Molecular Profiling and Tumor Biomarker Analysis of GOG281/LOGS: A Positive Late-Phase Trial of Trametinib for Recurrent/Persistent Low-Grade Serous Ovarian Carcinoma.

The GOG281/LOGS trial (NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared with physician's choice standard-of-care (SOC) in patients with LGSOC with persistent/recurrent disease.

GOG281/LOGS试验（NCT02101788）研究了MEK抑制剂trametinib与医生选择的标准治疗（SOC）在具有持续/复发性疾病的LGSOC患者中的疗效。

The study demonstrated significantly improved progression-free survival(PFS) in the trametinib-treated arm.

该研究显示，接受trametinib治疗的组别中无进展生存期（PFS）显著改善。

experimental_design

Two hundred and sixty patients with recurrent/persistent LGSOC were enrolled and randomly assigned in GOG281.

在GOG281研究中，共有260名复发/持续性低级别浆液性卵巢癌（LGSOC）患者被纳入并随机分配。

We performed molecular analysis of 170 patients with available tumor specimens, comprising whole-exome sequencing and phospho-ERK (pERK) IHC, to identify biomarkers of clinical benefit from trametinib.

我们对170名拥有肿瘤样本的患者进行了分子分析，包括全外显子组测序和磷酸化ERK（pERK）免疫组化，以识别从trametinib中获益的临床生物标志物。

The demographics of the translational cohort (n = 170) were comparable with those of the total trial cohort.

转化研究队列（n = 170）的人口统计学特征与总试验队列的特征相当。

Results

High tumor pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs. 5.6 months, log-rank P < 0.0001; test for interaction P = 0.023).

高肿瘤pERK表达（大于中位组织评分140）与接受trametinib治疗相比，总生存期显著延长（中位数20.1个月对比5.6个月，log-rank P < 0.0001；交互作用检验P = 0.023）。

Tumors harboring canonical RAS-RAF-MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs. 8.3%; Barnard's P = 0.0004; test for interaction P = 0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P = 0.719).

携带典型RAS-RAF-MAPK突变的肿瘤（KRAS/BRAF/NRAS：44/134，占病例的32.8%）对trametinib的反应率更高（50.0%对比8.3%；Barnard's P = 0.0004；交互作用检验P = 0.054），但KRAS/BRAF/NRAS状态并不能预测总生存期的延长（交互作用检验P = 0.719）。

KRAS amplification (n = 5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n = 25 without KRAS/NRAS/BRAF mutation or KRAS copy number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders.

KRAS扩增（n=5，无KRAS/NRAS/BRAF突变）和MAPK相关基因突变（n=25，无KRAS/NRAS/BRAF突变或KRAS拷贝数增加）将具有可识别的MAPK缺陷的病例数量扩大到55.2%，但考虑这些事件并未改善对trametinib反应者的区分。

Chr1p loss (49% of cases) was associated with lower pERK expression (P = 0.021).

Chr1p缺失（占病例的49%）与较低的pERK表达相关（P=0.021）。

Conclusions

This exploratory analysis suggests that pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

这项探索性分析表明，pERK表达和KRAS/BRAF/NRAS突变分别是改善无进展生存期（PFS）和对trametinib反应的潜在生物标志物。