A population-based study of 6,000 lung cancer patients shows that patients with the KRAS G12C mutation have a high risk of brain metastases. Surprisingly this is not linked to worse survival. The study was conducted by researchers affiliated with Genomic Medicine Sweden and the National Swedish Lung Cancer Registry with support from Amgen.
Each year, approximately 4,000 patients are diagnosed with lung cancer in Sweden. In the most common form, non-small cell lung cancer (NSCLC), the tumor development is propelled by changes in genes that control cell proliferation, so called “driver genes”. The most commonly affected gene is KRAS, where several different gene mutations, for unknown reason, result in a very heterogeneous group of tumors. One of these KRAS mutations, the G12C variant, has been in focus in recent years because it can be targeted by specific drugs.
The study includes more than 6,000 patients in the Swedish National Lung Cancer Registry where a gene sequencing analysis was performed at diagnosis. The results show that the KRAS G12C mutation is strongly linked to smoking, more common in female patients and affects the spread of the cancer in a unique way compared to other KRAS mutations.
“The most interesting finding is that lung cancer patients with the G12C mutation in KRAS are more likely to get brain metastases than patients with other mutations,” says Johan Botling, Senior consultant at Sahlgrenska University Hospital and professor of pathology at Gothenburg University, who led the study.
However, the survival analysis showed that patients with the KRAS G12C mutation who presented with brain metastases at diagnosis did not have a worse outcome compared to patients with other patterns of metastatic tumor dissemination.
“This finding surprised us. We noted that these lung cancer patients seem to get brain metastases earlier in their disease than others, but at the same time have fewer metastases in other organs. This might explain why these patients do better then expected,” says Johan Botling. In further studies, we will investigate how different KRAS mutations affect the response to treatment with chemotherapy, immunotherapy and targeted drugs.
An essential precondition of the study is that results from mutation diagnostics with NGS (next-generation sequencing) have been reported at a national level for lung cancer patients to the National Lung Cancer Registry since 2015.
“The National Lung Cancer Registry is a unique resource for research where we, in order to evaluate existing treatments and develop new therapeutic procedures, can link molecular data with other patient information such as age, gender and treatment outcome. This is the first study where we have linked mutation data from the tumors with patient data in the registry,” says Gunnar Wagenius, Associate Professor and Senior consultant oncologist at Karolinska University Hospital and registry holder of the National Lung Cancer Registry.
“Thanks to early adoption of diagnostic biomarker testing in Sweden, we have the opportunity to generate high-quality real-world-data on large patient populations. This is of utmost importance for the design of new clinical trials in the area of targeted treatment. For us at Amgen, working with GMS and the lung cancer registry has been a rewarding collaboration that has resulted in important knowledge with global impact beyond Sweden,” says Sandra Eketorp Sylvan, Medical Director of Amgen Sweden.
“In this project we looked at mutations in one gene and obtained interesting results. With even broader gene sequencing developed within the GMS network, it will possible to explore the impact of hundreds of genes on large national patient populations. This knowledge will help us to better understand different types of lung cancer and how to improve treatment for individual patients,” concludes Johan Botling.
KRAS G12C Mutant Non–Small Cell Lung Cancer Linked to Female Sex and High Risk of CNS Metastasis: Population-based Demographics and Survival Data from the National Swedish Lung Cancer Registry Isaksson J, Berglund A, Louie K, Willén L, Hamidian A, Edsjö A, Enlund F, Planck M, Vikström A, Johansson M, Hallqvist A, Wagenius G, Botling J. Clin Lung Cancer. 2023 Sep;24(6):507-518. doi: 10.1016/j.cllc.2023.05.002.
- Non-small cell lung cancer (NSCLC) is the most common type of lung cancer.
- NSCLC affects approximately 3,500 patients annually in Sweden.
- Currently, eight genes are tested to guide targeted therapies in lung cancer (EGFR, KRAS, BRAF, ALK, ROS1, RET, NTRK and METex14).
- KRAS is the most common of these ‘driver’ mutations (present in about 30% of tumors).
- Lung cancer with KRAS mutations is a very heterogeneous group of tumors.