Journal of Thoracic Oncology ® • Volume 10, Number 2, February 2015
Jeffrey Blume, PhD Department of Biostatistics Vanderbilt University Nashville, Tennessee Eric L. Grogan, MD, MPH, FACS Tennessee Valley Healthcare SystemVeterans Affairs Department of Thoracic Surgery Vanderbilt University Medical Center Nashville, Tennessee REFERENCES 1. Deppen S, Putnam JB Jr, Andrade G, et al. Accuracy of FDG-PET to diagnose lung cancer in a region of endemic granulomatous disease. Ann Thorac Surg 2011;92:428–432; discussion 433. 2. Keyes JW Jr. SUV: standard uptake or silly useless value? J Nucl Med 1995;36:1836–1839. 3. Delbeke D, Coleman RE, Guiberteau MJ, et al. Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0. J Nucl Med 2006;47:885–895. 4. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009;50(Suppl 1):122S–150S. 5. Grogan EL, Deppen SA, Ballman KV, et al. Accuracy of fluorodeoxyglucose-positron emission tomography within the clinical practice of the American College of Surgeons Oncology Group Z4031 trial to diagnose clinical stage I non-small cell lung cancer. Ann Thorac Surg 2014;97:1142–1148. 6. Deppen SA, Blume JD, Kensinger CD, et al. Accuracy of FDG-PET to diagnose lung cancer in areas with infectious lung disease: a meta-analysis. JAMA 2014;312:1227–1236.
Difference in Outcome between Types of KRAS Mutation May Point toward Difference in Tumor Biology To the Editor: With interest we read the article by Nadal et al.1 entitled “KRAS-G12C mutation is associated with poor Disclosure: The authors declare no conflict of interest. Address for Correspondence: Wouter W. Mellema, MD, Department of Pulmonary Diseases, VU University Medical Center, de Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000431 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1002-00e9
outcome in surgically resected lung adenocarcinoma”. The authors retrospectively studied a group of 179 patients with surgically resected adenocarcinoma of the lung with known KRAS mutational status. The aim of this study was to investigate the effects, if any, of KRAS mutant subtypes on survival probabilities. Here, patients with any KRAS mutation had significant poorer survival compared with patients with KRAS wild type. In particular, patients with a G12C mutation had worse outcome compared with other types of mutation. We would like to comment on this article. First, the authors report that patients with a G12C KRAS mutation have a poorer prognosis compared with other types of KRAS mutations, which is illustrated in Figure 1. The authors also refer to a univariate analysis presented in Table 3 (p.1518). However, the univariate analysis provides a comparison between G12C KRAS mutation and wild type, but not G12C and non-G12C KRAS mutations. A difference in prognosis between types of KRAS mutation could possibly point toward differences in tumor biology. This is relevant data and we would like to invite the author to present the data of a multivariate analysis comparing G12C and other types of KRAS mutations. Furthermore, it is interesting to know how many patients had an EGFR mutation among the patients with KRAS wild type. This group of patient is known to a have favorable prognosis2 and can provide a relevant bias. We agree that the prognostic value of KRAS mutation is a controversial topic. As discussed in the article, two large studies on KRAS mutational status in resected non–small-cell lung carcinoma did not found a prognostic value for KRAS mutation or types of mutation.3,4 Over the past decade, almost a dozen studies investigated the same question in non–smallcell lung carcinoma with conflicting results. The study by Nadal et al. should therefore be interpreted carefully, despite methodological differences. Nonetheless, the data on KRAS addiction is interesting and we hope that future studies will point out the clinical relevance. Wouter W. Mellema, MD Department of Pulmonary Diseases VU University Medical Center Amsterdam, The Netherlands
Copyright © 2014 by the International Association for the Study of Lung Cancer
Letters to the Editor
Anne-Marie C. Dingemans, MD, PhD Department of Pulmonary Diseases Maastricht University Medical Center Maastricht, The Netherlands Marianne Jonker, PhD Department of Epidemiology and Biostatistics VU University Medical Center Amsterdam, The Netherlands Egbert F. Smit, MD, PhD Department of Pulmonary Diseases VU University Medical Center Amsterdam, The Netherlands REFERENCES 1. Nadal E, Chen G, Prensner JR, et al. KRASG12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma. J Thorac Oncol 2014;9:1512–1522. 2. Marks JL, Broderick S, Zhou Q, et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol 2008;3:111–116. 3. Shepherd FA, Domerg C, Hainaut P, et al. Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol 2013;31:2173–2181. 4. Villaruz LC, Socinski MA, Cunningham DE, et al. The prognostic and predictive value of KRAS oncogene substitutions in lung adenocarcinoma. Cancer 2013;119:2268–2274.
KRAS-G12C Mutation is Associated with Poor Outcome in Surgically Resected Lung Adenocarcinoma In response: We appreciate the comments made by Dr. Egber Smit and collaborators to our article on KRAS codon variants as prognostic markers in resected Address for Correspondence: Ernest Nadal, MD, Department of Medical Oncology, Catalan Institute of Oncology, Avda Gran Via 199203, L'Hospitalet, Barcelona, Spain. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000438 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1002-00e9
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lung adenocarcinoma.1 In our article, we performed a multivariate analysis comparing KRAS-G12C and nonG12C versus KRAS wild-type, as shown in the Supplementary Table S4, but we agree with Dr. Smit that we did not present the multivariate analysis comparing KRASG12C with the other KRAS codon variants. Here, we show the results from the multivariate Cox analysis for overall survival according to KRAS amino acid substitution using each subtype of KRAS-nonG12C as a reference: G12D versus G12C, hazard ratio (HR): 2.81 (1.07–7.36, p = 0.035); G12A versus G12C, HR: 5.99 (1.39–25.7, p = 0.016); G12V versus G12C, HR: 1.62 (0.70– 3.76, p = 0.259). These data indicate that the patients harboring KRAS-G12C mutations have significantly worse overall survival as compared with KRAS-G12D and KRAS-G12A, but not with KRAS-G12V mutations. In keeping with this, Ihle et al. reported that patients whose tumors had KRAS-G12C or KRAS-G12V mutations also had significantly worse progression-free survival as compared with patients whose
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Journal of Thoracic Oncology ® • Volume 10, Number 2, February 2015
tumors had other KRAS codon variants or wild-type KRAS, albeit in metastatic non–small-cell lung cancer.2 We did not systematically assess the EGFR mutation status in early stage lung adenocarcinoma patients, but these data were available in a subset of patients included in this study. Among the patients whose tumors had wild-type KRAS (n = 94), nine patients (10%) harbored an EGFR mutation, 48 were EGFR wild-type, and in 37 patients the EGFR status was unknown. When nine patients harboring an EGFR mutation were excluded from survival analysis, KRAS mutation and KRASG12C remained an independent predictor of poor outcome. We indicated in the discussion of our manuscript that the prognostic value of KRAS mutation status in non–small-cell lung cancer remains controversial. Although effective therapies targeting KRAS represent an unmet crucial need, we consider that it is relevant to distinguish among the distinct KRAS codon variants that may in the future have important biological
and therapeutic implications for patients with surgically-resected lung adenocarcinoma. Ernest Nadal, MD Department of Medical Oncology Catalan Institute of Oncology Avda Gran Via 199-203, L'Hospitalet Barcelona, Spain David G. Beer, PhD Nithya Ramnath, MD University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan REFERENCES 1. Nadal E, Chen G, Prensner JR, et al. KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma. J Thoracic Oncol 2014;9:1513–1522. 2. Ihle NT, Byers LA, Kim ES, et al. Effect of KRAS oncogene substitutions on protein behavior: Implications for signaling and clinical outcome. J Natl Cancer Inst 2012;104:228–239.
Copyright © 2014 by the International Association for the Study of Lung Cancer
Jeffrey Blume, PhD Department of Biostatistics Vanderbilt University Nashville, Tennessee Eric L. Grogan, MD, MPH, FACS Tennessee Valley Healthcare SystemVeterans Affairs Department of Thoracic Surgery Vanderbilt University Medical Center Nashville, Tennessee REFERENCES 1. Deppen S, Putnam JB Jr, Andrade G, et al. Accuracy of FDG-PET to diagnose lung cancer in a region of endemic granulomatous disease. Ann Thorac Surg 2011;92:428–432; discussion 433. 2. Keyes JW Jr. SUV: standard uptake or silly useless value? J Nucl Med 1995;36:1836–1839. 3. Delbeke D, Coleman RE, Guiberteau MJ, et al. Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0. J Nucl Med 2006;47:885–895. 4. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009;50(Suppl 1):122S–150S. 5. Grogan EL, Deppen SA, Ballman KV, et al. Accuracy of fluorodeoxyglucose-positron emission tomography within the clinical practice of the American College of Surgeons Oncology Group Z4031 trial to diagnose clinical stage I non-small cell lung cancer. Ann Thorac Surg 2014;97:1142–1148. 6. Deppen SA, Blume JD, Kensinger CD, et al. Accuracy of FDG-PET to diagnose lung cancer in areas with infectious lung disease: a meta-analysis. JAMA 2014;312:1227–1236.
Difference in Outcome between Types of KRAS Mutation May Point toward Difference in Tumor Biology To the Editor: With interest we read the article by Nadal et al.1 entitled “KRAS-G12C mutation is associated with poor Disclosure: The authors declare no conflict of interest. Address for Correspondence: Wouter W. Mellema, MD, Department of Pulmonary Diseases, VU University Medical Center, de Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000431 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1002-00e9
outcome in surgically resected lung adenocarcinoma”. The authors retrospectively studied a group of 179 patients with surgically resected adenocarcinoma of the lung with known KRAS mutational status. The aim of this study was to investigate the effects, if any, of KRAS mutant subtypes on survival probabilities. Here, patients with any KRAS mutation had significant poorer survival compared with patients with KRAS wild type. In particular, patients with a G12C mutation had worse outcome compared with other types of mutation. We would like to comment on this article. First, the authors report that patients with a G12C KRAS mutation have a poorer prognosis compared with other types of KRAS mutations, which is illustrated in Figure 1. The authors also refer to a univariate analysis presented in Table 3 (p.1518). However, the univariate analysis provides a comparison between G12C KRAS mutation and wild type, but not G12C and non-G12C KRAS mutations. A difference in prognosis between types of KRAS mutation could possibly point toward differences in tumor biology. This is relevant data and we would like to invite the author to present the data of a multivariate analysis comparing G12C and other types of KRAS mutations. Furthermore, it is interesting to know how many patients had an EGFR mutation among the patients with KRAS wild type. This group of patient is known to a have favorable prognosis2 and can provide a relevant bias. We agree that the prognostic value of KRAS mutation is a controversial topic. As discussed in the article, two large studies on KRAS mutational status in resected non–small-cell lung carcinoma did not found a prognostic value for KRAS mutation or types of mutation.3,4 Over the past decade, almost a dozen studies investigated the same question in non–smallcell lung carcinoma with conflicting results. The study by Nadal et al. should therefore be interpreted carefully, despite methodological differences. Nonetheless, the data on KRAS addiction is interesting and we hope that future studies will point out the clinical relevance. Wouter W. Mellema, MD Department of Pulmonary Diseases VU University Medical Center Amsterdam, The Netherlands
Copyright © 2014 by the International Association for the Study of Lung Cancer
Letters to the Editor
Anne-Marie C. Dingemans, MD, PhD Department of Pulmonary Diseases Maastricht University Medical Center Maastricht, The Netherlands Marianne Jonker, PhD Department of Epidemiology and Biostatistics VU University Medical Center Amsterdam, The Netherlands Egbert F. Smit, MD, PhD Department of Pulmonary Diseases VU University Medical Center Amsterdam, The Netherlands REFERENCES 1. Nadal E, Chen G, Prensner JR, et al. KRASG12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma. J Thorac Oncol 2014;9:1512–1522. 2. Marks JL, Broderick S, Zhou Q, et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol 2008;3:111–116. 3. Shepherd FA, Domerg C, Hainaut P, et al. Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol 2013;31:2173–2181. 4. Villaruz LC, Socinski MA, Cunningham DE, et al. The prognostic and predictive value of KRAS oncogene substitutions in lung adenocarcinoma. Cancer 2013;119:2268–2274.
KRAS-G12C Mutation is Associated with Poor Outcome in Surgically Resected Lung Adenocarcinoma In response: We appreciate the comments made by Dr. Egber Smit and collaborators to our article on KRAS codon variants as prognostic markers in resected Address for Correspondence: Ernest Nadal, MD, Department of Medical Oncology, Catalan Institute of Oncology, Avda Gran Via 199203, L'Hospitalet, Barcelona, Spain. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000438 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1002-00e9
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Letters to the Editor
lung adenocarcinoma.1 In our article, we performed a multivariate analysis comparing KRAS-G12C and nonG12C versus KRAS wild-type, as shown in the Supplementary Table S4, but we agree with Dr. Smit that we did not present the multivariate analysis comparing KRASG12C with the other KRAS codon variants. Here, we show the results from the multivariate Cox analysis for overall survival according to KRAS amino acid substitution using each subtype of KRAS-nonG12C as a reference: G12D versus G12C, hazard ratio (HR): 2.81 (1.07–7.36, p = 0.035); G12A versus G12C, HR: 5.99 (1.39–25.7, p = 0.016); G12V versus G12C, HR: 1.62 (0.70– 3.76, p = 0.259). These data indicate that the patients harboring KRAS-G12C mutations have significantly worse overall survival as compared with KRAS-G12D and KRAS-G12A, but not with KRAS-G12V mutations. In keeping with this, Ihle et al. reported that patients whose tumors had KRAS-G12C or KRAS-G12V mutations also had significantly worse progression-free survival as compared with patients whose
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Journal of Thoracic Oncology ® • Volume 10, Number 2, February 2015
tumors had other KRAS codon variants or wild-type KRAS, albeit in metastatic non–small-cell lung cancer.2 We did not systematically assess the EGFR mutation status in early stage lung adenocarcinoma patients, but these data were available in a subset of patients included in this study. Among the patients whose tumors had wild-type KRAS (n = 94), nine patients (10%) harbored an EGFR mutation, 48 were EGFR wild-type, and in 37 patients the EGFR status was unknown. When nine patients harboring an EGFR mutation were excluded from survival analysis, KRAS mutation and KRASG12C remained an independent predictor of poor outcome. We indicated in the discussion of our manuscript that the prognostic value of KRAS mutation status in non–small-cell lung cancer remains controversial. Although effective therapies targeting KRAS represent an unmet crucial need, we consider that it is relevant to distinguish among the distinct KRAS codon variants that may in the future have important biological
and therapeutic implications for patients with surgically-resected lung adenocarcinoma. Ernest Nadal, MD Department of Medical Oncology Catalan Institute of Oncology Avda Gran Via 199-203, L'Hospitalet Barcelona, Spain David G. Beer, PhD Nithya Ramnath, MD University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan REFERENCES 1. Nadal E, Chen G, Prensner JR, et al. KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma. J Thoracic Oncol 2014;9:1513–1522. 2. Ihle NT, Byers LA, Kim ES, et al. Effect of KRAS oncogene substitutions on protein behavior: Implications for signaling and clinical outcome. J Natl Cancer Inst 2012;104:228–239.
Copyright © 2014 by the International Association for the Study of Lung Cancer
