{"doi":"10.1200/jco.2015.62.4726","title":"Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer","abstract":"<jats:sec><jats:title>Purpose</jats:title><jats:p> 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 (&gt; 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor. </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> 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. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> 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. </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> 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. </jats:p></jats:sec>","journal":"Journal of Clinical Oncology","year":2015,"id":614670,"datarank":0.7023196840686331,"base_score":4.68213122712422,"endowment":4.68213122712422,"self_citation_contribution":0.7023196840686331,"citation_network_contribution":0.0,"self_endowment_contribution":0.7023196840686331,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":107,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":487490,"name":"Brooke E. 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Soumerai","orcid":null,"position":12,"is_corresponding":false},{"id":90760,"name":"David M. Hyman","orcid":"0000-0001-8150-9762","position":13,"is_corresponding":false},{"id":14071,"name":"Nicholas D. Socci","orcid":"0000-0002-8254-6925","position":14,"is_corresponding":false},{"id":1353997,"name":"Agnes Viale","orcid":null,"position":15,"is_corresponding":false},{"id":328249,"name":"David M. Gershenson","orcid":"0000-0001-9712-2140","position":16,"is_corresponding":false},{"id":793219,"name":"John Farley","orcid":"0000-0002-5364-8682","position":17,"is_corresponding":false},{"id":1720,"name":"Douglas A. Levine","orcid":"0000-0003-1038-8232","position":18,"is_corresponding":false},{"id":227117,"name":"Neal Rosen","orcid":"0000-0002-8307-654X","position":19,"is_corresponding":false},{"id":1183545,"name":"Michael F. Berger","orcid":"0000-0002-0760-7177","position":20,"is_corresponding":false},{"id":404077,"name":"David R. Spriggs","orcid":"0000-0003-2174-4992","position":21,"is_corresponding":false},{"id":1583976,"name":"Carol A. Aghajanian","orcid":null,"position":22,"is_corresponding":false},{"id":75983,"name":"David B. Solit","orcid":"0000-0002-6614-802X","position":23,"is_corresponding":false},{"id":90739,"name":"Gopa Iyer","orcid":"0000-0002-5093-6099","position":24,"is_corresponding":false},{"id":230685,"name":"Rachel N. Grisham","orcid":"0000-0002-8631-9324","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer","abstract":"<jats:sec><jats:title>Purpose</jats:title><jats:p> 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 (&gt; 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor. </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> 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. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> 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. </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> 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. </jats:p></jats:sec>","is_dataset_classified":null,"base_score":4.68213122712422,"endowment":4.68213122712422,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"26324360","pmcid":"PMC4669594","openalex_id":"https://openalex.org/W2137332694","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"P30 CA008748","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P50 CA083639","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P01 CA052477","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA169351","title":null}],"total_grants":4,"fwci":16.1808,"citation_percentile":0.99297986,"influential_citations":0,"citation_trend":[{"year":2015,"count":4},{"year":2016,"count":13},{"year":2017,"count":13},{"year":2018,"count":13},{"year":2019,"count":14},{"year":2020,"count":15},{"year":2021,"count":13},{"year":2022,"count":6},{"year":2023,"count":6},{"year":2024,"count":4},{"year":2025,"count":5},{"year":2026,"count":1}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4669594","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4669594","host_type":"repository"},{"url":"https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2015.62.4726","host_type":"publisher"},{"url":"https://doi.org/10.1200/jco.2015.62.4726","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/26324360","host_type":"repository"}],"fields_of_study":["Ovarian cancer diagnosis and treatment","Melanoma and MAPK Pathways","Chromatin Remodeling and Cancer"],"mesh_terms":["Carcinoma, Ovarian Epithelial","Animals","Benzimidazoles","Female","Follow-Up Studies","Humans","Middle Aged","Mutation","Neoplasms, Glandular and Epithelial","Ovarian Neoplasms","Prognosis","Biomarkers, Tumor","Tumor Stem Cell Assay","Cystadenocarcinoma, Serous","Drug Resistance, Neoplasm","NIH 3T3 Cells","MAP Kinase Kinase 1","Mice","High-Throughput Nucleotide Sequencing","Neoplasm Grading"],"keywords":["Selumetinib","MEK inhibitor","KRAS","Cancer research","Medicine","Ovarian cancer","Kinase","Serous fluid","Mutation","Protein kinase A","MAPK/ERK pathway","Trametinib","Cancer","Internal medicine","Oncology","Gene","Biology","Genetics"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T15:16:38.434775Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}