Ovarian cancer is known as the "silent killer of gynecological tumors". Its early symptoms are insidious and more than 70% of patients are detected at an advanced stage. According to the latest global epidemiological estimates, there are about 310,000 new cases and nearly 200,000 deaths every year, of which high-grade serous carcinoma (HGSC) accounts for 80% of ovarian cancer deaths. In the past few decades, despite continuous advances in chemotherapy and surgery, the overall 5-year survival rate has hovered around 40-50% for a long time. For patients with non-BRCA mutations and advanced stages, this number is even as low as 30%.

2026 (III): "Rethinking ovarian cancer III: the past decade and future directions" - based on the 15th Helene Harris Memorial Trust International Forum in October 2024 (38 leading experts + four major ovarian cancer charitable foundations jointly jointed), a rigorous review of the past decade and a blueprint for the next decade. Published online on April 13.

Foundational work (2011): Ovarian cancer is not a "one" disease

In 2011, more than 20 international experts reached a consensus at the Helene Harris Memorial Trust meeting and published the first article in the series. There is only one core point: the biggest misunderstanding was to treat ovarian cancer as a "disease" in the past.

They make 9 key recommendations that lay the philosophical foundation for the entire series:

1. Clarify the molecular origin of different histological subtypes (HGSC, clear cell carcinoma, endometrial carcinoma, etc.) - HGSC mainly comes from the fallopian tubes, rather than the traditional ovarian surface epithelium;

2. To improve clinical trial design, it must be stratified by subtype and cannot be "one-size-fits-all";

3. Prioritize prevention and early detection, especially risk-reducing surgery for people at high risk of BRCA1/2 mutations;

4. Discover new therapeutic targets and take advantage of genomic instability (e.g., the prototype concept of PARP inhibitors);

5. Targeting tumor microenvironment (TME): angiogenesis, inflammation, immunity;

6. Dealing with tumor adaptation and drug resistance: study clonal diversity and encourage serial biopsies;

7. Establish an international alliance of large-scale multi-omics datasets;

8. Develop a more realistic human model (3D culture, animal model);

9. Incorporate quality of life as an endpoint: not only to prolong survival, but also to reduce toxicity.

This paper pushes "heterogeneity" to the forefront for the first time, telling doctors and researchers that they can no longer use the same set of schemes to fight all ovarian cancers, but must attack as accurately as they treat "different enemies".

Focus on tackling tough problems (2015): Locking in HGSC, 10-year roadmap

In 2015, the second article in the series, led by David D. Bowtell and written by more than 40 experts, was longer and more focused. The title directly states: Reducing mortality from high-grade serous ovarian cancer.

Core Upgrades:

1. HGSC accounts for 70-80% of ovarian cancer deaths and is the real "culprit".

2. Molecular origin consensus: The vast majority of HGSCs originate from the fallopian tube secretory epithelium (FTSEC), and TP53 mutation is an early event; Approximately 50% have homologous recombination defects (HRD, including BRCA1/2 mutations 15-17%).

3. Clinical pain points: Initially sensitive to platinum, but very easy to recur; Peritoneal metastasis preference; TME is highly immunosuppressed; Clonal heterogeneity is extremely high.

The roadmap emphasizes:

1. Develop better models (PDX, 3D culture, genetically engineered mice).

2. In-depth drug resistance mechanisms (BRCA revert mutation, metabolic reprogramming, microenvironment remodeling).

3. Immunotherapy potential: CD8+ T cell infiltration is positively correlated with survival in patients with BRCA mutations.

4. Prevention: opportunistic salpingectomy; Early detection of prototypes (liquid biopsy).

5. Surgical optimization: minimizing residual lesions.

Integrating multi-omics, personalised stratification, patient-centered outcomes (survival + quality of life).

This article, from focusing on "generalized ovarian cancer" to focusing on "HGSC specialization", sets the tone for research from 2015 to 2025. PARP inhibitors and BRCAness concepts have been quickly implemented under this framework.

Ten-year review + new blueprint (2026): hope is in sight

The third article, published on April 13, 2026, is the latest and most comprehensive "Ten-Year Review + New Chapter". It is based on the consensus of the 2024 forum and is the first time that the four major charitable foundations will participate. The full text is divided into seven sections: introduction, prevention and early detection, tumor ecosystem, immunity and immunotherapy, acquired drug resistance, new treatment strategies, and conclusions.

1. Real report card of the past ten years

PARP inhibitors are the biggest breakthrough: significantly prolonging progression-free survival in first-line maintenance therapy in patients with BRCA1/2 mutations or HRD.

Upgrade of surgical concept: even if the tumor load is high, the maximum tumor reduction surgery does not increase the mortality rate; Secondary debulking surgery also has clear inclusion criteria in the event of recurrence.

Bevacizumab (anti-angiogenic) and somituximab (FRα ADC) have become new standard options.

The cruel reality: the overall 5-year survival rate is still ≈ 50%; only 30% of patients with advanced non-BRCA mutations; 50-70% of patients have multiple relapses; Platinum + paclitaxel ± bevacizumab are still the first-line backbone for most patients.

2. Prevention and Early Detection: A Revolutionary Pivot

The origin of the fallopian tubes has been globally agreed upon. STIC (serous intraepithelial carcinoma of the fallopian tubes) is a precursor to HGSC, and TP53 mutations are prevalent.

A new mechanism was found: postmenopausal tubal remodeling + BRCA heterozygosity → replication stress + oxidative stress of high-risk mesenchymal stem cells (hrMSCs) → STIC formation.

Major upgrade of prevention strategies: high-risk groups are verifying that "fallopian tube removal first, ovary removal delayed" is being verified to preserve hormone function and quality of life; There has been a number of epidemiological evidence that "opportunistic salpingectomy" (cut during hysterectomy or sterilization) in the general population can significantly reduce the incidence of ovarian cancer, and the cost-benefit model supports its promotion and even extends to gallbladder resection and bariatric surgery.

Breakthroughs in early detection: cfDNA fragmentomics + protein markers, cervical sampling DNA methylation, LINE-1 ORF1p and other new biomarkers, the sensitivity far exceeds CA125. Older screening trials such as UKCTOCS have not shown survival benefit, but new tools are on the way.

3. Tumor ecosystem (TME): from "black box" to "targetable"

HGSC TME is highly complex: immune cells, cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), adipocytes, sensory neurons, extracellular matrix (ECM).

New findings: CAFs with high expression of NNMT promote tumor migration; LOXL2 inhibitors and versican regulate T cell migration; Sensory neuronectomy improves immunity; NACT remodels the TME and induces inflammatory CAF.

Appeal: Spatial transcriptome + proteome + AI, develop humanized complex models (organ-on-a-chip, tumor slice culture, humanized PDX).

4. Immunity and Immunotherapy: From Disappointment to New Concepts

HGSC was once considered an "immune cold" tumor, and large phase III trials of ICIs as a single agent or in combination with chemotherapy have mostly failed. However, endogenous immune responses (tumor-infiltrating T cells, tumor-infiltrating B cells, and tertiary lymphoid structures) are strongly associated with long-term survival.

Key insights: HRD tumor immunity is "hot", HRP tumor immunity is "cold"; Neoadjuvant chemotherapy can induce T cell depletion in the TIGIT–NECTIN2 axis; MYCN, PI3K-AKT and other pathways suppress immunity.

New strategies include personalized vaccines (targeting alternative splices, neoantigens, cryptic peptides), dual immune checkpoints, ADCs, CAR-T/γδ T cells, myeloid cell targeting (TREM2, COX-PGE2), metabolic regulation, etc. KEYNOTE-B96 and other trials showed that PD-1 combined with paclitaxel had a progression-free survival benefit in platinum-resistant patients, suggesting great potential for combination therapy.

5. Acquired resistance

BRCA revert mutations and other genetic mechanisms account for only a few; Non-genetic mechanisms (dormancy, dryness, ECM remodeling, metabolic reprogramming) are more critical. TME remodeling and immune escape are common after NACT. Calls for sequential biopsy, dynamic monitoring of ctDNA, and study of the vulnerability of "non-replying" tumor cells.

6. New treatment strategies and clinical trial design

ADC, CCNE1 amplification subset targeting (CDK2, WEE1), and DNA damage response inhibitors (ATR, CHK1).

Trial design upgrades: window-of-opportunity study, MRD monitoring, basket trial, patient stratification. Emphasize the opening of industry test samples and international cooperation.

Source: "Rethinking ovarian cancer III: the past decade and future directions"