Grisham Rachel N, Sylvester Brooke E, Won Helen, McDermott Gregory, DeLair Deborah, Ramirez Ricardo, Yao Zhan, Shen Ronglai, Dao Fanny, Bogomolniy Faina, Makker Vicky, Sala Evis, Soumerai Tara E, Hyman David M, Socci Nicholas D, Viale Agnes, Gershenson David M, Farley John, Levine Douglas A, Rosen Neal, Berger Michael F, Spriggs David R, Aghajanian Carol A, Solit David B, Iyer Gopa
Rachel N. Grisham, Brooke E. Sylvester, Helen Won, Deborah DeLair, Zhan Yao, Ronglai Shen, Fanny Dao, Faina Bogomolniy, Vicky Makker, Evis Sala, Tara E. Soumerai, David M. Hyman, Douglas A. Levine, Neal Rosen, Michael F. Berger, David R. Spriggs, Carol A. Aghajanian, David B. Solit, and Gopa Iyer, Memorial Sloan Kettering Cancer Center; Rachel N. Grisham, Gregory McDermott, Vicky Makker, David M. Hyman, Neal Rosen, Michael F. Berger, David R. Spriggs, Carol A. Aghajanian, David B. Solit, and Gopa Iyer, Weill Cornell Medical College; Ricardo Ramirez, Graduate School of Medical Sciences; Nicholas D. Socci and Agnes Viale, Michael F. Berger, and David B. Solit, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, New York, NY; David M. Gershenson, University of Texas MD Anderson Cancer Center, Houston, TX; and John Farley, St Joseph's Hospital and Medical Center, Phoenix, AZ.
J Clin Oncol. 2015 Dec 1;33(34):4099-105. doi: 10.1200/JCO.2015.62.4726. Epub 2015 Aug 31.
No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor.
Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed.
Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor-based combination therapy.
Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease.
对于转移性低级别浆液性（LGS）卵巢癌患者，目前尚无有效的全身治疗方法。BRAF和KRAS突变在浆液性交界性（SB）和LGS卵巢癌中很常见，并且已证明MEK抑制可在少数患者中诱导肿瘤消退；然而，尚未观察到突变状态与临床反应之间的相关性。为了确定对MEK抑制剂治疗敏感的生物标志物，我们对一名对非ATP竞争性MEK抑制剂司美替尼产生完全、持久且持续（>5年）反应的患者进行了离群值分析。
使用二代测序分析该患者的肿瘤以及另外28个SB/LGS肿瘤。对鉴定出的感兴趣的新型改变进行功能表征。
对这位特别有反应的患者的肿瘤分析发现，编码MEK1的MAP2K1基因的负调控螺旋中有一个15个核苷酸的缺失。功能表征表明，这种突变体诱导细胞外信号调节激酶途径激活，促进小鼠体内的非锚定依赖性生长和肿瘤形成，并对司美替尼保持敏感性。对其他LGS/SB肿瘤的分析发现，预计82%（28个中的23个）的突变会诱导细胞外信号调节激酶途径激活，其中包括两名BRAF融合患者，其中一名对基于MEK抑制剂的联合治疗产生了持续的完全反应。
大多数LGS卵巢癌患者存在影响丝裂原活化蛋白激酶途径的改变。二代测序分析揭示了较旧测序方法未检测到的缺失和融合。这些发现，再加上复发性LGS卵巢癌患者的一个亚组对MEK抑制剂治疗有显著且持久反应的观察结果，支持对MEK抑制剂在这种疾病中的进一步临床研究。
