Angela George

Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients

Advances in DNA sequencing have made genetic testing fast and affordable, but limitations of testing processes are impeding realisation of patient benefits. Ovarian cancer exemplifies the potential value of genetic testing and the shortcomings of current pathways to access testing. Approximately 15% of ovarian cancer patients have a germline BRCA1 or BRCA2 mutation which has substantial implications for their personal management and that of their relatives. Unfortunately, in most countries, routine implementation of BRCA testing for ovarian cancer patients has been inconsistent and largely unsuccessful. We developed a rapid, robust, mainstream genetic testing pathway in which testing is undertaken by the trained cancer team with cascade testing to relatives performed by the genetics team. 207 women with ovarian cancer were offered testing through the mainstream pathway. All accepted. 33 (16%) had a BRCA mutation. The result informed management of 79% (121/154) women with active disease. Patient and clinician feedback was very positive. The pathway offers a 4-fold reduction in time and 13-fold reduction in resource requirement compared to the conventional testing pathway. The mainstream genetic testing pathway we present is effective, efficient and patient-centred. It can deliver rapid, robust, large-scale, cost-effective genetic testing of BRCA1 and BRCA2 and may serve as an exemplar for other genes and other diseases.

Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer

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.

BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer

The significant activity of poly(ADP-ribose)polymerase (PARP) inhibitors in the treatment of germline BRCA mutation-associated ovarian cancer, which represents ∼15% of HGS cases, has recently led to European Medicines Agency and food and drug administration approval of olaparib. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic ovarian cancers. Up to 50% of HGS ovarian cancer patients may exhibit homologous recombination deficiency (HRD) through mechanisms including germline BRCA mutations, somatic BRCA mutations, and BRCA promoter methylation. In this review, we discuss the role of somatic BRCA mutations and BRCA methylation in ovarian cancer. There is accumulating evidence for routine somatic BRCA mutation testing, but the relevance of BRCA epigenetic modifications is less clear. We explore the challenges that need to be addressed if the full potential of these markers of HRD is to be utilised in clinical practice.

The integration of BRCA testing into oncology clinics.

PURPOSE The PARP inhibitor, Olaparib, is approved for women with BRCA-mutated ovarian cancer. Therefore there is an urgent need to test patients and obtain results in time to influence treatment. Models of BRCA testing, such as the mainstreaming oncogenetic pathway, involving oncology health professionals are being used. The authors report on the establishment of the extended role of the clinical nurse specialist in consenting women for BRCA testing in routine gynaecology-oncology clinics using the mainstreaming model. METHODS Nurses undertook generic consent training and specific counselling training for BRCA testing in the form of a series of online videos, written materials and checklists before obtaining approval to consent patients for germline BRCA1 and BRCA2 mutations. RESULTS Between July 2013 and December 2015, 108 women with ovarian cancer were counselled and consented by nurses in the medical oncology clinics at a single centre (The Royal Marsden, UK). This represented 36% of all ovarian cancer patients offered BRCA testing in the oncology clinics at the centre. Feedback from patients and nurses was encouraging with no significant issues raised in the counselling and consenting process. CONCLUSION The mainstreaming model allows for greater access to BRCA testing for ovarian cancer patients, many of whom may benefit from personalised therapy (PARP inhibitors). This is the first report of oncology nurses in the BRCA testing pathway. Specialist oncology nurses trained in BRCA testing have an important role within a multidisciplinary team counselling and consenting patients to undergo BRCA testing.

The current status of PARP inhibitors in ovarian cancer

Recent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach. Importantly, companion homologous recombination deficiency scores are being developed to help guide the selection of patients most likely to gain clinical benefit from PARP inhibition. Olaparib, the first and most extensively investigated PARP inhibitor, is now licensed in Europe for maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated (germline or somatic) high-grade serous ovarian cancer who have responded to platinum-based chemotherapy. In the United States, olaparib is licensed for treatment of patients with germline BRCA-mutated ovarian cancer who have received 3 or more lines of chemotherapy. There are a number of other PARP inhibitors in late phase clinical development in ovarian cancer including rucaparib, niraparib, veliparib, and talazoparib. This review will focus on the current evidence for PARP inhibitors in ovarian cancer and discuss ongoing clinical trials and future research directions in this rapidly evolving area.

A Cost-Effectiveness Evaluation of Germline BRCA1 and BRCA2 Testing in UK Women with Ovarian Cancer

Objectives To evaluate the long-term cost-effectiveness of germline BRCA1 and BRCA2 (collectively termed “BRCA”) testing in women with epithelial ovarian cancer, and testing for the relevant mutation in first- and second-degree relatives of BRCA mutation–positive individuals, compared with no testing. Female BRCA mutation–positive relatives of patients with ovarian cancer could undergo risk-reducing mastectomy and/or bilateral salpingo-oophorectomy. Methods A cost-effectiveness model was developed that included the risks of breast and ovarian cancer; the costs, utilities, and effects of risk-reducing surgery on cancer rates; and the costs, utilities, and mortality rates associated with cancer. Results BRCA testing of all women with epithelial ovarian cancer each year is cost-effective at a UK willingness-to-pay threshold of £20,000/quality-adjusted life-year (QALY) compared with no testing, with an incremental cost-effectiveness ratio of £4,339/QALY. The result was primarily driven by fewer cases of breast cancer (142) and ovarian cancer (141) and associated reductions in mortality (77 fewer deaths) in relatives over the subsequent 50 years. Sensitivity analyses showed that the results were robust to variations in the input parameters. Probabilistic sensitivity analysis showed that the probability of germline BRCA mutation testing being cost-effective at a threshold of £20,000/QALY was 99.9%. Conclusions Implementing germline BRCA testing in all patients with ovarian cancer would be cost-effective in the United Kingdom. The consequent reduction in future cases of breast and ovarian cancer in relatives of mutation–positive individuals would ease the burden of cancer treatments in subsequent years and result in significantly better outcomes and reduced mortality rates for these individuals.

The role of Cediranib in ovarian cancer

ABSTRACT Introduction: Treatment options for relapsed ovarian cancer have increased over the decade with the addition of targeted agents, such as PARP inhibitors and antiangiogenic agents. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), was the first anti-angiogenic agent to be incorporated in the ovarian cancer treatment landscape. Other molecules utilising different mechanisms of action to target angiogenesis have been developed, including cediranib, an oral potent inhibitor of VEGF Tyrosine Kinase Inhibitor that has demonstrated activity in both phase II and phase III studies. Areas covered: Herein we will review cediranib as well as the evidence for its use in ovarian cancer, both as monotherapy and in combination with chemotherapy, PARP inhibitors and immunotherapy. A literature search was made in PubMed and on ClinicalTrials.gov for clinical trials with cediranib. Expert opinion: The addition of cediranib for the treatment of ovarian cancer is promising, and has demonstrated a significant improvement in progression free survival in a phase III trial in combination with chemotherapy and maintenance treatment. Cediranib is currently being explored in ovarian cancer and other gynaecological malignancies aiming to improve patient care; further research will help define its role in standard clinical practice for patients with ovarian cancer.

Visualizing whole-body treatment response heterogeneity using multi-parametric magnetic resonance imaging:

A novel post-processing methodology able to assess whole-body tumor heterogeneity in patients with metastatic disease is proposed. The method is demonstrated on paired pre- and post-treatment data sets obtained from an initial cohort of six patients with metastatic disease from primary prostate or ovarian cancers. Whole-body diffusion-weighted imaging and T1-weighted contrast-enhanced imaging data were acquired covering the chest, abdomen, and pelvis. Joint histograms of Apparent Diffusion Coefficient and Fractional Enhancement values were calculated within volumes of interest and were modeled as a Gaussian mixture of two classes. Probability maps and volumetric estimates of the magnetic resonance data-derived classes providing visualization of pre- and post-treatment data are shown in three patient examples. This technique provided spatially heterogeneous characterization of regions following treatment as defined by the combined analysis of apparent diffusion coefficient and fractional enhancement. A new whole-body magnetic resonance data analysis has been demonstrated enabling visualization of intra-patient response heterogeneity in patients with metastatic cancer. Changes in the parameters of each subpopulation derived from this technique (apparent diffusion coefficient and fractional enhancement) reflect changes in the tissue properties of each subpopulation following treatment. Furthermore, the volume change of each population can be quantified. Such techniques may be essential for personalized anti-cancer therapy where there is a need to detect early drug-resistance and monitor heterogeneous response.

Personalisation of Therapy – clinical impact and relevance of genetic mutations in tumours

As technological advances in genetic sequencing and the parallel reduction in costs of sequencing make testing more accessible, genomic profiling of tumours is increasingly becoming integrated into routine clinical care. This personalisation of medical care is especially relevant in the area of oncology, where interest in tumour testing as part of standard care has dramatically increased. Tumour genomic profiles are particularly interesting, as they harbour mutations acquired temporally as somatic events, and less commonly, may reveal defects that have been inherited through the germline. Numerous techniques can be utilised to interrogate the tumour genomic landscape, ranging from tried and tested techniques, such as karyotyping, to full mutational analysis using more modern next and third generation technologies. The challenge for the clinician is no longer predominantly in accessing genomic technologies, but rather in interpreting complex reports, and separating relevant clinically actionable mutations from incidental mutations reflective of the damaged DNA repair mechanisms that are intrinsic to the neoplastic process. This may be especially difficult if the mutational spectrum includes variants in less well-studied genes, or in genes not commonly implicated as drivers of the cancer under investigation. Increasing utilisation of genomic profiling of cancers has informed our understanding that the timing of a mutation in a particular gene is as relevant as the gene in which it occurs in determining the neoplastic course. Once the key driver mutations in a cancer have been identified, the next challenge is to find and utilise an appropriate agent that targets the specific defect. Many hundreds of targeted agents have been designed and put through rigorous in vitro and phase 1 or even phase 2 trials, but few have made it into routine clinical use to date. In this review, we discuss the underlying mechanisms of genomic changes and mutational signatures that can be potentially targeted for therapeutic benefit, and some successful targeted agents that have been developed to date.

A discrete event simulation to evaluate the cost effectiveness of germline BRCA1 and BRCA2 testing in UK women with ovarian cancer

Objectives The objective of this study was to evaluate the long-term cost-effectiveness of germline BRCA1 and BRCA2 (collectively termed ‘BRCA’) testing in women with epithelial ovarian cancer, and testing for the relevant mutation in first and second degree relatives of BRCA mutation-positive individuals, compared with no testing. Female BRCA mutation-positive relatives of ovarian cancer patients could undergo risk-reducing mastectomy and/or bilateral salpingo-oophorectomy. Methods A discrete event simulation model was developed that included the risks of breast and ovarian cancer, the costs, utilities and effects of risk-reducing surgery on cancer rates, and the costs, utilities and mortality rates associated with cancer. Results BRCA testing all women with epithelial ovarian cancer each year is cost-effective at a UK willingness-to-pay threshold of £20,000/QALY compared with no testing, with an ICER of £4,339/QALY. The result was primarily driven by fewer cases of breast (142) and ovarian (141) cancer and associated reductions in mortality (77 fewer deaths) in relatives over the subsequent 50 years. Sensitivity analyses showed that the results were robust to variations in the input parameters. Probabilistic sensitivity analysis showed that the probability of germline BRCA mutation testing being cost-effective at a threshold of £20,000/QALY was 99.9%. Conclusions Implementing germline BRCA testing in all ovarian cancer patients would be cost-effective in the UK. The consequent reduction of future cases of breast and ovarian cancer in relatives of mutation-positive individuals would ease the burden of cancer treatments in subsequent years and result in significantly better outcomes and reduced mortality rates for these individuals.