New therapeutic targets for endometrial cancer: a glimpse into the preclinical sphere

ABSTRACT

Introduction

Endometrial cancer (EC) is the only gynecologic malignancy showing increasing trends in incidence and mortality. While standard treatment has been effective primarily for early-stage EC, precision medicine with tailored therapy has revolutionized the management of this disease. Genome sequencing analyses have identified four sub-types of EC. Treatments for primary and metastatic disease can now be tailored more accurately to achieve better oncologic results.

Areas covered

This review provides an overview of the most relevant and updated evidence in the literature regarding EC molecular analysis and its role in risk classification, prognostication, and guidance for tailored and target therapies in early and advanced/metastatic stages. In addition, it provides updated information on optimal surgical management based on molecular classification and highlights key advances and future strategies.

Expert opinion

EC molecular analysis yields the potential of tailoring adjuvant treatment by escalating or deescalating therapy, as shown for POLE-mutated and p53-mutated tumors. Moreover, the expression of specific molecular signatures offers the possibility to employ novel target therapies, such as immune-checkpoint inhibitors that have demonstrated a significant benefit on prognosis. New treatment guidelines are still being established, and ongoing studies are exploring the potential prognostic role of further sub-stratifications of the four molecular classes and treatment options.

Plain Language Summary

Endometrial cancer (EC) is the only female cancer that is increasing among women. While the usual treatments work best when the disease is caught early, new advances in genetic studies have greatly improved the management of the disease. Four sub-types of EC have been identified. They are called: POLE-mutated, MMR-deficient, p53-abnormal, and no specific molecular profile. Treatments for EC can now be tailored more accurately to achieve better results. This review gives an overview of the most new and important evidence in the scientific literature about the molecular analysis of EC and how it can be used to help tailor the best treatments and surgeries for women with EC.

KEYWORDS:

• Endometrial cancer
• molecular classification
• DNA polymerase epsilon ultra-mutated
• microsatellite unstable hypermutated, p-53-abnormal endometrial cancer
• mismatch repair deficient endometrial cancer

Article highlights

• The incidence and mortality of endometrial cancer are increasing and new improved treatment approaches are required.

• In recent years, endometrial cancer has been classified into four molecular groups: POLE-mutated, MMR-deficient, p53-abnormal, and no specific molecular profile.

• Molecular analysis has defined different prognostic outcomes for each subgroup of endometrial cancer; therefore, creating a more accurate method of targeting this malignancy.

• Currently, treatment for recurrent disease relies on standard (platinum-based) chemotherapy regimens. However, in recent studies on the MMR-deficient subgroup, additional, potentially better, targeted biological approaches for recurrent disease were observed.

• Tailored and targeted primary surgical staging for endometrial cancer subgroups is a promising way to consider the optimal surgical method.

• Tumor molecular biology has enormous potential and multiple studies are being conducted to provide more information on the optimal management of endometrial cancer based on the specific molecular signature.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.