Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer. George Angela,Kaye Stan,Banerjee Susana Nature reviews. Clinical oncology The treatment of patients with ovarian cancer is rapidly changing following the success of poly [ADP-ribose] polymerase (PARP) inhibitors in clinical trials. Olaparib is the first PARP inhibitor to be approved by the EMA and FDA for BRCA-mutated ovarian cancer. Germ line BRCA mutation status is now established as a predictive biomarker of potential benefit from treatment with a PARP inhibitor; therefore, knowledge of the BRCA status of an individual patient with ovarian cancer is essential, in order to guide treatment decisions. BRCA testing was previously offered only to women with a family or personal history of breast and/or ovarian cancer; however, almost 20% of women with high-grade serous ovarian cancer are now recognized to harbour a germ line BRCA mutation, and of these, >40% might not have a family history of cancer and would not have received BRCA testing. A strategy to enable more widespread implementation of BRCA testing in routine care is, therefore, necessary. In this Review, we summarize data from key clinical trials of PARP inhibitors and discuss how to integrate these agents into the current treatment landscape of ovarian cancer. The validity of germ line BRCA testing and other promising biomarkers of homologous-recombination deficiency will also be discussed. 10.1038/nrclinonc.2016.191
    Real-world evidence in the treatment of ovarian cancer. Eisenhauer E A Annals of oncology : official journal of the European Society for Medical Oncology Introduction:'Real-world evidence (RWE)' refers to information on the utilization and outcome of new therapies and technologies in clinical practice. RWE may include single institution cohort studies, population-based health services studies, or (inter)national data on survival and mortality. This paper reviews RWE on the impact of treatment in ovarian cancer. Materials and methods:A literature review of publications addressing population level survival outcomes of new surgical and systemic treatment interventions in ovarian cancer was undertaken. In addition, literature and international cancer registry trends in ovarian cancer survival, mortality and incidence rates were compiled. These latter were utilized to make inferences on the relative impact of new treatments as well as changing incidence rates on observed mortality trends. Results:The last four decades have seen new systemic and surgical treatments introduced into practice for ovarian cancer based on randomized trial evidence. However, there has been little published on population level uptake and survival outcomes of those interventions. Exceptions were population studies on intraperitoneal chemotherapy and neoadjuvant chemotherapy. One paper demonstrated modest uptake of intraperitoneal chemotherapy and evidence of improved survival. Cancer registry statistics revealed falling incidence rates (∼1%-2% per year) for ovarian cancer across Europe, North America and elsewhere over the last three to four decades. Mortality rates also declined by ∼1%-2% per year over this period. Population 5-year relative survival estimates also improved over this period [from 33.7% in 1975 to 46.2% in 2008 (SEER data)]. Conclusions:There are few RWE studies of specific treatments in ovarian cancer. Trends in relative survival and population mortality have shown improvements. Mortality changes can be explained in part by reductions in ovarian cancer incidence rates (speculated to be due to use of oral contraceptives and reduction in postmenopausal hormone use). However, it is plausible that at least some of the mortality reduction is related to improved survival of patients with the introduction of effective new treatments. 10.1093/annonc/mdx443
    Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline. Konstantinopoulos Panagiotis A,Norquist Barbara,Lacchetti Christina,Armstrong Deborah,Grisham Rachel N,Goodfellow Paul J,Kohn Elise C,Levine Douglas A,Liu Joyce F,Lu Karen H,Sparacio Dorinda,Annunziata Christina M Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus. METHODS:A literature search and prospectively defined study selection criteria sought systematic reviews, meta-analyses, randomized controlled trials (RCTs), and comparative observational studies published from 2007 through 2019. Guideline recommendations were based on the review of the evidence. RESULTS:The systematic review identified 19 eligible studies. The evidence consisted of systematic reviews of observational data, consensus guidelines, and RCTs. RECOMMENDATIONS:All women diagnosed with epithelial ovarian cancer should have germline genetic testing for and other ovarian cancer susceptibility genes. In women who do not carry a germline pathogenic or likely pathogenic variant, somatic tumor testing for pathogenic or likely pathogenic variants should be performed. Women with identified germline or somatic pathogenic or likely pathogenic variants in genes should be offered treatments that are US Food and Drug Administration (FDA) approved in the upfront and the recurrent setting. Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR). Women with identified dMMR should be offered FDA-approved treatment based on these results. Genetic evaluations should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer. First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene variant should be offered individualized genetic risk evaluation, counseling, and genetic testing. Clinical decision making should not be made based on a variant of uncertain significance. Women with epithelial ovarian cancer should have testing at the time of diagnosis. 10.1200/JCO.19.02960
    Ovarian cancer statistics, 2018. Torre Lindsey A,Trabert Britton,DeSantis Carol E,Miller Kimberly D,Samimi Goli,Runowicz Carolyn D,Gaudet Mia M,Jemal Ahmedin,Siegel Rebecca L CA: a cancer journal for clinicians In 2018, there will be approximately 22,240 new cases of ovarian cancer diagnosed and 14,070 ovarian cancer deaths in the United States. Herein, the American Cancer Society provides an overview of ovarian cancer occurrence based on incidence data from nationwide population-based cancer registries and mortality data from the National Center for Health Statistics. The status of early detection strategies is also reviewed. In the United States, the overall ovarian cancer incidence rate declined from 1985 (16.6 per 100,000) to 2014 (11.8 per 100,000) by 29% and the mortality rate declined between 1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. Ovarian cancer encompasses a heterogenous group of malignancies that vary in etiology, molecular biology, and numerous other characteristics. Ninety percent of ovarian cancers are epithelial, the most common being serous carcinoma, for which incidence is highest in non-Hispanic whites (NHWs) (5.2 per 100,000) and lowest in non-Hispanic blacks (NHBs) and Asians/Pacific Islanders (APIs) (3.4 per 100,000). Notably, however, APIs have the highest incidence of endometrioid and clear cell carcinomas, which occur at younger ages and help explain comparable epithelial cancer incidence for APIs and NHWs younger than 55 years. Most serous carcinomas are diagnosed at stage III (51%) or IV (29%), for which the 5-year cause-specific survival for patients diagnosed during 2007 through 2013 was 42% and 26%, respectively. For all stages of epithelial cancer combined, 5-year survival is highest in APIs (57%) and lowest in NHBs (35%), who have the lowest survival for almost every stage of diagnosis across cancer subtypes. Moreover, survival has plateaued in NHBs for decades despite increasing in NHWs, from 40% for cases diagnosed during 1992 through 1994 to 47% during 2007 through 2013. Progress in reducing ovarian cancer incidence and mortality can be accelerated by reducing racial disparities and furthering knowledge of etiology and tumorigenesis to facilitate strategies for prevention and early detection. CA Cancer J Clin 2018;68:284-296. © 2018 American Cancer Society. 10.3322/caac.21456
    Ovarian cancer stem cell: A potential therapeutic target for overcoming multidrug resistance. Mihanfar Aynaz,Aghazadeh Attari Javad,Mohebbi Iraj,Majidinia Maryam,Kaviani Mojtaba,Yousefi Mehdi,Yousefi Bahman Journal of cellular physiology The cancer stem cell (CSC) model encompasses an advantageous paradigm that in recent decades provides a better elucidation for many important biological aspects of cancer initiation, progression, metastasis, and, more important, development of multidrug resistance (MDR). Such several other hematological malignancies and solid tumors and the identification and isolation of ovarian cancer stem cells (OV-CSCs) show that ovarian cancer also follows this hierarchical model. Gaining a better insight into CSC-mediated resistance holds promise for improving current ovarian cancer therapies and prolonging the survival of recurrent ovarian cancer patients in the future. Therefore, in this review, we will discuss some important mechanisms by which CSCs can escape chemotherapy, and then review the recent and growing body of evidence that supports the contribution of CSCs to MDR in ovarian cancer. 10.1002/jcp.26768
    Therapeutic options following second-line platinum-based chemotherapy in patients with recurrent ovarian cancer: Comparison of active surveillance and maintenance treatment. Ray-Coquard Isabelle,Mirza Mansoor Raza,Pignata Sandro,Walther Axel,Romero Ignacio,du Bois Andreas Cancer treatment reviews Most women with advanced ovarian cancer respond to initial treatment, consisting of surgical resection and ≈6 cycles of platinum-based chemotherapy. However, disease recurrence occurs in most patients, and subsequent therapies become necessary. Historically, close monitoring following treatment (active surveillance) was the only available option, as continued maintenance chemotherapy treatment led to increased toxicity without providing any meaningful clinical benefit. Recently, targeted therapy with the angiogenesis inhibitor bevacizumab and the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib, niraparib, and rucaparib have demonstrated significant clinical benefits as maintenance treatment for recurrent disease. Despite consensus guidelines recommending their use, maintenance treatments are currently underutilized. Here, we review evidence from pivotal clinical trials of approved second-line maintenance treatments demonstrating efficacy in terms of progression-free survival and postprogression efficacy outcomes for patients with recurrent ovarian cancer. Adverse events frequently associated with bevacizumab include hypertension, proteinuria, and non-central nervous system bleeding, whereas PARP inhibitors are associated with nausea, vomiting, fatigue, and anemia. Patient-centered outcomes analyses show that PARP inhibitors provide significant benefits to patient health status, even when accounting for the toxicities associated with treatment. Many factors influence the selection of second-line maintenance treatment for patients with recurrent ovarian cancer, including the maintenance treatment received in the first-line setting. Overall, targeted maintenance treatment represents a new standard of care for patients with ovarian cancer, and we recommend that maintenance treatment should be offered to all eligible patients with recurrent ovarian cancer. 10.1016/j.ctrv.2020.102107
    Epithelial ovarian cancer: Evolution of management in the era of precision medicine. Lheureux Stephanie,Braunstein Marsela,Oza Amit M CA: a cancer journal for clinicians Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum-based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP-ribose) polymerase (PARP) molecules involved in the DNA damage-repair process, which have been approved in a recurrent setting and recently in a first-line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence-based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care. 10.3322/caac.21559
    The forefront of ovarian cancer therapy: update on PARP inhibitors. Mirza M R,Coleman R L,González-Martín A,Moore K N,Colombo N,Ray-Coquard I,Pignata S Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of PARP inhibitors earlier in the treatment algorithm. DESIGN:We review results from recent phase III trials evaluating PARP inhibitors as treatment and/or maintenance therapy for patients with newly diagnosed ovarian cancer. We discuss the efficacy and safety of these agents in the all-comer and biomarker-selected populations studied in clinical trials, and compare the strengths and limitations of the various trial designs. We also consider priorities for future research, with a particular focus on patient selection and future regimens for populations with high unmet need. RESULTS:Four phase III trials (SOLO-1, PAOLA-1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005) demonstrated remarkable improvements in progression-free survival with PARP inhibitor therapy (olaparib, niraparib or veliparib) for newly diagnosed ovarian cancer. Differences in trial design (treatment and/or maintenance setting; single agent or combination; bevacizumab or no bevacizumab), patient selection (surgical outcome, biomarker eligibility, prognosis) and primary analysis population (intention-to-treat, BRCA mutated or homologous recombination deficiency positive) affect the conclusions that can be drawn from these trials. Overall survival data are pending and there is limited experience regarding long-term safety. CONCLUSIONS:PARP inhibitors play a pivotal role in the management of newly diagnosed ovarian cancer, which will affect subsequent treatment choices. Refinement of testing for patient selection and identification of regimens to treat populations that appear to benefit less from PARP inhibitors are a priority. 10.1016/j.annonc.2020.06.004
    Epigenetic therapy for ovarian cancer: promise and progress. Moufarrij Sara,Dandapani Monica,Arthofer Elisa,Gomez Stephanie,Srivastava Aneil,Lopez-Acevedo Micael,Villagra Alejandro,Chiappinelli Katherine B Clinical epigenetics Ovarian cancer is the deadliest gynecologic malignancy, with a 5-year survival rate of approximately 47%, a number that has remained constant over the past two decades. Early diagnosis improves survival, but unfortunately only 15% of ovarian cancers are diagnosed at an early or localized stage. Most ovarian cancers are epithelial in origin and treatment prioritizes surgery and cytoreduction followed by cytotoxic platinum and taxane chemotherapy. While most tumors will initially respond to this treatment, recurrence is likely to occur within a median of 16 months for patients who present with advanced stage disease. New treatment options separate from traditional chemotherapy that take advantage of advances in understanding of the pathophysiology of ovarian cancer are needed to improve outcomes. Recent work has shown that mutations in genes encoding epigenetic regulators are mutated in ovarian cancer, driving tumorigenesis and resistance to treatment. Several of these epigenetic modifiers have emerged as promising drug targets for ovarian cancer therapy. In this article, we delineate epigenetic abnormalities in ovarian cancer, discuss key scientific advances using epigenetic therapies in preclinical ovarian cancer models, and review ongoing clinical trials utilizing epigenetic therapies in ovarian cancer. 10.1186/s13148-018-0602-0
    Targeting the PI3K pathway and DNA damage response as a therapeutic strategy in ovarian cancer. Huang Tzu-Ting,Lampert Erika J,Coots Cynthia,Lee Jung-Min Cancer treatment reviews Ovarian cancer is the most lethal gynecological malignancy worldwide although exponential progress has been made in its treatment over the last decade. New agents and novel combination treatments are on the horizon. Among many new drugs, a series of PI3K/AKT/mTOR pathway (referred to as the PI3K pathway) inhibitors are under development or already in clinical testing. The PI3K pathway is frequently upregulated in ovarian cancer and activated PI3K signaling contributes to increased cell survival and chemoresistance. However, no significant clinical success has been achieved with the PI3K pathway inhibitor(s) to date, reflecting the complex biology and also highlighting the need for combination treatment strategies. DNA damage repair pathways have been active therapeutic targets in ovarian cancer. Emerging data suggest the PI3K pathway is also involved in DNA replication and genome stability, making DNA damage response (DDR) inhibitors as an attractive combination treatment for PI3K pathway blockades. This review describes an expanded role for the PI3K pathway in the context of DDR and cell cycle regulation. We also present the novel treatment strategies combining PI3K pathway inhibitors with DDR blockades to improve the efficacy of these inhibitors for ovarian cancer. 10.1016/j.ctrv.2020.102021
    Defining and targeting wild-type BRCA high-grade serous ovarian cancer: DNA repair and cell cycle checkpoints. Ivy S Percy,Kunos Charles A,Arnaldez Fernanda I,Kohn Elise C Expert opinion on investigational drugs : Molecular analyzes including molecular descriptor/phenotype interactions have led to better characterization of epithelial ovarian cancer patients, including a definition of a BRCA wild-type (BRCAwt) phenotype. Understanding how and when to use agents targeted against dependent BRCAwt pathways or other molecular events at disease progression is an important translational and therapeutic direction in ovarian cancer research. : In this overview, we provide definitions and descriptions of a BRCAwt genotype and phenotype. We discuss novel investigational drugs that hold promise for the treatment of BRCAwt ovarian cancer, including inhibitors of poly(ADP-ribose) polymerase, ribonucleotide reductase, DNA protein kinase-catalytic subunit, ataxia-telangiectasia-mutated kinase (ATM), ataxia-telangiectasia mutated and Rad3-related kinase (ATR), CHK 1/2, cyclin kinases, glutaminase-1, WEE1 kinase, as well as tumor microenvironment and angiogenesis inhibitors. This article explores the known and the emerging areas of clinical research on patients with BRCAwt ovarian cancer. : Discovery of molecular changes tied to annotated disease information, along with an expanding array of pathway targets and targeted therapeutic agents, creates optimism and opportunity for women with ovarian cancer. Using precision oncology approaches, clinical researchers are, and will be, poised to select more effective treatments for ovarian cancer patients. 10.1080/13543784.2019.1657403
    ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease†. Colombo N,Sessa C,du Bois A,Ledermann J,McCluggage W G,McNeish I,Morice P,Pignata S,Ray-Coquard I,Vergote I,Baert T,Belaroussi I,Dashora A,Olbrecht S,Planchamp F,Querleu D, Annals of oncology : official journal of the European Society for Medical Oncology The development of guidelines recommendations is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on 12-14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation. 10.1093/annonc/mdz062