Abstract
Simple SummaryPatients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment with unsatisfactory clinical outcomes. The combination of carboplatin + paclitaxel is the standard first-line chemotherapy, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with mTOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high/mismatch repair (MMR)-deficient EC.Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results obtained with chemotherapy, hormonal therapy, biological agents and immune checkpoint inhibitors in this clinical setting. The combination of carboplatin (CBDCA) + paclitaxel (PTX) is the standard first-line chemotherapy capable of achieving objective response rates (ORRs) of 43–62%, a median progression-free survival (PFS) of 5.3–15 months and a median overall survival (OS) of 13.2–37.0 months, respectively, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with m-TOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Disappointing ORRs have been associated with epidermal growth factor receptor (EGFR) inhibitors, HER-2 inhibitors and multi-tyrosine kinase inhibitors used as single agents, and clinical trials evaluating the addition of bevacizumab to CBDCA + PTX have reported conflicting results. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient (-d) EC. In a recent study, the combination of lenvatinib + pembrolizumab produced a 24-week response rate of 38% in patients with highly pretreated EC, ranging from 64% in patients with MSI-H/MMR-d to 36% in those with microsatellite stable/MMR-proficient tumors. Four trials are currently investigating the addition of immune checkpoint inhibitors to PTX + CBDCA in primary advanced or recurrent EC, and two trials are comparing pembrolizumab + lenvatinib versus either CBDCA + PTX as a first-line treatment of advanced or recurrent EC or versus single-agent chemotherapy in advanced, recurrent or metastatic EC after one prior platinum-based chemotherapy.
Highlights
GLOBOCAN estimates of the worldwide incidence and mortality for 36 cancers in countries reported 382,069 new cases of endometrial carcinoma (EC) and 89,929 deaths due to this cancer in 2018 [1]
13.2–37.0 months respectively, whereas hormonal therapy is sometimes used in selected patients with slow growing, estrogen receptor (ER)- and/or progesterone receptor (PR)- positive EC
Whereas single-agent aromatase inhibitors or m-TOR inhibitors have limited activity, the combination of these agents has resulted in an objective response in approximately
Summary
GLOBOCAN estimates of the worldwide incidence and mortality for 36 cancers in countries reported 382,069 new cases of endometrial carcinoma (EC) and 89,929 deaths due to this cancer in 2018 [1]. Cancer (ProMisE) which does not require the expensive genomic methodology and that is applicable to formalin-fixed paraffin-embedded samples This system based on mismatch repair (MMR) protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry identifies four molecular subtypes that are similar but not identical to genomic TCGA subtypes. The analysis of 947 available early-stage endometrioid EC specimens from patients enrolled in the PORTEC-1 and PORTEC-2 trials, mostly at high-intermediate risk, revealed that 6% of the tumors were POLE-mutant, 9% were p53-mutant, 26% had MSI, and 59% had no specific molecular profile (NSMP) [9]. It is noteworthy that only one patient with a POLE-mutant EC (treated with radiotherapy alone) relapsed, resulting in a 5-year PFS and 5-year OS of 100% with combined chemotherapy and radiotherapy versus. The aim of this review was to evaluate the results following treatment with chemotherapy, hormone therapy, molecularly targeted agents and immune checkpoint inhibitors and analyze the promising perspectives of research in this clinical setting
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