Abstract 605: The clinical outcome of patients with FOXL2 402C-&gt;G mutation positive adult-type Granulosa Cell Tumor of the ovary - a population based study with analysis of tissue and plasma ctDNA
Authors: Färkkilä Anniina , McConechy Melissa K. , Yang Winnie , Rozenberg Nirit , Andersson Noora , Unkila-Kallio Leila , Bützow Ralf , Gilks Blake , Huntsman David G. , Anttonen Mikko 
Published: August 2015

Abstract
Adult-type Granulosa Cell Tumors (AGCTs) are rare ovarian neoplasms comprising of 5% of all ovarian cancers. The FOXL2 (C-&gt;G) C134W mutation has been identified in 95% of all AGCTs, making it a pathognomonic defining feature. The histological diagnosis of AGCT is challenging; false diagnoses have been reported in up to 30-50% of cases in historical series. AGCTs behave unpredictably, and recurrences occur in 30-60% of the patients. The clinical outcome of molecularly defined, FOXL2-mutation positive AGCTs remains unknown.
We conducted a partially prospective, population-based study of 248 AGCT patients diagnosed or treated at Helsinki University Central Hospital, Finland, during 3/1956-10/2013. Clinical data were collected from hospital records and the causes of death from the Finnish Causes of Death registry. FOXL2 mutation was analyzed from DNA extracted from FFPE (n = 171), and fresh tumor tissue samples (n = 51). Histological diagnosis was re-evaluated in Helsinki, and differential diagnostic cases (n = 24) were subjected to a blinded histological review in Vancouver. Serial plasma samples (n = 120) were collected prospectively during 8/2007- 4/2013 from 37 AGCT patients. The extracted ctDNA was preamplified using the C134W FOXL2 Taqman primer/probe. Tissue and plasma DNA were analyzed with Raindance Raindrop digital PCR technology. Statistical analyses were performed with Kaplan-Meier, and comparison of ctDNA positivity to tumor diameter with oneway ANOVA using JMP software.
Of the original cohort, 165 (74%) tumors were positive and 57 (26%) tumors were negative for the FOXL2 402C-&gt;G mutation. Upon pathological review, an alternate diagnosis was set for 35 mutation negative patients in the first review (Helsinki), and for 41 patients in the final review (Vancouver). The vast majority (n = 149, 90%) of the FOXL2 mutation positive AGCT patients were diagnosed at stage I. The 5-, 10, and 15-year disease-specific survival (DSS) rates were 99%, and 93%, and 89% for the FOXL2 positive AGCT patients, compared to 58%, 53%, and 51% for the FOXL2 wild-type/misdiagnosed other tumors (p&lt;0.0001, log-rank test). 51 (31%) of the FOXL2 positive AGCT patients had a recurrence at a median time of 7.6 years (range 1-26 years) after the diagnosis. FOXL2 mutation was detected in the plasma of 17% (n = 8) of samples from patients with primary or recurrent AGCT. ctDNA FOXL2 mutation was more likely detected in patients with large tumors (p = 0.003).
We have characterized the largest population based cohort of AGCT patients, and shown that the outcome of the patients with FOXL2 mutation positive AGCT was superior to those with original AGCT misdiagnosis. ctDNA is a promising tool to diagnose AGCT in a non-invasive manner. Testing FOXL2 mutation should be used as standard of care, especially in differential diagnostic cases.
Citation Format: Anniina Färkkilä, Melissa K. McConechy, Winnie Yang,, Nirit Rozenberg, Noora Andersson, Leila Unkila-Kallio, Ralf Bützow, Blake Gilks, David G. Huntsman, Mikko Anttonen. The clinical outcome of patients with FOXL2 402C-&gt;G mutation positive adult-type Granulosa Cell Tumor of the ovary - a population based study with analysis of tissue and plasma ctDNA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 605. doi:10.1158/1538-7445.AM2015-605