Mutations in KMT2C, BCOR and KDM5C Predict Response to Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer

Efficient predictive biomarkers are urgently needed to identify non-small cell lung cancer (NSCLC) patients who could benefit from immune checkpoint blockade (ICB) therapy. Since chromatin remodeling is required for DNA repair process, we asked whether mutations in chromatin remodeling genes could increase tumor mutational burden (TMB) and predict response to ICB therapy in NSCLC. Analysis of seven ICB-treated NSCLC cohorts revealed that mutations of three chromatin remodeling-related genes, including KMT2C, BCOR and KDM5C, were significantly associated with ICB response, and combined mutations of these three genes further enhance this association. NSCLC patients with KMT2C/BCOR/KDM5C mutations had comparable clinical outcomes to TMB-high patients in terms of objective response rate, durable clinical benefit and overall survival. Although KMT2C/BCOR/KDM5C mutations were positively correlated with TMB levels in NSCLC, the association of this mutation with better ICB response was independent of tumor TMB and programmed death-ligand 1 (PD-L1) level, and combination of KMT2C/BCOR/KDM5C mutations with TMB or PD-L1 further improve the prediction of ICB response in NSCLC patients. Cancer Genome Atlas (TCGA) pan-cancer analysis suggested that the association of KMT2C/BCOR/KDM5C mutations with ICB response observed here might not result from DNA repair defects. In conclusion, our data indicate that KMT2C/BCOR/KDM5C mutation has the potential to serve as a predictive biomarker, alone or combined with PD-L1 expression or TMB, for ICB therapy in NSCLC

Circulating Tumor Cell Detection in Lung Cancer: But to What End?

The understanding of the natural history and biology of lung cancer has been enhanced by studies into circulating tumor cells (CTCs). Fundamental and translational research, as well as clinical trials in the characterization and behavior of these cells, have constantly contributed to improving understanding within the domain of thoracic oncology. However, the use of these CTCs as prognostic and predictive biomarkers has not been adopted to the same extent as circulating free DNA (cf-DNA) in plasma, in the daily practice of thoracic oncologists. However, recent technological advances have firmly put the detection and characterization of CTCs in thoracic oncology back on the agenda, and have opened up perspectives for their routine clinical use. This review discusses the major advances of using CTCs in the domain of thoracic oncology, as well as the envisaged short- and long-term prospects

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

KRAS mutations are among the most frequent genomic alterations identified in non-squamous non-small cell lung carcinomas (NS-NSCLC), notably in lung adenocarcinomas. In most cases, these mutations are mutually exclusive, with different genomic alterations currently known to be sensitive to therapies targeting EGFR, ALK, BRAF, ROS1, and NTRK. Recently, several promising clinical trials targeting KRAS mutations, particularly for KRAS G12C-mutated NSCLC, have established new hope for better treatment of patients. In parallel, other studies have shown that NSCLC harboring co-mutations in KRAS and STK11 or KEAP1 have demonstrated primary resistance to immune checkpoint inhibitors. Thus, the assessment of the KRAS status in advanced-stage NS-NSCLC has become essential to setting up an optimal therapeutic strategy in these patients. This stimulated the development of new algorithms for the management of NSCLC samples in pathology laboratories and conditioned reorganization of optimal health care of lung cancer patients by the thoracic pathologists. This review addresses the recent data concerning the detection of KRAS mutations in NSCLC and focuses on the new challenges facing pathologists in daily practice for KRAS status assessment

Immunohistochemistry for Diagnosis of Metastatic Carcinomas of Unknown Primary Site

Immunohistochemistry has become an essential ancillary examination for the identification and classification of carcinomas of unknown primary site (CUPs). Over the last decade, the diagnostic accuracy of organ- or tumour-specific immunomarkers and the clinical validation of effective immunohistochemical panels has improved significantly. When dealing with small sample sizes, diagnostic accuracy is crucial, particularly in the current era of targeted molecular and immune-based therapies. Effective systematic use of appropriate immunohistochemical panels enables accurate classification of most of the undifferentiated carcinomas as well as careful preservation of tissues for potential molecular or other ancillary tests. This review discusses the algorithmic approach to the diagnosis of CUPs using CK7 and CK20 staining patterns. It outlines the most frequently used tissue-specific antibodies, provides some pitfalls essential in avoiding potential diagnostic errors and discusses the complementary tools, such as molecular tumour profiling and mutation-specific antibodies, for the improvement of diagnosis and prediction of the treatment response

The Third Joint Meeting on Lung Cancer of the FHU OncoAge (University Côte d’Azur, Nice, France) and the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Understanding New Therapeutic Options and Promising Predictive Biomarkers for Lung Cancer Patients

We are proud and happy to present this Special Issue, a follow-up to the third joint meeting on lung cancer of the FHU OncoAge (University Côte d’Azur, Nice, France) and the University of Texas MD Anderson Cancer Center (Houston, TX, USA), which was held virtually on 4 October 2021 [...

Molecular Profiling in Non-Squamous Non-Small Cell Lung Carcinoma: Towards a Switch to Next-Generation Sequencing Reflex Testing

Molecular diagnosis of lung cancer is a constantly evolving field thanks to major advances in precision oncology. The wide range of actionable molecular alterations in non-squamous non-small cell lung carcinoma (NS-NSCLC) and the multiplicity of mechanisms of resistance to treatment resulted in the need for repeated testing to establish an accurate molecular diagnosis, as well as to track disease evolution over time. While assessing the increasing complexity of the molecular composition of tumors at baseline, as well as over time, has become increasingly challenging, the emergence and implementation of next-generation sequencing (NGS) testing has extensively facilitated molecular profiling in NS-NSCLC. In this review, we discuss recent developments in the molecular profiling of NS-NSCLC and how NGS addresses current needs, as well as how it can be implemented to address future challenges in the management of NS-NSCLC