- Email: [email protected]
OA08.01 Exploration of the Underlying Mechanisms of Leptomeningeal Metastasis in NSCLC Patients through NGS of Cerebrospinal Fluid
January 2017
Abstracts
S271
Methods: we performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF) and matched normal controls from 11 EGFRm+ NSCLC patients with LM. Among them, 2 patients had LM at initial diagnosis, and 8 patients developed LM during 1st generation EGFR-TKI treatment, while such clinical information was missing for 1 patient.
Keywords: surgical upgrading, T-factor
margin,
sublobar
resection,
OA08.01 Exploration of the Underlying Mechanisms of Leptomeningeal Metastasis in NSCLC Patients through NGS of Cerebrospinal Fluid Yun Fan,1 Min Hu,2 Xuehua Zhu,3 Mengzhao Wang,4 Yanjun Xu,1 Xuesong Lv,2 Haiyan Xu,2 Jingyan Ding,2 Xin Ye,2 Luo Fang,5 Zhiyu Huang,5 Lulu Miao,5 Lei Gong,5 Weimin Mao,5 Hongyang Lu5 1 Chemotherapy, Zhejiang Cancer Hospital, Hangzhou/ China, 2Asia & Emerging Markets Imed, astrazeneca Innovative Medicine and Early Development, Shanghai/ China, 3Asia & Emerging Markets Imed, Astrazeneca Innovative Medicine and Early Development, Shanghai/ China, 4Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing/China, 5Zhejiang Cancer Hospital, key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Hangzhou, China, Hangzhou/China
Results: The status of EGFR active mutations was the same in the primary tumor and CSF of all the patients, except one whose EGFR mutation was undetectable in the primary site probably due to low sequence coverage. In total, there were 8 patients with EGFR L858R, 1 with 19Del, and 2 with L858R & 19Del dual mutation. One patient also had de novo EGFR T790M in the primary site. None of the CSF samples showed EGFR T790M mutation, suggesting that it was not the resistance mechanism for the 8 patients who developed LM during TKI treatment. PIK3CA E545K and H1047L, and PTEN R130Q were identified in primary site and/or CSF of 6 patients. Although with small sample size, this ratio is much higher than what was reported in general EGFR L858R or 19Del positive lung adenocarcinoma patient population (w2% from 4 datasets), implicating that alternations in PI3K pathway may associate with LM risk. Interestingly, in 9 of the 11 patients, only 0.9%-7.8% of variants in CSF samples overlapped with those in primary site, suggesting tumor heterogeneity, divergence and clonal evolution during LM development. Moreover, when we cataloged the recurrent CSF-unique somatic genomic alterations existing in 5 patients, we identified genes involved in DNA repair pathway, cell cycle regulation and epigenetic reprogramming (NPM1, RAD50, MRE11A, POLE, CHEK1, XPC, KMT2B, KMT2C, KMT2D, and ATRX). Conclusion: In summary, our study has shed light on the genomic variations of LM and paved the way for potential therapeutic approaches to this unmet medical need.
OA08.02 Phase II Study of Erlotinib in Advanced Non-Small Cell Lung Cancer Patients Background: About 10% of non-small cell lung cancer with Leptomeningeal Metastasis (NSCLC) patients with EGFR mutations will develop (LOGIK1101) leptomeningeal metastasis (LM) either at initial diagnosis or during treatment. LM is a devastating complication of NSCLC associated with poor prognosis. The median overall survival is 4.5-11 months, with w60% death due to LM or LM together with systemic lesions. However, the underlying mechanisms of the metastasis process are still poorly understood.
Keiichi Ota,1 Yoshimasa Shiraishi,2 Taishi Harada,1 Daisuke Himeji,3 Takeshi Kitazaki,4 Noriyuki Ebi,5 Akinobu Hamada,6 Takeharu Yamanaka,7 Kaname Nosaki,2 Mitsuhiro Takenoyama,2 Kenji Sugio8 1Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University,
Abstracts
S271
Methods: we performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF) and matched normal controls from 11 EGFRm+ NSCLC patients with LM. Among them, 2 patients had LM at initial diagnosis, and 8 patients developed LM during 1st generation EGFR-TKI treatment, while such clinical information was missing for 1 patient.
Keywords: surgical upgrading, T-factor
margin,
sublobar
resection,
OA08.01 Exploration of the Underlying Mechanisms of Leptomeningeal Metastasis in NSCLC Patients through NGS of Cerebrospinal Fluid Yun Fan,1 Min Hu,2 Xuehua Zhu,3 Mengzhao Wang,4 Yanjun Xu,1 Xuesong Lv,2 Haiyan Xu,2 Jingyan Ding,2 Xin Ye,2 Luo Fang,5 Zhiyu Huang,5 Lulu Miao,5 Lei Gong,5 Weimin Mao,5 Hongyang Lu5 1 Chemotherapy, Zhejiang Cancer Hospital, Hangzhou/ China, 2Asia & Emerging Markets Imed, astrazeneca Innovative Medicine and Early Development, Shanghai/ China, 3Asia & Emerging Markets Imed, Astrazeneca Innovative Medicine and Early Development, Shanghai/ China, 4Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing/China, 5Zhejiang Cancer Hospital, key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Hangzhou, China, Hangzhou/China
Results: The status of EGFR active mutations was the same in the primary tumor and CSF of all the patients, except one whose EGFR mutation was undetectable in the primary site probably due to low sequence coverage. In total, there were 8 patients with EGFR L858R, 1 with 19Del, and 2 with L858R & 19Del dual mutation. One patient also had de novo EGFR T790M in the primary site. None of the CSF samples showed EGFR T790M mutation, suggesting that it was not the resistance mechanism for the 8 patients who developed LM during TKI treatment. PIK3CA E545K and H1047L, and PTEN R130Q were identified in primary site and/or CSF of 6 patients. Although with small sample size, this ratio is much higher than what was reported in general EGFR L858R or 19Del positive lung adenocarcinoma patient population (w2% from 4 datasets), implicating that alternations in PI3K pathway may associate with LM risk. Interestingly, in 9 of the 11 patients, only 0.9%-7.8% of variants in CSF samples overlapped with those in primary site, suggesting tumor heterogeneity, divergence and clonal evolution during LM development. Moreover, when we cataloged the recurrent CSF-unique somatic genomic alterations existing in 5 patients, we identified genes involved in DNA repair pathway, cell cycle regulation and epigenetic reprogramming (NPM1, RAD50, MRE11A, POLE, CHEK1, XPC, KMT2B, KMT2C, KMT2D, and ATRX). Conclusion: In summary, our study has shed light on the genomic variations of LM and paved the way for potential therapeutic approaches to this unmet medical need.
OA08.02 Phase II Study of Erlotinib in Advanced Non-Small Cell Lung Cancer Patients Background: About 10% of non-small cell lung cancer with Leptomeningeal Metastasis (NSCLC) patients with EGFR mutations will develop (LOGIK1101) leptomeningeal metastasis (LM) either at initial diagnosis or during treatment. LM is a devastating complication of NSCLC associated with poor prognosis. The median overall survival is 4.5-11 months, with w60% death due to LM or LM together with systemic lesions. However, the underlying mechanisms of the metastasis process are still poorly understood.
Keiichi Ota,1 Yoshimasa Shiraishi,2 Taishi Harada,1 Daisuke Himeji,3 Takeshi Kitazaki,4 Noriyuki Ebi,5 Akinobu Hamada,6 Takeharu Yamanaka,7 Kaname Nosaki,2 Mitsuhiro Takenoyama,2 Kenji Sugio8 1Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University,