American Society of Clinical Oncology Educational Book

A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer

Approximately 30% of primary endometrial cancers are microsatellite instability high/hypermutated (MSI-H), and 13% to 30% of recurrent endometrial cancers are MSI-H or mismatch repair deficient (dMMR). Given the presence of immune dysregulation in endometrial cancer as described, immune checkpoint blockade (ICB) has been explored as a therapeutic mechanism, both as monotherapy and in combination with cytotoxic chemotherapy, other immunotherapy, or targeted agents. In MSI-H or dMMR advanced endometrial cancers, PD-1 inhibitors dostarlimab and pembrolizumab have shown response rates of 49% and 57%, respectively, whereas PD-L1 inhibitors avelumab and durvalumab have shown response rates of 27% and 43%, respectively. In microsatellite stable (MSS) or PD-L1–positive advanced endometrial cancers, modest activity of PD-1 inhibitors nivolumab and dostarlimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab has been seen, with response rates ranging from 3% to 23%. Based on substantial activity in a phase Ib/II study, the U.S. Food and Drug Administration (FDA) granted lenvatinib and pembrolizumab combination therapy accelerated approval in 2019 for the treatment of advanced endometrial cancer that is not MSI-H or dMMR and has progressed following prior therapy. Although these developments have been highly impactful, a more robust understanding of the molecular and immunologic drivers of response and resistance will be critical to optimally design next-generation studies in endometrial cancer.

Therapeutic Targets and Opportunities in Endometrial Cancer: Update on Endocrine Therapy and Nonimmunotherapy Targeted Options

Worldwide, the incidence of endometrial cancer is increasing. Although the prognosis remains good for patients diagnosed with early-stage disease, for those diagnosed with recurrent or metastatic disease, options have been limited, and prognosis is short. Optimizing and identifying new well-tolerated treatments for women living with endometrial cancer is a top priority. A new era is dawning where we are starting to see the integration of clinically relevant genomic and pathologic data to inform and refine treatment strategies for women with endometrial cancer. Here, we focus on reviewing nonimmunotherapy-based targeted treatment options and emerging directions for women with endometrial cancer.

Immune Therapy Opportunities in Ovarian Cancer

Immunotherapy has emerged as a highly promising approach in the treatment of epithelial ovarian cancer (EOC). Immune checkpoint blockade (ICB) therapy, PARP inhibitors (PARPis), neoantigen vaccines, and personalized T-cell therapy have been associated with encouraging clinical activity in a small subset of patients. To increase the proportion of patients who are likely to derive benefit, it will be important not only to generate sufficient numbers of antitumor T cells but also to overcome multiple inhibitory networks in the ovarian tumor microenvironment (TME). Therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies and allow treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies while minimizing toxicities. In this review, we provide progress on immune therapies and future directions for maximally exploiting immune-based strategies for the treatment of ovarian cancer.

Managing Adverse Effects Associated With Poly (ADP-ribose) Polymerase Inhibitors in Ovarian Cancer: A Synthesis of Clinical Trial and Real-World Data

The use of poly (ADP-ribose) polymerase (PARP) inhibitor therapy is standard care in the management of patients with various malignancies including ovarian, breast, prostate, and pancreatic cancers. PARP inhibitors have been approved in different settings for patients with specific hereditary pathogenic variants, most notably homologous recombination repair pathways such as BRCA1 and BRCA2 genes. The vast experience with PARP inhibitors (olaparib, niraparib, rucaparib) has been in the management of epithelial ovarian cancer. There have not been any head-to-head comparisons of PARP inhibitors in randomized trials, and we can only perform cross-comparison on the basis of the reported literature. The three approved PARP inhibitors share several common adverse effects because of a class effect including nausea, fatigue, and anemia, but there are notable differences likely because of variations in their poly-pharmacology and off-target effects. Finally, patients included in clinical trials are often younger with a good performance status and less comorbidities than the real-world population, and hence, the potential benefits and adverse effects may not be superimposable. In this review, we describe these differences and discuss strategies to mitigate and manage adverse side effects effectively.

Expanding Our Impact in Cervical Cancer Treatment: Novel Immunotherapies, Radiation Innovations, and Consideration of Rare Histologies

Cervical cancer is a socially and scientifically distinguishable disease. Its pathogenesis, sexual transmission of high-risk HPV to a metaplastic portion of the uterine cervix, makes cervical cancer preventable by safe and effective HPV vaccines commercially available since 2006. Despite this, cervical cancer remains the deadliest gynecologic cancer in the world. Regrettably, global incidence and mortality rates disproportionately affect populations where women are marginalized, where HIV infection is endemic, and where access to preventive vaccination and screening for preinvasive disease are limited. In the United States, cervical cancer incidence has gradually declined over the last 25 years, but mortality rates remain both constant and disparately higher among communities of color because of the adverse roles that racism and poverty play in outcome. Until these conditions improve and widespread prevention is possible, treatment innovations are warranted. The last standard-of-care treatment changes occurred in 1999 for locally advanced disease and in 2014 for metastatic and recurrent disease. The viral and immunologic nature of HPV-induced cervical cancer creates opportunities for both radiation and immunotherapy to improve outcomes. With the advent of T cell–directed therapy, immune checkpoint inhibition, and techniques to increase the therapeutic window of radiation treatment, an overdue wave of innovation is currently emerging in cervical cancer treatment. The purpose of this review is to describe the contemporary developmental therapeutic landscape for cervical cancer that applies to most tumors and to discuss notable rare histologic subtypes that will not be adequately addressed with these treatment innovations.

State of the Art: Therapies Now and Around the Corner for Gynecologic Cancers

Therapeutic advances across the gynecologic cancer continuum have resulted in improvements in patient care and outcomes over the past decade, yet challenges remain. In ovarian cancer, the evolution of poly (ADP-ribose) polymerase (PARP) inhibitor therapy has resulted in marked benefit for patients with BRCA-mutated cancers but has also unmasked the need for new therapies in patients whose cancers are proficient in homologous recombination and lack vulnerability to PARP inhibitors, as well as for those patients whose cancers progress on PARP inhibitors. In endometrial cancer, immune checkpoint inhibitors (ICIs) have improved outcomes for patients receiving first-line therapy for advanced or recurrent disease when combined with standard-of-care chemotherapy. However, there remains uncertainty around which patients are most likely to benefit from the addition of immunotherapy, and treatment beyond first-line therapy remains an area of high unmet need. Similarly, ICIs added to chemotherapy for recurrent or metastatic cervical cancer or to chemoradiation for high-risk locally advanced cervical cancers has resulted in improved outcomes, but treatment options beyond this remain limited. Across gynecologic cancers, antibody-drug conjugates (ADCs) hold the promise for further improvement in patient outcomes. A prime example is the demonstrated benefit of mirvetuximab soravtansine over other standard chemotherapy options in folate receptor alpha–high platinum-resistant ovarian cancer. Maximizing such potential will require developing a deeper understanding of relationships between ADC target expression and activity, mechanisms of resistance, and potential approaches to sequencing. Beyond ADCs, additional therapies, including those targeting DNA damage response, remain in development.

Innovations in Rare Gynecologic Cancer: Melanoma, Neuroendocrine, and Low-Grade Serous Ovarian

In the field of gynecologic cancer, low-grade serous ovarian cancer (LGSOC) has been poorly understood and underinvestigated until recently. Similarly, understanding of the distinct properties and therapeutic sensitivities of gynecologic melanoma and cervical neuroendocrine tumors has recently accelerated. For each of these rare cancers, we explore the epidemiology and natural history, discuss the prognosis, diagnostic testing, and contemporary molecular classification, and then deliberate existing and emerging therapeutic strategies. In LGSOC, we focus on the clinical relevance of recent molecular studies that shed light on the importance of mitogen-activated protein kinase (MAPK) pathway gene mutation and chromosome 1 copy-number change on prognosis and MEK inhibitor sensitivity. We also discuss the relative chemoresistance of this disease and the fact that attention is shifting to combinations of molecular therapies such as endocrine agents plus cyclin-dependent kinase 4/6 inhibitors or MEK inhibitors plus FAK inhibitors. Gynecologic tract melanomas harbor a lower frequency of canonical BRAF mutations, and have lower tumor mutational burden and immune cell infiltration than cutaneous melanomas (CMs). As a result, patients with this disease are less likely to respond to BRAF/MEK or immune checkpoint inhibition than patients with CM. Emerging strategies include the combination of antiangiogenic agents with immune checkpoint inhibitors and the use of adoptive cellular therapies. In cervical neuroendocrine cancer, we discuss the use of surgery in early-stage disease, and the uncertainties regarding the role of radiotherapy. We also explore the evidence for chemotherapy and emerging investigational strategies including the use of poly (ADP-ribose) polymerase inhibitors. For all situations, we explore the shared decision-making process with the patient.

Novel Cancer Prevention Strategies in Individuals With Hereditary Cancer Syndromes: Focus on BRCA1, BRCA2, and Lynch Syndrome

Germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes confer elevated risks of breast, ovarian, and other cancers. Lynch syndrome (LS) is associated with increased risks of multiple cancer types including colorectal and uterine cancers. Current cancer risk mitigation strategies have focused on pharmacologic risk reduction, enhanced surveillance, and preventive surgeries. While these approaches can be effective, they stand to be improved on because of either limited efficacy or undesirable impact on quality of life. The current review summarizes ongoing investigational efforts in cancer risk prevention strategies for patients with germline PVs in BRCA1, BRCA2, or LS-associated genes. These efforts span radiation, surgery, and pharmacology including vaccine strategies. Understanding the molecular events involved in the premalignant to malignant transformation in high-risk individuals may ultimately contribute significantly to novel prevention strategies.

Challenges and Opportunities for Global Cervical Cancer Elimination: How Can We Build a Model for Other Cancers?

Cervical cancer remains a leading cause of cancer-related death among women globally, despite the availability of effective prevention through human papillomavirus (HPV) vaccination and HPV-based screening. This review explores the state-of-the-art technologies for cervical cancer prevention, examining their efficacy, implementation challenges, and global disparities in access. Prophylactic HPV vaccination and HPV DNA testing have demonstrated high efficacy in reducing cervical cancer incidence, yet their uptake remains uneven—especially in low- and middle-income countries (LMICs), where the disease burden is greatest. Barriers include infrastructure limitations, workforce shortages, sociocultural obstacles, and competing health priorities. Strategies such as single-dose vaccination, early childhood immunization, self-sampling, and screen-and-treat approaches offer promising pathways to expand access. In high-income countries (HICs), where HPV vaccine uptake is higher and screening systems are more established, the reduced risk of infection and high negative predictive value of HPV testing support a shift toward screening deintensification. Precision prevention frameworks—leveraging biomarkers, genotyping, and artificial intelligence—offer further opportunities to enhance accuracy and efficiency. The review also underscores the importance of health system strengthening, international collaboration, and policy support to achieve the WHO's 90-70-90 targets for cervical cancer elimination. Moreover, innovations developed for cervical cancer prevention—such as decentralized screening, mobile health platforms, and task-shifting—offer a valuable model for improving strategies for primary and secondary prevention of other cancers.

Rare Uterine Tumors: What to Do?

Rare uterine malignancies present treatment challenges because of their clinical and biological heterogeneity. Among the rarest of the uterine cancers are leiomyosarcomas, uterine stromal tumors, and the mesonephric-like and serous carcinomas. In this article, we review recent advancements in diagnostic precision, risk stratification, and identification of biomarker-guided therapeutic options for these rare subtypes of uterine tumors. The improved understanding of the molecular profile of these tumors has led to the development of targeted treatment approaches. Further progress will depend on a coordinated, global effort to further characterize these diseases and enroll patients on biomarker-driven clinical trials.

Cancer Screening in Low- and Middle-Income Countries

The worldwide cancer burden is growing, and populations residing in low- and middle-income countries (LMICs) are experiencing a disproportionate extent of this growth. Breast, colorectal, and cervical cancers are among the top 10 most frequently diagnosed malignancies, and they also account for a substantial degree of cancer mortality internationally. Effective screening strategies are available for all three of these cancers. Individuals from LMICs face substantial cost and access barriers to early detection programs, and late stage at diagnosis continues to be a major cause for cancer mortality in these communities. This chapter will review the epidemiology of breast, colorectal, and cervical cancers, and will explore prospects for improving global control through novel approaches to screening in cost-constrained environments.

State of the Science: Screening, Surveillance, and Epidemiology of HPV-Related Malignancies

Oropharyngeal, cervical, vulvar, and anal cancers share a common risk factor of HPV infection. HPV vaccination is currently recommended at age 11 or 12 to prevent new HPV infections for all genders with catch-up vaccination recommened up to age 26. Despite the known effectiveness of HPV vaccination to prevent HPV-related cancer, there is continued low uptake in the United States; only 40% of eligible persons were vaccinated in 2018, though rates are 70% among teenagers. Current American Cancer Society cancer screening guidelines recommend cervical cancer screening, but do not have specific recommendations for screening for other HPV-related cancers. Oropharyngeal cancer precursors have yet to be identified, and there are currently no routine screening tests for oropharyngeal cancer recommended by the U.S. Preventive Services Task Force. The U.S. Preventive Services Task Force and American Cancer Society recommend cervical cancer screening for women at average risk up to age 65, and screening guidelines do not currently differ by HPV vaccination status. Primary HPV DNA testing was first approved for cervical cancer screening in 2016 and was shown to be superior for cervical cancer prevention. Vulvar and anal cancer precursors have been identified, but optimal screening remains unclear. Examination of the anal canal and perianus is best performed by trained clinicians using high-resolution anoscopy, and effectiveness of using high-resolution anoscopy to detect and treat anal high-grade squamous intraepithelial lesions to prevent cancer is actively being researched. Current multistep approaches to control HPV-related malignancies include HPV vaccination coupled with cervical cancer screening or surveillance for oropharyngeal, vulvar, and anal cancers.

Controversies in the Surgical Management of Gynecologic Cancer: Balancing the Decision to Operate or Hesitate

Cancer outcomes are largely measured in terms of disease-free survival or overall survival, which is highly dependent on timely diagnosis and access to treatment methods available within the country's existing health care system. Although cancer survival rates have markedly led in the past few decades, any improvement in the 5-year survival of gynecologic cancers has been modest, as in the case of ovarian and cervical cancers, or has declined, as in the case of endometrial cancer. The lack of effective screening options contributes to many women presenting with advanced-stage disease and the need for radical approaches to treatment. Although treatment for early-stage disease can lead to a cure, advanced-stage disease is fraught with a high potential for morbidity and mortality, and recent clinical trials have aimed to assess the noninferiority of minimally invasive options versus aggressive surgical approaches. Of particular interest is fertility-sparing treatments for endometrial and cervical cancers, which have recently been on the rise among younger women. Balancing morbidity with the risk of mortality, and loss of fertility and quality of life requires a targeted patient-centered approach to treatment. This is an ongoing area of intense research and sometimes may challenge current treatment paradigms. In this two-part review, we present an overview of current approaches to gynecologic cancer treatment and the need to de-escalate radical surgical approaches and preserve fertility. We also review the intricacies of ovarian and advanced endometrial cancer treatment, exploring the nuances in surgical debulking timing and its impact on outcomes.

Updates in the Use of Targeted Therapies for Gynecologic Cancers

Targeted therapies have changed the treatment landscape in gynecologic cancer. Studies released over the past year have led to the incorporation of immunotherapy (IO) into the treatment for all patients with endometrial and cervical cancers at some point during their disease course. Poly(ADP-ribose) polymerase (PARP) inhibitors continue to play a role in women with ovarian carcinoma, particularly in homologous repair deficient tumors. Furthermore, the benefit of PARP inhibitors in challenging subgroups continues to be elucidated. Biomarker identification has led to the approval or compendium listing of several antibody-drug conjugates (ADCs). This review will update on IO, ADCs, and PARP inhibition for the treatment of gynecologic cancers.

PARP Inhibitors for Ovarian Cancer: Current Indications, Future Combinations, and Novel Assets in Development to Target DNA Damage Repair

PARP inhibitors (PARPIs) have revolutionized the treatment of epithelial ovarian cancer, first for BRCA-associated cancer, and, recently, for all epithelial cancers of serous or high-grade endometrioid subtypes in the front line. Although there is hope that PARPIs will help prevent recurrences when used following frontline maintenance, cancer will still recur in most women, and the need for active combination strategies as well as continued development of novel assets, either as monotherapy or in combination, will be urgently needed. This review article discusses the current indications for PARPIs in both frontline and recurrent settings, current research in combination approaches, and finally, ongoing research on novel methods to target DNA damage response in an effort to exploit the common susceptibility to DNA damage repair in epithelial ovarian cancer and improve outcomes for patients.

Genetic Testing for All: Overcoming Disparities in Ovarian Cancer Genetic Testing

Nearly 3% of the population carries genetic variants that lead to conditions that include hereditary breast and ovarian cancer and Lynch syndrome. These pathogenic variants account for approximately 20% of ovarian cancer cases, and those with germline pathogenic variants have an odds ratio between 4 and 40 for developing ovarian cancer compared with noncarriers. Given the high prevalence of genetic variants, multiple organizations, including ASCO, recommend universal genetic counseling and testing for women diagnosed with epithelial ovarian cancer. Unfortunately, most individuals with a hereditary ovarian cancer syndrome are unaware of their underlying mutation, and racial and ethnic minority individuals as well as patients of low socioeconomic status experience disproportionate rates of underrecognition, leading to late and missed diagnoses. In this article, we review the current understanding of disparities in genetic testing for people with ovarian cancer, the role of population-based genetic testing, and innovative strategies to overcome the critical inequities present in current cancer genetic medicine. Underuse and disparities related to accessing recommended genetic services are complex and multifactorial, requiring improvements in processes related to provider identification, genetic counseling and testing referral, and patient uptake/adherence. Through the expansion of remote genetic counseling, offering online strategies for genetic testing, and reaching at-risk relatives through direct relative contact cascade testing and population-based genetic testing, there are a growing number of innovations in the field of genetic medicine, many of which emphasize health equity and offer promising alternatives to the current paradigm of genetic testing.

Breast and Gynecologic Cancer Care for Sexual Minority Women and Transgender People

Sexual and gender minority (SGM) individuals continue to experience disparities in cancer risk, screening, treatment, and outcomes. Despite advances following the 2017 ASCO recommendations, inequities persist, driven by systemic barriers, stigma, and discrimination in health care. State-level and federal-level actions threaten health care access to for sexual minority women (SMW) and transgender and gender-diverse (TGD) people creating additional barriers to safe and evidence-based health care. This review outlines the literature and gives practical recommendations for breast and gynecologic cancer care of SMW and TGD people. SMW and transgender men and nonbinary people with a cervix share multiple barriers to cervical cancer screening with lower uptake. TGD individuals face additional barriers, including gender dysphoria during examinations. Current evidence supports offering human papilloma virus self-sampling to improve screening uptake. Evidence supports lower breast cancer risk in TGD people compared with cisgender women but advice must be tailored to surgical history and hormone use. For TGD individuals with cancer, gender-affirming hormone therapy should be managed through shared decision making, balancing oncologic risk with quality-of-life considerations. Cancer care must account for the unique needs of SGM populations, emphasizing cultural humility, structural competency, and trauma-informed care. While broader health care reforms are needed to address the systemic inequities that underlie these disparities, clinicians have an obligation to provide affirming, patient-centered care that recognizes the impact of societal discrimination on health and fosters trust with SGM patients.

Antibody-Drug Conjugates in Gynecologic Cancer

The present article reviews the current evidence for antibody-drug conjugates (ADCs) in gynecologic cancer. ADCs consist of a highly selective monoclonal antibody for a tumor-associated antigen and a potent cytotoxic payload conjugated through a linker. Overall, the toxicity profiles of ADCs are manageable. Ocular toxicity is a known class effect of some ADCs and is managed with prophylactic corticosteroid and vasoconstrictor eye drops as well as dose interruptions/holds and dose modifications. In ovarian cancer, mirvetuximab soravtansine, an ADC targeting alpha-folate receptor (FRα), received US Food and Drug Administration (FDA) accelerated approval in November 2022 after data from the single-arm phase III SORAYA trial. A second ADC targeting FRα, STRO-002, received FDA fast track designation in August 2021. Multiple studies with upifitamab rilsodotin, an ADC comprising a NaPi2B-binding antibody, are underway. In cervical cancer, tisotumab vedotin, an ADC-targeting tissue factor, received FDA accelerated approval in September 2021 after the phase II innovaTV 204 trial. Tisotumab vedotin in combination with chemotherapy and other targeted agents is currently being evaluated. Although there are no currently approved ADCs for endometrial cancer, there are many under active evaluation, including mirvetuximab soravtansine. Trastuzumab-deruxtecan (T-DXd), an ADC targeting human epidermal growth factor receptor 2 (HER2), is currently approved for HER2-positive and HER2-low breast cancer and shows promise in endometrial cancer. Like all anticancer treatments, the decision for a patient to undergo therapy with an ADC is a personal choice that balances the potential benefits with the side effects and requires thorough and compassionate support of their physician and care team and shared decision making.

Novel Therapeutics in the Treatment of Uterine Sarcoma

Uterine sarcomas reflect the diversity of sarcoma as a whole. The most common histologies include leiomyosarcoma, high- and low-grade endometrial stromal sarcoma, and adenosarcoma. These are clinically and biologically heterogeneous diseases that are challenging to treat in the advanced setting. Recent advances in our understanding of the cancer biology of uterine sarcomas has improved diagnostic evaluation and therapeutic management. Promising approaches for patients with advanced uterine leiomyosarcoma include targeting DNA damage repair pathways and depleting immunosuppressive macrophage populations. A subset of endometrial stromal sarcomas harbor potentially actionable alterations in the Wnt, cyclin D-CDK4/6-Rb, and MDM2-p53 pathways. There remains an urgent need to translate molecular findings into prospective clinical trials of novel agents for patients with these diseases; progress will depend on academic collaborations and enrollment of patients with uterine sarcoma in biomarker-driven basket studies.

Novel Therapies in Gynecologic Cancer

During the past decade, considerable strides have been made in the understanding and treatment of gynecologic cancers. The advent of PARP inhibitors, antiangiogenic therapies, immunotherapy combinations, and targeted agents have altered the standard of care in ovarian, endometrial, and cervical cancers. However, continued advancement in the treatment of gynecologic cancers is critical. Fortunately, exciting work defining new therapeutic targets and novel treatment strategies is on the horizon. Here, we discuss emerging treatments for gynecologic cancers, including endometrial, cervical, ovarian, and rare gynecologic cancers. We highlight research that has deepened our understanding of the unique biology and molecular underpinnings of these cancers and is being translated into powerful new treatment approaches. We particularly highlight the advent of immunotherapy in endometrial cancer; radiosensitizers in cervical, vaginal, and vulvar cancers; targeted therapies in ovarian cancer; and molecularly driven approaches to treat rare gynecologic cancers. Continued basic, translational, and clinical research holds the promise to change the landscape of gynecologic cancer and improve the lives of all women impacted by these diseases.