Elsevier

European Journal of Cancer

Volume 59, May 2016, Pages 99-108
European Journal of Cancer

Review
Endometrial cancer—targeted therapies myth or reality? Review of current targeted treatments

https://doi.org/10.1016/j.ejca.2016.02.016Get rights and content

Highlights

  • Hormonal therapy remains the only targeted therapy approved in endometrial cancer.

  • Angiogenesis and phosphatidylinositide 3-kinase pathway are relevant targets with signal of activity.

  • The characterisation of endometrial cancer subtypes guides further development of targeted therapies.

Abstract

Endometrial cancer (EC) is the most common gynaecological malignancy in developed countries and its incidence is increasing related to obesity. EC is divided into histologic subtypes, most frequently endometrioid adenocarcinoma. Options for treatment of advanced or persistent disease remain limited, and survival has not changed in the last decade. No targeted therapy beyond hormonal therapy is approved for EC. Though hormonal therapy has been a ‘standard’ for four decades, prediction of its efficacy with receptor evaluation or understanding mechanisms of resistance remain important challenges. The clinical impact of deregulation of different pathways such as phosphatidylinositide 3-kinase, HER or MAPK warrant further investigation to use in a prognostic or predictive manner. The cell cycle and DNA repair pathways constitute potential targets for the development of precision therapies. Targeting the microenvironment and more recently immune infiltration are promising areas. Advances in the understanding of cell biology have allowed EC to be divided into multiple diseases that respond differently to targeted therapy. Translational clinical trials that link biology with precision targeted therapy are key to improve outcome and will require careful analysis or identification of potential biomarkers in early phase studies and validation in randomised trials. This approach requires collaborative efforts to achieve meaningful improvement in the prognosis of women with EC. This review aims to summarise the latest published trials on targeted therapies in EC and propose future directions.

Section snippets

Biology: background for targeted therapy

In North America and Europe, endometrial cancer (EC) is the most common gynaecological cancer with expected 54,870 new cases and 10,170 deaths in 2015 compared to 49,560 and 8190, respectively, in 2013 in the United States alone [1], [2]. This is a disease which is seen in older women, and more than 90% of cases occur in women over 50 years of age. Obesity is a well-described risk factor and has led to a worrying rise in the incidence of EC and it is likely to continue to increase.

Hormonal therapy: the sole approved targeted therapy

A significant proportion of EC—in particular, type I tumours—express oestrogen receptor (ER) or PR, described to be predictors of favourable survival and rendering hormonal therapy an attractive therapeutic strategy [23]. Agents investigated include progestogens, selective oestrogen receptor modulators (SERM), aromatase inhibitors (AI), and GnRH inhibitors. The most common hormonal treatment has been progestational agents, which demonstrate anti-tumour responses in as many as 15–30% of patients

Angiogenesis: an effective approach

Angiogenesis is one of the cardinal processes leading to invasion and metastasis in solid tumours [44]. In EC, elevated VEGF plasma levels correlate with poor prognosis [45]. Thalidomide was the first angiogenic agent assessed demonstrating an RR on 12.5% with only 8.3% surviving 6 months [45].

Bevacizumab, a recombinant humanised monoclonal antibody against VEGF-A, is the most commonly studied anti-angiogenic agent. From the 52 evaluable patients enrolled in the GOG 229-E study, a 13.5% RR and

PI3K pathway: a promising target

Based on the central importance of this pathway and biologic rationale in EC, several phase II trials have investigated this target in the recurrent EC setting [56].

The use of rapalogs as a single agent has demonstrated modest but reproducible anti-tumour activity across histologic subtypes, predominantly stable disease and an objective RR from 0% to 25%, higher in chemotherapy-naive patients [57], [58], [59], [60], [61], [62]. To date, the correlative analyses of specimens on these trials have

Epidermal growth factor receptor pathway: a specific subgroup

The epidermal growth factor receptor (EGFR) is a family of four tyrosine kinase receptors that are overexpressed in both types of EC which is important in growth and metastases [73]. To date, results with agents targeting this pathway have been relatively disappointing [29], [56].

Gefitinib and erlotinib are orally active inhibitors of EGFR tyrosine kinase activity. Gefitinib was found to be tolerable but did not demonstrate sufficient results to pursue further with an ORR of only 3.8% and a PFS

Metabolic pathway: exploiting vulnerabilities

Metformin, an oral biguanide, is known for its role in the management of diabetes and insulin resistance, known to be risk factor of EC [8]. Epidemiologic data suggests that use of metformin reduces the risk of EC death [82], [83] but may not decrease the risk of EC [84]. The anti-cancer effects of metformin are associated with both direct insulin-independent and indirect insulin-dependent actions of the drug [85], [86]. Metformin has demonstrated inhibition of proliferation and induction of

Perspectives: new area of therapeutic investigation

The presence of tumour-infiltrating lymphocytes (TILs) was associated with favourable outcome in EC [89]. POLE ultramutated and MSI are associated with high neo-antigen loads and number of TILs, which is counterbalanced by overexpression of PD-1 and PD-L1. These subgroups of EC tumours may be excellent candidates for PD-1-targeted immunotherapies [90]. This is a current area of investigation in monotherapy and combination treatment.

Moreover, based on the recent advances in EC characterisation,

Conflict of interest statement

None declared.

Acknowledgement

The authors gratefully acknowledge Katherine Karakasis for her comments and review.

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