Actionable Molecular Alterations Are Revealed in Majority of Advanced Non-Small Cell Lung Cancer Patients by Genomic Tumor Profiling at Progression after First Line Treatment.

Background: Genomic profiling in advanced Non-Small Cell Lung cancer (NSCLC) can reveal Actionable Molecular Alterations (AMAs). Our study aims to investigate clinical relevance of re-biopsy after first line treatment, by reporting on acquired and persistent AMAs and potential targeted treatments in a real-time cohort of NSCLC patients. Methods: Patients with advanced NSCLC receiving first-line treatment were prospectively included in an observational study (NCT03512847). Genomic profiling was performed by TruSight Oncology 500 HT gene panel on tumor tissue collected at diagnosis and at time of progression. Results: The 92 patients re-biopsied at progression had received immunotherapy (n = 44), chemotherapy (n = 44), or combination treatment (n = 4). In 87 of these patients (95%), successful genomic profiling was performed at both the diagnostic biopsy and the re-biopsy. In 74 patients (85%), ≥1 AMA were found. The AMAs were acquired in 28%. The most frequent AMAs were observed in TP53 (45%), KRAS (24%), PIK3CA (6%), and FGFR1 (6%). Only five patients (5%) received targeted treatment mainly due to deterioration in performance status. Conclusions: Re-biopsy at progression revealed acquired AMAs in approximately one third of patients, and 85% had at least one AMA with the potential of receiving targeted treatment, thus strengthening the clinical relevance of re-biopsy.

Quantifying sequencing error and effective sequencing depth of liquid biopsy NGS with UMI error correction.

Liquid biopsies are a minimally invasive method to diagnose and longitudinally monitor tumor mutations in patients when tissue biopsies are difficult (e.g., in lung cancer). The percentage of cell-free tumor DNA in blood plasma ranges from more than 65% to 0.1% or lower. To reliably diagnose tumor mutations at 0.1%, there are two options: unrealistically large volumes of patient blood or library preparation and sequencing depth optimized to low-input DNA. Here, we assess two library preparation methods and analysis workflows to determine feasibility and reliability based on standards with known allelic frequency (0 and 0.13% in PIK3CA). However, the implementation for patients is still costly and requires elaborate setups.

Re-biopsy after first line treatment in advanced NSCLC can reveal changes in PD-L1 expression.

OBJECTIVES: Re-biopsy in progressive advanced Non-Small-Cell Lung Cancer (NSCLC) after first line treatment may reveal information about evolving tumor biology during treatment. Our study aims to investigate the feasibility, risk of complications, and clinical relevance of performing re-biopsy systematically. MATERIALS AND METHODS: NSCLC patients with advanced, non-targetable disease, receiving first line systemic treatment, were included in a prospective single-centre study (NCT03512847). A diagnostic biopsy was performed at baseline and repeated at time of progression, preferentially from the progressive lesions as determined by CT or PET/CT. The primary endpoint was feasibility, including complication rate to re-biopsy. Secondary endpoints were clinical relevance, defined as a potential of changing treatment or follow-up, due to new histological evidence, specifically a change in PD-L1 Tumor Proportion Score (TPS). RESULTS: Fifty-one patients with progressive advanced NSCLC had re-biopsy performed. Median time from patients' acceptance to biopsy was seven days (range: 0-31). Complication rate was 6% (n = 3) represented by pneumothorax, hydro-pneumothorax and pneumonia, respectively. No severe or chronic complications occurred. Sufficient material for PD-L1 analyses was obtained in 46 of 51 patients: the remaining five cases had insufficient tissue for analyses, no malignant cells/only suspected malignant cells, questioning whether progression was real. PD-L1 TPS change was observed in 33% of patients (n = 15) and 17% (n = 8) had potentially clinically relevant changes. A significantly higher chance of PD-L1 TPS change was observed in chemotherapy-treated patients. CONCLUSION: Our study showed that re-biopsy is feasible, with low risk of complications, and can be clinically relevant in patients with suspected progression in advanced NSCLC.

Surveillance With PET/CT and Liquid Biopsies of Stage I-III Lung Cancer Patients After Completion of Definitive Therapy: A Randomized Controlled Trial (SUPER).

Despite increased focus on prevention as well as improved treatment possibilities, lung cancer remains among the most frequent and deadliest cancer diagnoses worldwide. Even lung cancer patients treated with curative intent have a high risk of relapse, leading to a dismal prognosis. More knowledge on the efficacy of surveillance with both current and new technologies as well as on the impact on patient treatment, quality of life, and survival are urgently needed. We therefore designed a randomized phase 3 trial. In one arm, every other computed tomography (CT) scan is replaced by positron emission tomography/CT, the other arm is the standard follow-up scheme with CT. The standard arm is identical to the current national Danish follow-up program. The primary endpoint is to compare the number of relapses treatable with curative intent in the 2 arms. We aim to include 750 patients over a 3-year period. Additionally, we will test the feasibility of noninvasive lung cancer diagnostics and surveillance in the form of circulating tumor DNA analysis. For this purpose, blood samples are collected before treatment and at each following control. The blood samples are stored in a biobank for later analysis and will not be used for guiding patient treatment decisions.