Abstract A79: Comprehensive genomic profiling (CGP) of adult granulosa cell tumors (aGCT) identifies clinically relevant genomic alterations (CRGA) and targeted therapy options
Authors: Rowland Michelle , McMeekin Scott , Moore Kathleen , Bailey Mark , Ali Siraj M. , Zuna Rosemary , Vergilio Jo-Anne , Suh James , Chmielecki Juliann , Frampton Garrett M. , Lipson Doron , Stephens Philip J. , Miller Vincent A. , Ross Jeffrey S. , Elvin Julia A. 
Published: May 2016

Background: Adult granulosa cell tumors account for ∼70% of sex cord stromal tumors of the ovary. Most behave as low-grade malignancies and present as stage I disease. However 20% recur, often after a prolonged time (median time to recurrence 6 years). Current therapeutic options (bleomycin/etoposide/cisplatin (BEP), hormone therapy, bevacizumab) have shown modest efficacy in the setting of advanced or recurrent disease. Prior genomic studies of aGCT identified recurrent FOXL2 mutations as characteristic of this tumor type, however this mutation is not currently amenable to targeted therapy. We present the CGP of 70 advanced/recurrent stage aGCT with identification of CRGAs and include a description of a patient response to CGP-matched targeted therapy.

Methods: DNA was extracted from 70 FFPE aGCT clinical specimens. Hybridization captured libraries of 236 (FoundationOne, n = 28) or 315 (FoundationOne, n = 42) genes, plus select introns frequently rearranged in cancer, which were sequenced to high (median 780x), uniform coverage. All classes of genomic alterations (base subs, small in/dels, rearrangements, and copy number alterations) were evaluated and reported. CRGA were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials.

Results: 70 samples, 10% from primary site tissue and 90% from metastatic sites were included. The patients were women aged 30-80 (median 56.5y) with predominantly advanced stage aGCT. 68 cases (97%) had the FOXL2 402C&gt;G mutation and 61% of cases had at least one additional GA (total n = 165) including 37 different genes (avg 2.4 GA per tumor) of which 27 were CRGA (avg 0.44 per tumor). 40% of aGCT cases featured ≥ 1 CRGA, including 14 (20%) cases with CRGA in the PI3K/Akt/mTOR pathway. The most common CRGAs observed were: MLL2 (10%),PIK3CA (8.6%), CDKN2A/B (8.6%), AKT1 (4.3%), KRAS (4.3%); and NRAS (2.8%). To date, we are aware of one patient with an AKT1 missense mutation in the pleckstrin homology domain (AKT1 Q79K) who showed a durable 6-month partial response to AKT-directed targeted treatment.

Conclusions: Almost two-thirds of advanced stage aGCT demonstrate GAs in addition to the pathognomonic FOXL2 mutation. 40% of cases demonstrate other targetable mutations, most commonly in the PI3K/Akt/mTOR pathway which present the opportunity for targeted therapy. This first account of a clinical response to CGP-directed targeted therapy in aGCT demonstrates potential efficacy of an AKT inhibitor in a subset of patients suffering from this otherwise treatment refractory tumor. Patients who have exhausted other SOC therapy for metastatic aGCT may similarly achieve clinical benefit from CGP-directed therapeutic decision-

making and this provides support for development of further mutation-matched therapeutic trial designs.

Citation Format: Michelle Rowland, Scott McMeekin, Kathleen Moore, Mark Bailey, Siraj M. Ali, Rosemary Zuna, Jo-Anne Vergilio, James Suh, Juliann Chmielecki, Garrett M. Frampton, Doron Lipson, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, Julia A. Elvin. Comprehensive genomic profiling (CGP) of adult granulosa cell tumors (aGCT) identifies clinically relevant genomic alterations (CRGA) and targeted therapy options. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A79.