Patterns of care in adult histone mutant gliomas: Results of an international survey.

Background: Histone mutant gliomas (HMG) with histone H3 K27 and G34 mutations are recognized as biologically discrete entities with distinct anatomical locations, younger age at presentation (in comparison to the most common high-grade gliomas, IDH wildtype glioblastoma), and poor prognosis. There is a paucity of data regarding the management of adult HMG patients and no consensus on management. This study aims to identify current patterns of Australian and US neuro-oncology clinical practice for this entity. Methods: Following institutional approvals, patterns of care questionnaire designed to capture relevant clinical variables was circulated through the Cooperative Trials Group for Neuro-Oncology (COGNO) in Australia and the Caris Precision Oncology Alliance in the United States (US). Results: Between 4/2021 and 10/2021, 43 responses were collected. 33% (n = 14) of responders tested all patients for HMGs routinely; 40.92% (n = 18) tested in select patients 26% (n = 11) did not test for HMGs. The common indications for testing selected patients were midline anatomic location (n = 18) and age (n = 11) (<50 years). 23 used molecular sequencing, 22 used IHC at their centers. Nine participants stated knowledge of histone H3 mutations did not affect their management of these gliomas, 11 said it affected their management at the time of recurrence, 23 stated it affected the management of midline K27M patients, 11 participants stated it affected the management of K27M mutant gliomas in other locations, and 3 felt it affected the management of G34R/V mutant gliomas. Conclusion: Here we present a description of how the discovery of a new molecular subtype of primary glial tumors, histone mutated gliomas in adults, is being introduced into clinical practice.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

Clinical and molecular profile of young adults with early-onset colorectal cancer: Experience from four Australian tertiary centers.

BACKGROUND: Patients with early-onset colorectal cancer (EO-CRC) have unique characteristics. Contemporary data on the pathological and molecular features, and survival of EO-CRC are limited in the Australian context. AIM: To determine the demographic, histopathological and molecular characteristics of adults with EO-CRC, and their survival. METHODS: We conducted a retrospective study of adults aged 18-49 years with EO-CRC who were referred to the Illawarra Shoalhaven Local Health District, South Eastern Sydney Local Health District and Royal North Shore Hospital in New South Wales, Australia, between 2014 and 2018. RESULTS: Of 257 patients included, 94 (37%) patients presented with de novo metastatic CRC, 80% patients had near-average risk family history and 89% had a symptomatic presentation. In 159 patients with nonmetastatic disease at diagnosis, stage III disease (OR 3.88 [95% CI: 1.13-13.3]; p = .03) and the presence of perineural invasion (PNI) (OR 6.63 [95% CI: 2.21-19.84]; p = .001) were risk factors associated with the development of metastatic disease. Among 94 patients with de novo metastatic disease, 43 (43%) and 12 (14%) patients harbored a KRAS or BRAF V600E mutation, respectively. The median overall survival was 29.6 months (95% CI: 20.4-38.7). BRAF mutation was associated with inferior survival (HR 3.00 [95% CI: 1.30-6.94]; p = .01). CONCLUSION: The prevalence of KRAS and BRAF mutations in our cohort is similar to the overseas experience. Stage III disease at diagnosis, presence of PNI and BRAF mutation are adverse prognostic indicators. A better understanding of the molecular landscape is needed for this patient cohort, so as to better tailor prevention strategies, screening and treatment pathways.

Relationship between PD-L1 expression and outcome in EGFR-mutant lung cancer patients treated with EGFR tyrosine kinase inhibitors.

OBJECTIVES: Predictive biomarkers for poor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is an area of ongoing research. This multicentre retrospective study sought to determine the impact of programmed death-ligand 1 (PD-L1) tumour proportional score (TPS) on outcome in EGFR TKI treated patients. MATERIALS AND METHODS: Patients with Stage IIIB/IV lung adenocarcinoma harbouring a sensitising EGFR mutation treated with first-line TKI at five metropolitan hospitals were included. PD-L1 TPS was determined using the Ventana anti-PD-L1 (SP263) assay. High PD-L1 expression was defined as TPS ≥ 50 %. Determinants of progression and survival hazards were modelled using Cox regression. RESULTS: A total of 186 patients were included. Mean age was 67 years, 66 % were female and 54 % were Asian. Patients with high PD-L1 expression (n = 23; 12 %) had significantly shorter progression free survival (6.6 vs 13.0 months, hazard ratio (HR) 2.6 95 % CI 1.6-4.2, p < 0.0001) and overall survival (11.5 vs 32.9 months, HR 3.3, 95 % CI 1.9-5.7, p < 0.0001) compared to patients with PD-L1 low/negative tumours. This remained significant in multivariate analyses. High PD-L1 in post-TKI progression biopsies was not associated with poorer survival. CONCLUSION: In this large, real-world cohort of EGFR-mutant lung adenocarcinoma patients, high PD-L1 expression was associated with early resistance to 1st generation EGFR TKIs and shorter survival, regardless of ethnicity.

Succinate dehydrogenase-deficient gastrointestinal stromal tumor: from diagnostic dilemma to novel personalised therapy in 2 case reports.

Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) is a unique and distinctive subtype of gastric GIST. The literature on this subtype from developing countries is exceedingly sparse. Patients with SDH-deficient GIST often experience a lack or delay in genomic profiling, despite stereotypical clinicopathologic features, potentially resulting in sub-optimal management. SDH-deficient GISTs are highly syndromic, typically have more indolent behavior, a prognosis not predicted by size and mitotic rate, a tendency to lymph node metastases, and are insensitive to standard tyrosine kinase inhibitors (TKIs). We report two women with SDH-deficient GIST. In the first case, SDH deficiency was identified late due to lack of awareness and poor access to diagnostic facilities. The patient progressed through TKI therapy, but responded to temozolomide, which is under investigation in clinical trials. In the second case, SDH deficiency was identified at diagnosis, and the patient responded well to 177Lutetium peptide radionuclide receptor therapy (PRRT) after progressing through two lines of TKIs. We aim to highlight the need for more awareness and access to genomic diagnostic facilities for GIST patients, temozolomide as a novel therapy for SDH-deficient GIST, and the potential value of DOTATATE positron emission tomography (PET) and PRRT as a novel imaging modality and therapy for TKI insensitive GIST patients.

A Rapid Access Clinic to improve delivery of ambulatory care to cancer patients.

BACKGROUND: Cancer patients may find it challenging to access timely advice and care. We evaluated the improvement in delivering ambulatory care in establishing a Rapid Assessment Clinic (RAC) in a cancer center. METHODS: Patients receiving chemotherapy who presented for assessment at the RAC from September 2013 to June 2014 were included for review. Patient demographics, tumor characteristics, presenting complaints, time to assessment, total time spent at the RAC and assessment outcome were extracted. Similar data for cancer patients presented to the emergency department (ED) but were appropriate for RAC assessment from February 2012 to August 2012 were reviewed for comparison. For patients with febrile neutropenia, time to empirical antibiotic therapy was also reviewed and analyzed. RESULTS: Comparing to ED presentation (n = 152), patients reviewed at the RAC (n = 217) had a shorter waiting time to medical review (28.5 vs 40 min, P = 0.12), shorter total time spent for review (3.1 vs 9.7 hrs, P < 0.001), lesser rate of hospital admission (14.3% vs 69.1%, P < 0.001) and shorter inpatient length of stay (4 vs 7 days, P = 0.013). Presentations of febrile neutropenia were reviewed more promptly in ED (6 vs 9.5 min, P = 0.37), but this did not result in earlier empirical antibiotic administration (79 vs 74 min, P = 0.84). CONCLUSION: Comparing to ED, RAC had improved timeliness of care, resulting in a lower rate of hospital admission and inpatient length of stay for cancer patients. There was, however, no difference in the management of febrile neutropenia.