Relationship between FOLR1 expression and pan-cancer subgroup of tumors with specific transcriptomic profile.

Abstract

3136 Background: Mirvetuximab soravtansine is an antibody–drug conjugate currently approved for the treatment of advanced platinum-resistant ovarian cancer. The efficacy of this therapy is correlated with high expression of folate receptor alpha (FRα), encoded by the FOLR1 gene. Treatment requires ≥ 75% of tumor cells to be stained positively for FRα by immunohistochemistry (IHC). Here we defined the FOLR1 RNA level that distinguishes ovarian cancers with very high FRα (≥ 75% by IHC), then compared the transcriptomic profile of these cases (FOLR1-H) with the transcriptomic profile of cases with very low FRα expression (FOLR1-L). We further explored the presence similar FOLR1-H signature in various types of cancers. Methods: RNA was extracted from 1450 solid tumor FFPE samples and sequenced using a targeted RNA panel of 1600 genes. The RNA expression levels of various genes were quantified and expressed as transcript per million (TPM). IHC for FRα protein was performed on ovarian cancers (N = 49) using VENTANA FOLR1 RxDx assay. Results: Based on comparing IHC with RNA expression of FOLR1, FOLR1-H samples were defined with RNA ≥ 300 TPM while FOLR1 mRNA < 100 was correlated with very low FRα by IHC and classified as FOLR1-L. Of the 312 ovarian cancers, 21% were classified as FOLR1-H and showed significantly (Log10FDR < -2) higher expression in 39 genes as compared with FOLR1-L. The Log10FDR was < -10 in 19 genes. The top highly expressed genes in FOLR1-H cases were TROP2, NECTIN4, ROR1, ROR2, ACVRL1, and NTHL1. In breast cases (N = 199) FOLR1-H was detected in 14.6% of cases and the most highly expressed genes were ACVRL1, NECTIN4, ROR1, and ACVRL1 (Log10FDR < -5). Of the 932 cases of lung cancer, 21.5% classified as FOLR1-H and had significantly (Log10FDR < -2) high expression of 137 genes, but similar to ovarian cancer TROP2, NECTIN4, ROR1, ROR2, ACVRL1, and NTHL1 were top expressed genes. Of the 174 pancreatic cancers 9.8% were FOLR1-H and top expressed genes were NECTIN4, ROR1, and ACVRL1. In sarcoma (N = 166), 8.4% had FOLR1-H and only three genes (NECTIN4, NTHL1 and SLC47A1) were significantly high. Of the 327 colorectal cancers, 8% met the criteria for FOLR1-H and 16 genes were significantly higher in FOLR1-H including NECTIN4, NTHL1, ACVRL1, ROR1/2. In 64 esophageal cancers 10.9% were FOLR1-H, but only 3 genes (GALNT12, ACVRL1 and NECTIN4) were significantly higher. Conclusions: This data suggests that cancers with significantly high expression of FOLR1 mRNA are a special subtype of tumors characterized by the expression of embryonic cell surface markers (FOLR1, TROP2, NECTIN4, ROR1/2). The pan-cancer marked overexpression of these genes suggests that cancers with FOLR1-H represent a subtype of cancers with similar biology. This subtype may benefit from combination therapy targeting more than one of these markers (e.g. anti-FOLR1 with anti-TROP2, or anti-NECTIN4) and clinical trial with such combination may be justified.