Abstract
BackgroundBrain metastases present a significant complication in lung cancer with an unmet therapeutic need. MethodsIn this single-centre, retrospective study, we genotyped a clinico-pathologically well-annotated cohort of consecutively resected brain metastases of lung adenocarcinomas and paired primary tumours, diagnosed from 2000 to 2015, using the Ion Torrent Oncomine Comprehensive Cancer Panel v3. ResultsAmong 444 consecutive brain metastases, 210 (49%) originated from lung cancer. Analysis was successful in 111 samples, including 54 pairs of brain metastasis and primary tumour. Most driver alterations were preserved in brain metastases. Private alterations exclusive to primary tumours, brain metastases or both sites (intersecting cases) were present in 22%, 26% and 26% of cases, respectively. Seven percent had no shared mutations. KRAS mutations were more frequent in primary tumours metastasised to the brain (32/55, 58%) compared to TCGA (33%, p < 0.005) and own data from routine diagnostics, independent from clinical or pathological characteristics. Fourteen cases showed alterations in the EGFR signalling pathway including additional KRAS alterations that were private to brain metastases. KRAS G12C was detected most frequently (26% of patients) and KRAS G12C and G13C variants were significantly enriched in brain metastases. Synchronous and metachronous cases had a similar mutation profile. ConclusionsOur results suggest an important role of KRAS alterations in the pathobiology of brain metastases from lung adenocarcinomas. This has direct therapeutic implications as inhibitors selectively targeting KRAS G12C are entering the clinics.
Highlights
Lung cancer is the most frequent and deadly malignant disease worldwide, and the most frequent origin of brain metastases [1]
The frequency of KRAS mutations detected at primary sites was significantly higher compared with TCGA (33%) and with own data derived from routine clinical diagnostics, where we detected 41 cases (35%) in all 116 evaluated UICC-stage IV lung cancer samples analysed in 2017, 3.2
We report a comprehensive genetic analysis of matched Lung adenocarcinomas (LUAD) and brain metastases
Summary
Lung cancer is the most frequent and deadly malignant disease worldwide, and the most frequent origin of brain metastases [1]. Up to 40% of patients with non-small cell lung cancer (NSCLC) will develop brain metastases in the course of their disease [2]. In patients with multiple symptomatic brain metastases, due to low benefit from chemotherapy, whole brain radiotherapy (WBRT) remains the standard of care, despite limited evidence from randomised trials and risk for neurocognitive decline [5]. In advanced NSCLC, immune checkpoint inhibitors are an effective alternative or addendum to chemotherapy, but only limited data is available for patients with brain metastases [5]. Oncogene addicted NSCLC are especially prone to metastasise to the brain and in patients with druggable oncogenes, next-generation tyrosine kinase inhibitors are a valuable choice inducing potent and durable responses [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
