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Objectives: Circulating tumor DNA (ctDNA) extracted from peripheral blood presents an alternative to tumor tissue for molecular testing when the latter is unavailable. We explored the landscape of genomic alterations (GA) from liquid biopsies of patients with advanced/recurrent EC to determine utility to inform prognosis, treatment selection, and clinical trial eligibility. Methods: Comprehensive genomic profiling (CGP) by hybrid capture sequencing on peripheral blood-derived cell-free DNA (cfDNA) from 193 patients with EC (b-EC cohort) interrogated 324 genes (including 75 with enhanced sensitivity and 21 with introns; F1LCDx) and assessed microsatellite instability-high status (MSI-H; detected/not detected) and blood tumor mutational burden (bTMB; muts/Mb). The proportion of cfDNA predicted to be tumor-derived (ctDNA) was calculated as tumor fraction (TF). Additionally, 7148 tissue samples from patients with advanced EC (t-EC cohort) were analyzed by a 324-gene CGP assay (F1CDx) for comparison to the b-EC cohort. Results: Sixty-seven of 193 b-EC were submitted with specified histologic diagnosis (25 endometrioid [13%], 21 serous [11%], 12 carcinosarcomas [6%], seven clear cells, and two of mixed histology), while the remaining 126 b-EC (65%) were not further specified. Patients had a median age of 69 years (range: 36 -87 years), 182 (94%) had detectable ctDNA, and 18% had a TF >10%. Among b-EC with detectable ctDNA, the median bTMB was 2.5mut/Mb. Eleven b-EC had MSI-H status detected, and among them, the median bTMB was 29 mut/Mb (range: 14 - 109). At least one GA in a potentially targetable pathway was identified in 48% of b-EC, including PI3K/mTOR, MEK, HRR, and receptor tyrosine kinases (Table 1). In cases with TF>10%, alteration frequencies for these genes were generally higher and more similar to rates detected in t-EC. Six b-EC with ERBB2 alterations (three amplifications and three activating short variants) and two b-EC with an activating ESR1 mutation (Y537S; commonly seen in endocrine-resistant breast cancer) were detected. Sixteen patients had BRCA1/2 alterations, of which six had variant allele frequencies suggesting possible germline origin. Other potentially targetable alterations were detected in EGFR (six short variants) and ALK rearrangements (two cases). The most frequently altered gene was TP53 , seen in 58% b-EC and 74% of TF>10 b-EC (vs 63% t-EC; p=0.28). Since clonal hematopoiesis (CH) can contribute to alterations in cfDNA, significantly more b-EC samples had one or more alterations in potential CH genes (DNMT3a , TET2, ASXL1) compared to t-EC (53% vs 11%; p<0.0001). Conclusions: A total of 94% of patients with b-EC had detectable ctDNA, and 48% had a potentially targetable alteration or biomarker, confirming liquid biopsy as a viable alternative in EC when appropriate tumor tissue is lacking and could increase access to clinical trials. MSI-H status, high-bTMB, and alterations detected in ctDNA could also suggest an EC subtype with associated prognostic implications and/or molecular mechanism of treatment resistance. Since sensitivity depends on ctDNA shed, negative liquid biopsy results must be confirmed with tumor tissue testing if clinically appropriate. [ABSTRACT FROM AUTHOR] |
