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Molecular Profiling of Clear Cell Ovarian Cancers: Identifying Potential Treatment Targets for Clinical Trials
  1. Michael L. Friedlander, MD, PhD,
  2. Kenneth Russell, PhD,
  3. Sherri Millis, PhD,
  4. Zoran Gatalica, MD,
  5. Ryan Bender, PhD, FACMG and
  6. Andreas Voss, MD
  1. Prince of Wales Hospital, Prince of Wales Clinical School UNSW, Sydney, New South Wales, Australia.
  1. Address correspondence and reprint requests to Michael Leonard Friedlander, MD, PhD, Department of Medical Oncology, Prince of Wales Hospital, Barker St, Randwick, Sydney, New South Wales 2031, Australia. E-mail: m.friedlander{at}


Background Advanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets.

Patients and Methods Tumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis.

Results The most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%).

Conclusions This large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials.

  • Clear cell ovarian cancer
  • Next-generation sequencing
  • Molecular profiling
  • Biomarkers
  • Targeted therapies

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