High rate of FGFR1 amplifications in brain metastases of squamous and non-squamous lung cancer
Introduction
Lung cancer is the leading cause of cancer-related mortality worldwide. Standard therapy for advanced lung cancer comprises platinum-based chemotherapy in many cases. However, recent advances have shown that molecular subtypes with sensitivity to specific therapeutic inhibitors exist. For lung adenocarcinomas (AC), inhibitors of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are active and have been approved for clinical use and promising inhibitors of further oncogenic aberrations such as proto-oncogene tyrosine-protein kinase 1 (ROS1) rearrangements, phosphatidylinositide 3-kinases (PI3K) mutations, v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, human epidermal growth factor receptor 2 (HER2) insertions, or RET rearrangements are under development [1]. The successful identification of drugable targets in lung AC has stimulated screening of squamous cell carcinoma (SCC) specimens and has led to identification of focal amplification of the FGFR1 gene in approximately 20% of cases [2], [3], [4]. Interestingly, FGFR1 amplifications have been shown to be rare in primary lung AC, where they are found in approximately 3% of cases [2], [4]. FGFR1 is a membrane-bound receptor tyrosine kinase that participates in the regulation of cell proliferation, differentiation and angiogenesis via PI3K and mitogen activated protein kinase (MAPK) pathways and FGFR1 inhibition has distinct anti-neoplastic effects in FGFR1-amplified tumors [2], [4]. Consequently, several FGFR1 inhibitors such as PD173074, AZD4547, brivanib (BMS-582664), NVP-BGJ398, FP-1039 and others are under preclinical and clinical development [2], [3], [5], [6], [7].
NSCLC is a frequent cause of brain metastases with up to 40% of patients developing secondary central nervous system (CNS) involvement during the disease course [8]. Brain metastases are associated with high morbidity and mortality and there is an urgent need for novel therapies besides the established standard treatment options including radiotherapy, radiosurgery and surgery. In specific subsets of BM patients, targeted agents have shown clinically meaningful activity. For example, the BRAF inhibitors vermurafenib and dabrafenib lead to tumor responses in many patients with brain metastases of BRAF-V600 mutated melanoma [9]. In NSCLC, EGFR inhibitors gefitinib and erlotinib have shown evidence for activity against established brain metastases, but also for prophylaxis of CNS relapse [9]. These data highlight the feasibility of targeted drug therapy for brain metastases and identification of further molecular drug targets may enlarge the therapeutic repertoire for NSCLC brain metastasis patients. However, so far to the best of our knowledge FGFR1 amplifications have not been investigated in brain metastases. Therefore, we performed this study to characterize the frequency and association with clinico-pathological factors of FGFR1 amplifications in a large cohort of NSCLC brain metastasis patients.
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Patients
All patients who underwent surgery for brain metastases of NSCLC at the Medical University of Vienna, Austria, between March 1990 and February 2011 were eligible for this retrospective study. A histologically confirmed primary lung cancer had to be evident for inclusion in this study. Clinical data were retrieved by chart review and death dates were retrieved by chart review and from the database of National Cancer Registry of Austria and the Austrian Brain Tumor Registry [10]. Institutional
Patients
Mean age of patients at time of brain metastasis operation was 57 ± 9 years, 110 patients were males, 65 females. Table 1 summarizes baseline and clinical data.
FGFR1 FISH results in brain metastases
FISH was performed in 175 NSCLC-BM samples, comprising 130 AC, 21 SCC, 12 adenosquamous carcinomas (ASC), 9 large cell carcinomas (LC) and 3 neuroendocrine large cell carcinomas (NLC). Fig. 1 shows representative FISH results.
In brain metastases, a loss of FGFR1 (only 1 gene copy) was seen in 8 out of 175 samples (4.6%). In 2 samples with
Discussion
Among SCC brain metastases we found FGFR1 amplifications in 19% of cases, which is well in line with the frequency reported for primary lung SCC. Furthermore, in three SCC cases with available matched primary tumors and BM of the same patients, the FGFR1 amplification status was similar between the lesions. Thus, our data indicate that in SCC the FGFR1 status is consistent in different tumor manifestation. It must be noted, however, that our sample of SCC is relatively small (n = 21), because the
Funding
This work was supported by the research budget of the Medical University of Vienna.
Conflicts of interest statement
The authors have declared no conflicts of interest.
Acknowledgements
We thank Irene Leisser and Gerda Ricken for excellent assistance with tissue handling and experimental procedures. The funding source had no role in the manuscript and the study design, data interpretation and manuscript preparation was solely the responsibility of the authors.
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2021, Clinical Neurology and NeurosurgeryCitation Excerpt :Of note, in this series all patients were male, and smoking status was active, showing the same risk factors for development of precocious BM with FGFR1 amplifications as reported for primary tumors [39,40]. Preusser et al. did not find any correlation between gender and FGFR1 amplification for BM [19]. Furthermore, we did not detect any ROS1, RET, and EML4/ALK rearrangements in our series, which is in line with Jünger et al. [36] as well as the current literature, reporting only low frequencies of 1–2% [29,42,43].
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2020, Clinical Genitourinary CancerCitation Excerpt :However, these trials excluded patients with brain metastases. Although there is high FGFR1 amplification seen in the brain metastases of patients with metastatic lung cancer,19 information regarding metastatic urothelial cancers to the brain are currently lacking. Treatment with FGFR inhibitors may cross the blood-brain barrier as described in a phase I trial on glioma,20 though it is unclear what the extent of response would be for brain metastases.21