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