Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: https://twitter.com/ChrisHeiligMD.
Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Eur J Cancer. 2022 Sep;172:107-118. doi: 10.1016/j.ejca.2022.05.025. Epub 2022 Jun 25.
The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug.
We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers.
Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p < 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib.
A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.
多受体酪氨酸激酶抑制剂帕唑帕尼已被批准用于治疗晚期软组织肉瘤，并且在其他肉瘤亚型中也显示出活性。然而，其临床疗效差异很大，目前尚无可靠的预测指标来选择可能从该药物中获益的患者。
我们分析了在德国癌症联合会 DKTK MASTER 进行的一项前瞻性观察性研究中接受帕唑帕尼治疗的肉瘤患者的分子谱和临床结果，该研究采用全基因组/外显子测序和转录组测序来为接受治疗的年轻成年患者和患有罕见癌症的患者提供治疗。
在 109 名可提供全基因组/外显子测序数据的患者中，临床参数、特定的遗传改变或突变特征与临床结果之间没有相关性。相比之下，对 62 名在接受帕唑帕尼治疗前进行了分子分析且有转录组测序数据的亚组患者的分析表明，NTRK3（风险比 [HR] = 0.53，p = 0.021）、IGF1R（HR = 1.82，p = 0.027）和 KDR（HR = 0.50，p = 0.011）的 mRNA 水平与无进展生存期（PFS）独立相关。基于这些受体酪氨酸激酶基因的表达，即 NTRK3-高、IGF1R-低和 KDR-高，我们开发了一种帕唑帕尼疗效预测因子，可将患者分为 PFS 明显不同的三组（p < 0.0001）。将帕唑帕尼疗效预测因子应用于 DKTK MASTER 中接受帕唑帕尼治疗的肉瘤患者的另一独立队列（n = 43）中，证实了其将 PFS 明显不同的患者分组的潜力（p = 0.02），而在未接受帕唑帕尼治疗的 DKTK MASTER 患者（n = 97）或癌症基因组图谱肉瘤队列（n = 256）中则未观察到这种关联。
基于 NTRK3、IGF1R 和 KDR 的联合表达得分可识别接受帕唑帕尼治疗后预后良好、中等和较差的肉瘤患者，并需要前瞻性研究作为优化该药物在临床上使用的预测工具。
