Erik Vassella1, Elham Kashani2, Philipp Zens3, Alexandra Kündig4, Christian Fung5, Amina Scherz6, Evelyn Herrmann7, Ekin Ermis8, Ralph A Schmid9, Sabina Berezowska10. 1. Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland. Electronic address: erik.vassella@pathology.unibe.ch. 2. Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland. Electronic address: elham.kashani@pathology.unibe.ch. 3. Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; Graduate School for Health Sciences, University of Bern, Mittelstrasse 43, CH-3012 Bern, Switzerland. Electronic address: philipp.zens@pathology.unibe.ch. 4. Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland. Electronic address: alexandra.kuendig@students.unibe.ch. 5. Department of Neurosurgery, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 8, CH-3010 Bern, Switzerland. Electronic address: christian.fung@uniklinik-freiburg.de. 6. Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 8, CH-3010 Bern, Switzerland. Electronic address: amina.scherz@insel.ch. 7. Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 8, CH-3010 Bern, Switzerland. Electronic address: evelyn.herrmann@insel.ch. 8. Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 8, CH-3010 Bern, Switzerland. Electronic address: ekin.ermis@insel.ch. 9. Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 8, CH-3010 Bern, Switzerland. Electronic address: ralph.schmid@insel.ch. 10. Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Bugnon 25, CH-1011 Lausanne, Switzerland. Electronic address: Sabina.berezowska@chuv.ch.
Abstract
BACKGROUND: Brain metastases present a significant complication in lung cancer with an unmet therapeutic need. METHODS: In 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. RESULTS: Among 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. CONCLUSIONS: Our 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.
BACKGROUND: Brain metastases present a significant complication in lung cancer with an unmet therapeutic need. METHODS: In 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. RESULTS: Among 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. CONCLUSIONS: Our 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.
Authors: Erica Shen; Amanda E D Van Swearingen; Meghan J Price; Ketan Bulsara; Roeland G W Verhaak; César Baëta; Brice D Painter; Zachary J Reitman; April K S Salama; Jeffrey M Clarke; Carey K Anders; Peter E Fecci; C Rory Goodwin; Kyle M Walsh Journal: Front Oncol Date: 2022-01-25 Impact factor: 6.244