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Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer.
- Source :
-
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2015 Dec 01; Vol. 33 (34), pp. 4099-105. Date of Electronic Publication: 2015 Aug 31. - Publication Year :
- 2015
-
Abstract
- 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.<br />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.<br />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.<br />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.<br /> (© 2015 by American Society of Clinical Oncology.)
- Subjects :
- Animals
Benzimidazoles pharmacology
Carcinoma, Ovarian Epithelial
Cystadenocarcinoma, Serous pathology
Female
Follow-Up Studies
High-Throughput Nucleotide Sequencing
Humans
MAP Kinase Kinase 1 antagonists & inhibitors
Mice
Middle Aged
NIH 3T3 Cells
Neoplasm Grading
Neoplasms, Glandular and Epithelial pathology
Ovarian Neoplasms pathology
Prognosis
Tumor Stem Cell Assay
Biomarkers, Tumor genetics
Cystadenocarcinoma, Serous genetics
Drug Resistance, Neoplasm genetics
MAP Kinase Kinase 1 genetics
Mutation genetics
Neoplasms, Glandular and Epithelial genetics
Ovarian Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1527-7755
- Volume :
- 33
- Issue :
- 34
- Database :
- MEDLINE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 26324360
- Full Text :
- https://doi.org/10.1200/JCO.2015.62.4726