Modified study designs to expand treatment options in personalised oncology: a multistakeholder view.

Personalised oncology, whereby patients are given therapies based on their molecular tumour profile, is rapidly becoming an essential part of optimal clinical care, at least partly facilitated by recent advances in next-generation sequencing-based technology using liquid- and tissue-based biopsies. Consequently, clinical trials have shifted in approach, from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to modified, biomarker-driven studies (e.g. basket, umbrella, platform) of molecularly guided therapies and cancer immunotherapies in selected patient subsets. Such modified study designs may assess, within the same trial structure, multiple cancer types and treatments, and should incorporate a multistakeholder perspective. This is key to generating complementary, fit-for-purpose and timely evidence for molecularly guided therapies that can be used as proof-of-concept to inform further study designs, lead to approval by regulatory authorities and be used as confirmation of clinical benefit for health technology assessment bodies. In general, the future of cancer clinical trials requires a framework for the application of innovative technologies and dynamic design methodologies, in order to efficiently transform scientific discoveries into clinical utility. Next-generation, modified studies that involve the joint efforts of all key stakeholders will offer individualised strategies that ultimately contribute to globalised knowledge and collective learning. In this review, we outline the background and purpose of such modified study designs and detail key aspects from a multistakeholder perspective. We also provide methodological considerations for designing the studies and highlight how insights from already-ongoing studies may address current challenges and opportunities in the era of personalised oncology.

Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare.

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Effective and Efficient Delivery of Genome-Based Testing-What Conditions Are Necessary for Health System Readiness?

Health systems internationally must prepare for a future of genetic/genomic testing to inform healthcare decision-making while creating research opportunities. High functioning testing services will require additional considerations and health system conditions beyond traditional diagnostic testing. Based on a literature review of good practices, key informant interviews, and expert discussion, this article attempts to synthesize what conditions are necessary, and what good practice may look like. It is intended to aid policymakers and others designing future systems of genome-based care and care prevention. These conditions include creating communities of practice and healthcare system networks; resource planning; across-region informatics; having a clear entry/exit point for innovation; evaluative function(s); concentrated or coordinated service models; mechanisms for awareness and care navigation; integrating innovation and healthcare delivery functions; and revisiting approaches to financing, education and training, regulation, and data privacy and security. The list of conditions we propose was developed with an emphasis on describing conditions that would be applicable to any healthcare system, regardless of capacity, organizational structure, financing, population characteristics, standardization of care processes, or underlying culture.

Challenges of Conducting Value Assessment for Comprehensive Genomic Profiling.

OBJECTIVES: Clinical practice is shifting toward an era of precision medicine. The use of comprehensive genomic profiling (CGP) in oncology has broad potential as a universal companion diagnostic for targeted therapies which may significantly improve health outcomes while using healthcare resources more efficiently. Given the nature of this technology, assessing the value of CGP presents unique challenges. METHODS: This paper draws on evidence from the academic and policy literature in oncology, as well as stakeholder interviews (health economists, payers, clinicians, and public policy officials) in countries using incremental cost-effectiveness ratios (ICER) as part of health technology assessment (HTA). RESULTS: The degree to which CGP is subject to a value assessment varies significantly across healthcare systems. Current HTA processes focus on evaluating diagnostic testing through co-dependent assessment of diagnostic testing and associated therapeutic interventions. Diagnostic tests with multiple associated therapeutic interventions are rapidly evolving and poorly unsuited to current HTA approaches. Moreover, HTA approaches are limited in their ability to consider broader systemic benefits of the expanded diagnostic capabilities and enhanced opportunities for clinical trial participation offered by CGP. CONCLUSIONS: The assessment of the overall value of CGP is limited by the current models of HTA. This paper suggests policy proposals for value assessment and funding reforms to help broaden patient access to CGP. These include investing in genomic testing infrastructure; decoupling the assessment of the value of CGP testing to identifying predetermined therapeutic interventions; tailoring evaluation methodology; and developing approaches to collecting evidence of clinical, healthcare system and societal benefit.

Unlocking Access to Broad Molecular Profiling: Benefits, Barriers, and Policy Solutions.

OBJECTIVES: "Personalized healthcare" is generating new approaches to disease management by considering inter-individual variability in genes, environment, and lifestyle. Technologies such as comprehensive genomic profiling (CGP) are drivers of this shift. Here, we address the significant hurdles to the equitable implementation of CGP into routine clinical practice. METHODS: This article draws on published evidence on the value of genomic profiling, as well as interviews with nine academic and clinical experts from six different countries to validate findings and test policy proposals for reforms. RESULTS: The potential benefits of CGP extend beyond direct patient outcomes, to healthcare systems with societal and economic impacts. Among key barriers impeding integration into routine clinical practice are the lack of infrastructure to ensure reliable clinical testing and the limited understanding of genomics among healthcare personnel. In addition, the absence of health economic evidence supporting broader use of CGP is creating concerns for payers regarding the systemic benefits and affordability of this technology. CONCLUSION: Policy proposals that aim to improve equitable patient access to CGP will need to consider new funding models, health technology assessment processes that capture both patient and systemic benefits, and appropriate regulatory standards to determine the quality of genomic profiling tests.

Suicide Assessment and Management Team-Based Learning Module.

Introduction: Suicide is a global health problem that health care providers must feel comfortable addressing. Unfortunately, many health care providers are not equipped to assess and treat patients at risk for suicide due to lack of training and education. Interactive resources are needed to educate health professions students about the management of suicidal patients. Methods: The suicide assessment and management team-based learning (TBL) module was developed to address the gap in suicide education. After completing the module, students were able to identify key elements for a comprehensive assessment of a patient's risk for suicide and to discuss clinical management for a suicidal patient. The activity was designed for second-year medical students during a psychopathology course, the last organ-system course prior to clerkships. This module could also be used or modified to meet the educational requirements for other health professions, including medical residents, nurse practitioner students, and physician assistant students. Results: A total of 342 students among 62 teams participated in the TBL over a period of 3 consecutive years. The class averages for the individual Readiness Assurance Test ranged from 80% to 88%. The class averages for the team Readiness Assurance Test and application questions were comparable across all 3 years. Course evaluations showed the TBL helped students think critically and integrate information to prepare them for their future careers. Discussion: Overall, this TBL was an effective educational tool that stimulated high-quality discussion, in which students remained engaged and asked thought-provoking questions.

Assessment of the Value of Tumor Variation Profiling Perceived by Patients With Cancer.

Importance: Use of tumor molecular profiling (MP) is entering routine clinical practice; however, little is known about how much and why patients value MP. Objective: To examine the perceived value of MP to patients with advanced cancer and factors associated with perceived value. Design, Setting, and Participants: A cross-sectional survey that included willingness-to-pay trade-off scenarios was administered to participants after consent and before MP. A total of 777 participants (94% response rate) were recruited from the Molecular Screening and Therapeutics Program. Eligible patients had advanced solid cancers of any histologic type, were receiving or had completed their last line of effective therapy, had an Eastern Cooperative Oncology Group Performance Status 0 to 3, and had sufficient accessible tissue for MP. The participants were recruited between October 24, 2017, and March 12, 2019, and data analysis was conducted from March 13 to April 14, 2019. Main Outcomes and Measures: Willingness to pay for MP was assessed via hypothetical trade-off scenarios varying in the actionable return rate (1%, 20%, or 40%) and cost (A$0, A$300 [US$210], A$1000 [US $700], A$3000 [US $2100], or A$10 000 [US $7000]). Ordinal regressions were used to explore factors associated with willingness to have and pay for MP. Results: Of 777 participants (405 women [52%]; mean [SD] age, 55.47 [14.26] years), 689 patients (89%) would have MP for as little as a 1% actionable return rate. Fifty-six patients (7%) would require at least a 20% return rate and 11 patients (1%) would require at least a 40% return rate. Fifteen patients (2%) consistently chose not to have the test; 6 participants (0.8%) had missing values on this item. Participants were willing to pay a median of A$1000 if the actionable return rate was 1% and A$3000 for an actionable return rate of 20% to 40%. Of 762 individuals who agreed to testing, 482 patients (64%) were consistently unwilling to pay A$10 000, regardless of the actionable return rate. Patients born in Australia or New Zealand were more likely to want MP (eg, participants born in South Asia had an ordered odds for the tipping point of 7.74 [95% CI, 1.67-36.05; P = .009] times higher than Australian- and/or New Zealand-born participants). Patients born in Australia or New Zealand were also more willing to pay A$1000 or A$3000 (eg, participants born in Western Europe had an ordered odds for the tipping point for paying A$1000 of 1.74 [95% CI, 1.01-3.00; P = .048] times higher than Australian- and/or New Zealand-born participants). People with a medical- or science-related occupation and with more negative attitudes toward uncertainty were more likely to pay A$10 000 (eg, A$10 000 tipping point-ordered odds of participants with a medical- or science-related occupation was 0.49 [95% CI, 0.7-0.87; P = .02] times that of participants without a medical- or science-related occupation). Conclusions and Relevance: This study found apparent high interest in but lower willingness to pay for MP among patients with advanced cancer. Ability to pay may limit access to MP. Ongoing societal debate is required to establish the value of MP and whether subsidization is needed to ensure equity of access.

Surveillance recommendations for patients with germline TP53 mutations.

PURPOSE OF REVIEW: Li-Fraumeni syndrome is associated with germline TP53 mutations and carriers have a high lifetime risk of cancer, the most common being sarcoma, breast cancer, brain tumors, adrenocortical carcinoma and leukemia. Germline TP53 mutation carriers are increasingly being identified as more genomic sequencing is performed in both clinical and research settings. There is a pressing clinical need for effective cancer risk management approaches in this group. RECENT FINDINGS: Current clinical surveillance guidelines mainly focus on breast and bowel cancer risk with little consideration for the other cancers common to the syndrome. Imaging technologies are such that the utilization of whole-body MRI imaging for surveillance is viable. Globally, several research groups have included whole-body MRI along with other diagnostic measures in formulating surveillance protocols for TP53 mutation carriers. Early reports suggest a survival benefit. SUMMARY: Surveillance protocols for TP53 mutation carriers have the potential to improve outcomes in individuals and families. Further research is needed to guide the development of an effective and comprehensive surveillance schedule.

Li-Fraumeni syndrome: cancer risk assessment and clinical management.

Carriers of germline mutations in the TP53 gene, encoding the cell-cycle regulator and tumour suppressor p53, have a markedly increased risk of cancer-related morbidity and mortality during both childhood and adulthood, and thus require appropriate and effective cancer risk management. However, the predisposition of such patients to multiorgan tumorigenesis presents a specific challenge for cancer risk management programmes. Herein, we review the clinical implications of germline mutations in TP53 and the evidence for cancer screening and prevention strategies in individuals carrying such mutations, as well as examining the potential psychosocial implications of lifelong management for a ubiquitous cancer risk. In addition, we propose an evidence-based framework for the clinical management of TP53 mutation carriers and provide a platform for addressing the management of other cancer predisposition syndromes that can affect multiple organs.

Multiomics medicine in oncology: assessing effectiveness, cost-effectiveness and future research priorities for the molecularly unique individual.

The development of genomic technologies has ushered in the era of pharmacogenomics. However, discoveries and clinical use of targeted therapies are still in their infancy. A focus on monogenic pharmacogenetic traits may contribute to this lack of progress. Variation in drug response is likely a complex paradigm involving not only genomic factors but proteomic, metabolomic and epigenomic influences. The incorporation of these omics elements into pharmaceutical development and clinical decision-making will ultimately require the use of methods to determine clinical and economic value. Current methodologies and guidelines for determining clinical effectiveness and cost-effectiveness may have limited applicability to the increasingly personalized nature of omics treatment strategies. Using examples from oncology, this article argues for the adaptation and tailoring of three existing methods for ensuring development and clinical use of multiomics-guided therapies that are effective, safe and offer value for money.

The relationship between unmet needs and distress amongst young people with cancer.

PURPOSE: Most psychosocial research in cancer has been restricted to paediatric or older adult populations. This study aimed to explore psychological distress and unmet needs in adolescents and young adults (AYA) with cancer and identify predictors of distress among demographic and illness characteristics and supportive care needs. METHODS: Fifty-three patients between 16 and 30 years completed a cross-sectional survey, administered shortly after presentation to an AYA oncology service and within 4 months of diagnosis. Measures included the Beck Depression Inventory-Fast Screen (BDI-FS), State-Trait Anxiety Inventory-State Form (STAI-S) and the Supportive Care Needs Survey. Level of distress-related sypmtomatology in this population was based on previous work, whereby a cut-off score of 4 or greater was used for the BDI-FS, and one standard deviation above the sample population mean was used for the STAI-S. RESULTS: Prevalence of distress (25%) was lower than that found previously in AYA with cancer. Physical and daily living needs were the most frequently unmet needs overall, followed by psychological needs, health system and information needs and care and support needs. Lastly, being pre-treatment predicted increased depression and state anxiety, while having treatment post-surgery predicted reduced state anxiety. After controlling for treatment status, however, the main predictors of depression and state anxiety were physical and daily living needs and health system and information needs, respectively. CONCLUSIONS: Lower levels of distress and unmet psychological needs were related to the few participants (17%) in this study who were pre-treatment, when distress was most likely. However, physical needs and information needs, which are almost inevitable throughout treatment and beyond, were more important predictors of distress. Further exploration must consider the psychosocial difficulties underlying this association and the needs of AYA at transitions between critical periods in their cancer journey (i.e., upon diagnosis, during treatment, etc.).