ABSTRACT
Background: Advanced non-small cell lung cancer (NSCLC) is often complicated by leptomeningeal metastases (LMs), especially in patients carrying EGFR mutations. EGFR tyrosine kinase inhibitors (TKIs) are the first-line drug for patients with specific gene mutations, such as EGFR exon 19 deletion or exon 21 L858R mutation. However, after long-term TKI use, patients eventually develop drug resistance and acquire new mutations. Acquiring the EGFR T790 M mutation during TKI treatment is a marker for first/second generation TKI resistance. Osimertinib (a third-generation TKI) could overcome this resistance, especially for patients who have already developed NSCLC-LM. Treating NSCLC patients with osimertinib resistance is challenging. Our aim was to investigate whether afatinib is effective in NSCLC-LM patient who showed resistance to osimertinib. Herein, we report two patients with resistance to first- and third-generation TKIs who benefited from second-generation TKI. Case summary: Case one: A 43-year-old man was diagnosed with stage 3A NSCLC with EGFR exon 19 deletion. He underwent surgery and received 4 rounds of chemotherapy (oxaliplatin combined with liposomal paclitaxel), after which the disease was controlled by icotinib (a first-generation TKI) for 4 years. Then, he showed poor drug response and bone metastasis. A liquid biopsy was carried out, and the EGFR L858R/T790 M compound mutation was found. The patient was given osimertinib (a third-generation TKI). The patient was in a stable condition for 2 years and then he developed bilateral peripheral facial palsy. Brain MRI showed enhancement in the left temporal lobe and meninges, and cerebrospinal fluid (CSF) cytology detected tumour cells in the CSF. NSCLC-LM was diagnosed. His performance status (PS) score was 3-4. Liquid biopsy and next-generation sequencing were performed again. Different gene mutations and copy number alterations were found this time, including EGFR L858R, but without the EGFR T790 M mutation. His disease was controlled with intrathecal methotrexate and oral afatinib (a second generation TKI). The patient has shown clinical remission (PS score: 1-2) until now, which is longer than 10 months. Case two: A 50-year-old man was diagnosed with NSCLC in May 2020. He underwent one round of chemotherapy before thoracoscopic partial lobectomy of the right upper lung. Histological study of the lung tissue showed lung adenocarcinoma with the EGFR L858R mutation. Then, the disease was controlled with icotinib. One year later, he was diagnosed with NSCLC-LM. Liquid biopsy and sequencing showed an EGFR L858R/S768I compound mutation. The patient was treated with osimertinib. His condition was stable for 5 months before his central nervous system (CNS) symptoms were exacerbated. Liquid biopsy and sequencing were carried out again, and his gene mutation profile had not changed much. Then, the patient was given afatinib, and his condition has remained stable for 11 months. Conclusion: Afatinib might be suitable for NSCLC-LM patients with EGFR compound mutations who show resistance to icotinib and osimertinib, since it might help overcome first- and third-generation TKI resistance.
ABSTRACT
Background: Brain metastases (BM), including brain parenchyma metastases (BPM) and leptomeningeal metastases (LM), are devastating metastatic complications in advanced cancer patients. Next-generation sequencing (NGS) is emerging as a new promising tool for profiling cancer mutation, which could facilitate the diagnosis of cancer. This retrospective study aimed to investigate the molecular genetic characteristics of non-small cell lung cancer (NSCLC) patients with BPM and LM using NGS. Methods: Cerebrospinal fluid (CSF) samples and paired plasma samples were collected from 37 patients of NSCLC-BM. We profiled genetic mutation characteristics using NGS from NSCLC-BM by comparing CSF circulating tumour DNA (ctDNA) with plasma ctDNA and primary tumour tissues. Results: Among the 37 patients with NSCLC-BM, 28 patients had LM with or without BPM, while 9 patients only had BPM. Driver and drug-resistant mutations in primary tumours with LM included: EGFR L858R (10, 35.7%), EGFR 19del (6, 21.4%), EGFR L858R+MET (1, 3.6%), EGFR L858R+S768I (1, 3.6%), ALK (2, 7.1%), ROS1 (1, 3.6%), negative (5, 17.9%), and unknown (2, 7.1%). In patients with NSCLC-LM, the detection rate and abundance of ctDNA in the CSF were significantly higher than those in paired plasma. The main driver mutations of NSCLC-LM remained highly consistent with those of the primary tumours, along with other unique mutations. Circulating tumour DNA was negative in the CSF samples of BPM patients. Patients with BMP had a higher ratio of EGFR 19del than L858R mutation (55.6% vs 11.1.%), whereas NSCLC patients with LM had a higher ratio of EGFR L858R than 19del mutation (50.0% vs 25.0%). Most patients with positive plasma ctDNA results were male (p = 0.058) and in an unstable state (p = 0.003). Conclusion: Our study indicated that the CSF ctDNA detected by NGS may reflect the molecular characteristics and heterogeneity of NSCLC-LM. Timely screening of patients with NSCLC for CSF ctDNA, especially for patients with positive plasma ctDNA, may facilitate the early detection of LM. Furthermore, patients with the EGFR 19del may have a higher risk of developing BPM.
