CGE23-072: The Frequency of Androgen Receptor Splice Variant 7 (AR-V7) in Solid Tumors

Background: Activation of the androgen receptor (AR) by androgenic ligands (testosterone, dihydrotestosterone) leads to activation of genes containing androgen response elements. This pathway plays a pivotal role in promoting prostate cancer (PC) growth and is targeted by androgen deprivation therapy (ADT). Resistance to ADT is common and often caused by development of the AR splice variant 7 (AR-V7), which lacks the ligand-binding domain and remains active in the absence of the androgenic ligands. The AR pathway is now increasingly recognized in other cancer types. We examined the frequency of the AR-V7 variant across a large cohort of diverse cancers. In addition, actionable fusions, associated with diagnosis/prognosis or a targeted therapy, were identified. Methods: Tumor and paired-normal samples from 6,974 patients aged 18–89 years were sequenced with the Oncomap ExTraTM assay, which uses whole-exome DNA sequencing to detect somatic single base substitutions, indels, and copy number alterations, and whole transcriptome RNA sequencing to detect gene fusions. The RNA sequencing data were used to identify AR-V7 variants and actionable fusions across cancers. Results: The AR-V7 splice variant was not detected in most tumor types including colorectal, ovarian, Non–Small Cell lung, among others. The AR-V7 splice variant was found in 40 (0.6%) patient samples across three cancer types. Specifically, 2 of 23 (8.7%) salivary gland, 18 of 506 (3.6%) PC, and 20 of 1939 (1%) breast cancer patient samples had the variant. Both AR-V7 salivary gland cancers were treatment-naïve ductal carcinomas. Within the breast cancer patient samples, AR-V7 was present in 13 of 1276 (1.0%) HR+HER2-, 3 of 317 (0.9%) HER2+, 3 of 273 (1.1%) triple negative, and 1 of 77 (1.3%) patients for whom HR and HER2 status was unknown. Within the 18 AR-V7 PC samples, 7 had no actionable gene fusions, 7 had a TMPRSS2/ERG fusion, and 4 had unique actionable fusions (CDH1/NTRK, DOT1L/AR, TMEFF/RSPO2, SCL45A3/ETV4). Of note, the sample with both AR-V7 and an AR fusion is a rare event potentially indicative of resistance to anti androgen therapy. Conclusion: The whole-transcriptome RNA sequencing component of the Oncomap ExTra assay allows detection of splice variants such as AR-V7 and rare AR gene fusions across cancer types. Presence of AR-V7 may provide critical information for treatment selection, identifying patients predicted to benefit more from taxane therapy than from antiandrogens.