Molecular typing guiding treatment and prognosis of endometrial cancer

Abstract

Genetic abnormalities, such as PTEN, PIK3CA, CTNNB1, ARID1A, and ERBB2, which frequently occur in endometrial cancer (EC), are potential therapeutic targets. In 2013, integrated genomic analysis conducted by The Cancer Genome Atlas identified four molecular subtypes, including POLE ultra-mutated, microsatellite instability hypermutated, copy-number low, and copy-number high, which strongly correlate with prognosis. Surrogate markers-based molecular classification methods have been developed to make these molecular classifications accessible and affordable, achieving classification into POLEmut, mismatch repair deficient (MMRd), p53abn, and no specific molecular profile (NSMP) with normal p53 expression. Although POLEmut EC has aggressive pathologic features, there are few cases of advanced and/or recurrence. Therefore, the possibility of de-escalating adjuvant therapy can be considered. Additionally, immune checkpoint inhibitors (ICI) may be a candidate for treating advanced and recurrent POLEmut EC because of their high immunogenicity. MMRd EC shows an intermediate prognosis between those of POLEmut and p53abn EC. MMRd EC is generally characterized by high immunogenicity similar to POLEmut EC, suggesting that ICI can also be a potential therapeutic agent. Among the four molecular subtypes, p53abn EC has the worst prognosis. However, some p53abn tumors have the molecular hallmark of homologous recombination deficiency and could be treated with poly (ADP-ribose) polymerase inhibitors. In addition, some p53abn tumors overexpress the human epidermal growth factor receptor 2, which can also be a potential therapeutic target. NSMP EC are a heterogeneous population because they lack characteristic molecular biological features. Approximately half of the NSMP EC show high expression of estrogen receptor/progesterone receptor, suggesting the possibility of hormonal therapy. In addition, the PI3K/AKT/mTOR pathway frequently altered in EC may be a therapeutic target. This review summarizes the molecular biological characteristics and potential therapeutic agents in molecularly featured EC. Several clinical trials are in progress to stratify EC into molecular classifications and demonstrate the efficacy and safety of molecularly matched treatment and management strategies.