Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product.

Circulating Tumor Cells (CTCs) in blood encompass DNA, RNA, and protein biomarkers, but clinical utility is limited by their rarity. To enable tumor epitope-agnostic interrogation of large blood volumes, we developed a high-throughput microfluidic device, depleting hematopoietic cells through high-flow channels and force-amplifying magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.

Alectinib combined with cobimetinib in ALK-Rearranged lung Cancer: A phase IB study.

Introduction: Anaplastic lymphoma kinase rearranged (ALK + ) lung cancers often develop ALK-independent resistance mechanisms that reactivate the mitogen-activated protein kinase pathway signaling pathway. We therefore evaluated alectinib combined with the MEK inhibitor cobimetinib in metastatic ALK + lung cancer.

Materials And Methods: This phase Ib study employed a 3 + 3 design.

Phase 2 Trial of Consolidative Stereotactic Body Radiation Therapy in Patients With Metastatic Oncogene-driven Non-small Cell Lung Carcinoma Treated With Tyrosine Kinase Inhibitors.

Purpose: The role of stereotactic body radiation therapy (SBRT) in the management of advanced EGFR/ALK/ROS1-driven non-small cell lung carcinoma (NSCLC) remains undefined. In EGFR-mutant NSCLC, 50-60% of recurrences on first-line tyrosine kinase inhibitors (TKIs) occur in originally involved sites and may lead to subsequent distant failures (DFs). We sought to determine whether consolidative SBRT to residual sites reduces DF.

Significance of Image Reconstruction Parameters for Future Lung Cancer Risk Prediction Using Low-Dose Chest Computed Tomography and the Open-Access Sybil Algorithm.

Purpose: Sybil is a validated publicly available deep learning-based algorithm that can accurately predict lung cancer risk from a single low-dose computed tomography (LDCT) scan. We aimed to study the effect of image reconstruction parameters and CT scanner manufacturer on Sybil's performance.

Materials And Methods: Using LDCTs of a subset of the National Lung Screening Trial participants, which we previously used for internal validation of the Sybil algorithm (test set), we ran the Sybil algorithm on LDCT series pairs matched on kilovoltage peak, milliampere-seconds, reconstruction interval, reconstruction diameter, and either reconstruction filter or axial slice thickness.

Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors.

Although the development of multiple primary tumors in smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple tumors at presentation in individuals with EGFR-mutant lung cancer who lack known environmental exposures remains unexplained. In the present study, we identified ten patients with early stage, resectable, non-small cell lung cancer who presented with multiple, anatomically distinct, EGFR-mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole-exome sequencing (WES) and hypermutable poly(guanine) (poly(G)) repeat genotyping as orthogonal methods for lineage tracing.

Capmatinib plus nazartinib in patients with EGFR-mutated non-small cell lung cancer.

Purpose: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC).

Methods: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFR; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFR; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFR; any T790M/MET).

Clinical Validation of a Cell-Free DNA Fragmentome Assay for Augmentation of Lung Cancer Early Detection.

Lung cancer screening via annual low-dose computed tomography has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by a low-dose computed tomography. Changes in genome-wide cell-free DNA fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer.

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

Background: The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC.

Patients And Methods: Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts.

Early Detection and Interception of Lung Cancer.

Recent advances in lung cancer treatment have led to dramatic improvements in 5-year survival rates. And yet, lung cancer remains the leading cause of cancer-related mortality, in large part, because it is often diagnosed at an advanced stage, when cure is no longer possible. Lung cancer screening (LCS) is essential for intercepting the disease at an earlier stage.

Phase II Study of Osimertinib in Patients With Epidermal Growth Factor Receptor Mutations: Results From the NCI-MATCH ECOG-ACRIN (EAY131) Trial Subprotocol E.

Purpose: The National Cancer Institute Molecular Analysis for Therapy Choice trial is a signal-finding genomically driven platform trial that assigns patients with any advanced refractory solid tumor, lymphoma, or myeloma to targeted therapies on the basis of next-generation sequencing results. Subprotocol E evaluated osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with mutations.

Methods: Eligible patients had mutations (T790M or rare activating) and received osimertinib 80 mg once daily.

Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product.

Circulating Tumor Cells (CTCs), interrogated by sampling blood from patients with cancer, contain multiple analytes, including intact RNA, high molecular weight DNA, proteins, and metabolic markers. However, the clinical utility of tumor cell-based liquid biopsy has been limited since CTCs are very rare, and current technologies cannot process the blood volumes required to isolate a sufficient number of tumor cells for in-depth assays. We previously described a high-throughput microfluidic prototype utilizing high-flow channels and amplification of cell sorting forces through magnetic lenses.

Pack-Year Smoking History: An Inadequate and Biased Measure to Determine Lung Cancer Screening Eligibility.

Purpose: Pack-year smoking history is an imperfect and biased measure of cumulative tobacco exposure. The use of pack-year smoking history to determine lung cancer screening eligibility in the current US Preventive Services Task Force (USPSTF) guideline may unintentionally exclude many high-risk individuals, especially those from racial and ethnic minority groups. It is unclear whether using a smoking duration cutoff instead of a smoking pack-year cutoff would improve the selection of individuals for screening.

Deploying blood-based cancer screening.

AI-based risk assessment may enable personalized blood-based multicancer screening.

Lung Cancer in Women: The Past, Present, and Future.

Lung cancer is the leading cause of cancer death for women in multiple countries including the United States. Women are exposed to unique risk factors that remain largely understudied such as indoor pollution, second-hand tobacco exposure, biological differences, gender differences in tolerability and response to therapy in lung cancer, and societal gender roles, that create distinct survivorship needs. Women continue to lack representation in lung cancer clinical trials and are typically treated with data generated from majority male patient study populations, which may be inappropriate to extrapolate and generalize to females.

Role of sex in lung cancer risk prediction based on single low-dose chest computed tomography.

A validated open-source deep-learning algorithm called Sybil can accurately predict long-term lung cancer risk from a single low-dose chest computed tomography (LDCT). However, Sybil was trained on a majority-male cohort. Use of artificial intelligence algorithms trained on imbalanced cohorts may lead to inequitable outcomes in real-world settings.

Germline mutations and developmental mosaicism underlying -mutant lung cancer.

While the development of multiple primary tumors in smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple primary tumors in individuals with -mutant lung cancer who lack known environmental exposures remains unexplained. We identified ten patients with early-stage, resectable non-small cell lung cancer who presented with multiple anatomically distinct -mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole exome sequencing (WES) and hypermutable poly-guanine (poly-G) repeat genotyping, as orthogonal methods for lineage tracing.

Artificial Intelligence and Machine Learning in Lung Cancer Screening.

Recent advances in artificial intelligence and machine learning (AI/ML) hold substantial promise to address some of the current challenges in lung cancer screening and improve health equity. This article reviews the status and future directions of AI/ML tools in the lung cancer screening workflow, focusing on determining screening eligibility, radiation dose reduction and image denoising for low-dose chest computed tomography (CT), lung nodule detection, lung nodule classification, and determining optimal screening intervals. AI/ML tools can assess for chronic diseases on CT, which creates opportunities to improve population health through opportunistic screening.

Therapy-induced APOBEC3A drives evolution of persistent cancer cells.

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined.

Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With Mutations.

Purpose: The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against mutations. A phase II study of afatinib in mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

Patients And Methods: In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for mutations.