- Email: [email protected]
Treatment of a NSCLC patient with osimertinib based on the detection of the EGFR T790M resistance mutation in cerebrospinal fluid
Lung Cancer xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Correspondence Treatment of a NSCLC patient with osimertinib based on the detection of the EGFR T790M resistance mutation in cerebrospinal fluid Dear Editor, Osimertinib (AZD9291), a third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has demonstrated efficiency [1] and has been approved for the treatment of patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC). Therefore, T790M testing is mandatory. The cobas® EGFR mutation test v2 (Roche Molecular Systems, Pleasanton, CA, USA) has been shown to be efficient for detecting the T790M mutation in DNA extracted from tumor samples [2] and from plasma [3]. It has been approved as the companion diagnostic test for osimertinib in the USA and in Japan. Satouchi et al. recently reported that the cobas® EGFR assay was also efficient for detecting EGFR alterations in cytology samples [4]. Here, we would like to share our experience about a woman with NSCLC who could be treated with osimertinib based on the detection of the T790M resistant mutation in circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF). A 48-year-old Caucasian female, with a 20 pack-year smoking history and who had a Langerhans cell histiocytosis, presented with persistent cough in March 2015. Computed tomography scan revealed the presence of a lung nodule in the upper right lobe and a biopsy confirmed lung adenocarcinoma with a sensitizing EGFR L858R mutation (exon 21). A brain magnetic resonance imaging (MRI) was also performed and showed several metastases. In June 2015, whole brain irradiation (30 Gy) and erlotinib (150 mg daily) was thus administered resulting in a partial response with progression-free survival of 11 months. In May 2016, the patient complained of headache and dizziness and her condition quickly deteriorated (epileptic seizures, phasic and swallowing disorders). A new MRI suggested the presence of leptomeningeal carcinomatosis. At this time, it was impossible to perform new biopsies, therefore molecular analyses were performed using ctDNA from plasma and CSF using the cobas® EGFR mutation test. Whereas no mutation was detected in plasma, CSF exhibited the previously identified sensitizing EGFR mutation (semi quantitative index SQI = 16.28) and also the T790M resistance mutation (SQI = 13,70). These data were confirmed by digital PCR (dPCR) (Fig. 1). Erlotinib treatment was stopped and replaced by osimertinib (80 mg daily). The patient experienced a rapid neurological improvement and restaging after 8 weeks of therapy demonstrated a significant decrease of leptomeningeal metastases (LM). Unfortunately, the disease progressed again and the patient died because of cerebral progression in October 2016. Patients with EGFR mutant NSCLC, treated with first and second generation of TKI, experience disease progression during treatment due to growth of central nervous system (CNS) metastases in about 30% of cases [5]. The main treatments of these metastases are surgical resection (for brain metastases (BM)), intra-thecal chemotherapy (for LM) or whole brain radiation therapy (for both locations). These therapies have significant side effects which impact the quality of life of patients. It is therefore necessary, when possible, to favor systemic treatments. Osimertinib targets sensitizing EGFR mutations as well as the T790M EGFR resistant mutation. The AURA (NCT01802632, NCT02094261, NCT02151981) and BLOOM (NCT02228369) clinical trials, have shown that osimertinib is efficient for the treatment of NSCLC patients with BM and/or LM [1,6]. In addition, several case reports demonstrated rapid intracranial response to osimertinib in patients with EGFR T790M-positive lung cancer [7,8]. According to pre-clinical data, this efficiency appears to be due to a greater penetration of the blood-brain barrier [9].
Fig. 1. Results of T790M testing by digital PCR on ctDNA from plasma (A) and CSF (B). Circulating DNA was extracted using the cobas cfDNA preparation kit (Roche), and analyzed by digital PCR using the QuantStudio 3D Digital PCR system (ThermoFisher). Dots in the upper left corner correspond to DNA molecules presenting the T790M mutation. Dots in the lower right corner correspond to EGFR genes presenting a wild type codon 790. Dots in the lower left corner corresponds to empty wells in the QuantStudio 3D Digital PCR 20K Chips. VAF, variant allele frequency.
http://dx.doi.org/10.1016/j.lungcan.2017.10.010 Received 17 October 2017 0169-5002/ © 2017 Elsevier B.V. All rights reserved.
Lung Cancer xxx (xxxx) xxx–xxx
Correspondence
In order to be treated with osimertinib, the EGFR status, in particular the presence of the T790M mutation, should be determined. However, depending on the performance status of the patient and/or the location of the tumor, it may be difficult to collect new tumor samples at progression. The test can be performed on ctDNA which can be extracted from several body fluids, such as plasma and CSF [10,11]. Liquid biopsy is a noninvasive approach, and is less affected by tumor heterogeneity [12]. Recent studies have demonstrated that ctDNA derived from CSF is better to detect mutations of brain tumors than plasma [13,14]. This is consistent with our results since we have detected both L858R and T790M mutations in CSF, but not in plasma. ctDNA analyses have to be performed with very high sensitivity techniques because of the low amount of material in body fluids. Unfortunately, albeit using ultra-sensitive techniques, the molecular alterations present in the tumor are not always detectable in ctDNA. Therefore, patients with a negative liquid biopsy result should undergo a tissue test when feasible. In conclusion, this report presents the case of a patient with NSCLC and leptomeningeal carcinomatosis who was able to benefit from a treatment with osimertinib through detection of the T790M mutation in ctDNA from CSF. This result highlights the necessity to test, in routine practice, CSF in addition to plasma for patients with NSCLC and brain metastases. References [1] T.S. Mok, Y.L. Wu, M.J. Ahn, M.C. Garassino, H.R. Kim, S.S. Ramalingam, et al., Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer, N. Engl. J. Med. 376 (2017) 629–640. [2] S. Dearden, H. Brown, S. Jenkins, K.S. Thress, M. Cantarini, R. Cole, et al., EGFR T790M mutation testing within the osimertinib AURA Phase I study, Lung Cancer 109 (2017) 9–13. [3] S. Jenkins, J.C. Yang, S.S. Ramalingam, K. Yu, S. Patel, S. Weston, et al., Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer, J. Thorac. Oncol. 12 (2017) 1061–1070. [4] M. Satouchi, H. Tanaka, H. Yoshioka, T. Shimokawaji, K. Mizuno, K. Takeda, et al., Detection of epidermal growth factor receptor gene T790M mutation in cytology samples using the cobas(R) EGFR mutation test, Lung Cancer 111 (2017) 190–194. [5] S. Heon, B.Y. Yeap, G.J. Britt, D.B. Costa, M.S. Rabin, D.M. Jackman, et al., Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib, Clin. Cancer Res. 16 (2010) 5873–5882. [6] J.C.-H. Yang, B.C. Cho, D.-W. Kim, S.-W. Kim, J.-S. Lee, W.-C. Su, et al., Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study, J. Clin. Oncol. 35 (2017) 2020. [7] H. Reichegger, W. Jochum, D. Forbs, C. Hader, M. Fruh, Rapid intracranial response to osimertinib in a patient with epidermal growth factor receptor T790M-positive adenocarcinoma of the lung, Oncol. Res. Treat. 39 (2016) 461–463. [8] T. Koba, T. Kijima, T. Takimoto, H. Hirata, Y. Naito, M. Hamaguchi, et al., Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation: two case reports, Medicine (Baltimore) 96 (2017) e6087. [9] P. Ballard, J.W. Yates, Z. Yang, D.W. Kim, J.C. Yang, M. Cantarini, et al., Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-Mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity, Clin. Cancer Res. 22 (2016) 5130–5140. [10] H. Yang, L. Cai, Y. Zhang, H. Tan, Q. Deng, M. Zhao, et al., Sensitive detection of EGFR mutations in cerebrospinal fluid from lung adenocarcinoma patients with brain metastases, J. Mol. Diagn. 16 (2014) 558–563. [11] A. Vallee, C. Audigier-Valette, G. Herbreteau, J. Merrien, L. Tessonnier, S. Theoleyre, et al., Rapid clearance of circulating tumor DNA during treatment with AZD9291 of a lung cancer patient presenting the resistance EGFR T790M mutation, Lung Cancer 91 (2016) 73–74. [12] J.J. Chabon, A.D. Simmons, A.F. Lovejoy, M.S. Esfahani, A.M. Newman, H.J. Haringsma, et al., Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients, Nat. Commun. 7 (2016) 11815. [13] L. De Mattos-Arruda, R. Mayor, C.K. Ng, B. Weigelt, F. Martinez-Ricarte, D. Torrejon, et al., Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma, Nat. Commun. 6 (2015) 8839. [14] J. Zhao, X. Ye, Y. Xu, M. Chen, W. Zhong, Y. Sun, et al., EGFR mutation status of paired cerebrospinal fluid and plasma samples in EGFR mutant non-small cell lung cancer with leptomeningeal metastases, Cancer Chemother. Pharmacol. 78 (2016) 1305–1310. ⁎
Sandrine Théoleyre, Ingrid Masson, Guillaume Herbreteau, Audrey Vallée, Hélène Sénellart, Marc G. Denis Nantes University Hospital & Integrated Center for Oncology, Nantes, France E-mail address: [email protected]
⁎
Corresponding author.
2
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Correspondence Treatment of a NSCLC patient with osimertinib based on the detection of the EGFR T790M resistance mutation in cerebrospinal fluid Dear Editor, Osimertinib (AZD9291), a third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has demonstrated efficiency [1] and has been approved for the treatment of patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC). Therefore, T790M testing is mandatory. The cobas® EGFR mutation test v2 (Roche Molecular Systems, Pleasanton, CA, USA) has been shown to be efficient for detecting the T790M mutation in DNA extracted from tumor samples [2] and from plasma [3]. It has been approved as the companion diagnostic test for osimertinib in the USA and in Japan. Satouchi et al. recently reported that the cobas® EGFR assay was also efficient for detecting EGFR alterations in cytology samples [4]. Here, we would like to share our experience about a woman with NSCLC who could be treated with osimertinib based on the detection of the T790M resistant mutation in circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF). A 48-year-old Caucasian female, with a 20 pack-year smoking history and who had a Langerhans cell histiocytosis, presented with persistent cough in March 2015. Computed tomography scan revealed the presence of a lung nodule in the upper right lobe and a biopsy confirmed lung adenocarcinoma with a sensitizing EGFR L858R mutation (exon 21). A brain magnetic resonance imaging (MRI) was also performed and showed several metastases. In June 2015, whole brain irradiation (30 Gy) and erlotinib (150 mg daily) was thus administered resulting in a partial response with progression-free survival of 11 months. In May 2016, the patient complained of headache and dizziness and her condition quickly deteriorated (epileptic seizures, phasic and swallowing disorders). A new MRI suggested the presence of leptomeningeal carcinomatosis. At this time, it was impossible to perform new biopsies, therefore molecular analyses were performed using ctDNA from plasma and CSF using the cobas® EGFR mutation test. Whereas no mutation was detected in plasma, CSF exhibited the previously identified sensitizing EGFR mutation (semi quantitative index SQI = 16.28) and also the T790M resistance mutation (SQI = 13,70). These data were confirmed by digital PCR (dPCR) (Fig. 1). Erlotinib treatment was stopped and replaced by osimertinib (80 mg daily). The patient experienced a rapid neurological improvement and restaging after 8 weeks of therapy demonstrated a significant decrease of leptomeningeal metastases (LM). Unfortunately, the disease progressed again and the patient died because of cerebral progression in October 2016. Patients with EGFR mutant NSCLC, treated with first and second generation of TKI, experience disease progression during treatment due to growth of central nervous system (CNS) metastases in about 30% of cases [5]. The main treatments of these metastases are surgical resection (for brain metastases (BM)), intra-thecal chemotherapy (for LM) or whole brain radiation therapy (for both locations). These therapies have significant side effects which impact the quality of life of patients. It is therefore necessary, when possible, to favor systemic treatments. Osimertinib targets sensitizing EGFR mutations as well as the T790M EGFR resistant mutation. The AURA (NCT01802632, NCT02094261, NCT02151981) and BLOOM (NCT02228369) clinical trials, have shown that osimertinib is efficient for the treatment of NSCLC patients with BM and/or LM [1,6]. In addition, several case reports demonstrated rapid intracranial response to osimertinib in patients with EGFR T790M-positive lung cancer [7,8]. According to pre-clinical data, this efficiency appears to be due to a greater penetration of the blood-brain barrier [9].
Fig. 1. Results of T790M testing by digital PCR on ctDNA from plasma (A) and CSF (B). Circulating DNA was extracted using the cobas cfDNA preparation kit (Roche), and analyzed by digital PCR using the QuantStudio 3D Digital PCR system (ThermoFisher). Dots in the upper left corner correspond to DNA molecules presenting the T790M mutation. Dots in the lower right corner correspond to EGFR genes presenting a wild type codon 790. Dots in the lower left corner corresponds to empty wells in the QuantStudio 3D Digital PCR 20K Chips. VAF, variant allele frequency.
http://dx.doi.org/10.1016/j.lungcan.2017.10.010 Received 17 October 2017 0169-5002/ © 2017 Elsevier B.V. All rights reserved.
Lung Cancer xxx (xxxx) xxx–xxx
Correspondence
In order to be treated with osimertinib, the EGFR status, in particular the presence of the T790M mutation, should be determined. However, depending on the performance status of the patient and/or the location of the tumor, it may be difficult to collect new tumor samples at progression. The test can be performed on ctDNA which can be extracted from several body fluids, such as plasma and CSF [10,11]. Liquid biopsy is a noninvasive approach, and is less affected by tumor heterogeneity [12]. Recent studies have demonstrated that ctDNA derived from CSF is better to detect mutations of brain tumors than plasma [13,14]. This is consistent with our results since we have detected both L858R and T790M mutations in CSF, but not in plasma. ctDNA analyses have to be performed with very high sensitivity techniques because of the low amount of material in body fluids. Unfortunately, albeit using ultra-sensitive techniques, the molecular alterations present in the tumor are not always detectable in ctDNA. Therefore, patients with a negative liquid biopsy result should undergo a tissue test when feasible. In conclusion, this report presents the case of a patient with NSCLC and leptomeningeal carcinomatosis who was able to benefit from a treatment with osimertinib through detection of the T790M mutation in ctDNA from CSF. This result highlights the necessity to test, in routine practice, CSF in addition to plasma for patients with NSCLC and brain metastases. References [1] T.S. Mok, Y.L. Wu, M.J. Ahn, M.C. Garassino, H.R. Kim, S.S. Ramalingam, et al., Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer, N. Engl. J. Med. 376 (2017) 629–640. [2] S. Dearden, H. Brown, S. Jenkins, K.S. Thress, M. Cantarini, R. Cole, et al., EGFR T790M mutation testing within the osimertinib AURA Phase I study, Lung Cancer 109 (2017) 9–13. [3] S. Jenkins, J.C. Yang, S.S. Ramalingam, K. Yu, S. Patel, S. Weston, et al., Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer, J. Thorac. Oncol. 12 (2017) 1061–1070. [4] M. Satouchi, H. Tanaka, H. Yoshioka, T. Shimokawaji, K. Mizuno, K. Takeda, et al., Detection of epidermal growth factor receptor gene T790M mutation in cytology samples using the cobas(R) EGFR mutation test, Lung Cancer 111 (2017) 190–194. [5] S. Heon, B.Y. Yeap, G.J. Britt, D.B. Costa, M.S. Rabin, D.M. Jackman, et al., Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib, Clin. Cancer Res. 16 (2010) 5873–5882. [6] J.C.-H. Yang, B.C. Cho, D.-W. Kim, S.-W. Kim, J.-S. Lee, W.-C. Su, et al., Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study, J. Clin. Oncol. 35 (2017) 2020. [7] H. Reichegger, W. Jochum, D. Forbs, C. Hader, M. Fruh, Rapid intracranial response to osimertinib in a patient with epidermal growth factor receptor T790M-positive adenocarcinoma of the lung, Oncol. Res. Treat. 39 (2016) 461–463. [8] T. Koba, T. Kijima, T. Takimoto, H. Hirata, Y. Naito, M. Hamaguchi, et al., Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation: two case reports, Medicine (Baltimore) 96 (2017) e6087. [9] P. Ballard, J.W. Yates, Z. Yang, D.W. Kim, J.C. Yang, M. Cantarini, et al., Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-Mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity, Clin. Cancer Res. 22 (2016) 5130–5140. [10] H. Yang, L. Cai, Y. Zhang, H. Tan, Q. Deng, M. Zhao, et al., Sensitive detection of EGFR mutations in cerebrospinal fluid from lung adenocarcinoma patients with brain metastases, J. Mol. Diagn. 16 (2014) 558–563. [11] A. Vallee, C. Audigier-Valette, G. Herbreteau, J. Merrien, L. Tessonnier, S. Theoleyre, et al., Rapid clearance of circulating tumor DNA during treatment with AZD9291 of a lung cancer patient presenting the resistance EGFR T790M mutation, Lung Cancer 91 (2016) 73–74. [12] J.J. Chabon, A.D. Simmons, A.F. Lovejoy, M.S. Esfahani, A.M. Newman, H.J. Haringsma, et al., Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients, Nat. Commun. 7 (2016) 11815. [13] L. De Mattos-Arruda, R. Mayor, C.K. Ng, B. Weigelt, F. Martinez-Ricarte, D. Torrejon, et al., Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma, Nat. Commun. 6 (2015) 8839. [14] J. Zhao, X. Ye, Y. Xu, M. Chen, W. Zhong, Y. Sun, et al., EGFR mutation status of paired cerebrospinal fluid and plasma samples in EGFR mutant non-small cell lung cancer with leptomeningeal metastases, Cancer Chemother. Pharmacol. 78 (2016) 1305–1310. ⁎
Sandrine Théoleyre, Ingrid Masson, Guillaume Herbreteau, Audrey Vallée, Hélène Sénellart, Marc G. Denis Nantes University Hospital & Integrated Center for Oncology, Nantes, France E-mail address: [email protected]
⁎
Corresponding author.
2