found in TP53 (42%), PTEN (35%), androgen receptor (AR) (30%), DNA repair (30%), PIK3CA signaling pathway (21%), cyclin-dependent kinases (15%), BRAF (9%), and MMR/MSI (6%) genes. Among the 45 (68%) tGA+ patients, tNGS influenced treatment in 13 (29%) [PARP inhibitor (n = 7), mTOR inhibitor (n = 4), anti-PD-1 (n = 2), anti-HER2 (n = 1)]. The median progression-free survival (PFS) was 4.1 months [95% confidence interval (CI), 2.8-5.4]. Among tGA+ patients who did not receive tNGS-based therapy, systemic treatment (n = 17) included chemotherapy (71%), new generation anti-androgen therapy (24%), and cabozantinib (6%); the median PFS was 4.3 months (95% CI, 2.6-6.0; p = 0.7 for tGA+ with personalized therapy vs. tGA+ without personalized therapy).
In this cohort, the use of tNGS was feasible, detected frequent genomic alterations, and was used late in the disease course. Further studies and larger portfolios of targeted therapy trials are needed to maximize the benefit of tNGS in this population.
肿瘤靶向二代测序（tNGS）的肿瘤分析以及基于这些结果的个体化治疗在转移性实体瘤患者中越来越常见，但尚不清楚这种策略是否对转移性前列腺癌（mPCa）患者有益。
评估 tNGS 在 mPCa 患者治疗决策中的临床应用价值。
纳入了可用肿瘤组织（FoundationOne，F1）或循环游离 DNA（FoundationACT，Guardant360）进行基因组分析的患者。可靶向的基因组改变（tGA）包括 DNA 修复基因、错配修复基因、PTEN、细胞周期蛋白依赖性激酶、ERBB2、BRAF、TSC 和 PIK3/mTOR 通路中的拷贝数改变或突变。
该研究纳入了 66 例患者，其中 86%患有转移性去势抵抗性前列腺癌（mCRPC），在接受 tNGS 之前，中位数接受了 3（0-7）种治疗。最常见的改变发生在 TP53（42%）、PTEN（35%）、雄激素受体（AR）（30%）、DNA 修复（30%）、PIK3CA 信号通路（21%）、细胞周期蛋白依赖性激酶（15%）、BRAF（9%）和 MMR/MSI（6%）基因。在 45 例（68%）tGA+患者中，tNGS 影响了 13 例（29%）的治疗[聚腺苷二磷酸核糖聚合酶抑制剂（n=7）、mTOR 抑制剂（n=4）、抗 PD-1（n=2）、抗 HER2（n=1）]。中位无进展生存期（PFS）为 4.1 个月[95%置信区间（CI），2.8-5.4]。在未接受 tNGS 治疗的 tGA+患者中，系统治疗（n=17）包括化疗（71%）、新一代抗雄激素治疗（24%）和卡博替尼（6%）；中位 PFS 为 4.3 个月（95%CI，2.6-6.0；tGA+接受个体化治疗与 tGA+未接受个体化治疗的 PFS 相比，p=0.7）。
在本队列中，tNGS 的使用是可行的，检测到了频繁的基因组改变，并在疾病晚期使用。需要进一步的研究和更大的靶向治疗试验组合，以最大限度地提高 tNGS 在该人群中的获益。
