Transforming treatment paradigms: Focus on personalized medicine for high‐grade serous ovarian cancer

Abstract

High‐grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of ovarian cancer, accounting for approximately 70% of all ovarian cancer cases and contributing significantly to the high mortality rates associated with this disease. Because of the asymptomatic nature of early stage disease, most patients are diagnosed at advanced stages when the cancer has already spread into the abdominal cavity, requiring complex and intensive surgical and chemotherapeutic interventions followed by maintenance therapies. Although a minority of cases are associated with well defined genetic syndromes, specific risk factors and a clear etiology in many cases remain elusive. HGSOC tumors are characterized by a high frequency of somatic gene copy number alterations, often associated with defects in homologous recombination repair of DNA. All attempts to introduce an effective screening for HGSOC to date have been unsuccessful. This review elucidates the complexities surrounding HGSOC and encompasses its etiology, epidemiology, classification, pathogenesis, and the current array of treatment strategies. Understanding molecular underpinnings is crucial for the development of targeted therapies and personalized multimodal treatment approaches in centralized therapeutic structures. This review also examines the importance of the tumor microenvironment. In addition, the authors' objective is to underscore the critical importance of placing the patient's perspective and diversity at the forefront of therapeutic strategies, thereby fostering a genuinely participatory decision‐making process and ultimately improving patient quality of life.

INTRODUCTION

High‐grade serous ovarian cancer (HGSOC) stands as the most prevalent and deadly subtype among ovarian malignancies, characterized by its aggressive nature and high recurrence rates. HGSOC is one of the most common gynecologic malignancies in women worldwide and, among common gynecologic tumors, carries the highest case lethality. ¹ , ² , ³ According to the American Cancer Society, in 2024, there will be approximately 19,680 new ovarian cancer cases and 12,740 ovarian cancer deaths in the United States. ⁴ Epithelial ovarian cancer accounts for 90% of cases, with high‐grade serous tumors having the poorest prognosis among the major subtypes. The low survival rates are primarily attributable to diagnoses at more advanced disease stages. ⁴ Contemporary analyses have provided valuable insights into the molecular drivers and heterogeneity of this disease, paving the way for personalized and multimodal strategies. In addition, we recommend that these approaches be taken from a patient‐oriented perspective, as discussed below in detail. The symptoms and early signs of HGSOC are typically vague and nonspecific, contributing to the challenges in early detection (Figure 1). Common symptoms include abdominal bloating, pelvic pain, early satiety, and urinary urgency or frequency. These symptoms are often mistaken for benign conditions, such as gastrointestinal disorders, leading to diagnostic delays. ⁵ , ⁶ As the disease progresses, symptoms become more pronounced and may include weight loss, fatigue, and changes in bowel habits. The insidious onset of symptoms underscores the importance of raising awareness and promoting early diagnostic initiatives to improve outcomes. It is noteworthy that thrombosis, paraneoplastic cerebellar symptoms, and paraneoplastic dermatitis are rare but well described presentations and should not be neglected or misinterpreted.

FIGURE 1.

Common presenting symptoms of patients with high‐grade serous ovarian cancer. The symptoms and early signs of high‐grade serous ovarian cancer are typically vague and nonspecific, contributing to the challenges in early detection. Common symptoms include abdominal bloating, pelvic pain, early satiety, and urinary urgency or frequency. These symptoms are often mistaken for benign conditions, such as gastrointestinal disorders, leading to diagnostic delayed diagnosis. As the disease progresses, symptoms become more pronounced and may include weight loss, fatigue, postmenopausal bleeding, and changes in bowel habits. Thrombosis, paraneoplastic cerebellar symptoms, or paraneoplastic dermatitis are rare symptoms. The insidious onset of symptoms underscores the importance of raising awareness and promoting early diagnostic initiatives to improve outcomes. Created with Biorender (License No. EL27ZKGY7G).

This review aims to elucidate the complexities surrounding HGSOC with a focus on its epidemiology, classification and staging, pathogenesis, and the current array of treatment strategies employed to combat this disease. Moreover, we delve into emerging research avenues and prospective advancements that hold the promise of transforming the management and outcomes of HGSOC. This review examines the importance of the tumor microenvironment (TME). In addition, we aim to underscore the critical importance of placing the patient's perspective and diversity at the forefront of therapeutic strategies, thereby fostering a genuinely participatory decision‐making process and ultimately improving patient quality of life (QoL). We advocate that a paradigm shift in centralized therapeutic structures is needed in personalized medicine for patients with HGSOC and should be urgently implemented.

ETIOLOGY AND EPIDEMIOLOGY

The interplay between genetics, environment, and lifestyle factors forms a complex web influencing the incidence and progression of HGSOC. The incidence and prevalence rates of HGSOC exhibit significant variation across diverse populations; however, disparities are well known and particularly striking in the gynecologic oncology care continuum and should be considered when interpreting these data. There is a compelling need to include minority groups in clinical trials, and this issue is broadly recognized by leading scientific societies and organizations, such as the Gynecologic Cancer Intergroup, the American Society of Clinical Oncology, and the World Health Organization. Therefore, we suggest a circumscribed interpretation of HGSOC studies with inadequate representation of the patient pool worldwide (Figure 2). Understanding health care disparities in patients with HGSOC is critical for developing effective prevention and personalized therapeutic approaches. We highlight the importance of diversity in HGSOC because diagnosis and treatment should be available regardless of race/ethnicity, age, gender, socioeconomic status, education, geographic region, sexual identity, disability, or language. ⁷ , ⁸ The analysis of epidemiologic data has highlighted significant variations in incidence and survival rates across different demographic groups. In particular, our review substantiates that racial and socioeconomic disparities play a central role in influencing HGSOC outcomes. This reinforces the notion that research approaches must integrate broad determinants of health, encompassing sociodemographic variables, educational level, and behavioral factors that may affect survivorship. Moreover, the clinical and societal implications of embracing a diversity‐informed approach are profound. Incorporating nuanced diversity metrics not only enhances our understanding of disease etiology but also ensures that treatment strategies are equitable and personalized. The emphasis on early detection, particularly among populations at elevated risk, is not merely a clinical imperative but also a matter of social justice. Emphasizing diversity fosters innovation in research methodologies and encourages collaboration among researchers from varied backgrounds. Diverse teams bring unique perspectives, driving creativity and enhancing problem solving (Figure 2). This inclusivity can lead to the discovery of novel biomarkers and treatment responses that may vary by ethnicity and genetic background.

FIGURE 2.

Diversity in gynecologic oncology. This scheme depicts the ultimate need to include underrepresented minorities and to promote diversity. Racial inequities are well known and particularly striking in the gynecologic oncology care continuum. There is a strong need to include racial and ethnic minority groups in clinical trials. We call for a circumscribed interpretation of high‐grade serous ovarian cancer studies, with inadequate representation of the patient pool. Understanding health care disparities in gynecologic oncology is critical for developing effective, personalized therapeutic approaches. Diversity in patients with high‐grade serous ovarian cancer and in gynecologic oncology should be respected and will be a benefit for the scientific community, leading to more robust data for publications based on innovative and creative research generated in an excellent team. Created with Biorender (License No. RD27ZKH4P1).

HGSOC is predominantly diagnosed in women aged 55–64 years, with incidence rates peaking for all women in their late 70s. ⁴ According to GLOBOCAN 2020 data, ovarian cancer, which includes HGSOC, is the seventh most common cancer among women and the eighth leading cause of cancer death worldwide. ⁹ The incidence and mortality rates of HGSOC exhibit considerable geographic variations. An association between socioeconomic conditions and HGSOC incidence is evident and significantly influences the disease's epidemiology and survival rates. ¹⁰ , ¹¹ , ¹² These analyses underline the existence of disparities affecting women with HGSOC in different geographic regions.

Environmental and lifestyle factors, obesity, use of hormone‐replacement therapy, and reproductive history are also implicated in the epidemiology of HGSOC. ¹³ , ¹⁴ Lower parity, earlier age of menarche, later age of menopause, higher body mass index, endometriosis, pelvic inflammatory disease, and longer use of hormone‐replacement therapy after menopause all increase HGSOC risk; whereas higher parity, use of hormonal contraception, breastfeeding, and tubal ligation all lower HGSOC risk. Familial aggregation of HGSOC and other cancers, such as breast, pancreatic, melanoma, and colon cancers, in first‐degree relatives underscores the importance of genetic epidemiology in HGSOC management. ¹⁵ Unfortunately, genetic testing is often less accessible to minority groups despite equal or high prevalence of mutations and although variants of unknown significance are more common among minority patients when genetic testing is offered. ¹⁶ This evidence underpins the rationale for incorporating comprehensive genetic assessments into the clinical pathway to optimize personalized treatment strategies.

PATHOGENESIS AND TUMOR MICROENVIRONMENT

Currently, the general consensus is that the fallopian tube epithelium is the primary origin for most HGSOC tumors. ¹⁷ , ¹⁸ , ¹⁹ HGSOC appears to develop from three precursors in the fallopian tube: secretory cell outgrowths, p53 signatures, and serous tubal intraperitoneal carcinomas (STICs; Figure 3). Secretory cell outgrowths are extended regions of secretory cells in the tubal epithelium without intervening ciliated cells. The p53 signatures are morphologically normal‐appearing regions of epithelium with contiguous stretches of secretory cells expressing mutant p53 identifiable by immunohistochemistry. STICs are noninvasive lesions with cytologic atypia, high proliferative index, and hyperplasia that develop in the distal fallopian tube epithelium and can progress to malignancy either on the tubal surface or in the periphery after they have implanted either on the ovarian surface or peritoneum. ²⁰ , ²¹ This exfoliative behavior is highly characteristic of HGSOC, and peritoneal metastases generally occur as a series of metastatic events, rather than stepwise outward growth from a single lesion. Notably, so‐called primary peritoneal carcinomas may exhibit STICs as well, making this a potential precursor lesion for this disease. Nuclear atypia, high mitotic activity, and apoptotic bodies are commonly observed in STICs, as are TP53 mutations, which may be nonsense or missense. STICs may be preceded by serous tubal intraepithelial lesions, which may or may not exhibit a mutant p53 signature, are characterized by a low Ki‐67 proliferation index (<10%), and are commonly referred to as dormant. ²² , ²³ Studies indicate that incidental STICs are more commonly seen in women at high risk of cancer because of germline BRCA1 and/or BRCA2 mutations. ²⁴ Although STICs are clearly linked with a heightened risk of HGSOC, not all STICs progress to HGSOC, nor do all HGSOCs arise from STICs, even among women with high‐risk factors. ²⁵

FIGURE 3.

High‐grade serous ovarian cancer origin and development. This scheme depicts the precursor lesions of HGSOC and the invasion of STICs on the ovarian surface in the distal fallopian tube epithelium. Immunophenotypic classification: the T‐cell inflamed or hot category means that T cells infiltrate deposits (islets) of malignant cells and the surrounding and intervening stroma; whereas the noninflamed category, also known as immune‐desert or cold tumors, lack this feature. The excluded classification means that T cells remain confined to the stroma, and there are no deposits of malignant cells. + indicates positive; HGSOC, high‐grade serous ovarian carcinoma; IGF, insulin‐like growth factor; ROS, reactive oxygen species; SCOUT, secretory cell outgrowth; SEE‐FIM, Sectioning and Extensively Examining the FIMbriated End; STICs, serous tubal intraperitoneal carcinomas; TAM, tumor‐associated macrophage. Created with Biorender (License No. MB27ZKHB14).

Moreover, in patients with HGSOC, we recommend that the tubal resections should be completely examined pathologically by applying the SEE‐FIM (Sectioning and Extensively Examining the FIMbriated End) protocol. Here, the fimbrial funnel is examined in longitudinal sections, and the tube is examined in cross sections. During opportunistic salpingectomy, at least the fimbrial funnel should be completely examined. ²⁶ Therefore, for lesions suspected of STIC, we recommend immunohistochemical examination for p53 and Ki‐67 that can be used to confirm the diagnosis.

The molecular and cellular mechanisms of HGSOC are predominantly driven by genetic mutations and dysregulated cellular signaling pathways. As mentioned above, mutations in the TP53 gene are nearly ubiquitous in HGSOC and are considered a hallmark of the disease. ¹⁴ , ¹⁹ , ²⁷ TP53 encodes the p53 tumor‐suppressor protein, which plays a critical role in maintaining genomic stability and preventing tumor development. Loss of p53 function caused by TP53 mutations can lead to inappropriate or unregulated cellular proliferation and tumor growth. ¹⁹ , ²⁸

Other genetic alterations implicated in HGSOC include mutations in BRCA1, BRCA2, and other genes involved in homologous recombination repair pathways, contributing to genomic instability and oncogenesis. ²⁹ , ³⁰ BRCA1 and BRCA2 mutations loom large in this context, increasing the lifetime risk for ovarian cancer and influencing the tumor's response to therapy. ³¹ , ³² Beyond these well‐established genetic abnormalities, emerging research has identified epigenetic alterations, including DNA methylation and histone modification, which may contribute to cancer pathogenesis by altering gene expression without changing the DNA sequence. ³³ , ³⁴

Importantly, the TME plays a critical role in the pathogenesis of HGSOC (Figure 4). The TME of HGSOC is a highly orchestrated and dynamic ecosystem composed of a diverse array of cellular and acellular components that collectively contribute to tumor progression, metastasis, and therapeutic resistance. ³⁵ Epithelial ovarian cancer cells engage in reciprocal crosstalk with various stromal cell types, including cancer‐associated fibroblasts, immune cells, stromal cells, extracellular matrix, exosomes, and neovascular blood vessels. ³⁶ , ³⁷ , ³⁸ Cancer‐associated fibroblasts (CAFs) are particularly significant because they modulate the TME to support tumor growth and metastasis. ³⁸ The intricate interactions between cancer cells and CAFs play a pivotal role in the progression and therapeutic resistance of HGSOC. In addition, the immune microenvironment, characterized by the presence of tumor‐infiltrating lymphocytes (TILs) and macrophages, influences tumor behavior and patient prognosis. ³⁹ , ⁴⁰ The above‐mentioned interactions promote the establishment of a favorable niche that supports tumor growth, angiogenesis, immune evasion, and the metastatic dissemination of ovarian cancer cells (Figure 3). CAFs secrete factors that promote angiogenesis, cancer cell proliferation, and survival while also altering the extracellular matrix to facilitate tumor invasion. ⁴¹ More precisely, CAFs within the ovarian TME (Figure 4) secrete a plethora of cytokines, chemokines, and extracellular matrix components that foster an immunosuppressive milieu, facilitate the epithelial‐mesenchymal transition of ovarian cancer cells, and prime the metastatic niche in the omentum. ⁴² , ⁴³ Ovarian cancer cells, in turn, can reprogram stromal cells to adopt a pro‐tumorigenic phenotype, thereby creating a self‐reinforcing cycle of reciprocal signaling that perpetuates disease progression. This reprogramming of stromal cells by ovarian cancer cells is a key mechanism that sustains the TME and facilitates continued tumor growth, invasion, and metastasis. Moreover, tumor cells possess an abnormal extracellular matrix deposition that leads to stiffness, proliferation, and resistance to cell death. ⁴⁴ The ability of ovarian cancer cells to alter the phenotype of surrounding stromal cells is a critical component of the dynamic interplay between the cancer cells of HGSOC and their microenvironment. ⁴⁵ Another one of the key factors that contribute to ovarian cancer development and progression is oxidative stress (OS), which can result from an imbalance between the production of reactive oxygen species (ROS) and the ability of the cell to neutralize them. ⁴⁶ Ovulation‐induced generation of ROS also influences the occurrence of HGSOC. ⁴⁷ Moreover, OS can trigger the angiogenic switch, a cascade of biologic events that are essential for tumor growth and metastasis. ⁴⁸

FIGURE 4.

The microenvironment of high‐grade serous ovarian cancer. In the tumor microenvironment, cancer‐associated fibroblasts (CAFs) are particularly important because they support tumor growth and metastasis. Tumor cells with increased DNA damage show signs of inflammation upon sensing DNA damage and the upregulation of stimulator of interferon genes (STING) and tumor‐intrinsic type I interferon signaling pathways. BRCA1/BRCA2 and TP53 gene mutations are common. Several mechanisms contribute to immunosuppression within tumors, including the secretion of IL‐10/IL‐6 with inhibition of the PD‐1 receptor and the immunosuppressive actions of myeloid‐derived suppressor cells (MDSCs), tumor‐associated macrophages (TAMs), or CAFs. CAFs indicates cancer‐associated fibroblasts; DC, dendritic cells; PD1, programmed death 1; PD‐L1, programmed death‐ligand 1; Treg, regulatory T cells. Created in Biorender (License No. VN27ZKHGXA).

Mitochondria are a significant source of ROS and are known to be affected by the TME. ⁴⁹ Mitochondrial dysfunction can lead to further OS, exacerbating the already hostile tumor environment. This interplay between OS, mitochondrial dysfunction, and the TME can have profound implications for cancer development (Figure 4), progression, and resistance to treatment. ⁵⁰ Interestingly, the chemoresistance of ovarian cancer relies in part on an enhanced antioxidant capacity of the cancer cells. HGSOC cells protect themselves by initiating antioxidant responses, such as upregulating SLC7A11 (solute carrier family 7 member 11), resulting in alterations in cysteine import into cancer cells and preserving redox balance. ⁵¹

In HGSOCs, there is a heterogeneous mixture of tumor cells infiltrated by, among others, various immune or stromal cells. Several mechanisms contribute to immunosuppression within tumors, including the inhibition of CD8‐positive T cells by regulatory T cells, secretion of IL‐10/IL‐6 with promotion of the programmed death 1 receptor (Figure 4), and the immunosuppressive actions of myeloid‐derived suppressor cells, tumor‐associated macrophages, and CAFs. ³⁸ Interestingly, among all ovarian cancers, HGSOC is the most likely to show significant CD8‐positive T‐cell infiltration, reported to be a favorable prognostic factor. ⁴⁵ The presence of intraepithelial TILs in tumor islets has been linked to improved survival in numerous studies, although these are present in less than one half of cases. ⁵² , ⁵³ It has been demonstrated in HGSOC that CD8‐positive T cells within so‐called inflamed tumors, also known as hot tumors, invade the stroma surrounding malignant cells and express transcriptional signatures of cytotoxic T cells, such as granzyme B (GZMB), GZMA, GZMH, granulysin (GNLY), and interferon γ (IFNG). ⁴⁵ , ⁵⁴ , ⁵⁵ Chemokine circuits precisely regulate the infiltration and retention of intraepithelial CD8‐positive TILs in the TME, whose presence is linked to slower tumor progression and extended survival. ⁴⁵ However, because HGSOC tends to metastasize as a series of episodic exfoliative events, different molecular changes and pathways are activated at different metastatic tumor sites, giving rise to a heterogeneous immunophenotype. ⁵⁶

Contemporary studies provide evidence that there is a significant link between mitochondria, apoptosis, induced glutathione inactivation, and platinum resistance in ovarian cancer, suggesting that mitochondrial metabolism could serve as a potential target in cancer precision medicine. ⁵⁷ Mutations in mitochondrial DNA, such as ND2 F40L, can impact proton transport pathways, affect mitochondrial complex I activity, increase ROS levels, and decrease sensitivity to cisplatin by activating the nuclear factor‐κB signaling pathway and inducing IAP (inhibitor of apoptosis) expression. ⁵⁸ Moreover, it has been established that mitochondria are involved in the intrinsic apoptotic signaling pathway to control cell death. ⁵⁹ Therefore, a thorough analysis of mitochondria‐related genes and their connection with apoptosis could enhance understanding of HGSOC progression and platinum resistance, paving the way for developing novel strategies to combat platinum resistance.

DIAGNOSIS, STAGING, AND MOVING TOWARD MOLECULAR CLASSIFICATION

It is our belief that a critical view on the current classification and staging systems commonly used in patients with HGSOC is needed. Ovarian cancers can be categorized by molecular classification and anatomic staging, although, given the heterogeneity of individual tumors, not every patient can be precisely categorized. Keeping this caveat in mind, we suggest using the concept of the five major, pathogenetically independent, histologically and molecularly different groups of ovarian carcinomas, namely: (1) high‐grade serous carcinomas; (2) endometrioid and (3) clear cell carcinomas, which often arise in the ovary and are often associated with endometriosis; (4) mucinous carcinomas; and (5) low‐grade serous carcinomas. An algorithm using molecular markers for the aforementioned five types is provided below (Figure 5).

FIGURE 5.

Algorithm for the diagnosis of histologic types. The scheme shows the diagnostic algorithm based on additional immunohistochemistry examinations. − indicates negative; +, positive; WT, wild type.

Traditionally, HGSOCs were classified as ovarian, tubal, or primary peritoneal in origin. However, as noted, most HGSOCs are thought to originate from tubal precursors. HGSOC is now classified as originating from the fallopian tube (Figure 3) when the tube is either affected by STICs, contains mucosal carcinoma, or is largely occupied by HGSOC. ⁶⁰ , ⁶¹ , ⁶² Consequently, the majority of HGSOCs are now regarded as having an extra ovarian origin, and a significant shift in the International Classification of Diseases for Oncology site codes from C56.1 (ovary) to C57 was introduced by the World Health Organization. ⁶³ Recent advancements in the molecular characterization of epithelial ovarian cancer have further refined these descriptions to include TP53 mutational status and homologous DNA damage repair proficiency.

HGSOC is pathologically staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system (Table 1). Staging and grading of ovarian cancer, guided by the FIGO system, are fundamental to determining the extent of the disease and tailoring treatment approaches. The FIGO system ranges from stage I (tumor confined to the ovaries) to stage IV (distant metastasis), thus offering a standardized framework for evaluating disease progression. ⁶⁴ Another classification is provided by the TNM (primary tumor [T], regional lymph nodes [N], and distant metastases [M]) system based on the anatomic spread of malignant tumors (Table 1). An effort to harmonize FIGO with TNM is underway. Moreover, histopathologic features are essential for the accurate diagnosis of HGSOC. ⁶⁵ , ⁶⁶ The presence of the aforementioned papillary structures and STICs in the fallopian tubes supports a diagnosis of HGSOC, highlighting the interplay between ovarian and fallopian tube origins. ⁶⁰ , ⁶¹ The Silverberg grading system adds to these descriptions by categorizing tumors based on architectural and nuclear features, providing further granularity that can inform prognosis and therapeutic decisions. ⁶⁷ Moreover, the Silverberg grading system appears to be preferable for categorizing patients with HGSOC for prognosis and disease management. ⁶⁸

TABLE 1.

Tumor, lymph node, and metastasis and International Federation of Gynecology and Obstetrics classification systems for ovarian cancer.

TNM	FIGO stage	Definition
TX		Primary tumors cannot be assessed
T0		No evidence of a primary tumor
T1	I	Tumor limited to ovaries (one or both) or fallopian tube(s)
T1a	IA	Tumor limited to one ovary; capsule intact, no tumor on the surface of the ovary or fallopian tube; no malignant cells in ascites or with peritoneal lavage
T1b	IB	Tumor limited to both ovaries or tubes; capsule intact, no tumor on the surface of both ovaries or tubes; no malignant cells in ascites or peritoneal lavage
T1c	IC	Tumor limited to one or both ovaries or tubes with one of the following:
T1c1	IC1	Tumor cell dissemination during surgery
T1c2	IC2	Capsule rupture before surgery or tumor on ovarian or tubal surface
T1c3	IC3	or malignant cells in ascites or peritoneal lavage
T2	II	Tumor affects one or both ovaries or tubes and spreads throughout the pelvis, below the edge of the pelvis
T2a	IIA	Spread to and/or implants on the uterus and/or tube(s) and/or ovaries
T2b	IIB	Spread to other pelvic tissues
T3 and/or N1	III	Tumor affecting one or both ovaries or tubes or primary carcinoma of the peritoneum with cytologic or histologic evidence, spread to the peritoneum outside the pelvis, and/or regional lymph node metastases
N1		Only retroperitoneal lymph node metastases
N1a	IIIA1i	Lymph node metastases ≤10 mm in greatest extent
N1b	IIIA1ii	Lymph node metastases >10 mm in greatest extent
T3a, every N	IIIA2	Microscopic spread beyond the pelvis (above the edge of the pelvis) with or without retroperitoneal lymph node metastases beyond the pelvis
T3b, every N	IIIB	Macroscopic peritoneal metastases beyond the pelvis, ≤2 cm in greatest extent
T3c every N	IIIC	Peritoneal metastases beyond the pelvis, ≥N1, 2 cm in greatest extent, and/or regional lymph node metastases, including tumor spread to the liver and spleen capsule without parenchymal involvement of these organs
M1	IV	Distant metastases (exclusively peritoneal metastases)
M1a	IVA	Pleural effusions and positive cytology
M1b	IVB	Parenchymal metastases and distant metastases in extra‐abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity

Note: Metastases to the liver capsule correspond to T3/stage III, liver parenchyma metastases correspond to M1/stage IV according to the German S3 guidelines (S3‐Leitlinie Diagnostik, Therapie und Nachsorge maligner Ovarialtumoren Version 6.0) and Feng 2024. ⁶⁴

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; TNM, primary tumor (T), regional lymph nodes (N), and distant metastases (M) system based on the anatomic spread of malignant tumors.

The clear distinction between low‐grade and high‐grade ovarian carcinomas was established in 2014. Although a dualistic classification (type I and II tumors) existed previously, it was the World Health Organization classification of 2014 that standardized this approach. Consequently, patients diagnosed before 2014, particularly those initially classified as grade 2, should be reclassified if and when a recurrence occurs according to these guidelines. For clinicians and specialists, it is important to distinguish high‐grade serous carcinoma from other serous neoplasms, such as low‐grade serous carcinoma and serous borderline tumors, which have different molecular features and clinical outcomes. Low‐grade serous carcinoma is characterized by minimal nuclear atypia and lower mitotic activity (as defined by the Ki‐67 index) compared with high‐grade serous carcinoma. It generally affects younger patients and has a slower rate of progression. In contrast, high‐grade serous carcinoma is marked by pronounced nuclear atypia, a high mitotic index, and a rapid proliferative rate, leading to a more aggressive clinical course. ⁵ As mentioned above, high‐grade serous carcinomas are characterized in most cases by mutations in the TP53 gene, which manifests on immunohistochemistry either as pronounced overexpression (overexpression pattern) or as the complete absence of staining (null pattern). Low‐grade serous carcinomas, in contrast, typically exhibit wild‐type p53 and more frequently harbor mutations in other genes, such as KRAS or BRAF. In practice, p53 staining is often used to complement morphologic classification or to confirm uncertain cases. Nevertheless, p53 assessment should be considered standard in the pathologic diagnosis of ovarian carcinoma to provide a comprehensive diagnostic framework and to guide optimal therapeutic decisions.

I could no longer cope with the psychological uncertainty. All samples were forwarded to the pathology department for further investigation. Ten days later, the doctor told me that a malignant carcinoma had been diagnosed by the pathologists in both the ovary and the uterus. The doctors initially assumed that it was a single tumor that had already metastasized—but whether the ovary or the uterus was primary was an issue doctors were still trying to clarify in the pathology department at that time.

In addition to the morphologic and anatomic classification systems, The Cancer Genome Atlas described four molecular subtypes of HGSOC based on unsupervised clusters from messenger RNA expression data. ⁶⁹ These have been called the immunoreactive subtype (chemokine expression), the proliferative subtype (proliferation marker expression), the differentiated subtype (ovarian tumor marker expression), and the mesenchymal subtype (expression of markers suggestive of increased stromal components). The immunoreactive subtype demonstrated the significantly highest progression‐free survival and overall survival, whereas the overall survival rate was lowest in the mesenchymal subtype. ⁷⁰

A summary of HGSOC characteristics is provided in Table 2. All these points emphasize the importance of specialized gynecologic oncologists and trained pathologists for the review of tissue. Importantly, this should be an expedited process, acknowledging that delays in final diagnosis can be exceptionally stressful for the patient.

TABLE 2.

Summary of high‐grade serous ovarian cancer characteristics.

Subtype specific information	High‐grade serous ovarian cancer
Purported cell of origin	Fallopian tube
Precursor lesion	Serous tubal intraepithelial carcinoma lesions
Inherited predisposition	15%–25%
Molecular features	Somatic tumor testing may reveal: Chromosomal instability; copy number alterations; homologous repair defects; alterations of the genes TP53 and CCNE1, PIK3CA amplifications, BRCA1/2 mutations, or other forms of homologous recombination deficiency; microsatellite instability; mismatch repair; HER2 expression; tumor mutational burden; BRAF V600E mutation; folate receptor alpha expression; RET mutations; NTRK gene fusion
Risk factors	Germline mutations in BRCA1, BRCA2, or other homologous DNA repair genes or Lynch syndrome; environmental and lifestyle factors; obesity; hormone‐replacement therapy and reproductive history, including parity, age at first birth, lifetime number of ovulatory cycles, and endometriosis; family history of ovarian, breast, or bowel cancer
Potential protective factors	Oral contraception treatment, tubal ligation, birth, and breastfeeding; bilateral salpingo‐oophorectomy recommended for patients with a BRCA mutation after childbearing is complete (or not desired), ideally between ages 35 and 40 years for BRCA1 and between ages 40 and 45 years for BRCA2
Platinum‐based chemotherapy	Usually sensitive
PARP inhibitor	Variably sensitive
Diagnostic clinical and pathologic features	Pelvic examination; imaging tests: Blood tests (CA 125, HE‐4, OVA1; diagnostic laparoscopy; surgery (removing mass to determine whether it is cancerous); biopsy (fine‐needle aspiration/fine‐needle aspiration biopsy of metastatic sites, core biopsy, or paracentesis) Pathologic features: Solid, papillary, and glandular areas with high mitotic activity and high‐grade atypia; often bilateral and advanced stage at clinical presentation
Diagnostic imaging	Pelvic ultrasound, CT chest CT or MRI abdomen/pelvis, PET (in select cases)
Prognostic feature	Postoperative residual disease is the most important prognostic factor

Abbreviations: CA 125, cancer antigen 125; CT, computed tomography; FNA, fine‐needle aspiration; HE‐4, human epididymis protein 4; MRI, magnetic resonance imaging; OVA1, blood test from Aspira Women's Health that measures five biomarkers assessing malignancy; PARP, poly(adenosine diphosphate‐ribose) polymerase; PET, positron emission tomography.

TREATMENT STRATEGIES FOR HIGH‐GRADE SEROUS OVARIAN CANCER

The treatment paradigm for HGSOC is evolving rapidly, encompassing a spectrum of therapeutic approaches that aim to extend survival and enhance QoL for patients. Surgical interventions, chemotherapy regimens, and emerging targeted therapies are being used in an expanding repertoire for treatment options. For the prediction of HGSOC therapy success, we suggest that patients should be categorized according to their general health status into the following three groups: (1) prefrail, (2) frail, and (3) nonfrail. Frailty is considered to be a state of elevated vulnerability to adverse outcomes. ⁷¹ More specifically, frailty represents a multisystem syndrome of low physiologic reserves combined with a lowered capacity to respond to stressors. In addition, frailty has been reported to affect the prediction of surgical outcomes more than the patient's age. ⁷² To measure frailty, a respective index has been established, representing a ratio of deficits that are present before surgery to the total number of deficits taken into consideration. ⁷¹ Based on this ratio, a patient will receive a frailty index of 0.2 (10 of 50) if, for example, 50 deficits have been considered and 10 were present. In other words, the frailty index principle reflects health deficits, such as diseases, disabilities, or abnormalities of laboratory, radiographic or electrocardiographic outcomes. However, the classification of patients according to their frailty status is not routinely performed. Moreover, we suggest a personalized prehabilitation therapeutic strategy (Figure 6) that is combined with an enhanced recovery after surgery approach to decrease postoperative morbidity. ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ It has been demonstrated that the preoperative quality‐of‐life evaluation can be a predictive marker for severe postoperative complications in patients with ovarian cancer. ⁷⁵ Importantly, the aforementioned study provided evidence that patients with limited mobility, debilitating symptoms, and cognitive impairment had a higher risk of developing severe postsurgery complications. ⁷⁵

The doctor gave me very helpful advice, telling me that experience has shown that it is recommended to be honest with children and family about such a diagnosis. I didn’t ask myself how I could deal with this in the future. The situation was too acute, with a 14‐year‐old girl at home. Nevertheless, the question always weighed on me as to whether my daughter might be genetically affected. At work, I was open with my colleagues about my cancer diagnosis and received a great deal of support and encouragement. However, I also felt that many of them were hesitant to remain close to me.

FIGURE 6.

Patient management. Scheme showing the proposed personalized prehabilitation therapeutic strategy that is combined with an enhanced recovery after surgery (ERAS) to decrease postoperative morbidity. For the prediction of cancer therapy success, patients should be precategorized according to their general status into the following groups: prefrail, frail, and nonfrail.

PATIENT PREFERENCES IN THE TREATMENT DECISION‐MAKING PROCESS

A key aspect of effective ovarian cancer management is the integration of patient preferences into the treatment decision‐making process. By actively involving patients in discussions about their therapeutic options, clinicians can enhance both adherence to the chosen treatments and patient satisfaction. This approach ensures that medical decisions align not only with clinical evidence but also with the individual values, goals, and circumstances of each patient. Studies, such as those from the North‐Eastern German Society for Gynecologic Oncology (Nord‐Ostdeutsche Gesellschaft fur Gynakologische Onkologie/NOGGO) expression series, highlight the importance of considering patient preferences as a central component of shared decision making. This collaborative process fosters a sense of empowerment among patients, enabling them to take an active role in their care, particularly when faced with the psychological uncertainty before definitive diagnosis. Moreover, aligning treatment strategies with patient priorities has been shown to improve adherence and optimize outcomes, in terms of both QoL and clinical effectiveness. Incorporating patient preferences is not only ethically essential but also is a practical strategy to build trust and strengthen the therapeutic alliance. This ensures that care is both patient‐centered and reflective of the diverse needs and aspirations of those living with ovarian cancer. ⁷⁶ , ⁷⁷ HGSOC management should be tailored to the unique priorities and concerns of each patient. By recognizing and addressing individual aspirations, goals, and preferences, care teams can develop personalized treatment plans that optimize not only medical outcomes but also enhance the overall QoL. Fertility‐preserving strategies should be provided to every patient in those with early stage disease and a low risk for recurrence. ⁷⁸ The quality‐of‐life aspect will be discussed in the management of HGSOC, and understanding the patient's perspective is indispensable because the disease exerts a profound impact on the physical, psychological, and social dimensions of life. Fear, often described as one of the most dominant emotions, significantly influences patient decision making and their overall treatment experience. ⁷⁹ , ⁸⁰ This fear is particularly pronounced in the context of ovarian cancer surgery, which is more extensive compared with surgeries for other malignancies. This highlights the need for early integration of psychological and psycho‐oncologic support to help patients navigate the emotional burden associated with their diagnosis and treatment (Figure 7).

FIGURE 7.

Summary box I. Key points for shared decision‐making during treatment selection in patients with high‐grade squamous ovarian cancer (HGSOC).

Surgical management

Current standard treatments for HGSOC include an aggressive surgical approach aimed at maximum cytoreduction, which remains indispensable in the therapeutic landscape of HGSOC. ³ , ⁸¹ For HGSOCs, primary surgical cytoreduction, including total abdominal hysterectomy, bilateral salpingo‐oophorectomy, omentectomy, and peritoneal biopsies, remains the standard of care. HGSOC surgery is one of the most invasive interventions in oncology. This complexity contributes to heightened anxiety among patients, often described as terrifying. For many patients, these fears extend beyond physical recovery, encompassing worries about body image, independence, and future QoL. Early psycho‐oncologic interventions are critical to addressing these concerns. Providing patients with preoperative counseling and fostering open discussions about their fears can alleviate anxiety and help them feel more prepared for the surgical journey. In early stage HGSOC, most guidelines continue to recommend pelvic and para‐aortic nodal staging because identifying lymph node metastases would upstage the disease from stage I to stage IIIA. This distinction carries significant therapeutic implications because maintenance treatments are generally indicated for stage III disease only. However, the therapeutic value of systematic lymph node dissection in this context remains unclear. Interestingly, in patients with macroscopically normal lymph nodes, lymphadenectomy has no influence on progression‐free survival or overall survival but significantly increases morbidity. ⁸² Although nodal metastases are prognostic, routine lymphadenectomy does not improve overall survival. ⁸³ Still, in patients with apparent pelvic‐confined disease, systematic pelvic and para‐aortic lymphadenectomy can upstage 15%–20% of patients. ⁸⁴ Identification of these patients with occult stage IIIC1 or IIIC2 disease can provide important prognostic information as well as select patients for poly(adenosine diphosphate‐ribose) polymerase (PARP)‐inhibitor (PARPi) or intravenous/intraperitoneal chemotherapy who otherwise might not be considered for these more aggressive modalities. ⁸⁵

For advanced‐stage ovarian cancer, the quantity of residual disease after surgery remains highly prognostic for progression‐free and overall survival. ⁸⁶ The definition of an optimal cytoreduction has shifted in recent years from no single residual deposit of disease <2 cm, to <1 cm, to no gross residual disease (R0). ⁸⁷ Achieving an R0 resection in patients with bulky stage IIIC or IV disease may require extensive procedures, such as low anterior resection, ileocectomy, multiple small bowel resections, splenectomy, partial gastrectomy, or diaphragmatic resection. This push for a complete resection creates a natural tension between surgical aggressiveness and surgical morbidity, making the appropriate selection of patients for primary cytoreduction vitally important. This assessment should include consideration of frailty, as noted above. Although a complete resection portends a more favorable clinical outcome, a suboptimal cytoreductive effort exposes a patient to a painful and potentially prolonged recovery without improving her survival. For patients with radiographic stage IIIC disease, diagnostic laparoscopy to assess the intraperitoneal disease burden is highly accurate for predicting the feasibility of an R0 resection and reduces the likelihood of a suboptimal or aborted attempt at cytoreduction. ⁸⁸ , ⁸⁹

For patients with disease not amenable to primary cytoreduction, whether because of medical frailty or anatomic localization of disease burden, three randomized trials have indicated that neoadjuvant therapy with three or four cycles of platinum‐based chemotherapy, followed by interval cytoreduction, and then from two to four cycles of adjuvant chemotherapy is a noninferior approach. ⁹⁰ , ⁹¹ , ⁹² According to the American Society of Clinical Oncology and Society of Gynecologic Oncology consensus, patients who have a high perioperative risk profile or a low likelihood of achieving cytoreduction to <1 cm (ideally to no visible disease) should receive neoadjuvant chemotherapy. ⁹³ Neoadjuvant chemotherapy in this population is associated with lower rates of surgical complications, perioperative mortality, and ostomy formation. ⁹⁴ Patients with bulky stage IIIC disease not amenable to primary cytoreduction who otherwise have good functional status, respond well to chemotherapy, and are able to achieve an optimal cytoreduction at interval surgery should be evaluated for possible heated intraperitoneal chemotherapy (HIPEC), typically with cisplatin, at the time of interval cytoreduction. ⁹⁵ , ⁹⁶ , ⁹⁷ Nonetheless, wide variation persists among reports in terms of technique, dosing, temperature, and patient selection. Complete cytoreductive surgery remains an essential part of HGSOC therapy; however, in underserved regions, complex and multispecialty procedures may be difficult to implement. Improved surgical training, well staffed operating room support services, safe blood banks, and adequate surgical equipment are prerequisites for high‐quality ovarian cancer care and should be included in advocacy efforts to promote improved outcomes for ovarian cancer globally. Policy changes, such as a separate International Classification of Diseases for Oncology 10th Revision code for HGSOC, might focus these efforts and ensure that policymakers devote sufficient resources to making these critical surgeries available in reference centers. There is a need for a fundamental understanding that enhanced funding and meticulous resource allocation can drive improvements in cytoreduction surgical efficacy, especially in underserved regions. Research has provided strong evidence that increased funding cultivates an environment in which high‐precision technologies and specialized training programs are routinely accessible and the administrative processes become more streamlined. ⁹⁸ , ⁹⁹ , ¹⁰⁰ The clear association between enhanced financial inputs and improved surgical outcomes underscores the need for more dynamic resource‐allocation models in oncologic surgery. ¹⁰¹ Policymakers must recognize that investing in health care infrastructure and clinical training can yield immediate and measurable benefits.

We advocate for a re‐examination of current budgeting practices within health care institutions. The causal relations between increased funding and improved surgical outcomes are multifaceted. ¹⁰² , ¹⁰³ , ¹⁰⁴ Enhanced funding directly translates into better surgical equipment, increased staffing ratios, and more comprehensive training programs. These improvements create a more conducive surgical environment that promotes precision and accountability. ¹⁰⁵ , ¹⁰⁶

Frontline chemotherapy

Platinum‐based combination regimens have been the first‐line therapy for HGSOC since the 1980s, initially with cisplatin, but the current worldwide standard consists of carboplatin and paclitaxel. The most commonly used regimen is six cycles of a 21‐day cycle with intravenous carboplatin at an area under the curve of 5 or 6 combined with intravenous paclitaxel, both given on cycle day 1. use carboplatin is generally well tolerated as a single agent, studies have examined withholding paclitaxel from older, more frail patients. However, even among more vulnerable populations, the doublet regimen is associated with better progression‐free and overall survival. ¹⁰⁷ Alternate platinum doublets, such as carboplatin/liposomal doxorubicin and carboplatin/docetaxel, are noninferior to carboplatin/paclitaxel but have different toxicity profiles (less neuropathy and alopecia, but at the expense of more hematologic toxicity). ¹⁰⁸ , ¹⁰⁹ Even so, the Gynecologic Oncology Group (GOG) GOG 182‐ICON5 study, one of the largest clinical trials ever performed for ovarian cancer, concluded that the addition of a third cytotoxic agent to carboplatin and paclitaxel offered no additional benefit. ¹¹⁰ Notably, cisplatin is still used as part of the GOG‐172 intravenous/intraperitoneal regimen because intravenous carboplatin is not as effective as intraperitoneal. For intravenous therapy, there are not a lot of compelling reasons to choose cisplatin over carboplatin given the higher rates of neuropathy and renal toxicity as well as nausea from cisplatin. In select cases, one might consider cisplatin because of the lower rates of myelosuppression with cisplatin compared with carboplatin; however, in practice, most oncologists would address this problem with growth factor support.

I underwent a full course of six cycles of chemotherapy (paclitaxel and carboplatin), even though my doctors expressed uncertainty about whether it was the ideal strategy. This made the process feel more difficult and discouraging. I was very concerned about potential side effects, especially given how poorly I recovered from the surgery.

It is noteworthy that the determination of homologous recombination deficiency (HRD) status in patients with HGSOC is commonly taken into consideration to predict response to platinum‐based or PARPi therapy. A recent study demonstrated that BRCA mutational status, in combination with the BRCA1 methylation status, lends the highest predictive power for favorable clinical outcomes, such as high sensitivity to platinum‐based therapeutic strategies, whereas HRD positivity (BRCA unrelated) does not similarly predict platinum response. ¹¹¹

Several studies have examined dosing variations of the carboplatin/paclitaxel doublet. A large phase 3 study in Japan reported weekly dosing of paclitaxel at 80 mg/m² combined with 3‐weekly carboplatin led to a substantial improvement in overall survival compared with the standard 3‐weekly regimen. ¹¹² However, this observation was not reproduced in confirmatory studies in the United States and in Europe. ¹¹³ , ¹¹⁴ A large, multicenter, phase 3 study in 810 patients with advanced ovarian cancer compared 3‐weekly versus weekly carboplatin‐paclitaxel treatment. The weekly regimen offered similar progression‐free survival but demonstrated a more stable QoL and fewer severe side effects. ¹¹⁵ , ¹¹⁶

Well selected patients may benefit from combining intraperitoneal chemotherapy with intravenous chemotherapy. For these patients, intravenous paclitaxel 135 mg/m² over 24 hours on cycle day 1, intraperitoneal cisplatin 100 mg/m² on cycle day 2, and intraperitoneal paclitaxel 60 mg/m² on cycle day 8 of a 21‐day cycle is prescribed based on the GOG‐172 regimen, in which it resulted in an almost 16‐month improvement in overall survival compared with intravenous cisplatin/paclitaxel. ¹¹⁷ However, in GOG‐172, only 42% of patients completed all six cycles of treatment, highlighting the difficulty of this regimen.

In contrast, GOG‐252, in which all patients received bevacizumab plus either (1) intravenous carboplatin with weekly intravenous paclitaxel; or (2) intraperitoneal carboplatin with weekly intravenous paclitaxel; or (3) a modification of the GOG‐172 regimen with a 3‐hour, cycle day 1 paclitaxel infusion, dose‐reduced intraperitoneal cisplatin 75 mg/m² on cycle day 2, plus intraperitoneal cisplatin intraperitoneal paclitaxel 60 mg/m² on cycle day 8, failed to produce an improvement with the intraperitoneal regimens. ¹¹⁸ However, there has yet to be a comparison between the GOG‐172 intravenous/intraperitoneal regimen and the bevacizumab‐containing regimen.

Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor receptor, may be added to cytotoxic chemotherapy for stage II–IV disease (Table 1). The ICON7 (EudraCT identifier ISRCTN91273375) and GOG‐218 phase 3 randomized trials both examined adding bevacizumab to standard chemotherapy followed by single‐agent bevacizumab maintenance therapy. ¹¹⁹ , ¹²⁰ Although neither study demonstrated an overall survival improvement with the addition of bevacizumab, an exploratory analysis suggested a modest benefit for women with a poor prognosis, although that group was not well defined. Bevacizumab is especially useful for symptomatic relief in patients with large‐volume ascites. ¹²¹

One outstanding question in the management of advanced HGSOC is whether the addition of bevacizumab to a PARPi regimen is truly mandatory. Although bevacizumab has demonstrated efficacy in combination with chemotherapy and in maintenance settings, definitive data regarding its obligatory role when paired specifically with a PARPi remain inconclusive. Ongoing and future trials are expected to clarify whether this combination offers a significant advantage over PARPi monotherapy, particularly in terms of overall survival and QoL. ¹²² In the N‐Plus study (ClinicalTrials.gov identifier NCT05460000), which is a prospective, multicenter clinical trial investigating a de‐escalation approach specifically for patients with stage III, HRD‐positive ovarian cancer, early findings suggest that carefully selected HRD‐positive patients may benefit from this tailored approach without compromising oncologic outcomes, potentially improving the overall QoL. ¹²³ Rather than administering a full‐intensity treatment regimen universally, the study explores whether a reduced or modified therapeutic strategy (e.g., fewer chemotherapy cycles or limited surgical intervention) can maintain efficacy while mitigating toxicity. ¹²³

Wide variation in the upfront management of HGSOC remains, reflecting the uncertainty that remains. Whether to initiate therapy with neoadjuvant chemotherapy or primary debulking depends on the frailty of the patient (Figure 6), the expected morbidity of surgical recovery, the feasibility of complete cytoreduction, and the availability of surgical resources. Although, in many centers, most patients may receive neoadjuvant chemotherapy by default, in others, primary cytoreduction remains the preferred approach. When neoadjuvant chemotherapy is given, there are no precise guidelines to indicate whether three, four, or even six cycles before interval cytoreduction are better. In practice, patients are reassessed at regular intervals for physical fitness and radiographic response until it seems that complete cytoreduction will be feasible and well tolerated. Several studies have suggested that administering HIPEC at interval cytoreduction may improve survival, but these results have not been consistent, and it is unclear which patients benefit most from this more intensive approach. There is even less support for HIPEC at primary cytoreduction. Whereas intravenous/intraperitoneal chemotherapy was strongly recommended after the publication of GOG‐172 in 2006, enthusiasm for this approach has waned with the advent of maintenance therapies and the higher resource use required for these treatments. Even so, for select patients with stage IIIC disease, good performance status, and complete primary cytoreduction, the GOG‐172 regimen may be considered at centers experienced in the technique.

Maintenance therapy

After adjuvant chemotherapy, maintenance regimens are determined primarily by genomic profiling (Figure 8). For patients with germline mutations in BRCA1 or BRCA2 or those who undergo somatic tumor profiling suggesting a homologous repair defect, the addition of a PARPi significantly improves progression‐free and overall survival. ¹²⁴ , ¹²⁵ , ¹²⁶ For patients receiving bevacizumab during primary chemotherapy, the addition of olaparib to bevacizumab improves progression‐free and overall survival compared with bevacizumab alone. ¹²⁷ , ¹²⁸ For patients without germline mutations in BRCA1 or evidence of a somatic homologous repair defect, PARPi with niraparib was previously a common option, but its use has been tempered given the potential for toxicity and likely modest clinical benefit, notably the finding of no improvement in overall survival. ¹²⁴ , ¹²⁹ , ¹³⁰ , ¹³¹ For patients receiving bevacizumab during primary chemotherapy but without a homologous repair defect, bevacizumab alone remains a maintenance option (Figure 8).

FIGURE 8.

Summary box II. Key points of maintenance therapy for patients with high‐grade squamous ovarian cancer. HR indicates homologous recombination; HRD, homologous recombination deficiency; PARP, poly(adenosine diphosphate‐ribose) polymerase.

Management of recurrent disease

While primary treatment of HGSOC is highly efficacious at putting patients into clinical remission, most patients with advanced‐stage disease will relapse. Relapse can be diagnosed by radiographic progression, rising cancer antigen 125 (CA 125), or physical examination. Biopsy confirmation may be helpful in cases of diagnostic discordance (e.g., no change in CA 125 but a new radiographic finding) or to obtain fresh tissue for molecular profiling. However, earlier treatment of asymptomatic relapse diagnosed by CA 125 changes alone is not associated with improved survival. ¹³² Measurement of circulating tumor DNA to assess minimal residual disease is prognostic for relapse, but there are no data to support using circulating tumor DNA to guide initiation of treatment for suspected recurrence. ¹³³

For women who relapse, the first action should be to assess the feasibility of repeat surgical resection. The DESKTOP III and SOC‐1 trials (ClinicalTrials.gov identifier NCT01166737 and NCT01611766, respectively) both established that, for patients with a platinum‐free interval of 6 months or more, good functional status, minimal ascites, a complete cytoreduction at the initial surgery, and a complete secondary cytoreduction followed by chemotherapy improve overall survival compared with chemotherapy alone. ³ , ¹³⁴ Tertiary cytoreduction may also be beneficial but is usually limited to patients with oligometastatic recurrence and long treatment‐free intervals. ¹³⁵ , ¹³⁶

The expected response to a repeat challenge with platinum‐based therapy informs clinical decision making in the recurrent setting. In general, the longer the time interval since completing the last cycle of platinum‐based chemotherapy, the higher the likelihood of a favorable response to a repeat platinum challenge. ¹³⁷ When relapse occurs more than 6 months from the completion of platinum‐based treatment, tumors are considered platinum‐sensitive. Tumors that recur less than 6 months from treatment are labeled platinum‐resistant, whereas those that progress during therapy or less than 1 month from treatment are called platinum‐refractory. ¹³⁸

Platinum‐sensitive ovarian cancer is treated with another platinum‐based doublet. Although this could be carboplatin/paclitaxel again, often, residual neuropathy from the initial treatment or a desire to avoid repeat alopecia motivates the selection of an alternative regimen. The most common options are carboplatin/liposomal doxorubicin, carboplatin/gemcitabine, or carboplatin/topotecan. ¹³⁹ , ¹⁴⁰ , ¹⁴¹ The doublets are similar in efficacy. Bevacizumab can be added to standard chemotherapy for well selected patients. ¹⁴² For patients receiving bevacizumab with initial treatment, there may be a modest benefit to including bevacizumab again, with treatment and maintenance for subsequent therapy. ¹¹⁵ After a complete or partial response to chemotherapy, patients with germline BRCA1/2 mutations or somatic homologous repair defects should receive maintenance PARPi therapy, especially if it was not used after frontline treatment. ¹⁴³ , ¹⁴⁴ , ¹⁴⁵ Patients without homologous repair defects may benefit from niraparib therapy. ¹⁴³ , ¹⁴⁶ For patients progressing after olaparib maintenance therapy, there may be a modest benefit from olaparib rechallenge, as demonstrated in the OReO/ENGOT‐ov38 trial. ¹⁴⁷

In our practice, patients are rarely rechallenged with the same maintenance drug but, instead, are usually rotated to the alternate maintenance therapy from what they received in the first‐line setting. For example, if PARPi was given as first‐line maintenance but bevacizumab was not included in first‐line chemotherapy, we use a platinum‐based doublet with bevacizumab for the treatment of platinum‐sensitive recurrence, followed by bevacizumab maintenance. In a recent real‐world, international study, the efficacy of subsequent chemotherapy after PARPi exposure in patients with HGSOC was evaluated. In those patients who progressed on PARPi with a platinum‐free interval of more than 6 months, the platinum‐based chemotherapy rechallenge remained the best option ¹⁴⁸ (Figure 9).

FIGURE 9.

Summary box III. Key points of recurrence therapy for patients with high‐grade squamous ovarian cancer. ER, estrogen therapy; ET, endocrine therapy; PARP, poly(adenosine diphosphate‐ribose) polymerase; TMB‐H, high tumor mutational burden.

Progression‐free intervals typically shorten with each subsequent round of platinum‐based therapy, such that platinum‐resistant ovarian cancer remains the leading cause of ovarian cancer deaths. ¹⁴⁹ Until recently, options for platinum‐resistant HGSOC were limited to cytotoxic agents, such as liposomal doxorubicin, topotecan, gemcitabine, or paclitaxel. Overall response rates were generally poor, with a median progression‐free survival of 3–4 months and an overall survival of about 1 year. ¹⁵⁰ Bevacizumab was the first drug to provide modest additional benefits. ¹⁵¹ There was hope that the introduction of immunotherapy would improve outcomes; however, unfortunately, checkpoint inhibitors have shown little effectiveness in platinum‐resistant or platinum‐refractory disease. ¹⁵² , ¹⁵³ However, new antibody–drug conjugates have started to provide new options for subgroups of patients. For example, patients with high folate receptor alpha expression saw a 42.3% objective response rate to mirvetuximab soravtansine‐gynx, whereas patients with high HER‐2 expression using gastric cancer scoring criteria saw a 45% objective response rate to trastuzumab deruxtecan. ¹⁵⁴ , ¹⁵⁵ These more individualized therapies require high expression of the requisite antibody target. Because these drugs are now being investigated in earlier lines of therapy and in rational drug combinations, testing for these markers is increasingly done with initial diagnosis.

Investigational therapies

Several new treatments for HGSOC remain on the horizon. To overcome PARPi resistance, new small‐molecule inhibitors are being studied that target other members of the DNA repair pathways, such as ATR and WEE1. ¹⁵⁶ , ¹⁵⁷ , ¹⁵⁸ , ¹⁵⁹ , ¹⁶⁰ , ¹⁶¹ , ¹⁶² Because repairing DNA damage requires functional cell cycling checkpoints, other approaches focus on targeting cell cycle checkpoints, such as CHK1 and CHK2. ¹⁶³ , ¹⁶⁴ Despite poor initial results, immunotherapy remains an active area of research as well. Therapeutic vaccines using tumor neoantigens, new combinations of immune checkpoint inhibitors, and adoptive cell therapies, such as chimeric antigen receptor T (CAR‐T) cells or chimeric antigen receptor natural killer cells, are all in early‐stage clinical trials and may provide new modalities with more durable treatment responses. ¹⁶⁵ , ¹⁶⁶ , ¹⁶⁷ , ¹⁶⁸ , ¹⁶⁹ , ¹⁷⁰ , ¹⁷¹ In the context of HGSOC, the molecular landscape, including the expression of various antigens and immune evasion mechanisms, offers a unique yet challenging environment for effective CAR‐T cell therapy. It is within this context that the design of CAR‐T cells must be rigorously evaluated, not only in terms of targeting and killing tumor cells but also regarding their ability to function amid the immunosuppressive signals prevalent in the ovarian cancer niche and side effects. The upregulation of immune checkpoints and their ligands, such as programmed death‐ligand 1, contributes to immune evasion by inhibiting T‐cell activation (Figure 4). This duality of immune regulation and suppression not only complicates the therapeutic environment but also emphasizes the necessity for advanced strategies that can overcome these suppression mechanisms. ¹⁷² , ¹⁷³ New immune checkpoint inhibitors targeting the proteins that regulate immune activation are being investigated for their potential to reinvigorate T‐cell responses against HGSOC cells. ¹⁷⁴ This raises the question of how to overcome resistance in T‐cell–inflamed tumors (Figure 1). The T‐cell–inflamed HGSOC tumors, in theory, should be ideal candidates for immune checkpoint blockade because their microenvironment is already favorable to immune attack. However, response rates to immune checkpoint inhibitors in ovarian cancer are very low. ¹⁷⁵ For patients with T‐cell–inflamed tumors, adoptive cell therapy using autologous TILs offers a potential treatment option. Briefly, TILs are extracted from the patient's own tumor; then, the patient undergoes lymphodepletion on chemotherapy followed by infusion of the expanded TILs and receives systemic IL‐2 treatment to support further TIL expansion within the body. ⁴⁵ However, challenges like the immunosuppressive TME and low immunogenicity of HGSOC necessitate combinatorial approaches, such as integrating immunotherapy with other treatment modalities, to enhance efficacy. ¹⁷⁶

Emerging research and potential innovations in the treatment of HGSOC are strongly geared toward personalized medicine. ¹⁷⁷ Advances in genomics and epigenetics have unveiled novel biomarkers and therapeutic targets, paving the way for precision oncology. ¹⁷⁸ Epigenetic therapies, including those targeting DNA methylation and histone modification, show promise in overcoming drug resistance and sensitizing tumors to conventional treatments. ¹⁷⁹ , ¹⁸⁰ , ¹⁸¹ The integration of comprehensive genetic profiling into clinical practice could revolutionize treatment algorithms, enabling tailored therapeutic regimens that reflect the unique molecular landscape of each tumor. For example, relacorilant, an antiglucocorticoid, is currently under clinical investigation in advanced ovarian cancer, aiming to determine its efficacy in combination with standard chemotherapy. In parallel, Artistry‐7 (ClinicalTrials.gov identifier NCT05092360) is a phase 3 trial evaluating nemvaleukin alfa, a selective IL‐2 pathway agonist designed to expand CD8‐positive T cells while sparing regulatory T cells, together with pembrolizumab in patients with platinum‐resistant advanced ovarian cancer. Both trials build on earlier phase data indicating tolerable safety and encouraging immunologic responses, highlighting the potential of these novel therapeutic strategies. However, the above‐mentioned novel therapies for HGSOC, including targeted therapies and immunotherapies, can lead to various side effects. The efficacy of CAR‐T cell treatment has been accompanied by several significant negative outcomes, including cytokine release syndrome, hemophagocytic lymphohistiocytosis/macrophage activation‐like syndrome, neurologic toxicity, and on‐target off‐tumor toxicity. One of the main challenges in cytokine release syndrome is that the stimulation and expansion of CAR‐T cells leads to an excess production of proinflammatory cytokines, resulting in a systemic inflammatory reaction. This occurs in up to 50%–90% of individuals and is characterized by symptoms ranging from fever and fatigue to more severe issues, such as shock, disseminated intravascular coagulation, multiorgan failure, and mortality. ¹⁸² , ¹⁸³ , ¹⁸⁴ Monitoring and managing these adverse effects are crucial to maintaining patient QoL. Patient education on potential side effects is essential for informed decision making. Ongoing research is necessary to better understand the full spectrum of side effects and their impact on treatment outcomes.

QUALITY OF LIFE AND SURVIVORSHIP

It’s not just about survival. I want to live in a way that feels meaningful and balanced—physically, emotionally, and socially.

QoL is emerging as a cornerstone in the management of ovarian cancer, transcending survival to address the broader experiences of patients. QoL must be understood as a multidimensional concept encompassing physical, mental, and social health. For numerous patients, maintaining QoL is pivotal. Beyond its immediate relevance to patient well‐being, QoL is increasingly recognized as a key predictive and prognostic factor. Studies like that by Armbrust et al. have demonstrated that lower preoperative QoL scores can predict higher rates of postoperative complications. Furthermore, QoL holds significant prognostic value, with better scores correlating to improved survival outcomes. These findings highlight the necessity of integrating QoL assessments into routine care and using them to guide both therapeutic decisions and supportive interventions. ¹⁸⁵ QoL and supportive care are integral components of the treatment strategy for HGSOC. An important element in HGSOC management is the psychological well‐being of patients because it is a crucial aspect of their overall health care, personalized treatment outcomes, and survival. Cancer, in general, can have a significant impact on a person's mental health, with issues like depression, anxiety, and a need for help with coping skills being common. This is particularly relevant for patients who face unique challenges throughout their disease journey. Notably, a primary psychological concern for patients with ovarian cancer is the fear of recurrence. ¹⁸⁶ Many survivors report persistently worrying about their cancer returning, which can lead to heightened anxiety and stress.

It is worth mentioning that a restrictive inclusion of patients into investigations on HGSOC or ovarian cancer, in general, has been widely criticized for inappropriate representation of patients worldwide (Figure 2). Data generated from underrepresented groups and sociodemographic domains, such as race and ethnicity, need to be included in studies to draw robust conclusions regarding QoL as well. Keeping the diversity aspect in mind, therefore, we suggest and encourage more clinical research on ovarian cancer with the inclusion of diverse trial participants in which patients from broad and diverse backgrounds are enrolled to enhance external validity and facilitate the translation of results across all relevant groups. ⁷ , ⁸ This will also shed light on essential factors that may affect clinical outcomes.

In the management of ovarian cancer, understanding the patient's perspective is indispensable because the disease exerts a profound impact on the physical, psychological, and social dimensions of life (Figure 10). Fear, often described as one of the most dominant emotions, significantly influences patient decision making and their overall treatment experience. This fear is particularly pronounced in the context of HGSOC surgery, which is more extensive compared with surgeries for other malignancies. This highlights the need for early integration of psychological and psycho‐oncologic support to help patients navigate the emotional burden associated with their diagnosis and treatment (Figure 10).

FIGURE 10.

Summary box IV. Key points of a cancer survivorship care plan for patients with high‐grade squamous ovarian cancer. PARP indicates poly(adenosine diphosphate‐ribose) polymerase.

The diagnosis of ovarian cancer deeply affects personal relationships. Many patients experience a strain on their partnerships, compounded by a reluctance to openly share their fears to avoid burdening their loved ones. This emotional restraint can create a cycle of isolation and distance, further complicating the patient's psychological well‐being. In addition, geographic separation from family members, such as children living abroad, adds to the sense of loneliness.

Importantly, the shift in focus from active treatment to long‐term survivorship can be disorienting because patients may feel a loss of support. During this critical transition period, it is essential to monitor the mental health of ovarian cancer survivors and provide appropriate interventions. Nurses play a vital role in addressing the psychosocial needs of patients with ovarian cancer. ¹⁸⁷ Furthermore, screening for distress and referring patients to appropriate resources, such as counseling or support groups, can help mitigate the psychological burden of the disease. ¹⁸⁸ Understanding the importance of psycho‐oncology, the above‐mentioned molecular underpinnings, the mixed phenotypic nature of HGSOC, and the ethnic diversity of patients with HGSOC is crucial for developing targeted therapies and personalized multimodal treatment approaches in centralized therapeutic structures.

Addressing the physical and psychological toll of HGSOC and its treatment involves multidisciplinary approaches, encompassing pain management, nutritional support, and psychosocial interventions. Palliative care, introduced early in the treatment continuum, plays a crucial role in alleviating symptoms, enhancing life quality, and supporting patients and their families through the complexities of the disease trajectory. ¹⁸⁹ , ¹⁹⁰ , ¹⁹¹

It is worth noting that the time constraints of cancer care for patients and care partners have been highlighted and termed time toxicity. ¹⁹² , ¹⁹³ , ¹⁹⁴ This concept is particularly important in the context of advanced metastatic disease, in which life expectancy is limited and time becomes very precious. ¹⁹⁵ Future studies should also focus on the aspect of time toxicity from the patients' perspective, particularly in the context of HGSOC therapy. Time toxicity also refers to the temporal burden that patients experience because of medical interventions, including travel time to appointments, waiting periods, and the duration of treatments, such as infusions. This aspect is particularly relevant for patients with HGSOC, who often require extensive and time‐consuming therapies. Understanding the implications of time toxicity is crucial for developing patient‐centered care approaches and improving the overall treatment experience. By investigating the impact of time toxicity on patients with HGSOC, research can optimize health care delivery to enhance both efficiency and patient satisfaction.

CONCLUSION AND FUTURE RESEARCH DIRECTIONS

HGSOC continues to represent a significant challenge in the realm of gynecologic oncology because of its aggressive nature, often late stage diagnosis, and complex treatment landscape. The multifaceted approach encompassing epidemiology, pathogenesis, diagnosis, and treatment strategies highlights the intricate nature of managing this formidable malignancy. We have explored the incidence, prevalence rates, and risk factors of HGSOC. In addition, survival rates exhibit notable variability. The landscape of HGSOC treatment and research is characterized by an ongoing pursuit of innovation and holistic patient management. Through a deeper understanding of the disease's epidemiologic patterns, TME, and comprehensive treatment strategies, the goal remains to transform HGSOC from a perilous diagnosis to a manageable condition with enhanced survival and QoL outcomes.

Patient‐centered care is fundamental for the effective management of ovarian cancer. The heightened fear associated with ovarian cancer surgery necessitates early psychological and psycho‐oncological support to address emotional and psychological challenges. Moreover, integrating QoL as a multidimensional and actionable measure into routine care ensures that treatment strategies align with the lived experiences and priorities of patients. Because of the complexity of patient perspectives and backgrounds, there is an ultimate need for holistic approaches that encompass physical, emotional, and social dimensions. Future research should continue to explore the predictive and prognostic value of QoL and develop interventions that empower patients throughout their journey.

As research advances and new therapies emerge, the combined efforts of health care providers, researchers, and policymakers will be crucial in overcoming the existing challenges and forging a path toward improved prognoses for patients afflicted with HGSOC. Current treatment paradigms for HGSOC involve a combination of surgical cytoreduction, platinum‐based chemotherapy, and emerging targeted therapies, such as PARPi and angiogenesis inhibitors. We advocate new research to clarify whether the above‐mentioned treatment combination or PARPi alone in HRD and BRCA‐positive patients with more limited disease is more adequate. Despite their efficacy, these therapies are often hampered by significant toxicities and the eventual emergence of chemoresistance. Therefore, we encourage more research on the topic of whether chemotherapy in all patients with HGSOC is recommended or whether surgery and PARPi alone would be more favorable to avoid chemotherapy‐related side effects. Immunotherapy and precision oncology represent promising frontiers, with ongoing research into immune checkpoint inhibitors and personalized treatment plans based on genetic profiling demonstrating the potential to revolutionize patient care. In HRD‐negative patients, we suggest new research experiments investigating the potential for checkpoint inhibitors, for which applications still remain elusive. ADCs are emerging as a very promising direction of future clinical research in HGSOC, with results rarely seen in this deadly disease that is usually diagnosed at an advanced stage and in which relapse and resistance to standard‐of‐care treatment are possible. We encourage research to ascertain whether ADCs should be taken into consideration either as frontline therapy or only in disease relapse cases. Furthermore, supportive care strategies are indispensable for managing the physical and psychological toll of HGSOC, improving patient QoL and overall well‐being. We advocate for patient‐centered communication with explicit emphasis on diversity and cultural sensitivity. We strongly suggest new clinical trials on HGSOC with increased representation of underrepresented groups, including, but not limited to, socioeconomic status, geographic regions, ethnicity, age, gender, physical ability, and sexual orientation.

In summary, the treatment strategies for HGSOC are multifaceted and should respect patient diversity, combining current standards involving surgery and chemotherapy with emerging targeted therapies and immunotherapy. Future directions in research and clinical practice should address the importance of including underrepresented groups, paradigm shifts in personalized medicine, innovative therapeutic approaches, and comprehensive supportive care to improve patient outcomes and QoL.

CONFLICT OF INTEREST STATEMENT

Kevin M. Elias reports a patent with Aspira Women's Health Inc. Marcia C. Haigis reports personal/consulting fees from Alixia and Mitoq outside the submitted work. Ioana Elena Braicu reports support for professional activities from AbbVie, AstraZeneca, GlaxoSmithKline, ImmunoGen Inc., Merck, and Myriad; and travel support from AstraZeneca outside the submitted work. The remaining authors declared no conflicts of interest. Jalid Sehouli reports research activities by Roche Pharma, AstraZeneca, Bayer, Clovis Oncology, GlaxoSmithKline, Lilly, Iqvia, Mural, and MSD; receiving honoraries by GlaxoSmithKline, PharmaMar, AstraZeneca, Clovis Oncology, Bayer, Roche Pharma, Vifor Pharma, Hexal AG, Novartis Pharma, Eisai, Esteve Pharmaceuticals, Incyte Biosciences, Phytolife Nutrition, JenaPharm, Kyowa Kirin, Oncoinvent AS, Daiichi, Medtronic Covidien, AMGEN, AbbVie, Corcept Therapeutics, Gilead Sciences, and Myriad; and consulting activities for Merck /Pfizer, PharmaMar, Clovis Oncology, AstraZeneca, Roche Pharma, GlaxoSmithKline, MSD, Eisai, Novocure, Oncoinvent, Intuitive Surgical, Seagen, Bayer Vital, Mundipharma, Sanofi‐Aventis Deutschland GmbH, Immunogen, Tubulis GmbH, Daiichi Sankyo, Bristol Myers Squibb, Karyopharm Therapeutics, and Corcept Therapeutics.

Kordowitzki P, Lange B, Elias KM, et al. Transforming treatment paradigms: focus on personalized medicine for high‐grade serous ovarian cancer. CA Cancer J Clin. 2025;75(5):436‐460. doi: 10.3322/caac.70008