May 2018 Case Cedars-Sinai Skip to content Close Select your preferred language English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog English English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog Translation is unavailable for Internet Explorer Cedars-Sinai Home 1-800-CEDARS-1 1-800-CEDARS-1 Close Find a Doctor Locations Programs & Services Health Library Patient & Visitors Community My CS-Link Education clear Go Close Academics Academics Faculty Development Community Engagement Calendar Research Research Areas Research Labs Departments & Institutes Find Clinical Trials Research Cores Research Administration Basic Science Research Clinical & Translational Research Center (CTRC) Technology & Innovations News & Breakthroughs Education Graduate Medical Education Continuing Medical Education Graduate School of Biomedical Sciences Professional Training Programs Medical Students Campus Life Office of the Dean Simulation Center Medical Library Program in the History of Medicine About Us All Education Programs Departments & Institutes Faculty Directory Anatomic and Clinical Pathology Residency Back to Anatomic and Clinical Pathology Residency Application Information Explore the Residency Training Curriculum Autopsy Pathology Rotation Bone and Soft Tissue Head and Neck Pathology Rotation Breast Pathology Rotation Cardiovascular Pathology Rotation Clinical Chemistry Rotation Coagulation Rotation Cytopathology Rotation Dermatopathology Rotation Forensic Pathology Rotation Frozen Section Rotation Gastrointestinal and Liver Pathology Genitourinary Pathology Rotation Genomic Pathology Rotation Gynecologic Pathology Rotation Hematopathology Rotation Laboratory Management Rotation Microbiology Rotation Neuropathology Rotation Pulmonary and Mediastinal Pathology Rotation Renal Pathology Rotation Transfusion Medicine Rotation Surgical Pathology Pathology Physician Scientist Training Program Residents Graduates Case of the Month Archive Publications Leadership Frequently Asked Questions May 2018 Case Authors Eric Vail, MD (Fellow), Jean Lopategui, MD (Faculty) Subject Molecular Pathology Clinical History The patient is a 57 year old female with history of heavy second hand smoke exposure, found incidentally to have a lung nodule. Biopsy showed squamous cell carcinoma. She presented for surgical excision and management. A lobectomy and lymph node dissection was performed. Diagnosis Pulmonary adenosquamous carcinoma with a somatic EGFR L858R and germline T790M Discussion EGFR is one of the most commonly mutated driver genes in NSCLC (10-15% of patients in the United States) with the L858R variant and exon 19 deletions encompassing almost 90% of de novo cases. These variants are concentrated in never smokers, women and people of East Asian descent but can occur outside of these populations. Both of these variants are amenable to EGFR tyrosine kinase inhibitor (TKI) therapy and patients tend to respond well until resistance is inevitably developed, usually within 12-15 months. The most common resistance mechanism to first and second generation TKIs is the EGFR T790M variant (~50%) which can then subsequently be treated with the third generation TKI, osimertinib. This varianthas also been rarely described in both the de novo setting (1-2%) and as a germline variant, as seen in this case. Osimertinib is the treatment of choice in both of these scenarios. Germline T790M is associated with familial lung cancer syndromes and has a lifetime lung cancer risk in never smokers of 30-50% (Background risk ~1%) often presenting with multiple primary tumors and at a later stage. Due to this, it is necessary to perform genetic counselling and screening of family members. Interestingly, almost all cases reported to date have also been associated with a concurrent somatic EGFR mutation as was also seen in this case (L858R). Why this is has yet to be elucidated, especially considering that somatic T790M variants are known to independently drive carcinogenesis. References 1. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proceedings of the National Academy of Sciences of the United States of America. 2004 Sep 7;101(36):13306-11. 2. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. New England Journal of Medicine. 2005 Feb 24;352(8):786-92. 3. Gazdar A, Robinson L, Oliver D, Xing C, Travis WD, Soh J, Toyooka S, Watumull L, Xie Y, Kernstine K, Schiller JH. Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations. Journal of Thoracic Oncology. 2014 Apr 1;9(4):456-63. 4. Helena AY, Arcila ME, Fleischut MH, Stadler Z, Ladanyi M, Berger MF, Robson M, Riely GJ. Germline EGFR T790M mutation found in multiple members of a familial cohort. Journal of Thoracic Oncology. 2014 Apr 1;9(4):554-8. 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