Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 33, Issue 34, Pages 4099-+Publisher
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2015.62.4726
Keywords
-
Categories
Funding
- Cycle for Survival
- Laura Mercier Ovarian Cancer Fund
- Kaleidoscope of Hope Foundation
- Liz Tilberis Early Career Award by Ovarian Cancer Research Fund
- Starr Foundation
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- Integrated Genomics Operation Core - National Cancer Institute Cancer Center Core Grant [P30 CA008748]
- SPORE in Ovarian Cancer Grant [P5083639]
Ask authors/readers for more resources
Purpose 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. Patients and Methods 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. Results 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. Conclusion 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. (C) 2015 by American Society of Clinical Oncology
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available