Characterizing FOLR1 expression in low-grade serous ovarian carcinoma.

person Tullia Rushton Johns Hopkins Hospital, Baltimore, MD info_outline Tullia Rushton, Harris Benjamin Krause, Andrew Elliott, Anthony Karnezis, Michael Driscoll Toboni, Premal H. Thaker, David R. Braxton, Matthew James Oberley, David Marc Gershenson, Deborah Kay Armstrong

Authors person Tullia Rushton Johns Hopkins Hospital, Baltimore, MD info_outline Tullia Rushton, Harris Benjamin Krause, Andrew Elliott, Anthony Karnezis, Michael Driscoll Toboni, Premal H. Thaker, David R. Braxton, Matthew James Oberley, David Marc Gershenson, Deborah Kay Armstrong Organizations Johns Hopkins Hospital, Baltimore, MD, Caris Life Sciences, Irving, TX, Caris Life Sciences, Phoenix, AZ, University of California Davis, Davis, CA, University of Alabama at Birmingham, Birmingham, AL, Washington University School of Medicine, St. Louis, MO, Hoag Memor Hosp, Newport Beach, CA, The University of Texas MD Anderson Cancer Center, Houston, TX, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD Abstract Disclosures Research Funding No funding sources reported Background: Targeted therapy in folate receptor alpha (FOLR1)-positive high grade serous ovarian carcinoma (HG) is now a mainstay for platinum-resistant disease, though the rate of FOLR1-positivity in low grade serous ovarian carcinoma (LG) is unknown. We compared the genomic and transcriptomic landscapes in FOLR1-positive/negative LG in comparison to its HG counterpart. Methods: LG (N = 281) and HG (N = 5086) tumors were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or whole exome) and RNA (whole transcriptome). PD-L1+ (22C3, TPS > 1%) and FOLR1 (Positive [F+], ⩾ 2+, ⩾75%) expression was assessed by IHC. Mutations were defined as pathogenic SNVs/indels (-Mt). Transcriptomic signatures associated with response to immunotherapy (T cell-inflamed) or with MAPK pathway activation (MPAS) were applied. Fisher’s exact/χ 2 and Mann-Whitney U tests were applied as appropriate ( p < .05, adjusted for multiple comparisons). Real-world overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined patients. This study was reviewed by the Johns Hopkins Medicine IRB and determined to qualify as exempt human subjects research. Results: HG tumors had a higher prevalence of F+ tumors (43.5%) as compared to LG (24.6%). HG tumors had a higher prevalence of TP53 -Mt compared to LG (LG F+: 11.1%, LG F-: 4.1, HG F+: 97.1, HG F-: 95.6, p < .001). Conversely, KRAS-Mt and NRAS-Mt were enriched in LG tumors (KRAS [LG F+: 22.2%, LG F-: 21.6, HG F+: 0.4, HG F-: 3.3, p < .001], NRAS [LG F+: 0%, LG F-: 10.2, HG F+: 0.2, HG F-: 0.1, p < .001]). BRAF -Mt were also almost exclusively present in LG tumors although more prevalent in LG F- as compared to LG F+ (LG F+: 7.4%, LG F-: 14.3, HG F+: 0.2, HG F-: 0.3, p < .001). There was a higher prevalence of PDL1+ tumors in HG vs LG (LG F+: 39.3%, LG F-: 35.9, HG F+: 70.0, HG F-: 72.4, p < .001). LG tumors had a significantly higher MPAS than HG tumors (LG F+: 1.38 arbitrary units, LG F-: 1.66, HG F+: -0.35, HG F-: -0.25, p < .001). LG F- and HG F- tumors had a similar proportion of T cell-inflamed tumors (LG F-: 36 vs HG F-: 33, p > .05), whereas LG F+ tumors have a significantly lower proportion of T cell-inflamed tumors as compared to HG F+ (LG F+: 18% vs HG F+: 42, p < .001). Amongst tumors that had not received mirvetuximab soravtansine, no difference in OS was observed between HG F- v HG F+ (HR 1.3, p = .072; median OS HG F-: 87 months [N = 1092], HG F+: 98 [N = 756]). No difference in OS was observed when comparing LG F- vs LG F+ (HR 1.0 , p = .93; median OS LG F-: 98 months [N = 116], LG F+: not reached [N = 37]). Conclusions: A notable portion of LG tumors were FOLR1+, which suggests that FOLR1 expression in LG could be a viable target for this rare histology, particularly in the recurrent setting. MAPK activation was significantly higher in LG tumors when compared to HG, yet no difference between LG F+ and F- tumors was observed.