ECPPF stratification identifies occult high-risk subgroups in stage I, grade 1 or 2, ≤50 % invasive endometrial cancer: Candidates for adjuvant therapy

Objective

To determine whether stratification with ECPPF (E2F1 + CCNA2 log2 expression and POLE, PPP2R1A, and FBXW7 variants) could identify occult cases of high-risk endometrial cancer (EC) in a traditionally low-risk cohort.

Methods

We identified 97 cases of clinicopathologic low-risk endometrioid EC (defined as stage I, grade 1 or 2, limited [≤50 %] myometrial invasion) from The Cancer Genome Atlas (TCGA). Twelve cases had POLE mutations (mu) and 15 had PPP2R1Amu or FBXW7mu. Log2 CCNA2 + E2F1 expression was low (<4.75) for 56 cases and high (>4.75) for 19 (termed CCNA2 + E2F1 low or high, respectively). CCNA2 + E2F1 high and PPP2R1Amu/FBXW7mu were simultaneously present for 5 cases. Survival comparisons were based on log-rank tests.

Results

Five-year progression-free survival (PFS) curves for POLEmu and CCNA2 + E2F1 low differed substantially from CCNA2 + E2F1 high and PPP2R1mu/FBXW7mu cases (P < .001). The latter 2 subgroups, combined (n = 29) and designated as molecular high risk (MHR), had an estimated 5-year PFS <50 %. Adverse outcomes were associated with MHR for cases harboring CTNNB1mu (P < .001), ARID1Amu (P = .03), and PTENmu (P = .002). TCGA classification was not prognostically significant for this cohort (P = .10), but ECPPF MHR identified compromised subgroups within major TCGA subclasses (P = .004). CCNA2 + E2F1 high and expression of its downstream targets were positively correlated (P < .001) with expression of genes involved in chemoresistance (ie, homologous recombination, cell cycle regulation, antiapoptotic processes).

Conclusions

ECPPF supports a taxonomy in which occult, high-risk disease is identified among cases traditionally considered low risk. With high-risk cases unlikely to respond to current first-line chemotherapy, case identification should prompt proactive therapeutic intervention with alternative molecular-based treatment targets.