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Purpose: Genomic profiling is a major component for first-line treatment decisions in patients with non-small cell lung cancer (NSCLC) and the timeliness of biomarker testing is essential to improve time to treatment initiation (TTI) or avoid inappropriate treatment., Patients and Methods: The phase III LIBELULE trial (NCT03721120) included patients with radiological suspicion of advanced lung cancer. They were randomized (1:1), the control arm receiving diagnostic procedures according to each center's practice and the liquid biopsy arm with additional testing performed at the first visit using the InVisionFirst®-Lung assay. Treatment initiation and type were defined according to ESMO guidelines. Primary endpoint was the time from randomization to initiation of appropriate treatment based on informative genomic and pathological results in the intention-to-treat population., Results: 319 patients were enrolled (LB: 161; control: 158). Median age was 68 years, 28.8% were non-smokers, 18.1% had PS≥2 and 56.7% had adenocarcinoma. In LB arm, 81% of patients had circulating tumor DNA findings. The mean TTI was not significantly reduced (LB: 29.0 days (d); control 34d (p=0.26)). Sensitivity analyses showed a shorter TTI in patients from the LB arm who received systemic treatment (LB: 29.1d; control: 38.8d, p=0.01), in patients with advanced non-squamous NSCLC (LB: 29.5d; control: 40.3d, p=0.01), and in patients with first-line targetable alterations (LB: 21d; control 37.4d) (p=0.004). Time to contributory genomic results was significantly reduced (LB: 17.9d; control 25.6d, p<0.001)., Conclusion: Early liquid biopsy testing did not significantly shorten the TTI in unselected patients referred for suspected advanced lung cancer. Nevertheless, it could reduce the TTI in patients eligible for systemic treatment, particularly for those with actionable alterations., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Detection of circulating tumor DNA (ctDNA) in patients who have completed treatment for early-stage breast cancer is associated with a high risk of relapse, yet the optimal assay for ctDNA detection is unknown., Experimental Design: The cTRAK-TN clinical trial prospectively used tumor-informed digital PCR (dPCR) assays for ctDNA molecular residual disease (MRD) detection in early-stage triple-negative breast cancer. We compared tumor-informed dPCR assays with tumor-informed personalized multimutation sequencing assays in 141 patients from cTRAK-TN., Results: MRD was first detected by personalized sequencing in 47.9% of patients, 0% first detected by dPCR, and 52.1% with both assays simultaneously (P < 0.001; Fisher exact test). The median lead time from ctDNA detection to relapse was 6.1 months with personalized sequencing and 3.9 months with dPCR (P = 0.004, mixed-effects Cox model). Detection of MRD at the first time point was associated with a shorter time to relapse compared with detection at subsequent time points (median lead time 4.2 vs. 7.1 months; P = 0.02)., Conclusions: Personalized multimutation sequencing assays have potential clinically important improvements in clinical outcome in the early detection of MRD., (©2023 The Authors; Published by the American Association for Cancer Research.)

Importance: Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear., Objective: To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment., Design, Setting, and Participants: This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis., Interventions: Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care., Main Outcome and Measures: The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis., Results: Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing., Conclusions and Relevance: This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing., Trial Registration: ClinicalTrials.gov Identifier: NCT04863924.

Cohort 1 of the phase 1B NABUCCO trial showed high pathological complete response (pCR) rates with preoperative ipilimumab plus nivolumab in stage III urothelial cancer (UC). In cohort 2, the aim was dose adjustment to optimize responses. Additionally, we report secondary endpoints, including efficacy and tolerability, in cohort 2 and the association of presurgical absence of circulating tumor DNA (ctDNA) in urine and plasma with clinical outcome in both cohorts. Thirty patients received two cycles of either ipilimumab 3 mg kg -1 plus nivolumab 1 mg kg -1 (cohort 2A) or ipilimumab 1 mg kg -1 plus nivolumab 3 mg kg -1 (cohort 2B), both followed by nivolumab 3 mg kg -1 . We observed a pCR in six (43%) patients in cohort 2A and a pCR in one (7%) patient in cohort 2B. Absence of urinary ctDNA correlated with pCR in the bladder (ypT0Nx) but not with progression-free survival (PFS). Absence of plasma ctDNA correlated with pCR (odds ratio: 45.0; 95% confidence interval (CI): 4.9-416.5) and PFS (hazard ratio: 10.4; 95% CI: 2.9-37.5). Our data suggest that high-dose ipilimumab plus nivolumab is required in stage III UC and that absence of ctDNA in plasma can predict PFS. ClinicalTrials.gov registration: NCT03387761 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Head and neck squamous cell carcinoma (HNSCC) remain a substantial burden to global health. Cell-free circulating tumour DNA (ctDNA) is an emerging biomarker but has not been studied sufficiently in HNSCC., Methods: We conducted a single-centre prospective cohort study to investigate ctDNA in patients with p16-negative HNSCC who received curative-intent primary surgical treatment. Whole-exome sequencing was performed on formalin-fixed paraffin-embedded (FFPE) tumour tissue. We utilised RaDaR TM , a highly sensitive personalised assay using deep sequencing for tumour-specific variants, to analyse serial pre- and post-operative plasma samples for evidence of minimal residual disease and recurrence., Results: In 17 patients analysed, personalised panels were designed to detect 34 to 52 somatic variants. Data show ctDNA detection in baseline samples taken prior to surgery in 17 of 17 patients. In post-surgery samples, ctDNA could be detected at levels as low as 0.0006% variant allele frequency. In all cases with clinical recurrence to date, ctDNA was detected prior to progression, with lead times ranging from 108 to 253 days., Conclusions: This study illustrates the potential of ctDNA as a biomarker for detecting minimal residual disease and recurrence in HNSCC and demonstrates the feasibility of personalised ctDNA assays for the detection of disease prior to clinical recurrence., (© 2022. The Author(s).)

Introduction: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy., Methods: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT]( 177 Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763)., Results: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD)., Conclusions: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease., Competing Interests: Conflict of interest statement NL receives research funding from Merck Inc., not related to this manuscript, and was a consultant for CoolTech Inc. and holds stock in Navigen Pharmaceuticals, both of which are unrelated to this manuscript. SW is on the advisory board of ALK, Genentech, OptiNose, SinopSys and a Consultant to NeurENT, Stryker, all of which are unrelated to this manuscript. All other authors declare no potential relevant conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Neuroendocrine neoplasms (NENs) arise from cells of neuronal and endocrine differentiation. While they are a rare entity, an increasing proportion of patients with NEN present with metastatic disease and no evident primary site using routine imaging or histopathology. NENs of unknown primary site have a poorer prognosis, often due to the challenge of selecting appropriate evidence-based management. We review the available literature and guidelines for the management of NENs of unknown primary site including clinical features, biochemical tests, histopathology, imaging, surgical exploration and localised and systemic treatments. We also discuss novel molecular techniques currently under investigation to aid primary site identification., (© 2019 S. Karger AG, Basel.)

Purpose: Small intestinal neuroendocrine tumors (SINET) are the commonest malignancy of the small intestine; however, underlying pathogenic mechanisms remain poorly characterized. Whole-genome and -exome sequencing has demonstrated that SINETs are mutationally quiet, with the most frequent known mutation in the cyclin-dependent kinase inhibitor 1B gene (CDKN1B) occurring in only ∼8% of tumors, suggesting that alternative mechanisms may drive tumorigenesis. The aim of this study is to perform genome-wide molecular profiling of SINETs in order to identify pathogenic drivers based on molecular profiling. This study represents the largest unbiased integrated genomic, epigenomic, and transcriptomic analysis undertaken in this tumor type., Experimental Design: Here, we present data from integrated molecular analysis of SINETs (n = 97), including whole-exome or targeted CDKN1B sequencing (n = 29), HumanMethylation450 BeadChip (Illumina) array profiling (n = 69), methylated DNA immunoprecipitation sequencing (n = 16), copy-number variance analysis (n = 47), and Whole-Genome DASL (Illumina) expression array profiling (n = 43)., Results: Based on molecular profiling, SINETs can be classified into three groups, which demonstrate significantly different progression-free survival after resection of primary tumor (not reached at 10 years vs. 56 months vs. 21 months, P = 0.04). Epimutations were found at a recurrence rate of up to 85%, and 21 epigenetically dysregulated genes were identified, including CDX1 (86%), CELSR3 (84%), FBP1 (84%), and GIPR (74%)., Conclusions: This is the first comprehensive integrated molecular analysis of SINETs. We have demonstrated that these tumors are highly epigenetically dysregulated. Furthermore, we have identified novel molecular subtypes with significant impact on progression-free survival., (©2015 American Association for Cancer Research.)