World Ovarian Cancer Day: unravelling the molecular anatomy of a silent killer

INTRODUCTION Ovarian cancer has no widely recognised ribbon, no screening programmes and no celebrity-endorsed awareness campaigns. It kills silently, with approximately 80% of women diagnosed at an advanced stage.[1] It ranks seventh in incidence and eighth in mortality globally.[2] To raise awareness of the disease, World Ovarian Cancer Day was established on 8 May 2013 by patient advocacy organisations across 18 countries and is now supported by more than 200 organisations worldwide. There is no good way to screen for or prevent ovarian cancer. As an immunologically ‘cold’ cancer with few infiltrating T cells,[3] poor vascularisation[4] and biological heterogeneity,[5,6] there is no biomarker that is consistently and adequately shed into the circulation to facilitate early detection. CA-125, most commonly associated with epithelial ovarian cancers (EOCs), is raised in only 50% of early ovarian cancers[7,8] and is absent in 20% of ovarian cancers overall.[9] Large screening trials such as the UKCTOCS (>200,000 participants)[10] and PLCO Cancer Screening (~78,000 participants)[11] did not demonstrate a reduction in mortality with CA-125-based and transvaginal ultrasound-based algorithms. This indicates that CA-125 is a disease-monitoring and presurgical risk- stratification tool rather than a screening test. Retrospective and observational data report a duration-related association between combined oral contraceptive pill (COCP) use and reduced ovarian cancer risk—approximately 20% reduction per 5 years of use[12] or 30% lower risk in ever- versus never-users[13]—although no prospective randomised controlled trials have been conducted. Targeted treatments are beginning to augment systemic therapy. The standard of care for EOCs, the largest and most lethal category of ovarian cancers, is cytoreductive surgery, followed by platinum–taxane chemotherapy. Despite an initial response rate of around 80%, 75% of patients relapse within 2 years, and only 10%–40% survive to 5 years and beyond.[8] In 2011, bevacizumab first demonstrated a progression-free survival benefit as an anti-angiogenic adjunct to chemotherapy.[14,15] Although the role of poly (ADP ribose) polymerase (PARP) in DNA repair had been recognised since the 1980s, its therapeutic potential was not realised until 2005 when PARP inhibition was shown to be selectively lethal in cancers with defective double-stranded DNA repair, a phenomenon now termed Homologous Recombination Deficiency (HRD).[16,17] This reached clinical fruition with the SOLO-1 trial in 2018,[18] where maintenance olaparib demonstrated a clear survival benefit in women with inherited BRCA mutations and newly diagnosed ovarian cancer. MOLECULAR PROFILING AND HRD Over the subsequent decade, targeted therapies have begun to supplement systemic treatment as molecular profiling reshapes our understanding of ovarian cancer. Immunohistochemistry and characteristic molecular alterations now routinely complement conventional histotype-based classification, clarifying genetic drivers, oncogenic pathways, tumour biology and treatment response, and challenging the traditional view of ovarian cancer as a monolithic entity. For today’s patients, this molecular granularity increasingly determines which targeted therapies are most likely to benefit them. High-grade serous carcinoma (HGSC), for example, is the histotype responsible for most ovarian cancer-related mortality due to its early intraperitoneal dissemination and high recurrence rates despite initial platinum sensitivity. Likely arising from precursor serous tubal intraepithelial carcinoma lesions in the fimbrial end of the fallopian tube, HGSCs are characterised at a molecular level by near-universal TP53 mutations. In addition, approximately half of HGSCs are HRD-positive[19] due to mutations or silencing in BRCA-related genes, which may be inherited (germline) or may arise within the tumour itself (somatic). This molecular understanding supports the extension of PARP inhibitors beyond germline BRCA carriers to the broader HRD-positive population, exploiting impaired DNA repair to drive tumour cell death. The PAOLA-1 and PRIMA trials demonstrated significantly improved progression-free survival, from 17.7 to 37.2 months[20] and from 10.4 to 21.9 months, respectively,[21] in HRD-positive patients, although an overall survival benefit was not consistently demonstrated.[22,23] Universal BRCA mutation and tumour HRD testing are now standard practice for determining suitability for PARP inhibitor maintenance.[24] SURGERY IN PARALLEL Surgical practice in ovarian cancer has evolved alongside medical therapy. For decades, the reflex was to operate first to remove as much tumour as possible before chemotherapy. Since then, randomised trials have demonstrated non-inferior survival outcomes and lower perioperative morbidity in selected patients who received chemotherapy before surgery (i.e. neoadjuvant chemotherapy followed by interval debulking surgery).[25,26] Nevertheless, high-volume centres that consistently achieve high rates of complete resection continue to report superior outcomes with upfront surgery, making it the preferred approach for non-frail, operable patients.[27] For highly selected women who relapse with platinum-sensitive disease, secondary cytoreductive surgery, guided by validated clinical scoring tools, can extend survival.[28,29] While intraoperative hyperthermic intraperitoneal chemotherapy has demonstrated significant survival benefits in randomised controlled trials for both newly diagnosed and recurrent disease by targeting microscopic residual disease,[30,31,32] its widespread adoption has been limited by concerns about trial generalisability, increased perioperative morbidity, and the need for specialised centres and resources. MORTALITY AND THE ASIAN PERSPECTIVE Thirteen years on, despite the wealth of knowledge gained on the molecular basis of ovarian cancer, mortality remains largely unchanged. Global age-adjusted ovarian cancer mortality has declined by only 9.3% between 1990 and 2023, compared with 23.9% for all cancers.[33] While ovarian cancer incidence rates have declined in Western countries, they have doubled in Singapore since the 1960s, and age-adjusted mortality has plateaued at 3.5–3.9 per 100,000,[34] with a similar pattern seen in East Asian countries.[35] As with many cancers, data and perspectives from Asia continue to lag. A greater proportion of ovarian cancers in East Asia are endometriosis-associated histotypes, such as endometrioid and ovarian clear cell carcinomas (OCCCs).[35] The dividends of decades of HGSC-focused research do not extend to OCCCs—intrinsically platinum-resistant, rarely HRD-positive (