What are the consequences of ‘pandemomics’ in gynaecological cancers?

Over the last few years, in spite of pandemic-related constraints, our understanding of gynaecological cancer biology and the development of new treatments has progressed at pace. We have witnessed a sort of ‘pandemomics’ – i.e., the increased use of multi-omics on the background of disrupted in-person interactions – and this has the potential to impact sharing of knowledge as well as the care we have been able to provide to our patients.

One assumption we need to challenge is the true origin of epithelial ‘ovarian’ cancer, which is perhaps more accurately described as ‘cancers that involve the ovaries’. It is well recognised that many high-grade serous cancers originate from precursor lesions within the fallopian tubes; however, extra-ovarian sources are likely to be a more general phenomenon for epithelial tumours than previously appreciated. At least 50% of ovarian mucinous cancers are now known to originate from gastrointestinal locations. In addition, perhaps all endometrioid tumours arise in the setting of endometriosis or ‘synchronous’ endometrial cancers, which share clinical and clonal molecular features with endometrioid ovarian tumours. Many clear cell tumours also arise in association with endometriosis or endometrioid carcinoma, suggesting similar origins.

The entire peritoneal cavity is accessible to detached cells that migrate from the uterus and fallopian tubes, often without the need to exhibit deep invasion or cross tissue boundaries. The ovary provides a good environment for these detached cancer cells to implant and grow due to its thin exposed epithelial layer, its rich supply of blood vessels, growth factors and hormones, and the wound healing-like process that occurs with cyclic ovulation, resulting in the creation of inclusion cysts. As our knowledge of clinical and molecular biology evolves, there is a concurrent re-alignment in diagnosis, staging and treatment. For example, agents with regulatory approval in endometrial cancer are being applied in the management of endometrioid ovarian and peritoneal cancers. Along these lines, ‘synchronous primaries’ are best considered as one clonal malignancy involving multiple sites, challenging conventional staging assumptions and treatment recommendations.

Molecular evaluation has become an integral part of screening and treatment planning for women with some gynaecological cancers, but there are nuances that can be misinterpreted. Perhaps most importantly, we need to appreciate the footprint of certain mutations, not just make assumptions based on the individual mutations called out in a report. As an example, if POLE is mutated, many other errors in DNA repair will follow with reporting of ‘pathogenic’ alterations in cancer-related genes, but at low allele frequencies that are more consistent with bystander effects. Clinicians may see a BRCA mutation on a molecular profiling report and use this as a basis for prescribing a PARP inhibitor. However, in this setting, the BRCA mutation is usually a bystander mutation that occurred as a result of the POLE mutation rather than an early driver of carcinogenesis. A different situation can arise in women with an increased risk of cancer associated with Lynch syndrome, whereby they may still develop cancers associated with other sporadic mutations (such as TP53) that are microsatellite stable and unrelated to germline mutations in mismatch repair genes.

The intense search for new treatments and race for regulatory approval in recent times have resulted in some important unanswered questions related to patient selection, dose, schedule, duration and sequence of individual interventions. An example is the trend for approved doses of some new agents – such as certain PARP inhibitors and tyrosine kinase inhibitors – being too high, resulting in excessive toxicity and frequent dose and/or schedule modifications. In the absence of prospective data regarding drug optimisation, experienced physicians frequently initiate treatments at a lower dose to ensure patient safety and tolerability, which may then raise a concern from the patient that we are not being sufficiently ‘aggressive’. Pragmatic trials comparing the approved dose with commonly used modifications would be valuable and may help guide physicians – especially those who do not have the experience to question approved doses – and avoid unnecessary side-effects.

Another area that needs to be revisited is the role of hormonal therapies in the primary treatment of certain gynaecological cancers. Given experience in breast and prostate cancers, it seems likely that hormonal therapy could play a larger role, for example, as post-surgical adjuvant therapy for advanced-stage low-grade endometrioid cancer involving the uterus, peritoneal cavity and/or ovary, providing a more effective and less toxic option than chemotherapy. However, we lack prospective randomised data to validate this approach. Research funding is difficult to acquire in the current resource-stretched climate, particularly post-marketing. As such, it is also important to consider less expensive, less intensive pragmatic trials, which may help to fill these gaps in our clinical knowledge and help challenge assumptions made as the field marches forward. In addition, regulatory agencies, including the US FDA, are developing new guidance documents to promote more detailed optimisation of dose and schedule prior to regulatory approval, which will benefit everyone.