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Department of Gynaecology and Obstetrics
Medical University Innsbruck
Consultant in Gynaecological Oncology
Department of Gynaecology and Gynaecologocial Oncology
KEM Evang. Kliniken Essen-Mitte
Prof Nicole Concin, MD, PhD, has disclosed that she has received consulting fees from Akesobio, AstraZeneca, Eisai, eTheRNA, GlaxoSmithKline, Mersana, and Seagen and fees for non-CME/CE services from Amgen, Genmab, MSD, and Roche.
Surgery remains the mainstay of treatment for ovarian and endometrial cancers. Throughout 2021, practice-changing clinical data were presented at various gynecologic cancer congresses reporting on the impact of surgical outcome in ovarian cancer and novel immunotherapy-based options for endometrial cancer. In this commentary, I provide an overview of the latest clinical data regarding the role of surgery in the management of patients with different histological subtypes of advanced epithelial ovarian cancer and explore the role of new approvals for single-agent immunotherapy and immunotherapy in combination with a multikinase inhibitor in endometrial cancer.
Role of Surgical Outcome in Different Histological Subtypes of Advanced Epithelial Ovarian Cancer
When a patient with advanced‑stage ovarian cancer goes to see her doctor, the standard treatment consists of up-front primary debulking surgery (PDS) followed by adjuvant platinum-based chemotherapy. Maintenance therapy options include a PARP inhibitor (PARPi), or PARPi and bevacizumab combination, or bevacizumab alone depending on BRCA1/2 mutational status, homologous recombination deficiency status, and individual patient factors. Recent clinical data presented at the annual meeting of the European Society of Gynaecological Oncology indicate that complete macroscopic resection following PDS remains the best prognostic factor of overall survival in patients with advanced epithelial ovarian cancer (high-grade serous, low-grade serous, mucinous, and clear cell). PDS should be offered to all patients in whom a complete macroscopic resection is achievable with acceptable morbidity.
Patients with advanced epithelial ovarian cancer achieve substantial survival benefit when macroscopic complete resection is achieved with up-front PDS. In addition, patients with high-grade serous ovarian cancer with postoperative residual disease ≤10 mm experience a moderate survival benefit. Data also suggest a numerical benefit in survival for low-grade serous histology if postoperative residual disease is ≤10 mm (compared with residual disease >10 mm), yet this difference was not statistically significant. However, in patients with mucinous ovarian cancer, only a complete macroscopic resection confers a survival benefit compared with small (1-10 mm) or gross (>10 mm) residual disease after PDS.
Molecular Characterization of Endometrial Cancer
The Triple-European guidelines, which were jointly developed by the European Society of Gynaecological Oncology, the European Society for Radiotherapy and Oncology, and the European Society of Pathology, encourage molecular classification in all patients with endometrial cancer. In brief, endometrial cancer can be classified into 4 distinct molecular subtypes with the use of surrogate markers. Mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) and p53 aberrations can be determined by immunohistochemistry; for the determination of POLE exonuclease domain mutations, DNA sequencing techniques are needed. These 3 tests enable us to categorize endometrial cancer into the 4 distinct molecular subtypes―POLEmutant, mismatch repair deficient (dMMR), nonspecific molecular profile, and p53 abnormal―all of which are associated with distinct survival outcomes in patients with endometrial cancer.
Recent Developments in Recurrent or Advanced Endometrial Cancer
Until recently, in Europe, treatment options for patients with advanced or recurrent endometrial cancer were limited. In April 2021, the European Medicines Agency (EMA) approved the anti–PD-1 monoclonal antibody dostarlimab for adult patients with dMMR/microsatellite instability‒high (MSI-H) recurrent or advanced endometrial cancer with progression on or after a platinum-containing regimen based on data from the phase I GARNET study. In addition, in October 2021, the EMA gave a positive opinion for the marketing authorization regarding the combination of lenvatinib and pembrolizumab for adult patients with advanced or recurrent endometrial cancer following disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation. The later approval was based on data from the phase III KEYNOTE‑775 trial evaluating lenvatinib plus pembrolizumab vs single-agent chemotherapy.
The European approval for lenvatinib and pembrolizumab is for all‑comers―dMMR and proficient mismatch repair status. For the dMMR/MSI-H endometrial tumors, we already have single‑agent dostarlimab as an option. Whether we use single-agent dostarlimab or the combination of lenvatinib and pembrolizumab in patients whose tumors are dMMR of course will depend on the evaluation of the benefits vs the risks. A combination is clearly more toxic, and the added value of lenvatinib to single-agent PD-1 inhibition in patients with dMMR disease remains unknown, because the KEYNOTE‑775 trial did not compare the combination vs PD-1 inhibition alone. Notwithstanding, these are exciting times now that we have various options for patients with advanced or recurrent endometrial cancer when previously options were restricted only to chemotherapy with particularly low response rates.
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