- Email: [email protected]
Tissue Is the Issue for Diagnosis of EGFR T790M Mutation
July 2016
lung cancer. As a result, it remains true that updated guidelines for lymphadenectomy during lobectomy for lung cancer should follow, and thus allow for better measurement of the impact of quality metrics on patient outcomes. Rachel L. Medbery, MD, Felix G. Fernandez, MD, MSc Section of General Thoracic Surgery Department of Surgery Emory University School of Medicine Emory University Atlanta, Georgia
Tissue Is the Issue for Diagnosis of EGFR T790M Mutation To the Editor: The epidermal growth factor receptor gene (EGFR) T790M mutation accounts for more than half of resistance to the tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Osimertinib is the first U. S. Food and Drug Administration–approved therapy for EGFR-mutant non–small cell lung cancer (NSCLC) with progression due to acquired T790M-mediated TKI resistance. It was approved on the basis of an objective response rate of 61% and a median progression-free survival of 9.6 months.1 We describe two patients with disease progression while receiving erlotinib who were negative for the T790M mutation by genotyping of circulating tumor DNA (ctDNA) using a clinically validated digital droplet polymerase chain reaction test at a Clinical Laboratory Improvement Amendments–certified laboratory.2 On subsequent evaluation of biopsy tissue they were found to be T790M positive. Both patients had a clinical response to osimertinib therapy. Patient 1 is a 45-year-old man with EGFR L858Rmutated NSCLC with new bone metastases. ctDNA testing for T790M in blood was done initially because of the challenge of a bone biopsy, with no mutation detected. Two months later, he exhibited worsening neurological symptoms and development of new brain
Disclosure: The authors declare no conflict of interest. Address for correspondence: Jenna Khan, MD, Department of Library Medicine, University of Washington, 1959 NE Pacific St., Seattle, WA 98105. E-mail: [email protected] ª 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2016.03.017
Letters to the Editor
e91
References 1. Decaluwé H, De Ruysscher D, D’Amico T. Location of the tumor is a “central” predictor of nodal upstaging. J Thorac Oncol. 2016;11:e89–e90. 2. Medbery RL, Gillespie TW, Liu Y, et al. Nodal upstaging is more common with thoracotomy than with VATS during lobectomy for early-stage lung cancer: an analysis from the National Cancer Data Base. J Thorac Oncol. 2016;11:222–233. 3. Yang CF, Sun Z, Speicher PJ, et al. Use and outcomes of minimally invasive lobectomy for stage I non-small cell lung cancer in the National Cancer Data Base. Ann Thorac Surg. 2016;101:1037–1042.
lesions. A biopsy was performed on his rib metastasis and found to be positive for T790M (variant allele fraction, 19%). The patient started receiving osimertinib and had a clinical response within 3 weeks that included decreased pain, stabilization of his neurological symptoms, and a reduction in size of his chest wall metastases. Patient 2 is a 57-year-old woman with EGFR exon 19 deletion–mutated NSCLC and mediastinal adenopathy due to metastatic disease. To avoid an invasive procedure, ctDNA testing for T790M was performed on a sample of her blood, with no mutation detected. One month later, the results of a biopsy of her mediastinal adenopathy were positive for T790M (variant allele fraction, 3.5%). She was given osimertinib, with evidence of a response at 5 weeks that included a decrease in size of her lymph node metastases and no new metastatic lesions. Detection of the EGFR T790M resistance mutation is critical to guide management. Genotyping of ctDNA in blood is appealing because it is noninvasive and may be representative of multiple metastases. The lesson from these two patients, the only two patients on whom we have done clinical ctDNA testing to date, highlights the potential for discordant results with tissue testing. This is consistent with recent studies showing 48% to 74% concordance rates between biopsy and ctDNA testing results, depending on the assay method and location of metastatic disease (in comparison with concordance rates of 87% to 97% for EGFR TKI–sensitizing mutations).3–4 Clinicians should be aware that a negative ctDNA result for T790M does not preclude the presence of this mutation and further or concurrent evaluation in tissue is warranted when clinical suspicion is high. Jenna Khan, MD Colin C. Pritchard, MD, PhD Department of Laboratory Medicine University of Washington School of Medicine Seattle, Washington
e92 Letters to the Editor
Renato G. Martins, MD, MPH Department of Medicine Division of Medical Oncology University of Washington School of Medicine Seattle, Washington
References 1. Jänne PA, Yang JC, Kim D, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372:1689–1699.
Reliability Assurance of EML4-ALK Rearrangement Detection in Non–Small Cell Lung Cancer: A Methodological and Statistical Issue To the Editor: I was interested to read the article by Li et al. published in the June 2016 issue of the Journal of Thoracic Oncology.1 The authors tried to assess reliability assurance of detection of echinoderm microtubule associated protein like 4 gene (EML4)–anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement in non–small cell lung cancer.1 They received results from 94 laboratories that used different methods. They reported that 75.5% of participants correctly identified the entire proficiency test panel. Among the errors made by participants, false-negative errors were prone to occur. According to the methodology applied, 82.8%, 76.6%, 77.7%, and 66.6% of laboratories using reversetranscriptase polymerase chain reaction, fluorescence in situ hybridization, next-generation sequencing, and
Disclosure: The author declares no conflict of interest. Advances in Knowledge: (1) Reliability (precision) and validity (accuracy) are two important methodological issues in all fields of researches, and (2) as a take-home message, for reliability and validity analysis, appropriate tests should be applied by clinical researchers. Implication for patient care: Misdiagnosis and mismanagement of patients in routine clinical care cannot be avoided by using inappropriate tests to assess reliability (precision) and validity (accuracy). Address for correspondence: Siamak Sabour, MD, MSc, DSc, PhD, Department of Clinical Epidemiology, School of Health, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran. E-mail: [email protected] ª 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2016.04.022
Journal of Thoracic Oncology
Vol. 11 No. 7
2. Hellwig S, Welker NC, Vaughn CP, et al. ST68. EGFR T790M lung cancer mutation detection by digital droplet PCR in circulating free tumor DNA. J Molec Diag. 2015;17:829. 3. Sundaresan TK, Sequist LV, Heymach JV, et al. Detection of T790M, the acquired resistance egfr mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin Cancer Res. 2016;22:1103–1110. 4. Thress KS, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: a cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer. 2015;90:509–515.
immunohistochemical analysis, respectively, could analyze all the samples correctly.1 It is important to recognize that reliability (precision, agreement, or repeatability) and validity (accuracy or actual state) are two completely different methodological issues that should not be confused with each other.2–8 Moreover, why did the authors not use well-known statistical tests to assess reliability and validity? To assess the reliability (precision) for qualitative variables, weighted k should be used with caution because k has its own limitation too.2-8 However, sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio positive and negative, diagnostic accuracy, and OR of preferably more than 50 are among the tests to evaluate the validity (accuracy) of a single test compared with the accepted standard.2-4 Briefly, use of an inappropriate statistical test to assess agreement and confusion of reliability and validity (precision and accuracy), as well as incomplete use of a statistical test to assess discriminative abilities, are among common mistakes of the authors.2–8 As a take-home message, clinicians should be familiar with principles of research methodology and biostatistics; otherwise, misdiagnosis and mismanagement of the patients cannot be avoided. Siamak Sabour, MD, MSc, DSc, PhD Safety Promotion and Injury Prevention Research Center Shahid Beheshti University of Medical Sciences Tehran, Islamic Republic of Iran Department of Clinical Epidemiology School of Health Shahid Beheshti University of Medical Sciences Tehran, Islamic Republic of Iran
References 1. Li Y, Zhang R, Peng R, et al. Reliability assurance of EML4-ALK rearrangement detection in non-small cell lung cancer: the results of a proficiency testing in China. J Thorac Oncol. 2016;11:924–929.
lung cancer. As a result, it remains true that updated guidelines for lymphadenectomy during lobectomy for lung cancer should follow, and thus allow for better measurement of the impact of quality metrics on patient outcomes. Rachel L. Medbery, MD, Felix G. Fernandez, MD, MSc Section of General Thoracic Surgery Department of Surgery Emory University School of Medicine Emory University Atlanta, Georgia
Tissue Is the Issue for Diagnosis of EGFR T790M Mutation To the Editor: The epidermal growth factor receptor gene (EGFR) T790M mutation accounts for more than half of resistance to the tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Osimertinib is the first U. S. Food and Drug Administration–approved therapy for EGFR-mutant non–small cell lung cancer (NSCLC) with progression due to acquired T790M-mediated TKI resistance. It was approved on the basis of an objective response rate of 61% and a median progression-free survival of 9.6 months.1 We describe two patients with disease progression while receiving erlotinib who were negative for the T790M mutation by genotyping of circulating tumor DNA (ctDNA) using a clinically validated digital droplet polymerase chain reaction test at a Clinical Laboratory Improvement Amendments–certified laboratory.2 On subsequent evaluation of biopsy tissue they were found to be T790M positive. Both patients had a clinical response to osimertinib therapy. Patient 1 is a 45-year-old man with EGFR L858Rmutated NSCLC with new bone metastases. ctDNA testing for T790M in blood was done initially because of the challenge of a bone biopsy, with no mutation detected. Two months later, he exhibited worsening neurological symptoms and development of new brain
Disclosure: The authors declare no conflict of interest. Address for correspondence: Jenna Khan, MD, Department of Library Medicine, University of Washington, 1959 NE Pacific St., Seattle, WA 98105. E-mail: [email protected] ª 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2016.03.017
Letters to the Editor
e91
References 1. Decaluwé H, De Ruysscher D, D’Amico T. Location of the tumor is a “central” predictor of nodal upstaging. J Thorac Oncol. 2016;11:e89–e90. 2. Medbery RL, Gillespie TW, Liu Y, et al. Nodal upstaging is more common with thoracotomy than with VATS during lobectomy for early-stage lung cancer: an analysis from the National Cancer Data Base. J Thorac Oncol. 2016;11:222–233. 3. Yang CF, Sun Z, Speicher PJ, et al. Use and outcomes of minimally invasive lobectomy for stage I non-small cell lung cancer in the National Cancer Data Base. Ann Thorac Surg. 2016;101:1037–1042.
lesions. A biopsy was performed on his rib metastasis and found to be positive for T790M (variant allele fraction, 19%). The patient started receiving osimertinib and had a clinical response within 3 weeks that included decreased pain, stabilization of his neurological symptoms, and a reduction in size of his chest wall metastases. Patient 2 is a 57-year-old woman with EGFR exon 19 deletion–mutated NSCLC and mediastinal adenopathy due to metastatic disease. To avoid an invasive procedure, ctDNA testing for T790M was performed on a sample of her blood, with no mutation detected. One month later, the results of a biopsy of her mediastinal adenopathy were positive for T790M (variant allele fraction, 3.5%). She was given osimertinib, with evidence of a response at 5 weeks that included a decrease in size of her lymph node metastases and no new metastatic lesions. Detection of the EGFR T790M resistance mutation is critical to guide management. Genotyping of ctDNA in blood is appealing because it is noninvasive and may be representative of multiple metastases. The lesson from these two patients, the only two patients on whom we have done clinical ctDNA testing to date, highlights the potential for discordant results with tissue testing. This is consistent with recent studies showing 48% to 74% concordance rates between biopsy and ctDNA testing results, depending on the assay method and location of metastatic disease (in comparison with concordance rates of 87% to 97% for EGFR TKI–sensitizing mutations).3–4 Clinicians should be aware that a negative ctDNA result for T790M does not preclude the presence of this mutation and further or concurrent evaluation in tissue is warranted when clinical suspicion is high. Jenna Khan, MD Colin C. Pritchard, MD, PhD Department of Laboratory Medicine University of Washington School of Medicine Seattle, Washington
e92 Letters to the Editor
Renato G. Martins, MD, MPH Department of Medicine Division of Medical Oncology University of Washington School of Medicine Seattle, Washington
References 1. Jänne PA, Yang JC, Kim D, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372:1689–1699.
Reliability Assurance of EML4-ALK Rearrangement Detection in Non–Small Cell Lung Cancer: A Methodological and Statistical Issue To the Editor: I was interested to read the article by Li et al. published in the June 2016 issue of the Journal of Thoracic Oncology.1 The authors tried to assess reliability assurance of detection of echinoderm microtubule associated protein like 4 gene (EML4)–anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement in non–small cell lung cancer.1 They received results from 94 laboratories that used different methods. They reported that 75.5% of participants correctly identified the entire proficiency test panel. Among the errors made by participants, false-negative errors were prone to occur. According to the methodology applied, 82.8%, 76.6%, 77.7%, and 66.6% of laboratories using reversetranscriptase polymerase chain reaction, fluorescence in situ hybridization, next-generation sequencing, and
Disclosure: The author declares no conflict of interest. Advances in Knowledge: (1) Reliability (precision) and validity (accuracy) are two important methodological issues in all fields of researches, and (2) as a take-home message, for reliability and validity analysis, appropriate tests should be applied by clinical researchers. Implication for patient care: Misdiagnosis and mismanagement of patients in routine clinical care cannot be avoided by using inappropriate tests to assess reliability (precision) and validity (accuracy). Address for correspondence: Siamak Sabour, MD, MSc, DSc, PhD, Department of Clinical Epidemiology, School of Health, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran. E-mail: [email protected] ª 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2016.04.022
Journal of Thoracic Oncology
Vol. 11 No. 7
2. Hellwig S, Welker NC, Vaughn CP, et al. ST68. EGFR T790M lung cancer mutation detection by digital droplet PCR in circulating free tumor DNA. J Molec Diag. 2015;17:829. 3. Sundaresan TK, Sequist LV, Heymach JV, et al. Detection of T790M, the acquired resistance egfr mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin Cancer Res. 2016;22:1103–1110. 4. Thress KS, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: a cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer. 2015;90:509–515.
immunohistochemical analysis, respectively, could analyze all the samples correctly.1 It is important to recognize that reliability (precision, agreement, or repeatability) and validity (accuracy or actual state) are two completely different methodological issues that should not be confused with each other.2–8 Moreover, why did the authors not use well-known statistical tests to assess reliability and validity? To assess the reliability (precision) for qualitative variables, weighted k should be used with caution because k has its own limitation too.2-8 However, sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio positive and negative, diagnostic accuracy, and OR of preferably more than 50 are among the tests to evaluate the validity (accuracy) of a single test compared with the accepted standard.2-4 Briefly, use of an inappropriate statistical test to assess agreement and confusion of reliability and validity (precision and accuracy), as well as incomplete use of a statistical test to assess discriminative abilities, are among common mistakes of the authors.2–8 As a take-home message, clinicians should be familiar with principles of research methodology and biostatistics; otherwise, misdiagnosis and mismanagement of the patients cannot be avoided. Siamak Sabour, MD, MSc, DSc, PhD Safety Promotion and Injury Prevention Research Center Shahid Beheshti University of Medical Sciences Tehran, Islamic Republic of Iran Department of Clinical Epidemiology School of Health Shahid Beheshti University of Medical Sciences Tehran, Islamic Republic of Iran
References 1. Li Y, Zhang R, Peng R, et al. Reliability assurance of EML4-ALK rearrangement detection in non-small cell lung cancer: the results of a proficiency testing in China. J Thorac Oncol. 2016;11:924–929.