Personalized Medicine Is Reshaping How We Treat the Deadliest Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy, responsible for approximately 70% of all ovarian cancer diagnoses and an estimated 12,740 deaths in the United States in 2024 alone. Because early symptoms — abdominal bloating, pelvic pain, early satiety, urinary urgency — are nonspecific and easily mistaken for benign gastrointestinal conditions, over 75% of patients are diagnosed at advanced International Federation of Gynecology and Obstetrics (FIGO) stages III or IV. This 25-page, 17,000-word review published in CA: A Cancer Journal for Clinicians synthesizes the full spectrum of HGSOC biology, treatment, and patient-centered care to advocate for a comprehensive paradigm shift toward personalized, multimodal management.

The pathogenesis section details that HGSOC originates predominantly from fallopian tube secretory epithelium, progressing through three recognized precursor lesions: secretory cell outgrowths (SCOUTs), p53 signatures, and serous tubal intraepithelial carcinomas (STICs). STICs are characterized by nuclear atypia, high mitotic activity, apoptotic bodies, and near-universal TP53 mutations — either missense or nonsense. STICs are found more frequently in women carrying germline BRCA1 or BRCA2 mutations, yet not all STICs progress to invasive cancer, and not all HGSOCs arise from STICs. The authors recommend complete fimbriated-end sectioning (SEE-FIM protocol) in all tubal resections to identify occult precursor lesions.

Molecularly, HGSOC is defined by a near-universal somatic TP53 mutation rate (>95%), frequent homologous recombination deficiency (HRD) — present in approximately 50% of tumors including ~15–20% with germline BRCA1/2 mutations — extensive copy number alterations, and rare but targetable alterations such as CCNE1 amplification and CDK12 mutations. The tumor microenvironment (TME) is extensively discussed: HGSOC tumors are classified immunophenotypically as 'hot' (T-cell inflamed), 'excluded' (T cells confined to stroma), or 'cold' (immune desert). Tumor-associated macrophages, cancer-associated fibroblasts, reactive oxygen species, and insulin-like growth factor signaling all shape therapeutic response. High tumor-infiltrating lymphocyte density correlates with better outcomes and predicts immunotherapy benefit.

First-line treatment remains debulking surgery combined with platinum-taxane chemotherapy, with the goal of complete gross resection (R0) strongly associated with improved overall survival. The integration of bevacizumab (anti-VEGF) as maintenance therapy and, crucially, PARP inhibitors (olaparib, niraparib, rucaparib) as maintenance post-response has transformed care for HRD-positive patients, extending progression-free survival by 12–22 months in landmark trials such as SOLO-1, PRIMA, and PAOLA-1. The review thoroughly covers resistance mechanisms to PARP inhibitors, including BRCA reversion mutations and restoration of the replication fork protection complex, and emerging strategies to overcome resistance. Antibody-drug conjugates targeting FOLR1 (mirvetuximab soravtansine), which received FDA approval in 2022 for platinum-resistant HGSOC, are highlighted as a meaningful advance for patients with high folate receptor alpha expression.

The review devotes substantial attention to health equity, noting that racial and ethnic minority women face barriers to genetic testing — despite equal or higher prevalence of pathogenic variants — and are systematically underrepresented in clinical trials that have shaped current treatment standards. The authors call on oncology societies, including the Gynecologic Cancer Intergroup and ASCO, to enforce diversity requirements. A patient-centered framework integrating quality-of-life endpoints, participatory decision-making, and survivorship planning is presented as an ethical imperative alongside a clinical one. The authors conclude that centralizing HGSOC care in high-volume expert centers, expanding germline and somatic molecular profiling, and ensuring equitable trial enrollment are the most actionable near-term steps to close outcome gaps.