Biomarkers for CNS metastasis in non-small cell lung cancer (NSCLC)

Non-small cell lung cancer (NSCLC) comprises more than 75% of lung cancer cases and is usually diagnosed in advanced stages. Lung cancer is the leading cause of cancer death among all solid tumours and the second most common malignancy globally. The prognosis of NSCLC patients with brain metastases (BM) is poor with a median overall survival of 4–11 weeks in untreated patients and 4–15 months in treated patients. Approximately 45% of patients with non-oncogenic driven NSCLC and 70% of patients with EML4-ALK rearrangements or EGFR mutations will be diagnosed with BM during the course of the disease. The incidence of BM appears to be increasing mostly owing to improvements in diagnostic imaging and in survival associated with more effective systemic therapies. The main purpose of this thesis is to identify clinical and molecular biomarkers for BM of NSCLC, as well as to explore the molecular diversity between CNS metastases and primary NSCLC.

Paper I was a single institution cohort study including brain metastasized lung cancer patients who received Whole Brain Radiotherapy (WBRT) at Karolinska University Hospital, Stockholm, Sweden. The aim of this trial was to find prognostic factors that can influence OS in lung cancer patients with BM treated with WBRT, in order to identify which patients will live long enough to experience the palliative benefit of WBRT, regarding disease control in the CNS. This study provided additional information on the selection of BM NSCLC patients who should receive WBRT by combining RPA and GRA prognostic indexes. In paper II we analysed a total of 43 tissue samples from NSCLC patients for systematic mRNA expression; 13 primary tumours and 30 brain metastases. The material was obtained from 25 patients, of which 13 underwent surgery of the primary tumour. The paired samples were 26 (13 patients with both available lung and brain tissue samples). A unique gene downregulation pattern in brain metastases compared with primary tumours was observed. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in the brain metastatic setting. In paper III the validity of Lung-molGPA index in an ALK-positive lung cancer cohort with BM (n= 44) was explored, and a new prognostic scoring system, the ALK-BPI score, which can be easily applicable in clinical practice was proposed. PS, sex and BM at diagnosis, were used as prognostic variables in ALK-BPI. The aim of paper IV - a retrospective cohort study consisting of 304 patients with surgically removed NSCLC- was to investigate whether high expression of NRF2 or TrxR1 in early stage NSCLC is predictive for relapse in CNS or other organs. High expression of NRF2 in cytokeratine positive cells in the whole tissue core compartment was correlated with higher risk for CNS relapse. This is to our knowledge the first study to report a predictive biomarker for CNS relapse in early stage NSCLC. In summary, this thesis expands the knowledge regarding the molecular diversity between CNS metastases and primary NSCLC, and proposes new clinical and molecular biomarkers for BM of NSCLC.

List of scientific papers

I. Tsakonas, G.; Hellman, F.; Gubanski, M.; Friesland, S.; Tendler, S.; Lewensohn, R.; Ekman, S.; de Petris, L. Prognostic factors affecting survival after whole brain radiotherapy in patients with brain metastasized lung cancer. Acta oncologica. 2018, 57, 231-238.
https://doi.org/10.1080/0284186X.2017.1386799

II. Tsakonas, G.; Lewensohn, R.; Botling, J.; Ortiz-Villalon, C.; Micke, P.; Friesland, S.; Nord, H.; Lindskog, M.; Sandelin, M.; Hydbring, P., et al. An immune gene expression signature distinguishes central nervous system metastases from primary tumours in non-small-cell lung cancer. European journal of cancer. 2020, 132, 24-34.
https://doi.org/10.1016/j.ejca.2020.03.014

III. Tsakonas, G.; Kamali, C.; De Petris, L.; Friesland, S.; Lewensohn, R.; Ekman, S. ALK-Brain Prognostic Index-Preliminary Study of a Prognostic Tool for Patients with ALK-Rearranged, Non-small Cell Lung Cancer and Brain Metastases. Cancers (Basel). 2020, 12.
https://doi.org/10.3390/cancers12071804

IV. Tsakonas, G; Martín-Bernabé, A; Moreno-Ruiz, P; Micke, P; Botling, J; De Petris, L; Ylipää, A; Mezheyeuski, A; Östman2, A; Ekman, S. NRF2 expression in malignant cells of early stage NSCLC is predictive for relapse in the CNS. [Manuscript]