Recent advances fuelled by translational research reflect a greater focus on patients’ quality of life

One of the main drivers responsible for recent advances in the management of gynaecological cancers is our greater understanding of tumour biology, in particular, increased knowledge of the role of homologous recombination repair pathways. Approximately one-quarter of ovarian carcinomas have a hereditary predisposition (Int J Gynecol Cancer. 2020;30:1803–1810) and prevention is possible via detection of germline BRCA mutations. In addition, we are becoming increasingly aware of other key germline mutations affecting DNA repair, beyond BRCA, and we have worked these into our clinical practice. For example, mutations in DNA mismatch repair genes (e.g., MLH1, MSH2, MSH6 and PMS2) (Oncol Lett. 2019;17:3048–3054) are now being detected by screening for Lynch syndrome in patients with endometrial cancer.

Enhanced translational research and the wider availability of genetic testing means that biological knowledge is now being brought to the clinic as novel treatments. PARP inhibitors have transformed outcomes for patients with ovarian cancer and BRCA1/2 mutations (N Engl J Med. 2018; 379:2495–2505; N Engl J Med. 2019;381:2391–2402), and more recently, have demonstrated efficacy in cancers with an homologous recombination deficiency (HRD) phenotype other than BRCA mutations (Ann Oncol. 2020;31:1606–1622). However, remaining challenges include tackling resistance to PARP inhibitors and also exploring treatment targets for patients with ovarian cancer without HRD. High-grade ovarian tumours that are homologous repair proficient are a heterogeneous group, but a much-needed therapeutic opportunity may arise from the finding that CCNE1 amplification is an early genomic event in high-grade serous carcinoma (Gynecol Oncol Rep. 2021;37:100850).

Unlike in other cancers, immunotherapy is very much in its infancy – we are searching for the key to unleash the immune system in ovarian cancers. Blocking immune checkpoint proteins such as PD-1/PD-L1 and CTLA-4 does not appear to be efficacious in ovarian cancer; however, immune checkpoint inhibitors are valuable in advanced endometrial cancer that is mismatch-repair deficient or has high microsatellite instability after failure of platinum-based chemotherapy (J Adv Pract Oncol. 2022;13:45–59). Combination therapies are being actively studied, such as dual therapy with pembrolizumab plus lenvatinib, which has recently been shown to improve progression-free survival (PFS) and overall survival (OS) compared with chemotherapy among patients with advanced endometrial cancer (N Engl J Med. 2022;386:437-448). In cervical cancer, pembrolizumab is indicated in combination with chemotherapy with or without bevacizumab for the treatment of metastatic or recurrent cervical cancer with PD-L1 expression and a combined positive score (CPS) ≥1. The question is raised whether immune checkpoint inhibitors could have a role earlier in patients with high-risk localised disease.

In low-grade ovarian or endometrial cancer, new treatment opportunities may not arise from complex mechanisms such as DNA repair or immune regulation, but may instead be found in hormone therapy. In low-grade tumours where chemotherapy is not active, the potential value of hormone therapy, with a boost from a CDK4/6 inhibitor, is currently being explored.

The surgical management of gynaecological cancers has evolved considerably, focussing on better patient selection. For example, in ovarian cancer, laparoscopy is increasingly used to select the patients who will benefit from upfront surgery or interval debulking surgery. In patients with relapsed ovarian cancer, a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score (Eastern Cooperative Oncology Group performance-status score of 0, ascites <500 mL and complete resection at initial surgery) was used to select patients for cytoreductive surgery in the DESKTOP III trial (N Engl J Med. 2021;385:2123–2131). AGO-positive patients who underwent cytoreductive surgery followed by chemotherapy had longer OS than those who received chemotherapy alone.

Lymph nodes have also been gaining attention. Systematic pelvic and paraaortic lymphadenectomy was widely used in the surgical management of patients with advanced ovarian cancer; however, results from the LION trial indicate no better outcomes and higher complication and mortality rates with lymphadenectomy (N Engl J Med. 2019;380:822–832). In endometrial, cervical and vulval cancer, sentinel lymph node dissection is becoming increasingly popular as a less morbid alternative to systematic lymphadenectomy.

All these recent advances in the management of gynaecological cancers reflect a greater focus on patients’ quality of life. Research on patient-reported outcomes (PROs) is even more prominent now than in previous years with medical treatments – we understand the need to assess PROs as well as PFS – but there is still much work to be done to gain a fuller evaluation of the benefits of different treatments. Further challenges for the future include building on the progress made with under-represented groups, such as elderly patients with ovarian cancer and also younger patients with rare forms of ovarian cancer, which actually make up a considerable proportion of patients.

I strongly believe that the advances made in recent years have been facilitated by sharing our knowledge. The network of cooperative groups, such as the Gynecologic Cancer InterGroup (GCIG) and the European Network for Gynaecological Oncological Trial groups (ENGOT), partnering with other collaborative groups from different geographical areas, have really helped to bring about changes in practice. Long may such collaborations continue.