766 Background: MTAP loss is an emerging biomarker guiding investigational use of PRMT5 and MAT2A inhibitors in a wide variety of tumor types including pancreatic ductal adenocarcinoma (PDAC). Detecting homozygous deletions 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 PDAC, the small size needle core biopsies and fine-needle aspiration cytology samples used for diagnosis purposes hold significant limitations for immunohistochemistry (IHC) and comprehensive genomic profiling (CGP), both critical for treatment selection and clinical trials enrollment. We queried whether blood based liquid biopsy (LBx) CGP could provide treatment impacting information regarding MTAP loss compared to tissue testing (TBx) for patients with PDAC. Methods: Hybrid capture based CGP was performed on 23,451 PDAC TBx using the FoundationOneCDx assay and on 2,700 PDAC LBx using the FoundationOneLiquid CDx assay. The ctDNA tumor fraction (TF) for each LBx sample was determined using assessments of aneuploidy and variant allele frequencies, as previously described. Results: Overall, 6,837 (29.2%) PDAC TBx featured MTAP loss. For LBx, this proportion reached up to 28.4% and was directly dependent on the LBx TF (Table). Among PDAC LBx samples with TF of less than 5%, none had MTAP loss detected. However, applying LBx TF cutoffs of ≥10% and ≥20%, the detection rates increased to 25.2% and 28.2%, respectively. Specimens with TF ≥1% represented a minority of cases, with even fewer cases reaching higher TF thresholds (TF ≥10%: 10.1%; TF ≥20%: 5.3% of PDAC LBx). Regarding complete versus partial MTAP exon loss, TBx and LBx showed similar identification rates: 88.8% and 87.3%, respectively, for complete or near-complete loss (loss of 7 or 8 out of 8 exons), and 11.2% and 12.7% for partial loss (loss of 1 to 5 out of 8 exons), respectively. Conclusions: LBx emerges as a promising tool for detecting MTAP loss in PDAC. 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%. Our findings have the potential to increase clinical trial enrollment for patients with this lethal disease, which has limited treatment options and often lacks sufficient tissue for tissue-based CGP. MTAP no loss MTAP loss MTAP loss freq TBx 16614 6837 29.2% LBx TF ≥0% (100% of LBx) 2700 71 2.6% LBx TF ≥1.0% (26.6% of LBx) 646 71 9.9% LBx TF ≥5.0% (14.6% of LBx) 324 71 18.0% LBx TF ≥10.0% (10.1% of LBx) 205 69 25.2% LBx TF ≥20.0% (5.3% of LBx) 102 40 28.2% LBx TF ≥30% (3.0% of LBx) 58 23 28.4%
Xavier et al. (Sat,) studied this question.