Epithelial Ovarian Cancer: Rationale for Changing the One-Fits-All Standard Treatment Regimen to Subtype-Specific Treatment

Despierre, Evelyn MD*†; Yesilyurt, Betül T. MSc†‡; Lambrechts, Sandrina MD*; Johnson, Nick MD§; Verheijen, René MD, PhD; van der Burg, Maria MD, PhD; Casado, Antonio MD, PhD#; Rustin, Gordon MD**; Berns, Els PhD; Leunen, Karin MD, PhD*; Amant, Frédéric MD, PhD*; Moerman, Philippe MD, PhD††; Lambrechts, Diether MSc, PhD; Vergote, Ignace MD, PhD*; on behalf of the EORTC GCG and EORTC GCG Translational Research Group

International Journal of Gynecological Cancer: March 2014 - Volume 24 - Issue 3 - p 468–477
doi: 10.1097/IGC.0000000000000089
Ovarian Cancer

Objective: Epithelial ovarian cancers (EOCs) are, although still treated as a single disease entity, often classified into type I tumors (low-grade serous, mucinous, endometrioid, clear cell) and type II tumors (high-grade serous, undifferentiated cancers, carcinosarcomas). The aim of our study was to determine the incidence, clinical relevance, and prognostic and predictive impact of somatic mutations in both types I and II EOCs.

Methods: Two hundred sixty-two evaluable, primary, high-risk stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) and stage II-IV EOCs, collected at the University Hospitals Leuven and within the European Organisation for Research and Treatment of Cancer 55971 trial, were genotyped for hotspot mutations in KRAS (COSMIC [Catalogue of Somatic Mutations in Cancer] coverage >97%), BRAF (>94%), NRAS (>97%), PIK3CA (>79%), PTEN, FBXW7 (>57%), AKT2, AKT3, and FOXL2, using Sequenom MassARRAY.

Results: Of the 13% histopathologically classified type I tumors, 49% were KRAS or PIK3CA mutant versus only 2.9% in the type II tumors (87%). Mucinous subtypes harbored significantly more KRAS mutations than all nonmucinous tumors (50% vs 4%, P < 0.001). PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis. Moreover, low-grade serous tumors were more frequently KRAS or BRAF mutated (44%) than high-grade serous tumors (0.6%). KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival. Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%).

Conclusions: Somatic mutations are rare in type II EOCs, whereas type I EOCs contain distinct diseases with different driver mutations. In general, these tumors respond worse to standard paclitaxel carboplatin therapy. Clinical trials with molecular targeted therapy in the different subtypes of type I tumors are urgently needed using this theragnostic information.

*Gynecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven; and †Laboratory for Translational Genetics, Department of Oncology, Katholieke Universiteit Leuven; and ‡Vesalius Research Center, VIB, Leuven, Belgium; §Royal United Hospital NHS Trust, Gynaecological Oncology, Bath, United Kingdom; ∥Division of Women and Baby, Department of Gynaecological Oncology, University Medical Centre Utrecht; and ¶Department of Medical Oncology, Erasmus University Medical Center–Cancer Institute, Rotterdam, the Netherlands; #Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain; **Medical Oncology, Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex, United Kingdom; and ††Department of Pathology, University Hospitals Leuven, Belgium.

Address correspondence and reprint requests to Evelyn Despierre, MD, Division of Gynecologic Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: evelyn.despierre@uzleuven.be.

F.A. is senior researcher for the Research Foundation Flanders (F.W.O.).

Financial support to this work was provided by the Belgian Cancer Plan, Ministry of Health, Belgium (Cancer Plan Action 29), and the European Organisation for Research and Treatment of Cancer board (STrF 2009).

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The authors declare no conflicts of interest.

Received June 5, 2013

Accepted December 19, 2013

© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.