Extreme outlier analysis identifies occult mitogen-activated protein kinase pathway mutations in patients with low-grade serous ovarian cancer Journal Article


Authors: Grisham, R. N.; Sylvester, B. E.; Won, H.; McDermott, G.; DeLair, D.; Ramirez, R.; Yao, Z.; Shen, R. L.; Dao, F.; Bogomolniy, F.; Makker, V.; Sala, E.; Soumerai, T. E.; Hyman, D. M.; Socci, N. D.; Viale, A.; Gershenson, D. M.; Farley, J.; Levine, D. A.; Rosen, N.; Berger, M. F.; Spriggs, D. R.; Aghajanian, C. A.; Solit, D. B.; Iyer, G.
Article Title: Extreme outlier analysis identifies occult mitogen-activated protein kinase pathway mutations in patients with low-grade serous ovarian cancer
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. 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
Keywords: genes; carcinoma; kras; braf mutation; borderline tumors; acquired-resistance; mek inhibition; melanomas; combinations; (v600e)braf
Journal Title: Journal of Clinical Oncology
Volume: 33
Issue: 34
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2015-12-01
Start Page: 4099
End Page: 4105
Language: English
ACCESSION: WOS:000366021000019
DOI: 10.1200/jco.2015.62.4726
PROVIDER: wos
PMCID: PMC4669594
PUBMED: 26324360
Notes: Article -- Source: Wos
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MSK Authors
  1. Vicky Makker
    71 Makker
  2. Evis Sala
    93 Sala
  3. Neal Rosen
    352 Rosen
  4. David Solit
    421 Solit
  5. Douglas A Levine
    351 Levine
  6. Ronglai Shen
    126 Shen
  7. Gopakumar Vasudeva Iyer
    122 Iyer
  8. Rachel Nicole Grisham
    32 Grisham
  9. David Hyman
    176 Hyman
  10. Agnes Viale
    203 Viale
  11. David R Spriggs
    302 Spriggs
  12. Nicholas D Socci
    182 Socci
  13. Michael Forman Berger
    373 Berger
  14. Deborah F DeLair
    85 DeLair
  15. Fanny Dao
    56 Dao
  16. Helen Hyeong-Eun Won
    78 Won
  17. Zhan Yao
    21 Yao