Detecting <i>MTAP</i> loss in liquid biopsies from patients (pts) with clinically advanced urothelial bladder cancer (CAUBC).

Abstract

819 Background: MTAP loss is an emerging biomarker guiding investigational assessment of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferease-2A (MAT2A) inhibitors in a wide variety of tumor types including CAUBC. Detecting homozygous loss and copy number changes in solid tumors is often challenging and requires a robust assay and analysis pipeline, especially when the amount of extracted DNA is small. In CAUBC, there is sometimes small tumor size from trans-urethral resection of bladder tumor (TURBT) and/or metastatic tissue biopsy, which may limit immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) required for treatment selection and clinical trials enrollment. We queried whether blood-based liquid biopsy (LBx) CGP could provide information regarding MTAP loss in pts with CAUBC. Methods: Hybrid capture–based CGP was performed on 10,532 CAUBC tissue-based (TBx) samples using the FoundationOne CDx assay and on 1,637 CAUBC LBx samples using the FoundationOne Liquid CDx assay. The ctDNA tumor fraction (TF) for each LBx sample was determined using assessments of aneuploidy and variant allele frequencies, as previously described. Analyses were conducted on independent TBx and LBx cohorts; samples were not matched within the same patients. Results: For the TBx group, 7,685 (27.0%) CAUBC featured MTAP loss. For the LBx group, MTAP loss detection increased as the TF increased (Table). For CAUBC LBx samples with TF &lt; 5%, MTAP loss detection was only 5.4%. As the LBx TF increased, the frequency of detection of MTAP homozygous loss increased significantly reaching &gt; 18.0% when TF was ≥30%. Regarding complete vs partial MTAP exon loss, TBx and LBx showed similar identification rates: 92.2% and 85.3% of MTAP losses were complete or near complete (loss of 7-8 of 8 exons) in TBx and LBx, respectively; 7.4% and 11.8% were partial losses (loss of 1-5 of 8 exons). Conclusions: LBx emerges as a promising tool for detecting MTAP loss in CAUBC. Importantly, LBx TF plays a crucial role in CGP evaluation, as MTAP loss detection rates using LBx approach those of TBx when TF is ≥10-20%. However, when TF levels are &lt; 10%, homozygous MTAP loss can be challenging to detect and may be missed. Study limitations include retrospective nature, lack of outcomes data, lack of paired/matched samples in the same patient, selection and confounding biases. Our findings have the potential to increase clinical trial accrual for pts with this disease, who have relatively limited treatment options and may sometimes lack sufficient tumor tissue for CGP. Tissue and liquid biopsies can have complementary value. CAUBC MTAP no loss CAUBC MTAP loss MTAP loss freq TBx 7685 2846 27.0% LBx TF ≥0% 590 34 5.4% LBx TF ≥1% 288 34 10.6% LBx TF ≥5% 190 34 15.2% LBx TF ≥10% 142 33 18.9% LBx TF ≥20% 96 22 18.6% LBx TF ≥30% 68 14 17.1%