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.

From ownership to custodianship of tumor biopsy tissue in genomic testing: a mixed methods study of patient views.

Tumor mutation profiling (MP) is often conducted on tissue from biopsies conducted for clinical purposes (diagnostic tissue). We aimed to explore the views of patients with cancer on who should own tumor biopsy tissue, pay for its storage, and decide on its future use; and determine their attitudes to and predictors of undergoing additional biopsies if required for research purposes. In this mixed methods, cross-sectional study, patients with advanced solid cancers enrolled in the Molecular Screening and Therapeutics Program (n = 397) completed a questionnaire prior to undergoing MP (n = 356/397). A subset (n = 23) also completed a qualitative interview. Fifty percent of participants believed they and/or relatives should own and control access to diagnostic tissue. Most (65.5%) believed the government should pay for tissue preparation. Qualitative themes included (1) custodianship of diagnostic tissue, (2) changing value of tissue across time and between cultures, (3) equity regarding payment, and (4) cost-benefit considerations in deciding on additional biopsies. Policy and regulation should consider patient perspectives. Extension of publicly funded health care to include tissue retrieval for clinical trials should be considered.

ASPiRATION: Australian observational cohort study of comprehensive genomic profiling in metastatic lung cancer tissue.

ASPiRATION is a national prospective observational cohort study assessing the feasibility, clinical and economic value of up-front tissue-based comprehensive genomic profiling (CGP) to identify actionable genomic alterations in participants with newly diagnosed metastatic non-squamous non-small-cell lung cancer in Australia. This study will enrol 1000 participants with tumor available for CGP and standard of care molecular testing (EGFR/ALK/ROS1). Participants with actionable variants may receive novel targeted treatments through ASPiRATION-specific substudies, other trials/programs. Clinical outcome data will be collected for a minimum of 2 years. Study outcomes are descriptive, including the ability of CGP to identify additional actionable variants, leading to personalized treatment recommendations, and will describe the feasibility, efficiency, cost and utility of implementation of CGP nationally.

Lung cancer is the most common cause of cancer death in Australia and worldwide. This disease often happens due to alterations in specific genes that allow cancer cells to develop and spread. Scientists have designed targeted drugs that are better at attacking cancer cells that have specific 'actionable' gene alterations and have less effect on other cells in the body. The result is often more benefit from treatment and fewer side effects than other standard treatments (chemotherapy or immunotherapy). The targeted drugs are well established as the best initial treatments for some gene alterations, but more research is needed to know if this is true for some of the less common or recently identified gene alterations, and where the targeted drugs are very new. Comprehensive genomic profiling is a new way of testing lung cancer cells for all the gene alterations (the well-known ones as well as the rare ones) in a single test. It is expected that this test will find many more of these gene alterations, which will allow more people to have safer and more effective targeted treatments leading to potentially better outcomes, and will allow some people to join clinical trials testing newer targeted treatments. The ASPiRATION study will help work out whether comprehensive genomic profiling is better than the current way of testing for gene alterations in Australia, and if it is feasible to use in all people diagnosed with advanced lung cancer in Australia. Clinical Trial Registration: ACTRN12621000221853 (ANZCTR).

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials.

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations.

PURPOSE: To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects. PATIENTS AND METHODS: In total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers. The primary objective of this single-arm Phase II trial was a progression-free survival rate at 6 months (PFS6). Post hoc exploratory analyses were conducted on archival tumour tissue and serial bloods. RESULTS: The PFS6 rate was 35% and 38% with durable objective tumour responses (OTR) in 3(19%) and 3(9%) in groups 1 and 2, respectively. Rare cancers achieving an OTR included cholangiocarcinoma, perivascular epithelioid cell (PEComa), neuroendocrine, gallbladder and endometrial cancer. O + D was safe, with five serious adverse events related to the study drug(s) in 3 (6%) patients. A higher proportion of CD38 high B cells in the blood and higher CD40 expression in tumour was prognostic of survival. CONCLUSIONS: O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers.

Psychological predictors of advanced cancer patients' preferences for return of results from comprehensive tumor genomic profiling.

This study assessed the psychological predictors of preferences for return of comprehensive tumor genomic profiling (CTGP) results in patients with advanced cancers, enrolled in the Molecular Screening and Therapeutics Program. Patients completed a questionnaire prior to undergoing CTGP. Of the 1434 who completed a questionnaire, 96% would like to receive results that can guide treatment for their cancer, and preference for receiving this type of result was associated with lower tolerance of uncertainty. Sixty-four percent would like to receive results that cannot guide treatment, and lower tolerance of uncertainty, self-efficacy, and perceived importance were associated with this preference. Fifty-nine percent would like to receive variants of unknown significance, which was associated with lower tolerance of uncertainty, higher self-efficacy, and perceived importance. Eighty-six percent wanted to receive germline results that could inform family risk. This was associated with higher self-efficacy, perceived importance, and perceived susceptibility. Although most patients wanted to receive all types of results, given the differing patient preferences regarding the return of results depending on the utility of the different types of results, it appears critical to safeguard patient understanding of result utility to achieve informed patient choices. This should be accompanied by appropriate consent processes.

Return of comprehensive tumour genomic profiling results to advanced cancer patients: a qualitative study.

PURPOSE: The introduction of comprehensive tumour genomic profiling (CGP) into clinical oncology allows the identification of molecular therapeutic targets. However, the potential complexity of genomic results and their implications may cause confusion and distress for patients undergoing CGP. We investigated the experience of advanced cancer patients receiving CGP results in a research setting. METHODS: Semi-structured interviews with 37 advanced cancer patients were conducted within two weeks of patients receiving CGP results. Interviewees were purposively sampled based on CGP result, cancer type, age and gender to ensure diversity. Themes were derived from interview transcripts using a framework analysis approach. RESULTS: We identified six themes: (1) hoping against the odds; (2) managing expectations; (3) understanding is cursory; (4) communication of results is cursory; (5) genomics and incurable cancer; and (6) decisions about treatment. CONCLUSION: Despite enthusiasm regarding CGP about the hope it provides for new treatments, participants experienced challenges in understanding results, and acceptance of identified treatments was not automatic. Support is needed for patients undergoing CGP to understand the implications of testing and cope with non-actionable results.

Germline RET variants underlie a subset of paediatric osteosarcoma.

BACKGROUND: Although considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone. METHODS AND RESULTS: We followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1, suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma. CONCLUSIONS: After Li-Fraumeni-predisposing mutations in TP53, RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures.

Value of whole-genome sequencing to Australian cancer patients and their first-degree relatives participating in a genomic sequencing study.

Genomic Sequencing (GS) to identify high cancer risk will soon enter clinical practice at significant cost to the health system. This study aimed to quantify perceived value of GS to Australian cancer patients and their first-degree relatives participating in a genomic sequencing study, and factors associated with value. Participants were recruited upon consent to the genomics study. Eligible participants (with cancer of likely genetic etiology, or a first-degree relative) completed a questionnaire prior to GS. Willingness to pay was assessed via hypothetical trade-off scenarios of actionable result return rates of 1%, 10%, 20%, 30%, 40% or 50%. Of 348 probands and 213 relatives (92% and 93% response rate), 81% would consistently have GS for as little as a 1% actionable return rate. Participants would pay a median of $1,000 for return rates of at least 20% (probands) or 30% (relatives), and $300 for lower return rates. Probands with common cancers and negative attitudes to uncertainty were more likely to have GS; those with higher education were more willing to pay $1,000 and $3,000 for lower return rates. This study found high interest in, but lower willingness to pay for GS in cancer patients and their first-degree relatives, possibly due to inability to pay. Further research is needed to improve our understanding of how individuals in different risk circumstances, trade-off the risks, harms, and benefits of GS.

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.

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.

BACKGROUND: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. METHODS: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. RESULTS: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. CONCLUSIONS: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.

Optical mapping reveals a higher level of genomic architecture of chained fusions in cancer.

Genomic rearrangements are common in cancer, with demonstrated links to disease progression and treatment response. These rearrangements can be complex, resulting in fusions of multiple chromosomal fragments and generation of derivative chromosomes. Although methods exist for detecting individual fusions, they are generally unable to reconstruct complex chained events. To overcome these limitations, we adopted a new optical mapping approach, allowing megabase-length genome maps to be reconstructed and rearranged genomes to be visualized without loss of integrity. Whole-genome mapping (Bionano Genomics) of a well-studied highly rearranged liposarcoma cell line resulted in 3338 assembled consensus genome maps, including 72 fusion maps. These fusion maps represent 112.3 Mb of highly rearranged genomic regions, illuminating the complex architecture of chained fusions, including content, order, orientation, and size. Spanning the junction of 147 chromosomal translocations, we found a total of 28 Mb of interspersed sequences that could not be aligned to the reference genome. Traversing these interspersed sequences using short-read sequencing breakpoint calls, we were able to identify and place 399 sequencing fragments within the optical mapping gaps, thus illustrating the complementary nature of optical mapping and short-read sequencing. We demonstrate that optical mapping provides a powerful new approach for capturing a higher level of complex genomic architecture, creating a scaffold for renewed interpretation of sequencing data of particular relevance to human cancer.

Germline PALB2 Variants and PARP Inhibitors in Endometrial Cancer.

PARP inhibitors are orally administered antineoplastic agents that affect the homologous recombination (HR) repair pathway, and are approved by the FDA for the treatment of ovarian, breast, pancreatic, and prostate cancers. This report presents a case of recurrent endometrial carcinoma occurring in a woman with a germline pathogenic PALB2 whole-exon deletion. This uncommon finding in a patient with endometrial carcinoma provided the opportunity to use a management strategy of PARP inhibition with olaparib, resulting in a prolonged response to treatment; however, disease progression eventually occurred. Further studies are required to elucidate the mechanisms underlying resistance to PARP inhibition, and the potential future treatment options in this setting. Current recommendations for risk management of female carriers of PALB2 variants focus on breast and ovarian cancer risk. This case raises the additional question of a potential role for risk-reducing hysterectomy in female carriers of PALB2 variants.

Longitudinal patterns in fear of cancer progression in patients with rare, advanced cancers undergoing comprehensive tumour genomic profiling.

INTRODUCTION: Fear of cancer progression (FCP) impacts quality of life and is a prevalent unmet need in patients diagnosed with advanced cancer, particularly as treatment options are reduced. We aimed to identify longitudinal patterns in FCP over 6 months in patients with advanced cancer receiving comprehensive tumour genomic profiling (CTGP) results, and their correlates. METHODS: Patients with pathologically confirmed metastatic disease (∼70% rare cancers) receiving or post their last line of standard therapy completed questionnaires at T0 (prior to CTGP), T1 (immediately post CTGP results) and T2 (2 months later). RESULTS: High stable (N = 52; 7.3%) and low/moderate stable (N = 56; 7.8%) FCP patterns over time typified the largest participant groups (N = 721). Those with an immediately actionable variant versus a non-actionable variant (p = 0.045), with higher FCP (p < 0.001), and lower Functional Assessment of Chronic Illness Therapy-Spiritual Well-being (FACIT-Sp) scores (p = 0.006) at T0, had higher FCP at T1. Those with higher FCP at T0 (p < 0.001) and at T1 (p < 0.001), lower FACIT-Sp scores at T1 (p = 0.001), lower education (p = 0.031) and female gender (p = 0.027) had higher FCP at T2. DISCUSSION: Routine screening for psychological/spiritual characteristics in those about to undergo CTGP may help to identify patients who may benefit from closer monitoring and provision of psychosocial support. Future studies should explore interventions to best address FCP in this vulnerable group, as interventions assessed to date have almost all addressed patients with curative cancers or newly diagnosed advanced disease.

Fear of cancer recurrence in patients undergoing germline genome sequencing.

PURPOSE: Fear of cancer recurrence/occurrence (FCR/O) is prevalent and associated with poorer psychological outcomes but can also motivate individuals to pursue genomic information about cancer risk. Guided by Protection Motivation Theory, this study investigated FCR/O prevalence and associated factors among probands previously diagnosed with a cancer of likely heritable origin, and their relatives, who had agreed to have germline genome sequencing. METHODS: Three hundred and forty-eight probands and 167 relatives completed the Concerns about Recurrence Questionnaire (adapted for occurrence for some relatives) within 1 month of agreeing to undertake genome sequencing. Linear regressions investigated demographic, disease, attitude and behavioral associations with FCR/O. RESULTS: Probands demonstrated greater FCR compared to relatives. In probands, greater FCR was associated with being female, non-English speaking at home, less time since diagnosis, greater intention to change behavior if gene variant found, lower perceived ability to cope with results, higher perceived susceptibility to having a recurrence, and more negative attitudes towards uncertainty. For relatives with cancer, greater FCR was associated with being male, greater intention to change behavior if a gene variant found, and higher perceived susceptibility to recurrence. In relatives without cancer, greater FCO was associated with not having had genetic testing prior to this study, lower perceived ability to cope with results, and higher perceived susceptibility to developing cancer. CONCLUSION: Current findings on FCR/O prevalence and associated demographic and attitudinal variables in those who pursue genomic risk information might be used to target interventions that can prevent adverse psychological outcomes in vulnerable patients.

Cancer patients' views and understanding of genome sequencing: a qualitative study.

BACKGROUND: Little is known about knowledge of, and attitudes towards, genome sequencing (GS) among individuals with a personal history of cancer who decide to undergo GS. This qualitative study aimed to investigate baseline knowledge and attitudes among individuals previously diagnosed with a cancer of likely genetic origin who have consented to GS. METHODS: Semistructured interviews were conducted with purposively selected participants (n=20) from the longitudinal Psychosocial Issues in Genomic Oncology study, within a month of consenting to GS and prior to receiving any results. Participants were adults with a cancer of likely genetic aetiology who are undertaking GS as part of a larger genetic study. RESULTS: Analysis identified three main themes: limited understanding of genomics; multifactorial motivation; and complex decision making. While motivations such as obtaining health information about self and family appear to be the main drivers for undertaking GS, these motivations are sometimes based on limited knowledge of the accuracy and utility of GS, creating unrealistic expectations. This in turn can prolong the deliberation process and lead to ongoing decisional conflict. CONCLUSION: Understanding the degree and nature of patient understanding of GS, as well as their attitudes and decision-making processes, will enable healthcare professionals to better manage patient expectations and appropriately engage and support patients to make an informed decision when pursuing GS.

Influence of lived experience on risk perception among women who received a breast cancer polygenic risk score: 'Another piece of the pie'.

Polygenic risk scores (PRS) are personalized assessments of disease risk based on the cumulative effect of common low-risk genetic variants. PRS have been shown to accurately predict women's breast cancer risk and are likely to be incorporated into personalized breast cancer risk management programs. However, there are few studies investigating the individual impact of receiving a breast cancer PRS. Existing studies have not demonstrated significant changes in perceived risk or risk management behaviors after receipt of polygenic risk information. The aim of this qualitative study was to explore how women with a family history of breast cancer construct breast cancer risk perceptions after receipt of a breast cancer PRS. Unaffected women with a family history of breast cancer who had not previously received genetic counseling regarding their breast cancer risk were invited to participate in this study. In-depth, semi-structured interviews were conducted with 20 women who attended a familial cancer clinic in the Australian states of Victoria and Tasmania. Data were analyzed using an inductive thematic approach. Women's lived experience played a significant role in the construction and maintenance of their breast cancer risk perception. Women's pre-existing risk perceptions were informed by their family history and their knowledge that breast cancer is a multifactorial disease. Knowing that breast cancer is a multifactorial disease enabled most women to integrate genetic information with their pre-existing notions of risk. Women reported that the information they received was consistent with their existing notions of personal risk and screening advice. Therefore, the PRS did not lead to a change in perceived risk or risk management behaviors for most women. The results of this study provide insight into how polygenic risk information is integrated with pre-existing notions of risk, which will inform its implementation into clinical practice.

Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial.

BACKGROUND: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection. METHODS: This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369. FINDINGS: Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27-53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy. INTERPRETATION: Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery. FUNDING: Daiichi Sankyo.

Who should access germline genome sequencing? A mixed methods study of patient views.

Implementation of any new medical test, including germline genome sequencing (GS) to inform cancer risk, should take place only when a test is effective, ethically justifiable and acceptable to a population. Little empirical evidence exists on patient views regarding GS for cancer risk. The aim of this study was to elicit opinions on who should be offered GS and who should pay for it. Participants with a probable genetic basis for their cancer (n = 335) and blood relatives (n = 199) were recruited to undergo GS and invited to complete questionnaires at baseline. A subset (n = 40) also participated in qualitative interviews about their views regarding access to GS to detect cancer risk. Our response rate was 92% for questionnaires and 100% for interviews. Participants expressed high enthusiasm overall for access to GS for those with a family history of cancer and anyone who requested testing, but enthusiasm was lower for universal access, if opting out was possible and finances not an issue. Rationales for these views reflected maximising the sound use of resources. Challenges to introducing community screening via GS to limit cancer burden were raised, including the current limits of science and individual ability to cope with uncertain results. Participants undergoing GS supported cancer risk testing for those with a family history of cancer but were concerned about the challenges of designing and implementing a population-based GS cancer-screening program.

Translating genomic risk into an early detection strategy for sarcoma.

Sarcomas have a strong genetic etiology, and the study of families affected by sarcomas has informed much of what we now understand of modern cancer biology. The recent emergence of powerful genetic technologies has led to astonishing reductions in costs and increased throughput. In the clinic, these technologies are revealing a previously unappreciated and rich landscape of genetic cancer risk. In addition to both known and new cancer risk mutations, genomic tools are cataloguing complex and polygenic risk patterns, collectively explaining between 15-25% of apparently sporadic sarcoma cases. The impact on clinical management is exemplified by Li-Fraumeni Syndrome, the most penetrant sarcoma syndrome. Whole body magnetic resonance imaging can identify surgically resectable cancers in up to one in ten individuals with Li-Fraumeni Syndrome. Taken together, parallel developments in genomics, therapeutics and imaging technologies will drive closer engagement between genetics and multidisciplinary care of the sarcoma patient in the 21st century.