The use of mutant isocitrate dehydrogenase (mIDH) inhibitors has been investigated and has shown significant improvement in survival outcomes in patients with a range of mIDH cancers, including acute myeloid leukaemia (AML), cholangiocarcinoma (CCA), glioma and conventional chondrosarcoma. In the phase 3 clinical trial ClarIDHy, patients with mIDH1 CCA treated with ivosidenib had improved overall survival (OS) compared to those treated with placebo (hazard ratio [HR]: 0.79 [95% confidence interval [CI]: 0.56-1.12]; P=0.09). In the phase 3 AGILE study, patients with mIDH1 AML treated with ivosidenib plus azacitidine showed improved OS compared to those treated with placebo plus azacitidine (HR: 0.42 [95% CI: 0.27-0.73]; P=0.001). In conventional chondrosarcoma, ivosidenib demonstrated efficacy in a phase 1 trial and the ongoing phase 3, placebo-controlled clinical trial CHONQUER will investigate the use of ivosidenib in patients with unresectable, progressive, conventional mIDH1 chondrosarcoma. The phase 3 clinical trial INDIGO explored the use of vorasidenib for the treatment of Central Nervous System World Health Organization grade 2 mIDH glioma and showed that vorasidenib had a progression-free survival benefit over placebo in previously untreated patients (HR: 0.39 [95% CI: 0.27-0.56]; P<0.0001). Across these studies, mIDH inhibitors were well-tolerated. Current efforts focus on further evaluating the efficacy and safety of mIDH inhibitors in different lines of therapy, in combination with other anti-neoplastic agents, and in other mIDH cancers.
The isocitrate dehydrogenase (IDH) family of proteins comprises three important metabolic enzymes that convert isocitrate to alpha ketoglutarate (α-KG) via oxidative decarboxylation. The IDH enzymes play important roles in epigenetic regulation, DNA repair, and cellular metabolism and biosynthesis. In mutant IDH (mIDH) cells, α-KG is converted into the functional oncometabolite 2-hydroxyglutarate (2-HG) in a process that consumes the reduced form of nicotinamide adenine dinucleotide phosphate to generate its oxidised form. 2-HG competitively inhibits α-KG from binding to the active site of histone and DNA demethylases, leading to hypermethylation, which inhibits cellular differentiation and induces tumour cell proliferation. Increased 2-HG also has other effects on cellular biology, including altered metabolism, dysregulation of gene expression, alterations in the DNA damage repair pathway, inflammation, and cell death, therefore supporting and promoting tumorigenesis. mIDH genes are associated with a variety of cancers, including but not limited to, cholangiocarcinoma, acute myeloid leukaemia, glioma, and chondrosarcoma, and the incidences of mIDH in these cancers varies and is approximately 13%, 33%, 73%, and 56%, respectively. The biological effects of mIDH are distinct in different cancers, but the reason that mIDH promotes tumour development in some tissues and not others is not clear. mIDH has no definitive prognostic impact in these cancers, except glioma, in which it is a disease-defining marker due to its distinct prognostic significance. mIDH1/2 are actionable mutations that represent therapeutic targets, however available targeted therapies to treat mIDH cancers are lacking. This article discusses mIDH genes and their importance in each of these cancers.
•A three-state partitioned survival model of GEP-NET patients was developed.•Base case ICERs for [177Lu]Lu-DOTA-TATE were under £30,000 per QALY for all comparators.•[177Lu]Lu-DOTA-TATE is cost-effective for the treatment of GEP-NETs from a NICE perspective.
Head-to-head comparisons of the efficacy of treatments for gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have not yet been reported. This study used a series of matching-adjusted indirect comparisons to indirectly compare the effectiveness of [177Lu]Lu-DOTA-TATE to everolimus, sunitinib and best supportive care (BSC) for extending progression-free survival and overall survival in patients with advanced, unresectable gastrointestinal (GI)-NETs and P-NETs. The results of the main analysis suggest that after accounting for differences in key prognostic variables, the hazard of progression was 62% (hazard ratio [HR], 0.38; confidence interval [CI]95 0.25–0.58) and 65% (HR 0.35 CI95 0.21–0.59) lower in patients with GI-NETs treated with [177Lu]Lu-DOTA-TATE than in those treated with everolimus and BSC, respectively. Similarly, the hazard of progression was 64% (HR 0.36 CI95 0.18–0.70), 54% (HR 0.46 CI95 0.30–0.71) and 79–87% (HR 0.21 CI95 0.13–0.32; HR 0.13 CI95 0.08–0.22) lower in patients with P-NET treated with [177Lu]Lu-DOTA-TATE than in those treated with sunitinib, everolimus and BSC, respectively. The hazard of death was 58% (HR 0.42 CI95 0.25–0.72), 47% (HR 0.53 CI95 0.33–0.87) and 44–64% (HR 0.56 CI95 0.36–0.90; HR 0.34 CI95 0.20–0.57) lower in P-patients with NET treated with [177Lu]Lu-DOTA-TATE than in those treated with sunitinib, everolimus and BSC, respectively. While our results must be interpreted with caution given the non-randomised nature of the comparisons and the potential for residual confounding, the magnitude of the effect sizes we observe and their consistency across comparators suggest that [177Lu]Lu-DOTA-TATE may be a more effective treatment option than everolimus, sunitinib and BSC in advanced, unresectable GEP-NETs.
BACKGROUND AND PURPOSE:Ovarian cancer (OC) is the deadliest gynaecologic cancer characterised by a high heterogeneity not only at the clinical point of view but also at the molecular level. This review focuses on the new insights about the OC molecular classification.MATERIALS AND METHODS:We performed a bibliographic search for different indexed articles focused on the new molecular classification of OC. All of them have been published in PubMed and included information about the most frequent molecular alterations in OC confirmed by omics approaches. In addition, we have extracted information about the role of liquid biopsy in the OC diagnosis and prognosis.RESULTS:New molecular insights into OC have allowed novel clinical entities to be defined. Among OC, high-grade serous ovarian carcinoma (HGSOC) which is the most common OC is characterised by omics approaches, mutations in TP53 and in other genes involved in the homologous recombination repair, especially BRCA1/2. Recent studies in HGSOC have allowed a new molecular classification in subgroups according to their mutational, transcriptional, methylation and copy number variation signatures with a real impact in the characterisation of new therapeutic targets for OC to be defined. Furthermore, despite the intrinsic intra-tumour heterogeneity, the advances in next generation sequencing (NGS) analyses of ascetic liquid from OC have opened new ways for its characterisation and treatment.CONCLUSIONS:The advances in genomic approaches have been used for the identification of new molecular profiling techniques which define OC subgroups and has supposed advances in the diagnosis and in the personalised treatment of OC.
The standard first-line therapy for ovarian cancer is a combination of surgery and carboplatin/paclitaxel-based chemotherapy. Patients with longer survival and improved response to chemotherapy usually present T-cell inflamed tumours. The presence of tumour-infiltrating T cells (TILs) notably varies among the different subtypes of ovarian tumours, being highest in high-grade serous ovarian carcinoma, intermediate in endometrioid tumours, and lowest in low-grade serous, mucinous and clear cell tumours. Interestingly, the presence of TILs is often accompanied by a strong immunosuppressive tumour environment. A better understanding of the immune response against ovarian cancer and the tumour immune evasion mechanisms will enable improved prognostication, response prediction and immunotherapy of this disease. This article provides an overview of some ovarian cancer cell features relevant for antitumour response, such as tumour-associated antigens, including neoantigens, expression of inhibitory molecules, and other mechanisms of immune evasion. Moreover, we describe relevant immune cell types found in epithelial ovarian tumours, including T and B lymphocytes, regulatory T cells, natural killer cells, tumour-associated macrophages, myeloid-derived suppressor cells and neutrophils. We focus on how these components influence the burden of the tumour and the clinical outcome.
Cancer is characterised by uncontrolled proliferation and prolonged cell survival. In some cases, tumour formation is the result from aberrant activity of various cell-cycle regulators leading to chromosome instability or from alteration of the apoptosis pathway. Ovarian cancer is an entity in which cell-cycle alterations are common. P53, a key regulator of checkpoint G1, is frequently altered in high-grade serous ovarian cancer. Targeting cell-cycle regulators will lead to mitotic catastrophe and cell death in these tumours. Promoting apoptosis is another target that is gaining interest in ovarian cancer. In this review, the most relevant evidence of clinical studies in ovarian cancer with compounds targeting cell cycle or promoting apoptosis is summarised.
Angiogenesis is a known hallmark in cancer and plays a crucial role in ovarian cancer carcinogenesis and invasion. Anti- angiogenic agents are active in ovarian cancer treatment either as monotherapy or combined with chemotherapy, immunotherapy or poly ADP ribose polymerase (PARP) inhibitors. We review the mechanism of action, clinical activity and safety profile of the most important drugs either in the actual treatment or in current evaluation in the ovarian cancer treatment scenario (neoadjuvant, first line and relapse).
Ovarian epithelial cancer (OEC) is the most lethal gynecologic malignancy. Despite current chemotherapeutic and surgical options, this high lethality can be attributed to multiple factors, including late-stage presentation. In order to optimize OEC treatment, it is important to highlight that it is composed of five main subtypes: high-grade serous ovarian carcinoma (HGSOC), low-grade serous ovarian carcinoma (LGSOC), endometrioid ovarian carcinoma (EOC), ovarian clear cell carcinoma (CCOC), and mucinous ovarian carcinoma (MOC). These subtypes differ in their precursor lesions, as well as in epidemiological, morphological, molecular and clinical features. OEC is one of the tumours in which most pathogenic germline mutations have been identified. Accordingly, up to 20% OC show alterations in BRCA1/2 genes, and also, although with a lower frequency, in other low penetrance genes associated with homologous recombination deficiency (HRD), mismatch repair genes (Lynch syndrome) and TP53. The most important prognostic factor is the 2014 FIGO staging, while older age is also associated with worse survival. HGSOC in all stages and CCC and MOC in advanced stages have the worse prognosis among histological types. Molecular markers have emerged as prognostic factors, particularly mutations in BRCA1/2, which are associated with a better outcome. Regarding treatment, whereas a proportion of HGSOC is sensible to platinum-based treatment and PARP inhibitors due to HRD, the rest of the histological types are relatively chemoresistant. New treatments based in specific molecular alterations are being tested in different histological types. In addition, immunotherapy could be an option, especially for EOC carrying mismatch repair deficiency or POLE mutations.
Epithelial ovarian cancer (EOC) is very sensitive to upfront chemotherapy. This condition is attributable to defects in the DNA damage repair system. Agents that damage DNA are the main drugs used for its treatment. Many EOC cells have DNA repair deficiencies that confer susceptibility to these agents. Platinum is the most important agent for first-line and also for relapses, together with other drugs that can be given as monotherapy or along with platinum or other drugs. Lately, the emerging role of PARP inhibitors has changed the landscape of opportunities for patients with EOC. All these strategies will be reviewed in this article.
Epithelial ovarian cancer (EOC) is a heterogeneous group of diseases with distinct biological and clinical behaviour. Despite the differences between them, the capability of tumour cells to continuously proliferate and avoid death is maintained among histotypes. This ability is the result of alterations at different levels, causing the deregulation of cell cycle and proliferative-related pathways. Even if the leading role is played by RB and TP53, changes in other molecular pathways are involved in the development of EOC. This ability can be exploited to generate in vitro and in vivo models resembling the conditions of tumour development in a patient. In vivo models, such as patient-derived xenografts (PDX) or genetically engineered mouse models (GEMM), represent a fundamental tool in the study of the molecular mechanisms implicated in each EOC biotype for testing new therapeutic approaches. Herein we describe the major proliferation-related pathways and its disruption found in EOC and how these features can be used to establish in vivo models for translational research.
Cancers develop by sustained growth, migration and invasion properties of tumour cells, supported by complex interactions with stromal cells within the tumour micro-environment.
Ovarian cancer cells mainly metastasise within the peritoneal cavity, the lethal consequence of tumour progression in this cancer type. Classically, changes in tumour cells, such as epithelial to mesenchymal transition, involve the down-regulatinon of E-cadherin, activation of extracellular proteases and integrin-mediated adhesion. However, our current understanding of ovarian tumour progression suggests the implication of both intrinsic and extrinsic factors. It has been proposed that ovarian cancer metastases are a consequence of the crosstalk between cancer cells and the tumour microenvironment by soluble factors and extracellular vesicles. Characterisation of the alterations in both the tumour cells and the surrounding microenvironment has emerged as a new research field to understand ovarian cancer metastasis. In this mini review, we will summarise the most recent findings, focusing our attention on the role of secreted factors and extracellular vesicles in ovarian cancer metastasis.
•Rare Malignant Ovarian Tumors need a specific diagnosis and treatment.•Hormonotherapy is suitable for some ovarian cancers.•Molecular alterations analyses permits targeted therapy as a personalized medicine.
Ovarian cancer is the leading cause of death for gynaecological cancer, and new therapies are urgently awaited. Although the presence of tumour-infiltrating lymphocytes has been confirmed to be associated to a better prognosis, immunotherapy is not yet incorporated to the armamentarium in ovarian cancer. This review briefly summarises the strategies that have been tested or are under study for the three different groups of tumours: immune desert, inflamed and immune-excluded ovarian tumours. Finally, a better knowledge of the biology and immune microenvironment is needed for successfully developing new immunotherapy strategies.
Strategies to improve cancer care in the field of urothelial carcinoma (UC) in the elderly or in patients unfit to receive cisplatin treatment are urgently needed. This effort requires multidisciplinary collaboration to provide the best care for these patients. An international multidisciplinary summit was held in Geneva on April 11th 2015 to discuss unmet medical needs in urothelial cancer. Key topics covered in the meeting included defining difficult-to-treat UC patients and the challenges encountered with both surgical and systemic treatment in these patients. The delegates discussed potential therapies, from neoadjuvant treatment to combinations or sequential regimens, maintenance therapy up to second-line management, and future treatment opportunities that could improve on current patient outcomes. Molecular specificities and future perspectives of UC were also discussed. Each individual topic of the meeting is outlined in the chapters below.
Biological anticancer therapies developed in recent decades have contributed to improvements in patient care for serious illnesses. Patents for several biologics will soon expire, paving the way for initiating approval processes for biosimilars—defined as highly similar versions of already licensed or approved biological therapies. The aim of developing a biosimilar is to establish similarity in terms of quality, safety, and efficacy rather than to reestablish clinical benefit. Fundamentally if two products are highly similar, all aspects of their therapeutic effects (ie, safety, immunogenicity, and efficacy) should also be highly similar. This introduces a different way of thinking about drug development for clinicians, who will ultimately analyze and integrate biosimilars into existing treatment paradigms. As such, oncologists across specialties need to understand the core concepts of biosimilarity, including extrapolation—the approval of a biosimilar for use in an indication held by the previously approved biological therapy (deemed the reference product), but not directly studied in a comparative clinical trial with the biosimilar. Extrapolation is the highly scrutinized scientific rationale that bridges data collected across indications and has important implications in oncology, where biological anticancer therapies are currently licensed for use across tumor types and in supportive care. In this roundtable discussion, experts specializing in breast, lung, hematologic, and gynecologic cancers highlight the scientific and clinical rationale behind establishment of biosimilarity and extrapolation. They provide practical insight into the implications of biosimilars for clinical practices, including their potential to expand global access to important medicines for patients and clinicians.
Currently, 17–19% of all new primary malignancies occur in survivors of cancer, causing substantial morbidity and mortality. Research has shown that cancer treatments are important contributors to second malignant neoplasm (SMN) risk. In this paper we summarise current knowledge with regard to treatment-related SMNs and provide recommendations for future research. We address the risks associated with radiotherapy and systemic treatments, modifying factors of treatment-related risks (genetic susceptibility, lifestyle) and the potential benefits of screening and interventions. Research priorities were identified during a workshop at the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer. Recently, both systemic cancer treatments and radiotherapy approaches have evolved rapidly, with the carcinogenic potential of new treatments being unknown. Also, little knowledge is available about modifying factors of treatment-associated risk, such as genetic variants and lifestyle. Therefore, large prospective studies with biobanking, high quality treatment data (radiation dose–volume, cumulative drug doses), and data on other cancer risk factors are needed. International collaboration will be essential to have adequate statistical power for such investigations. While screening for SMNs is included in several follow-up guidelines for cancer survivors, its effectiveness in this special population has not been demonstrated. Research into the pathogenesis, tumour characteristics and survival of SMNs is essential, as well as the development of interventions to reduce SMN-related morbidity and mortality. Prediction models for SMN risk are needed to inform initial treatment decisions, balancing chances of cure and SMNs and to identify high-risk subgroups of survivors eligible for screening.
Sexual dysfunction is a common consequence of cancer treatment, affecting at least half of men and women treated for pelvic malignancies and over a quarter of people with other types of cancer. Problems are usually linked to damage to nerves, blood vessels, and hormones that underlie normal sexual function. Sexual dysfunction also may be associated with depression, anxiety, relationship conflict, and loss of self-esteem. Innovations in cancer treatment such as robotic surgery or more targeted radiation therapy have not had the anticipated result of reducing sexual dysfunction. Some new and effective cancer treatments, including aromatase inhibitors for breast cancer or chemoradiation for anal cancer also have very severe sexual morbidity. Cancer-related infertility is an issue for younger patients, who comprise a much smaller percentage of total cancer survivors. However, the long-term emotional impact of being unable to have a child after cancer can be extremely distressing. Advances in knowledge about how cancer treatments may damage fertility, as well as newer techniques to preserve fertility, offer hope to patients who have not completed their childbearing at cancer diagnosis. Unfortunately, surveys in industrialised nations confirm that many cancer patients are still not informed about potential changes to their sexual function or fertility, and all modalities of fertility preservation remain underutilised. After cancer treatment, many patients continue to have unmet needs for information about restoring sexual function or becoming a parent. Although more research is needed on optimal clinical practice, current studies suggest a multidisciplinary approach, including both medical and psychosocial treatment options.
