Desmoid tumours are rare locally invasive soft tissue neoplasms arising from mesenchymal tissue that lack metastatic potential but have a high propensity for local recurrence. For unresectable mesenteric desmoid tumours requiring systemic therapy, the therapeutic landscape spans anti-hormonal combinations, chemotherapy, tyrosine kinase inhibitors, and gamma-secretase inhibitors. Imatinib is a multi-target tyrosine kinase inhibitor targeting PDGFR-alpha/beta and c-KIT that has demonstrated clinical activity in desmoid tumours with a favourable toxicity profile. We present a case of a 27-year-old white Australian man who presented with a large abdominal mass and weight loss. Imaging revealed a 23 × 12 × 21 cm mass that was diagnosed as a desmoid tumour via biopsy. The tumour was deemed to be unresectable and radiotherapy was considered to carry an unacceptable risk of toxicity. Initial treatment with tamoxifen and sulindac was unable to halt disease progression. The patient was subsequently commenced on imatinib 400 mg daily. Imaging after four months showed partial response, and over six years, complete radiological remission was achieved despite intermittent medication compliance. Aside from one episode of grade 1 photosensitivity, no significant toxicities were observed. Imatinib was self-ceased after ten years of treatment, and the patient remains disease-free at eleven years post-diagnosis under active surveillance. We describe a case of complete and durable remission achieved with imatinib monotherapy in an unresectable mesenteric desmoid tumour with the patient remaining disease-free at 10 years. This case highlights the potential for long-term complete response and underscores the need for prospective data to guide treatment duration and cessation criteria.

Astrocytoma is a highly malignant tumor of the central nervous system with limited survival, despite standard multimodal therapies. While typically remains confined to the central nervous system, rare instances of extraneural and extracranial metastasis have been documented. The underlying pathophysiology remains poorly understood, with very few reported cases—particularly in tumors harboring isocitrate dehydrogenase mutations. We describe the case of a 21-year-old female New Zealander of European descent with O6-methylguanine-DNA methyltransferase promoter-methylated, IDH1-R132H-mutant astrocytoma (World Health Organization 2021 central nervous system grade 4) containing a primitive neuroectodermal tumor-like component, which exhibited diffuse skeletal and leptomeningeal metastases. This case represents an unusual presentation of extraneural and extracranial metastatic spread in a young female New Zealander of European descent with an isocitrate dehydrogenase-mutant astrocytoma. Compared with recent literature, it is notable for early systemic dissemination and the coexistence of bone and leptomeningeal disease. A multidisciplinary discussion concluded that additional biopsy of metastatic sites was unwarranted owing to clear pathological correlation, clinical decline, and poor prognosis. Molecular characteristics such as cyclin-dependent kinase inhibitor 2A/2B deletion may further refine classification. A review of current literature underscores the importance of the 2021 World Health Organization classification updates and highlights potential roles for epithelial–mesenchymal transition and glymphatic dissemination in metastasis. Targeted therapies—particularly isocitrate dehydrogenase inhibitors—are under active investigation. This case reinforces the need for ongoing research into predictive biomarkers and individualized treatment strategies.

People with malignancy of undefined primary origin (MUO) have a poor prognosis and may undergo a protracted diagnostic workup causing patient distress and high cancer related costs. Not having a primary diagnosis limits timely site-specific treatment and access to precision medicine. There is a need to improve the diagnostic process, and healthcare delivery and support for these patients. This trial aims to implement and evaluate an optimal model of care for people presenting with MUO to reduce time to diagnosis, improve patient experiences and reduce healthcare costs. This is a pragmatic stepped-wedge cluster randomised trial comparing a control phase of standard practice with an intervention phase. Patient inclusion criteria are: 1) age 18 years or older, 2) presenting with suspected metastatic malignancy without an obvious primary site on imaging, 3) clinically appropriate to undergo diagnostic work-up and 4) able to provide written or verbal consent. The intervention is a new model of care comprising four key components: standardised diagnostic workup, dedicated cancer care coordinators, virtual multidisciplinary meetings and a website resource for patients, carers and clinicians. The primary endpoint is the time to completion of minimum diagnostic workup. Secondary outcomes are whether the type of tumour is diagnosed, clinical trial participation, referral to palliative care, patient-reported physical, social and mental health, patient-reported understanding and uncertainty. Implementation outcomes include acceptability, feasibility, fidelity and adoption and health care use and costs. Intervention implementation will be supported using clinical leadership, education and reinforcement. Patients who consent to having their data collected will receive the model of care active at the site at the time of recruitment. Patients will complete a patient-reported outcomes questionnaire four months after study enrolment. A health economic analysis will be included. Across 15 hospitals, a total sample size of 240 is planned. There is a lack of intervention research for people presenting with MUO. The stepped-wedge design seeks to mitigate the potential challenge of enrolling people with a poor prognosis and high symptom burden in trials. This research will generate important evidence with scalability for future research at trial completion. ACTRN12622001504707

Genomics can inform both tissue-of-origin (TOO) and precision treatments for patients with cancer of unknown primary (CUP). Here, we use whole genome and transcriptome sequencing (WGTS) for 72 patients and show diagnostic superiority of WGTS over panel testing (386-523 genes) in 71 paired cases. WGTS detects all reportable DNA features found by panel as well as additional mutations of diagnostic or therapeutic relevance in 76% of cases. Curated WGTS features and a CUP prediction algorithm (CUPPA) trained on WGTS data of known cancer types informs TOO in 71% of cases otherwise undiagnosed by clinicopathology review. WGTS informs treatments for 79% of patients, compared to 59% by panel testing. Finally, WGS of cell-free DNA (cfDNA) from patients with a high cfDNA tumour fraction (>7%), enables high-likelihood CUPPA predictions in 41% of cases. WGTS is therefore superior to panel testing, broadens treatment options, and is feasible using routine pathology samples and cfDNA.

AbstractIntroductionThere are limited data on chest computed tomography (CT) findings in the assessment of lung nodules among adult Aboriginal Australians. In this retrospective study, we assessed lung nodules among a group of adult Aboriginal Australians in the Northern Territory of Australia.MethodsPatients who underwent at least two chest CT scans between 2012 and 2020 among those referred to undergo lung function testing (spirometry) were included. Chest CT scans were assessed for the number, location, size and morphological characteristics of lung nodules.ResultsOf the 402 chest CTs assessed, 75 patients (18.7%) had lung nodules, and 57 patients were included in the final analysis with at least two CT scans available for assessment over a median follow‐up of 87 weeks. Most patients (68%) were women, with a median age of 58 years and smoking history in 83%. The majority recorded only a single nodule 43 (74%). Six patients (10%) were diagnosed with malignancy, five with primary lung cancer and one with metastatic thyroid cancer. Of the 51 (90%) patients assessed to be benign, 64 nodules were identified, of which 25 (39%) resolved, 38 (59%) remained stable and one (1.8%) enlarged on follow‐up. Nodules among patients with malignancy were typically initially larger and enlarged over time, had spiculated margins and were solid, showing no specific lobar predilection.ConclusionsMost lung nodules in Aboriginal Australians are likely to be benign. However, a proportion could be malignant. Further prospective studies are required for prognostication and monitoring of lung nodules in this population.

BACKGROUND:Use of immune checkpoint inhibitors is growing, but clinical trial data may not apply to Indigenous patients or patients living in remote areas. AIMS:To provide real-world incidence of immune-related adverse events (irAE) in the Top End of the Northern Territory and compare incidence between demographic subgroups. METHODS:This retrospective, observational, cohort study collected data from electronic records of patients living in the Top End with solid organ cancer treated with immunotherapy between January 2016 and December 2021. The primary outcome was cumulative incidence of any-grade and severe irAE. Secondary outcomes were overall survival, treatment duration and reason for treatment discontinuation. RESULTS:Two hundred and twenty-six patients received immunotherapy. Forty-eight (21%) lived in a remote or very remote area, and 36 (16%) were Indigenous. Cumulative incidence of any-grade irAE was 54% (122/226 patients); incidence of severe irAE was 26% (59/226 patients). Rates were similar between Indigenous and non-Indigenous patients of any-grade (42% vs 56%, P = 0.11) and severe (11% vs 18%, P = 0.29) irAE. However, Indigenous patients had shorter treatment duration, more frequently discontinued treatment due to patient preference and appeared to have shorter median overall survival than non-Indigenous patients (17.1 vs 30.4 months; hazard ratio (HR) = 1.5, 95% confidence interval (CI) = 0.92-2.66). There was no difference in mortality between remote and urban patients (median overall survival 27.5 vs 30.2 months; HR = 1.1, 95% CI = 0.7-1.7). CONCLUSIONS:Rates of irAE in our cohort are comparable to those in the published literature. There was no significant difference in any-grade or severe irAE incidence observed between Indigenous and non-Indigenous patients.

AimIndigenous Australians with lung cancer have poorer survival than non-Indigenous Australians. The reasons for the disparity are not fully understood and this study hypothesized that there may be a difference in the molecular profiles of tumors. The aim of this study, therefore, was to describe and compare the characteristics of non-small cell lung cancer (NSCLC) in the Northern Territory's Top End, between Indigenous and non-Indigenous patients, and describe the molecular profile of tumors in the two groups. MethodsA retrospective review was conducted of all adults with a new diagnosis of NSCLC in the Top End from 2017 to 2019. Patient characteristics assessed were Indigenous status, age, sex, smoking status, disease stage, and performance status. Molecular characteristics assessed were epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B (BRAF), ROS proto-oncogene 1 (ROS1), Kirsten rat sarcoma viral oncogene homolog (KRAS), mesenchymal-epithelial transition (MET), human epidermal growth factor receptor 2 (HER2), and programmed death-ligand 1 (PD-L1). Student's t-test and Fisher's Exact Test were used in the statistical analysis. ResultsThere were 152 patients diagnosed with NSCLC in the Top End from 2017-2019. Thirty (19.7%) were Indigenous and 122 (80.3%) were non-Indigenous. Indigenous patients compared to non-Indigenous patients were younger at diagnosis (median age 60.7 years versus 67.1 years, p = 0.00036) but were otherwise similar in demographics. PD-L1 expression was similar between Indigenous and non-Indigenous patients (p = 0.91). The only mutations identified among stage IV non-squamous NSCLC patients were EGFR and KRAS but testing rates and overall numbers were too small to draw conclusions about differences in prevalence between Indigenous and non-Indigenous patients. ConclusionThis is the first study to investigate the molecular characteristics of NSCLC in the Top End.

e18841 Background: Immune checkpoint inhibitors (ICI) have transformed the oncological landscape, but are associated with immune-related adverse events (irAE) of varying frequency and severity. This regional single-centre experiential study evaluates the real-world incidence of irAE in patients in the Top End of the Northern Territory of Australia. The Top End represents a diverse population with high proportions of Aboriginal and Torres Strait Islander (ATSI) patients and patients living in remote and very remote areas. This captured cohort is under-represented in clinical trials. Methods: We identified all patients with solid tumours who were prescribed ICI between January 2016 and December 2021. We manually reviewed electronic and paper hospital records to record patient characteristics, treatments received, irAE, irAE treatment and patient outcomes. Results: 226 patients across 11 solid tumour streams received ICI. Of these, 58% had lung cancer, 27% melanoma, 5% head & neck cancer, 4% renal cell carcinoma, and the remainder other tumour streams. 70% were male and the median age at diagnosis was 63 years [28-84 years]. 16% identified as ATSI(compared to 2.8% ATSI nation-wide and 26.3% ATSI in the Northern Territory). Of the investigational cohort, 13% were treated in the adjuvant and 87% in the palliative setting. 11% received combination versus 89% single-agent ICI. 30% of patients had concurrent chemotherapy. 122 patients (54%) experienced any grade irAE as documented by the treating oncologist in the medical records. 59 patients (26%) had a severe (grade 3, 4, or 5) irAE. The fatality rate was 0.88% (2 patients); both were treated with a PD-L1 inhibitor for non-small cell lung cancer (NSCLC) and diagnosed with immune-related pneumonitis. The most common irAE were rash (18%), colitis (16%), arthralgia/myalgia (13%), pneumonitis (12%), thyroiditis/hypothyroidism (12%), hepatitis (9%), and adrenal insufficiency (7%). 24% of irAE required hospitalisation and 32% led to discontinuation of treatment. The median number of irAE per patient was 1. Among patients with the most common tumour types (melanoma and NSCLC), rates of irAE were, in both cases, 59% any grade irAE and 20% severe irAE. When compared to published literature, real-world rates of any grade adverse event were significantly lower than reported number in trials – likely due to exclusion of common non-immune-related adverse events in our data set. Rates of severe and fatal irAE were in line with published data. Conclusions: Immune-related adverse events are common among patients in the Top End and reflect rates in the published literature. We did not identify any safety concerns in our cohort of patients – including amongst ATSI patients and those living in remote and very remote areas. Further data analysis is needed to assess frequency and severity of irAE by specific tumour type and ICI.

BACKGROUND:There is a disparity in health outcomes between indigenous and nonindigenous Australians, with higher chronic disease burden and shorter life expectancy in this minority population. Although rates of breast cancer among indigenous women are lower than nonindigenous women, they face a higher breast cancer-associated mortality, which may not entirely be explained by socio-economic disadvantage. METHODS:This retrospective cohort study investigated previously described pathologic prognostic factors in indigenous Australians in the Northern Territory. RESULTS:Data analyzed confirmed that indigenous women were more likely to have poorer prognostic disease features, including ER/PR negative and human epidermal growth factor receptor 2 amplified tumors, larger tumors, and higher stage disease. CONCLUSION:These pathologic features portend to a poor prognosis, raising the possibility these factors contribute to the disparity in health outcomes between indigenous and nonindigenous women with breast cancer, in addition to known socio-economic factors.

Background Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs. Methods Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed. Results A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p<0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease. Conclusions A significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.

This study aimed to determine the healthcare experiences, quality of life, and psychosocial needs of patients with cancer of unknown primary (CUP) early after diagnosis; comparing their experiences to patients with advanced cancer of a known primary (non-CUP control patients) and published general population reference data where available. This study was a cross-sectional, multi-site study comparing CUP patients (n = 139) compared to non-CUP controls (n = 45). Demographic, clinical information and patient-reported outcome questionnaire data were collected at baseline. Differences in healthcare experienced were found between CUP and non-CUP controls with CUP patients reporting higher scores for unmet medical communication/information needs compared with non-CUP control patients (p = 0.013) as well as greater uncertainty in illness (p = 0.042). Whilst no differences were found between CUP and non-CUP controls on the EORTC and PROMIS measures, of those that ‘received written information about your cancer…’ and asked ‘…how useful was it?’ fewer CUP patients reported finding the information useful 40% vs 61%, and more were likely to not have received written information at all 59% vs 32%; (p = 0.002). Additionally, of those that found information about their cancer online, fewer patients with CUP reported finding it useful 32% vs 48% control patients (p = 0.005). CUP patients have unmet medical communication/information needs and greater uncertainty in illness but do not differ in health-related quality of life domains compared to patients with advanced cancer of a known primary.

Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18‐class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high–medium confidence predictions. Classification performance was similar in clinicopathology‐resolved CUPs – 80% had high–medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology‐unresolved CUPs had high–medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology‐unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one‐third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Background Paraneoplastic neurological syndrome is an immune-mediated phenomenon where antibodies from tumor cells are produced against neuronal proteins. Amphiphysin antibody is an onconeural antibody linked to the diagnosis of breast cancer and small-cell lung cancer. It is uncommon and typically associated with stiff-person syndrome, of which 90% of patients are eventually diagnosed with breast cancer. Case presentation We present a case of a 47-year-old Caucasian woman with metastatic hormone receptor-positive breast cancer who developed bilateral facial nerve palsy while on treatment with nab-paclitaxel. The patient was found to have anti-amphiphysin antibody in the serum and cerebrospinal fluid. She was treated with methylprednisolone and intravenous immunoglobulin, which resulted in partial improvement in her facial nerve palsy. Conclusions This case highlights a rare presentation of bilateral facial nerve palsy that likely related to paraneoplastic syndrome associated with the presence of anti-amphiphysin antibody.

e15252 Background: Cancer of unknown primary (CUP) is a metastatic cancer where the primary tissue of origin (ToO) evades detection despite extensive clinical investigation. Recent approaches to the management of CUP have involved gene-expression profiling to resolve the likely ToO and mutational profiling to identify targeted treatments. Current evidence is that both of these methods can have some clinical benefit but only in a minority of cases. Immunotherapy may also be effective in CUP, but clinical trials looking at this are yet to report and the best way to select patients who may benefit is uncertain. Methods: Through a national cohort study called Solving Unknown Primary Cancer (SUPER), 245 CUP patients had molecular profiling performed and clinical follow-up. Variant detection from DNA sequencing using a targeted panel of 386 genes (SureSelect Agilent) was used to calculate tumour mutation burden (TMB). Additionally, a custom gene expression assay including 225 genes associated with ToO and 35 immune genes (SUPERDx, nCounter NanoString) was used to classify the likely ToO and immune profile the tumours. We used the genomic data from 217 of these patients to explore interdependencies between immune gene-expression patterns and TMB. We also retrospectively reviewed the outcomes of patients treated with anti-PD1/PD-L1 immune checkpoint inhibition (ICI) therapy in whom genomic data was available. Results: TMB was weakly correlated with a gene-expression score for immune response (IR) based on averaged z-score values of six genes (CD8A, IFNG, PRF1, PD-L1, GZMA, GZMB) (Spearman rho = 0.21) with many outliers exhibiting low TMB but high IR scores. Among twenty patients treated with ICIs, with both molecular data and response data available, 6 had a partial response (PR), 5 had stable disease (SD) and 9 had progressive disease (PD). We found that an elevated IR score was more predictive of ICI response than TMB. Most patients with either PR or SD to ICI treatment had a high IR score (9/10), and most patients with PD had low IR scores. However, only 3/10 patients with TMB available and a PR or SD had a high TMB ( > 10). Conclusions: Our results demonstrate that ICI therapy may benefit some CUP patients and that an immune response gene-expression scoremay predict ICI treatment response.