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 vascularisation4 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 cancers7,8 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 use12 or 30% lower risk in ever- versus never-users13—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-positive19 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 months20 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 (<5%),36 and driven instead by ARID1A and PIK3CA mutations,37 leading to a worse stage-adjusted prognosis. Pembrolizumab monotherapy, largely transformative across many other solid tumours, has achieved response rates of only 8%–11% across all EOCs.38,39 In OCCC, the lack of HRD-associated neoantigen generation and ARID1A loss-driven immune evasion reinforce an already immunologically ‘cold’ tumour microenvironment.35 ‘Heating up’ ovarian cancers by combining immune checkpoint inhibitors with existing drugs, however, has been promising. The DUO-O trial showed a progression-free survival benefit from 19.3 to 24.2 months when durvalumab and olaparib (a PARP inhibitor) were added to bevacizumab and chemotherapy in newly diagnosed non-BRCA-mutated advanced ovarian cancer,40 while KEYNOTE-B96’s combination of pembrolizumab with weekly paclitaxel in platinum-resistant recurrent disease41 was the first immunotherapy trial to demonstrate an overall survival benefit in ovarian cancer, from 14.0 to 17.7 months. Other surface markers are expanding the therapeutic toolset against platinum-resistant ovarian cancer. HER2 amplification, long established as a cornerstone target in breast cancer, is being repurposed as a homing beacon, with trastuzumab-based antibody–drug conjugates (ADCs) delivering a cytotoxic payload directly to HER2-amplified ovarian cancer cells regardless of DNA repair status.42 Folate receptor alpha (FRα), although highly expressed in many ovarian cancers, has long resisted exploitation by earlier immune-mediated naked antibody strategies. Mirvetuximab soravtansine is an ADC that reframes FRα from an immune effector target into a cytotoxic delivery vehicle and has demonstrated a significant overall survival benefit (16.5 vs. 12.8 months), in platinum-resistant disease.43 SCREENING REMAINS ELUSIVE Screening, however, remains elusive. Novel biomarker strategies based on circulating cell-free DNA, microRNA, and extracellular vesicle-based assays report high detection performance in symptomatic women or those with adnexal masses. However, notwithstanding costs and methodological heterogeneity, early-stage tumour-derived signals are often too low and prospective validation too limited to support asymptomatic screening. Therefore, they are not screening tests. Polygenic risk scores, derived from germline DNA, offer only modest risk stratification (area under the curve ~ 0.54–0.62).44,45 In the UKFOCSS study, multimodal screening using regular CA-125 and transvaginal ultrasonography showed a stage shift towards earlier detection in high-risk women but no demonstrable survival benefit.46 Given that HGSC is estimated to have a preclinical detectable window of approximately 1.7 years and progresses from early to advanced stage over about 12 months,47,48,49 high detection performance in disease-enriched settings does not necessarily translate into survival benefit through early detection. FALLOPIAN TUBES AS OPPORTUNITY The fallopian tubes represent a risk-reducing opportunity. While increasing COCP use may have contributed to lower ovarian cancer incidence,12,13 especially in high-income countries, sociocultural barriers and perceived risks limit population-level implementation. Extrapolated from the 80% lifetime ovarian cancer risk reduction conferred by bilateral salpingo-oophorectomy among BRCA mutation carriers, and supported by the tubal origin hypothesis of EOCs, opportunistic salpingectomy during intra-abdominal surgery in post-reproductive women is gaining traction50 as a low-risk approach that avoids the health and quality-of-life consequences of menopause.51 The efficacy of this strategy, however, awaits prospective data in low-risk populations and may not prevent ovarian cancer subtypes arising from alternative pathways of carcinogenesis, including metaplasia and chronic ovulation-related inflammation. CONCLUSION This year, around 400 women in Singapore will be diagnosed with ovarian cancer and approximately 160 will die from the disease. While HRD-positive disease has gained more therapeutic options and antibody–drug conjugates offer new avenues in platinum-resistant disease, durable remission for advanced ovarian cancer remains elusive. Ovarian clear cell carcinoma, with its Asian predilection, remains poorly understood. Despite clonal studies supporting a direct evolutionary relationship between endometriosis and OCCC through shared cancer-associated mutations,52 the molecular evidence is largely cross-sectional. To develop a mechanistic understanding of why only some women with endometriosis develop OCCC and other endometriosis-related malignancies—and to identify diagnostic and therapeutic targets—we need to understand how driver mutations such as ARID1A and PIK3CA are acquired, and quantify how germline susceptibility, hormonal milieu and treatment, and environmental factors contribute to oncogenesis. The lack of biomarkers capable of facilitating a meaningful stage shift limits early detection through population-level screening. A multimodal approach utilising polygenic risk scores, baseline family history, longitudinal molecular and environmental data, and machine learning may help stratify higher-risk women who could benefit from risk-reducing strategies after completing their reproductive goals, but prospective studies are needed to reconcile efficacy with quality-of-life implications. The biology is coming into focus; translating this understanding into prevention, earlier diagnosis and new therapeutic gains is the work of the next thirteen years. Financial support and sponsorship Nil. Conflicts of interest Choolani M is a member of the SMJ Editorial Board and was thus not involved in the peer review and publication decisions of this article.
Kanneganti et al. (Fri,) studied this question.