Evolutionary pathways in early-stage, non-myoinvasive endometrioid endometrial cancers of no specific molecular profile.

Objective: To characterize the genomic landscape of FIGO 2009 stage IA, non-myometrial invasive endometrioid endometrial cancers (ECs) of no specific molecular profile (NSMP) and define the earliest driver genetic alterations and subsequent tumor evolution.

Methods: Early-stage (FIGO 2009 stage IA), non-myoinvasive endometrioid NSMP ECs subjected to clinical tumor-normal targeted sequencing between 2014 and 2022 were identified. ECs were dichotomized into low- and high-volume disease based on gross and histologic measurement using a cutoff of 1.8 cm. Cancer cell fractions (CCF) of somatic mutations were determined.

Results: A total of 171 noninvasive, FIGO 2009 stage I endometrioid ECs of NSMP subtype were identified, of which the majority (n = 139; 81 %) were FIGO grade 1. The median calculated volume of disease was 1.8 cm at diagnosis. The ECs had on average 6 pathogenic mutations, affecting known EC cancer-related genes, including PTEN (80 %), ARID1A (52 %), PIK3CA (52 %), CTNNB1 (39 %), PIK3R1 (37 %), and KRAS (29 %). Genomic alterations did not correlate with tumor volume. PTEN mutations had the highest CCFs. Unsupervised hierarchical clustering based on CCF revealed 4 main groups characterized by: 1. clonal alterations in PTEN accompanied by PIK3CA, PIK3R1, or ARID1A alterations, 2. mutations in PIK3CA co-occurring with ARID1A alterations, 3. KRAS mutations, particularly associated with 1q high-level gain, or 4. AKT1 mutations, which uniquely occurred without concurrent PTEN, PIK3CA, or PIK3R1 alterations.

Conclusion: Stage IA non-myoinvasive NSMP ECs show genomic heterogeneity suggestive of multiple evolutionary pathways. Further studies are warranted to define whether this is a sign of early genomic drift.