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Two Cases of Non–Small-Cell Lung Cancer with Rare Complex Mutation of EGFR Exon 18 But Different Response to Targeted Therapy
Letters to the Editor
Journal of Thoracic Oncology ® • Volume 9, Number 10, October 2014
involved in colonization of brain metastases from breast cancer. Breast Cancer Res 2010;12:R46. 3. Bamford S, Dawson E, Forbes S, et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer 2004;91:355–358. 4. Aoki Y, Niihori T, Kawame H, et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 2005;37:1038–1040. 5. Lea IA, Jackson MA, Li X, et al. Genetic pathways and mutation profiles of human cancers: site- and exposure-specific patterns. Carcinogenesis 2007;28:1851–1858.
FIGURE 1. Computed tomography scan of chest of patient 1 (left) before treatment and (right) after 3 months of gefitinib treatment.
Two Cases of Non– Small-Cell Lung Cancer with Rare Complex Mutation of EGFR Exon 18 But Different Response to Targeted Therapy To the Editor: In non–small-cell lung cancer (NSCLC) besides the common exons 19 and 21 EGFR-activating mutations (>90%), exon 18-point mutations (mainly p.G719X) are rare (4%).1 They are associated with a favorable response rate to EGFR tyrosine kinase inhibitors (EGFR-TKI),2,3 but are lower than common mutations.4 More than one mutation per sample represents complex mutations. Their clinical significance is uncertain, because they are rare (3.4–6.9%).2,3 Here, we present two cases of NSCLC with rare complex mutation that respond differently to EGFR-TKI.
Address for correspondence: Patricia de Cremoux, MD, PhD, Department of Biochemistry, Molecular Oncology Unit, Hôpital Saint Louis, 1, Avenue Claude Vellefaux, 75010 Paris, France. E-mail: patricia.de-cremoux@ sls.aphp.fr DOI: 10.1097/JTO.0000000000000328 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0910-0e78
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CASES PRESENTATION In July of 2012, an Asian, 52-year-old male smoker presented with a right cervical lymph node. A stage IV adenocarcinoma in the right lung; lymphangitis carcinomatosis; mediastinal, cervical, and susclavicular lymph nodes; and sacrum and hip bone osteoblastic metastases were diagnosed. Two-point mutations in exon 18 of the EGFR, p.I706T, and p.G719A were detected. Gefitinib treatment started in August of 2012. After 3 months, computed tomography -scan showed a partial response (Fig. 1).The clinical response was maintained under gefitinib treatment with 22 months of follow up. The second patient was a Caucasian, 58-year-old female smoker, referred in February of 2013. A stage IV lung adenocarcinoma, in the lower right lobe, with mediastinal lymph nodes as well as cerebral and right adrenal gland metastases was diagnosed. Twopoint mutations in exon 18, p.E709K and p.G719A, were detected. Erlotinib treatment and whole brain radiotherapy began. After 2 months, the patient’s performance status improved and computed tomography scan demonstrated a partial response on brain metastases and primary tumor. Then she presented with a progression of extracerebral metastases. Erlotinib was stopped. A chemotherapy combining cisplatin and pemetrexed was administered. In September of 2013, due to disease progression, carboplatin and paclitaxel were proposed. The patient presented a stable disease for 4 months and then
progressed. She died 11 months after diagnosis of metastatic disease.
DISCUSSION The clinical significance of EGFR complex mutations differs whether complex mutations include the most frequent mutations or not. Hata et al5 showed that tumours with complex mutations, including deletion of exon 19 or L858R point mutation, had the same response rate to EGFR-TKI than those with the same mutations alone. Wu et al2 showed that patients with rare and complex mutations, compared with patients with classic or rare mutation alone or classic mutation with rare mutations, had a worse response rate to EGFRTKI (25% versus 74.8, 68.8, and 80%, respectively) and a poorer progressionfree survival (1.4 versus 11.9, 8.1, and 8.0 months). Beau-Faller et al6 showed that EGFR-TKI efficacy was similar or slightly poorer in patients with complex mutations including p.G719X. Keam et al3 reported only two double mutations in exon 18, including the G719A + I706T, in a series of 306 patients. The overall survival of this patient, treated with erlotinib, was 53 months.3 This is the first description of the p.E709K + p.G719A mutation. To date, the behavior of these NSCLCs with complex mutations are not completely understood. The report of these rare and complex mutations and their response to EGFR-TKI should be very useful for the constitution of wellannotated databases and to improve the knowledge of their specific response to EGFR-TKI.
Copyright © 2014 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology ® • Volume 9, Number 10, October 2014
Hélène Gauthier, MD Gaelle Douchet Department of Medical Oncology Saint Louis Hospital Paris, France Jacqueline Lehmann-Che, PharmD, PhD Molecular Oncology Unit Department of Biochemistry, Saint Louis Hospital Paris, France Paris-Diderot University Press Sorbonne Cité Paris, France Véronique Meignin, MD, PhD Department of Pathology Saint Louis Hospital Paris, France Christine Raynaud, MD, PhD Department of Pneumology CH V Dupouy Argenteuil, France Pierre Sabatier, MD Department of Pathology CH V Dupouy Argenteuil, France Hubert de Cremoux, MD Department of Pneumology
CH V Dupouy Argenteuil, France Brigitte Poirot, PharmD Molecular Oncology Unit Department of Biochemistry, Saint Louis Hospital Paris, France Paris-Diderot University Press Sorbonne Cité Paris, France Stéphane Culine, MD, PhD Department of Medical Oncology Saint Louis Hospital Paris, France Paris-Diderot University Press Sorbonne Cité Paris, France Damien Pouessel, MD Department of Medical Oncology Saint Louis Hospital Paris, France Patricia de Cremoux, MD, PhD Molecular Oncology Unit Department of Biochemistry, Saint Louis Hospital Paris, France Paris-Diderot University Press Sorbonne Cité Paris, France
Copyright © 2014 by the International Association for the Study of Lung Cancer
Letters to the Editor
ACKNOWLEDGMENTS
We thank Mrs. L Françoise, C Bocquet, and C Dupont for their excellent technical assistance. REFERENCES 1. Massarelli E, Johnson FM, Erickson HS, Wistuba II, Papadimitrakopoulou V. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. Lung Cancer 2013;80:235–241. 2. Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812–3821. 3. Keam B, Kim DW, Park JH, et al. Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer. Int J Clin Oncol 2014;19:594–600. 4. Watanabe S, Minegishi Y, Yoshizawa H, et al. Effectiveness of gefitinib against non-smallcell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol 2014;9:189–194. 5. Hata A, Yoshioka H, Fujita S, et al. Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer. J Thorac Oncol 2010;5:1524–1528. 6. Beau-Faller M, Prim N, Ruppert AM, et al. Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol 2014;25:126–131.
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Journal of Thoracic Oncology ® • Volume 9, Number 10, October 2014
involved in colonization of brain metastases from breast cancer. Breast Cancer Res 2010;12:R46. 3. Bamford S, Dawson E, Forbes S, et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer 2004;91:355–358. 4. Aoki Y, Niihori T, Kawame H, et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 2005;37:1038–1040. 5. Lea IA, Jackson MA, Li X, et al. Genetic pathways and mutation profiles of human cancers: site- and exposure-specific patterns. Carcinogenesis 2007;28:1851–1858.
FIGURE 1. Computed tomography scan of chest of patient 1 (left) before treatment and (right) after 3 months of gefitinib treatment.
Two Cases of Non– Small-Cell Lung Cancer with Rare Complex Mutation of EGFR Exon 18 But Different Response to Targeted Therapy To the Editor: In non–small-cell lung cancer (NSCLC) besides the common exons 19 and 21 EGFR-activating mutations (>90%), exon 18-point mutations (mainly p.G719X) are rare (4%).1 They are associated with a favorable response rate to EGFR tyrosine kinase inhibitors (EGFR-TKI),2,3 but are lower than common mutations.4 More than one mutation per sample represents complex mutations. Their clinical significance is uncertain, because they are rare (3.4–6.9%).2,3 Here, we present two cases of NSCLC with rare complex mutation that respond differently to EGFR-TKI.
Address for correspondence: Patricia de Cremoux, MD, PhD, Department of Biochemistry, Molecular Oncology Unit, Hôpital Saint Louis, 1, Avenue Claude Vellefaux, 75010 Paris, France. E-mail: patricia.de-cremoux@ sls.aphp.fr DOI: 10.1097/JTO.0000000000000328 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0910-0e78
e78
CASES PRESENTATION In July of 2012, an Asian, 52-year-old male smoker presented with a right cervical lymph node. A stage IV adenocarcinoma in the right lung; lymphangitis carcinomatosis; mediastinal, cervical, and susclavicular lymph nodes; and sacrum and hip bone osteoblastic metastases were diagnosed. Two-point mutations in exon 18 of the EGFR, p.I706T, and p.G719A were detected. Gefitinib treatment started in August of 2012. After 3 months, computed tomography -scan showed a partial response (Fig. 1).The clinical response was maintained under gefitinib treatment with 22 months of follow up. The second patient was a Caucasian, 58-year-old female smoker, referred in February of 2013. A stage IV lung adenocarcinoma, in the lower right lobe, with mediastinal lymph nodes as well as cerebral and right adrenal gland metastases was diagnosed. Twopoint mutations in exon 18, p.E709K and p.G719A, were detected. Erlotinib treatment and whole brain radiotherapy began. After 2 months, the patient’s performance status improved and computed tomography scan demonstrated a partial response on brain metastases and primary tumor. Then she presented with a progression of extracerebral metastases. Erlotinib was stopped. A chemotherapy combining cisplatin and pemetrexed was administered. In September of 2013, due to disease progression, carboplatin and paclitaxel were proposed. The patient presented a stable disease for 4 months and then
progressed. She died 11 months after diagnosis of metastatic disease.
DISCUSSION The clinical significance of EGFR complex mutations differs whether complex mutations include the most frequent mutations or not. Hata et al5 showed that tumours with complex mutations, including deletion of exon 19 or L858R point mutation, had the same response rate to EGFR-TKI than those with the same mutations alone. Wu et al2 showed that patients with rare and complex mutations, compared with patients with classic or rare mutation alone or classic mutation with rare mutations, had a worse response rate to EGFRTKI (25% versus 74.8, 68.8, and 80%, respectively) and a poorer progressionfree survival (1.4 versus 11.9, 8.1, and 8.0 months). Beau-Faller et al6 showed that EGFR-TKI efficacy was similar or slightly poorer in patients with complex mutations including p.G719X. Keam et al3 reported only two double mutations in exon 18, including the G719A + I706T, in a series of 306 patients. The overall survival of this patient, treated with erlotinib, was 53 months.3 This is the first description of the p.E709K + p.G719A mutation. To date, the behavior of these NSCLCs with complex mutations are not completely understood. The report of these rare and complex mutations and their response to EGFR-TKI should be very useful for the constitution of wellannotated databases and to improve the knowledge of their specific response to EGFR-TKI.
Copyright © 2014 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology ® • Volume 9, Number 10, October 2014
Hélène Gauthier, MD Gaelle Douchet Department of Medical Oncology Saint Louis Hospital Paris, France Jacqueline Lehmann-Che, PharmD, PhD Molecular Oncology Unit Department of Biochemistry, Saint Louis Hospital Paris, France Paris-Diderot University Press Sorbonne Cité Paris, France Véronique Meignin, MD, PhD Department of Pathology Saint Louis Hospital Paris, France Christine Raynaud, MD, PhD Department of Pneumology CH V Dupouy Argenteuil, France Pierre Sabatier, MD Department of Pathology CH V Dupouy Argenteuil, France Hubert de Cremoux, MD Department of Pneumology
CH V Dupouy Argenteuil, France Brigitte Poirot, PharmD Molecular Oncology Unit Department of Biochemistry, Saint Louis Hospital Paris, France Paris-Diderot University Press Sorbonne Cité Paris, France Stéphane Culine, MD, PhD Department of Medical Oncology Saint Louis Hospital Paris, France Paris-Diderot University Press Sorbonne Cité Paris, France Damien Pouessel, MD Department of Medical Oncology Saint Louis Hospital Paris, France Patricia de Cremoux, MD, PhD Molecular Oncology Unit Department of Biochemistry, Saint Louis Hospital Paris, France Paris-Diderot University Press Sorbonne Cité Paris, France
Copyright © 2014 by the International Association for the Study of Lung Cancer
Letters to the Editor
ACKNOWLEDGMENTS
We thank Mrs. L Françoise, C Bocquet, and C Dupont for their excellent technical assistance. REFERENCES 1. Massarelli E, Johnson FM, Erickson HS, Wistuba II, Papadimitrakopoulou V. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. Lung Cancer 2013;80:235–241. 2. Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812–3821. 3. Keam B, Kim DW, Park JH, et al. Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer. Int J Clin Oncol 2014;19:594–600. 4. Watanabe S, Minegishi Y, Yoshizawa H, et al. Effectiveness of gefitinib against non-smallcell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol 2014;9:189–194. 5. Hata A, Yoshioka H, Fujita S, et al. Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer. J Thorac Oncol 2010;5:1524–1528. 6. Beau-Faller M, Prim N, Ruppert AM, et al. Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol 2014;25:126–131.
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