Overall survival comparison in patients with and without brain metastases treated with osimertinib for metastatic EGFR mutation positive non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21216-e21216
Author(s):  
Danilo Giffoni de Mello Morais Mata ◽  
Maria Luisa Romero ◽  
Carlos Amir Carmona Gonzalez ◽  
Alia Thawer ◽  
Mark Doherty ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Egfr Mutation ◽  
Leptomeningeal Metastasis ◽  
Small Cell ◽  
Small Cell Lung ◽  
Exon 19 Deletion ◽  
Exon 19

e21216 Background: With the development of Epidermal Growth factor receptor (EGFR) tyrosine kinase inhibitors such as Osimertinib, the landscape of lung cancer treatment and outcomes has changed. We aimed to describe the outcomes of patients treated with Osimertinib who have brain metastasis compared to those without brain metastases. Methods: This study involved patients diagnosed with metastatic non-small cell lung cancer (NSCLC) with EGFR mutation, from January 2010 to December 2018, who had treatment with Osimertinib at a dose of 80 mg daily. Retrospective data was collected through the electronic medical records from Sunnybrook Health Sciences Centre. Descriptive statistics were used to summarize the population characteristics. The log rank test was used to compare the survival distributions. Results: A total of 56 patients were included, the mean age at initial diagnosis was 63 years (range 27 – 85 years). Overall, 82.2% of this patient population received Osimertinib in 2nd line setting. A total of 50% (n = 28) had brain metastasis, and14.3% (n = 8) had leptomeningeal metastasis. Of the patients with brain metastasis, 14.3% (n = 4) had brain surgery. All patients with brain metastasis received central nervous system (CNS) radiation. With respect to radiotherapy modalities, 67.9% (n = 19) of patients with brain metastasis received gamma knife radiation, 42.85% (n = 12) were treated with stereotactic radiosurgery (SRS), and whole brain radiation was given to 57.1% (n = 16). Of those with brain metastasis, equal numbers of patients, 46.4% (n = 13), had EGFR mutations with exon 19-deletion and exon 21-L858R, 7.1% (n = 2) had unknown gene location EGFR mutation. The median OS for patients without brain metastasis was 38.6 months (95% confidence interval [CI] 37.5 – 39.8 months], compared to 35.9 months (95% [CI] 28.3 – 43.5 months] for those with brain metastasis ; log Rank (Mantel-Cox) p = 0.874. The median OS for patients diagnosed with leptomeningeal metastasis was 21 months (95% [CI] 2.9 – 39.0 months); log rank (mantel-cox). When brain metastasis was examined by EGFR mutation sub-groups, the median OS for patients with EGFR-exon 19-deletion was 26.4 months (95% CI [14.3 – 38.4 months], compared to 36.8 months, 95% CI [34.3 – 39.2 months] for those with EGFR-Exon 21-L858R; log Rank (Mantel-Cox) p = 0.49. Conclusions: Although there is an equivalent prevalence of brain metastasis between the two NSCLC EGFR mutation populations, in unadjusted analyses, no difference in OS was seen between patients with brain metastases compared to those without brain metastases. However, in the small number of patients with leptomeningeal disease, survival was shorter and a larger population should be studied to further explore this finding.

scholarly journals The structure of blood–tumor barrier and distribution of chemotherapeutic drugs in non-small cell lung cancer brain metastases

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ling-yun Ye ◽  
Li-xiang Sun ◽  
Xiu-hua Zhong ◽  
Xue-song Chen ◽  
Song Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Blood Vessels ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Chemotherapeutic Drugs ◽  
Small Cell Lung ◽  
Metastatic Lesions

Abstract Background Brain metastasis is an important cause of increased mortality in patients with non-small cell lung cancer (NSCLC). In brain metastasis, the blood–brain barrier (BBB) is frequently impaired, forming blood–tumor barrier (BTB). The efficacy of chemotherapy is usually very poor. However, the characteristics of BTB and the impacts of BTB on chemotherapeutic drug delivery remain unclear. The present study investigated the structure of BTB, as well as the distribution of routine clinical chemotherapeutic drugs in both brain and peripheral tumors. Methods Bioluminescent image was used to monitor the tumor load after intracranial injection of lung cancer Lewis cells in mice. The permeability of BBB and BTB was measured by fluorescent tracers of evans blue and fluorescein sodium. Transmission electron microscopy (TEM), immunohistochemistry and immunofluorescence were performed to analyze structural differences between BBB and BTB. The concentrations of chemotherapeutic drugs (gemcitabine, paclitaxel and pemetrexed) in tissues were assayed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Results Brain metastases exhibited increased BTB permeability compared with normal BBB detected by fluorescence tracers. TEM showed abnormal blood vessels, damaged endothelial cells, thick basement membranes, impaired intercellular endothelial tight junctions, as well as increased fenestrae and pinocytotic vesicles in metastatic lesions. Immunohistochemistry and immunofluorescence revealed that astrocytes were distributed surrounded the blood vessels both in normal brain and the tumor border, but no astrocytes were found in the inner metastatic lesions. By LC-MS/MS analysis, gemcitabine showed higher permeability in brain metastases. Conclusions Brain metastases of lung cancer disrupted the structure of BBB, and this disruption was heterogeneous. Chemotherapeutic drugs can cross the BTB of brain metastases of lung cancer but have difficulty crossing the normal BBB. Among the three commonly used chemotherapy drugs, gemcitabine has the highest distribution in brain metastases. The permeability of chemotherapeutic agents is related to their molecular weight and liposolubility.

scholarly journals Histological transformation of lung adenocarcinoma to small cell lung cancer with mutant C797S conferring acquired resistance to osimertinib

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052092791 ◽  
Author(s):  
Xiaohui Ren ◽  
Xinfeng Cai ◽  
Jing Li ◽  
Xia Zhang ◽  
Jianfei Yu ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Exon 19 Deletion ◽  
Exon 19

Epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer may initially respond to EGFR tyrosine kinase inhibitors (TKIs), but may subsequently become resistant; however, the resistance mechanisms remain unclear. We report a rare case of acquired resistance to osimertinib associated with transformation to small cell lung cancer (SCLC) with cis-C797S mutation. A man with recurrent lung adenocarcinoma harboring an EGFR exon 19 deletion received erlotinib for 10 months following curative surgery and adjuvant chemotherapy. However, he switched to osimertinib after repeat biopsy showed EGFR exon 19 deletion and T790M mutation leading to erlotinib resistance. His disease progressed after 15 months and repeat biopsy showed SCLC. Next-generation sequencing of peripheral blood detected EGFR exon 19 deletion, T790M mutation, cis-C797S mutation, and RB1 inactivation. The tumor was reduced after four cycles of etoposide and cisplatin and his respiratory symptoms improved. However, computed tomography after six cycles of chemotherapy showed multiple bilateral lung lesions, and single-photon emission computed tomography showed bone metastasis. The patient received paclitaxel plus cisplatin for two cycles with partial response. Because heterogeneous genetic and phenotypic mechanisms of TKI-resistance may occur at different times and locations, histopathological and molecular testing both provide evidence to support appropriate treatment.

scholarly journals The impact of EGFR exon 19 deletion subtypes on clinical outcomes in non-small cell lung cancer

2020 ◽  
Vol 9 (4) ◽  
pp. 1149-1158
Author(s):  
Chao Zhao ◽  
Tao Jiang ◽  
Jiayu Li ◽  
Yan Wang ◽  
Chunxia Su ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Exon 19 Deletion ◽  
The Impact ◽  
Exon 19

Survival benefit of gefitinib treated non-small-cell lung cancer patients with exon 19 deletion mutations in epidermal growth factor receptor (EGFR), detected by a new sensitive PCR-based method

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10614-10614
Author(s):  
E. Nakajima ◽  
M. Sugita ◽  
R. Dziadziuszko ◽  
M. Tsuboi ◽  
H. Kato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Survival Benefit ◽  
Objective Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Deletion Mutations ◽  
Exon 19 Deletion ◽  
Exon 19

10614 Background: As for two common types of EGFR mutations, patients with exon 19 deletion mutations have longer survival than those with the L858R point mutations in exon 21 after treatment with EGFR inhibitors. We have developed a simple, polymerase chain reaction (PCR)-based method to detect exon 19 deletion mutations, and evaluated survival benefit of gefitinib treated patients with exon 19 deletion mutations versus patients without these mutations. Patients and methods: Tumor tissue was microdissected under stereoscopic microscopy from formalin-fixed paraffin-embedded sections, and DNA was extracted from tumor cells with DNeasy (Qiagen). Our method consisted of two different semi-nested PCRs with the deletion screening PCR and the common deletion specific PCR. All of the known deletions present in cell lines were detected by this method without direct sequencing. The result was validated by sequencing of exon 19. 73 non-small-cell lung cancer (NSCLC) Japanese patients treated with gefitinib were analyzed with this method. Study group consisted of 28 females (38%), 29 never smokers (40%) and 57 patients with adenocarcinoma (78%). Results: The PCR-based method detected mutations at mutant to wild type DNA copy ratio of 1/600, and in samples as small as 30 ng of purified DNA. Exon 19 deletion mutations were found in 25 (34%) patients. This method was more sensitive than conventional sequencing. The sequencing was performed in 19 patients with mutations and could not detect 3 deletions. Among 60 assessable patients 14 had overall response (23%). Objective response rates to gefitinib were observed in 7/21 patients with exon 19 deletion mutations (33%), and 7/39 patients without exon 19 deletion mutations (17%) (P = .211). Patients with exon 19 deletion mutations survived significantly longer than those without exon 19 deletion mutations (P = .017). Conclusions: The PCR-based method to detect exon 19 deletion mutations is cost effective and very sensitive, compared to previously described methods. We demonstrated survival benefit in NSCLC patients with exon 19 deletion mutations treated with gefitinib, and our PCR-based method is easily applicable for clinical use. No significant financial relationships to disclose.

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