ABSTRACT
The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Gastrointestinal Microbiome , Immunotherapy , Lung Neoplasms , Neoplasms , Female , Humans , Male , Akkermansia , Carcinoma, Non-Small-Cell Lung/microbiology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/immunology , Dysbiosis/microbiology , Feces/microbiology , Gastrointestinal Microbiome/drug effects , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy/methods , Lung Neoplasms/microbiology , Lung Neoplasms/drug therapy , Metagenomics/methods , Neoplasms/microbiology , Treatment OutcomeABSTRACT
OBJECTIVES: With the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), sequential therapy could potentially render EGFR mutation-positive non-small cell lung cancer a chronic disease in some patients. In this retrospective analysis of EGFR mutation-positive (Del19/L858R) patients receiving first-line afatinib in LUX-Lung 3, 6, and 7, we assessed uptake of, and outcomes following, subsequent therapies including the third-generation EGFR TKI, osimertinib. METHODS: Post-progression therapy data were prospectively collected during follow-up. Molecular testing of tumours at progression/discontinuation of afatinib was not mandatory. Duration of subsequent therapies, and survival following osimertinib, were calculated with Kaplan-Meier estimates. RESULTS: Among 553 patients who discontinued first-line afatinib, second-, third- and fourth-line therapy was administered in 394 (71%), 265 (48%), and 156 (28%) patients. The most common post-progression therapy was platinum-based chemotherapy (46%). Thirty-seven patients received subsequent osimertinib, 10 as second-line treatment. Median progression-free survival on afatinib in these 37 patients was 21.9 months. Median duration of osimertinib therapy was 20.2 months; median overall survival was not reached after a median follow-up of 4.7 years. CONCLUSIONS: Most patients treated with first-line afatinib received subsequent therapy. Although limited by sample size, enrichment, and a retrospective nature, data from patients who received sequential afatinib and osimertinib are encouraging, warranting further investigation.
Subject(s)
Acrylamides/therapeutic use , Afatinib/therapeutic use , Aniline Compounds/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Platinum Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Middle Aged , Mutation/genetics , Neoplasm Staging , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
MET exon 14 splicing mutations are new targetable oncogenic drivers reported in 3% of non-small cell lung cancer (NSCLC) cases and have been shown to be more common in pulmonary sarcomatoid carcinomas (PSCs). This study sought to screen mutations affecting MET exon 14 splice sites in a large SC cohort of Caucasian patients, with a large adenocarcinoma cohort as internal control.We tested 81 patients with SC and 150 with adenocarcinoma for splice site DNA mutations leading to RNA splicing-based skipping of MET exon 14. To this end, we employed a mass spectrometry-based custom-designed PCR assay for routine analysis of whole MET exon 14 and flanking intronic regions using formalin-fixed paraffin-embedded (FFPE) tumor samples.Our results revealed a 4.9% mutation rate for MET exon 14 mutations in Caucasian SC patients, which is, though highly variable, within the usual range reported in NSCLC. Discrepancies with previous results reported in SC could be accounted for the small number of cases, ethnicity, epithelial component, and percentage of other driver mutations, such as KRAS, in the patient populations studied. Based on our study findings, SC patients should be screened for MET exon 14 mutations in the same manner as adenocarcinoma patients.
