With a mission to expand the boundaries of cancer care, the annual European Society for Medical Oncology (ESMO) Congress will be held both in person in Paris, France, and virtually on September 9th. The ESMO congress is a global gathering of oncology professionals to share their latest research and state-of-the-art education on disease characteristics, clinical practices, and therapeutics. This year, Geneseeq continuously shares more interesting discoveries made in cancer detection, diagnosis and monitoring.
Pan-cancer Studies
Study highlight: Immune checkpoint blockade (ICB) produces durable responses on difficult-to-treat tumors, but its effects are heterogeneous on patients. DNA damage response (DDR) is a network of multiple functional pathways to maintain genomic stability, and mutations in DDR genes are a major determinant of response to ICB. However, only a subset of DDR-altered patients benefits from ICB, and their responses vary across cancer types. In this study, the authors retrospectively assessed the prognostic value of pre-defined core DDR pathways using a pan-cancer cohort of 1751 patients derived from cBioPortal TMB/Immunotherapy datasets. The tumor-infiltrating lymphocyte (TIL) scores of 3164 samples derived from TCGA transcriptome datasets were also investigated to evaluate the tumor environment (TME) with different types of DDR statue. The result showed that the prognostic role of DNA damage sensing may provide insights into current biomarkers and help stratify DDR-deficient patients for ICB treatment.
Study highlight: The use of cfDNA fragmentomic features has recently shown a strong surge in cancer early detection models. Although many individual studies have demonstrated successful applications in cancer detection, their generalizability remains unclear due to the lack of cross-study validations. A generalized model across studies will allow for robust diagnosis of high-risk individuals. This study evaluated the window-level cfDNA size summary (WINDOW-FSS) feature from the commonly used method profiling the short (100 -150bp) and long (151-220 bp) cfDNA fragments and our in-house developed feature mapping chromosome arm-level fragment size distribution (ARM-FSD) in both lung cancer and pan-cancer models. The cross-study analysis revealed performance variation of models implementing different cfDNA fragmentomic features. The ARM-FSD-based models have consistently demonstrated higher generalizability and robustness in cohorts from diverse sources, highlighting the necessity of cross-study feature verification for future predictive model development.
Lung Cancer Studies:
Study highlight: Afatinib, an irreversible pan-ErbB family inhibitor, has demonstrated promising efficacy in non-small cell lung cancer (NSCLC) patients with uncommon EGFR activating mutations. However, besides the acquisition of secondary T790M mutation, other resistance mechanisms to afatinib remained to be explored. This study interrogated the baseline and post-treatment samples from 40 NSCLC patients harboring either EGFR or ERBB2 activating mutations, who had received afatinib as first-line treatment. The authors identified multiple genetic factors associated with afatinib efficacy and resistance as well as genomic characteristics that might serve as biomarkers for afatinib response.
Abstract 107P Systematic characterization of MET activating mutations in non-small cell lung cancer
Study highlight: Alterations in mesenchymal epithelial transition factor (MET) as primary oncogenic drivers or secondary resistance mechanisms to tyrosine kinase inhibitors (TKI) often involve distinct MET mutation subtypes. While MET activating mutations primarily mediates resistance to MET TKIs, increasing evidence suggest that MET activating mutations also exist in the primary tissues. The molecular signatures and clinical relevance of MET activating mutations remain to be elucidated. Here next-generation sequencing data from patients with MET activating mutations were analyzed, and association analyses of genetic and clinical features were conducted. The findings shed light into the diversity of mechanisms underlying TKI resistance and highlight the potential of sequential use of MET TKI.
Study highlight: The second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), alectinib, has shown prolonged survival in naïve ALK-rearranged advanced non-small cell lung cancer (NSCLC), with median progression-free survival (PFS) reaching 34.8 months. This study explored the mechanisms of early resistance to alectinib in ALK-rearranged NSCLCs by interrogating the targeted sequencing data from 108 ALK-rearranged NSCLC patients had confirmed clinical relapse on alectinib. The results revealed off-target alterations in MET and NF2 might confer early resistance to 1L alectinib, whereas resistance to 2L alectinib was mainly induced by ALK point mutations. These different mechanisms might be informative in guiding future tailored treatment for ALK-positive NSCLCs.