Verifying the role of surgical pathologists in the precision medicine of lung cancer.
The discovery in 2004 by several different research groups that somatic mutations in the EGFR gene predicted which lung cancers were likely to respond to therapy with EGFR tyrosine kinase inhibitors (TKIs) was a momentous stride in the treatment of lung cancer. (4-6) Pathologists had long known that EGFR protein was overexpressed in the majority of NSCLCs. (7) The first generation of selective, reversible EGFR TKIs was introduced in the early 21st century and consisted of gefitinib (Iressa; AstraZeneca, London, United Kingdom) and erlotinib (Tarceva; Genentech, South San Francisco, California, and OSI Pharmaceuticals, Long Island, New York). However, in early clinical trials of unselected patients with advanced lung cancer, the results showed limited value of these drugs prior to the discovery of the predictive value of the EGFR mutations. (8-15)
In 2009, the first report of a clinical trial (IRESSA Pan-Asia Study) was published in which a better response rate and progression-free survival with gefitinib therapy was observed, compared to conventional chemotherapy, in patients whose advanced-stage NSCLC had EGFR mutations. (16,17) These observations were confirmed for gefitinib versus conventional chemotherapy in 2 other clinical trials (WJTOG3405 and NEJ002) published in 2010, (18,19) and similar results were reported for erlotinib versus conventional chemotherapy in the OPTIMAL and EURTAC studies. (20,21)
Also see p. 1255
In these and other clinical trials, EGFR mutation analysis has proven to be the best test to select patients for EGFR TKI therapy. Studies have shown that EGFR mutations occur in adenocarcinomas, adenosquamous carcinomas and subtypes, or poorly differentiated carcinomas that are likely to be adenocarcinomas, and rarely, and possibly not at all, in squamous cell carcinomas. (22-34) Because 70% of NSCLCs present in advanced stage, typically the only specimens for EGFR mutation testing are small biopsies and cytology specimens. (35-38) Institutional policies and/or requests by the oncologist determine when EGFR mutation testing is done. Currently, EGFR mutation analysis is widely and increasingly reflexively performed on adenocarcinomas. (39,40) It may also be performed when the cell type cannot be determined or when an adenocarcinoma component cannot be excluded because of the limitations of the sample.
EGFR polysomy and amplification do not predict response to EGFR TKI therapy as consistently in clinical trials and, therefore, EGFR fluorescence in situ hybridization is not as dependable for selecting patients for EGFR TKI therapy. (22-32,41-43) Traditional EGFR IHC, which detects total EGFR expression, is not applicable for EGFR TKI therapy because it is not mutation specific. (22-32,44) Mutation-specific EGFR antibodies do not yet account for all potentially actionable mutations, although they may have a possible role in initial screening. (45-47)
The EGFR mutation/EGFR TKI story has generated a great deal of excitement and hope among lung cancer patients, their families and friends, oncologists, pathologists, and the lay public. However, EGFR TKI therapy, as exciting as it is and as important as it is to a subset of patients, is far from a cure-all for lung cancer. For one thing, EGFR mutations occur in only a minority of NSCLCs and, therefore, a limited number of lung cancer patients are potential candidates for this therapy. EGFR mutation frequency ranges up to 32% of NSCLC in East Asians and up to 15% of NSCLC in whites and is about 20% of NSCLC in African Americans, accounting for about 30 000 new cases of EGFR mutation-positive NSCLC in the United States every year. (30, 48-52) In addition, patients who respond to EGFR TKI therapy eventually develop acquired resistance and relapse, creating a need for additional lines of therapy. Therefore, other types of targeted therapy for lung cancer are in varying stages of clinical validation or investigation. (22-30)
To identify candidates for EGFR TKI therapy, the surgical pathologist or cytopathologist makes the diagnosis of a primary pulmonary adenocarcinoma with the caveats mentioned above and then selects tissue and sends it to the molecular diagnostics laboratory for mutation analysis. This role is very important and requires specialized knowledge and skills, but, unless the pathologist is also directly involved in the molecular diagnostics laboratory, the surgical pathologist or cytopathologist does not personally supervise the EGFR mutation testing.
The likely addition of cetuximab to the treatment options for advanced NSCLC patients provides an opportunity for direct predictive biomarker testing by the anatomic pathologist. Cetuximab has been approved for therapy of advanced colon adenocarcinoma and advanced head and neck squamous cell carcinoma. (53-57) In 2011 and 2012, subgroup analysis of the First Line Erbitux in Lung Cancer Phase III clinical trial concluded that an EGFR IHC score of 200 or more (high expression) using the Dako (Glostrup, Denmark) pharmDx kit was associated with increased overall survival in advanced NSCLC patients receiving first-line platinum-based chemotherapy plus cetuximab versus chemotherapy alone for both squamous cell carcinomas and adenocarcinomas. (1-3)
Cetuximab therapy opens the door for EGFR IHC as a predictive biomarker test for NSCLC. Immunohistochemistry is a technique familiar to the surgical pathologist and is performed routinely in many hospital laboratories. It requires the ordinary light microscope for interpretation and presents some advantages over molecular testing. Direct observation of tissues by the light microscope allows accurate interpretation even when the number of tumor cells is minimal and/or when the tumor cells are dispersed or diluted by nonmalignant or necrotic tissues that might hamper molecular tests. We have previously discussed these same advantages in regards to the new sensitive antibodies for anaplastic lymphoma kinase protein in NSCLC. (58) By following up on recent observations of the First Line Erbitux in Lung Cancer clinical trials with their validation of the reproducibility of the EGFR IHC scoring system, Dr Ruschoff and colleagues have further verified the direct role that surgical pathologists can contribute to the personalized health care of lung cancer patients.
(1.) Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012;13(1):33-42.
(2.) Pirker R, Pereira JR, Szczesna A, et al. Prognostic factors in patients with advanced non-small cell lung cancer: data from the phase III FLEX study. Lung Cancer. 2012;77(2):376-382.
(3.) O'Byrne KJ, Gatzemeier U, Bondarenko I, et al. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol. 2011;12(8):795-805.
(4.) Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-2139.
(5.) Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500.
(6.) Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004; 101(36):13306-13311.
(7.) Sobol RE, Astarita RW, Hofeditz C, et al. Epidermal growth factor receptor expression in human lung carcinomas defined by a monoclonal antibody. J Natl Cancer Inst. 1987;79(3):403-407.
(8.) Blackhall FH, Rehman S, Thatcher N. Erlotinib in non-small cell lung cancer: a review. Expert Opin Pharmacother. 2005;6(6):995-1002.
(9.) Chang AY. The role of gefitinib in the management of Asian patients with non-small cell lung cancer. Expert Opin Investig Drugs. 2008;17(3):401-411.
(10.) Costa DB, Kobayashi S, Tenen DG, Huberman MS. Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer. 2007;58(1):95-103.
(11.) Costa DB, Nguyen KS, Cho BC, et al. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin Cancer Res. 2008; 14(21):7060-7067.
(12.) Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005; 23(25):5892-5899.
(13.) Perez-Soler R. Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. Clin Lung Cancer. 2004;6(suppl 1):S20-S23.
(14.) Schettino C, Bareschino MA, Ricci V, Ciardiello F. Erlotinib: an EGF receptor tyrosine kinase inhibitor in non-small-cell lung cancer treatment. Expert Rev Respir Med. 2008;2(2):167-178.
(15.) Wheatley-Price P, Shepherd FA. Epidermal growth factor receptor inhibitors in the treatment of lung cancer: reality and hopes. Curr Opin Oncol. 2008;20(2):162-175.
(16.) Mok TS, Wu YL, ThongprasertS, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
(17.) Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011; 29(21):2866-2874.
(18.) Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121-128.
(19.) Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25): 2380-2388.
(20.) Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246.
(21.) Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742.
(22.) Cagle PT, Allen TC, Dacic S, et al. Revolution in lung cancer: new challenges for the surgical pathologist. Arch Pathol Lab Med. 2011;135(1):110 116.
(23.) Cagle PT, Dacic S. Lung cancer and the future of pathology. Arch Pathol Lab Med. 2011;135(3):293-295.
(24.) Chirieac LR, Dacic S. Targeted therapies in lung cancer. Surg Pathol Clin. 2010;3(1):71-82.
(25.) Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.
(26.) Dacic S. Lung carcinoma morphology or mutational profile: that is the question. Arch Pathol Lab Med. 2011;135(10):1242-1243.
(27.) Hirsch FR, Wynes MW, Gandara DR, Bunn PA Jr. The tissue is the issue: personalized medicine for non-small cell lung cancer. Clin Cancer Res. 2010; 16(20):4909-4911.
(28.) Kerr KM. Personalized medicine for lung cancer: new challenges for pathology. Histopathology. 2012;60(4):531-546.
(29.) Mok TS, Zhou Q, Leung L, Loong HH. Personalized medicine for non-small-cell lung cancer. Expert Rev Anticancer Ther. 2010;10(10):1601-1611.
(30.) Gaughan EM, Costa DB. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol. 2011;3(3):113-125.
(31.) Girard N, Sima CS, Jackman DM, et al. Nomogram to predict the presence of EGFR activating mutation in lung adenocarcinoma. Eur Respir J. 2012;39(2): 366-372.
(32.) Gately K, O'FlahertyJ, Cappuzzo F, Pirker R, Kerr K, O'Byrne K. The role of the molecular footprint of EGFR in tailoring treatment decisions in NSCLC. J Clin Pathol. 2012;65(1):1-7.
(33.) Rekhtman N, Paik PK, Arcila ME, et al. Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res. 2012; 18(4):1167-1176.
(34.) Tochigi N, Dacic S, Nikiforova M, Cieply KM, Yousem SA. Adenosquamous carcinoma of the lung: a microdissection study of KRAS and EGFR mutational and amplification status in a Western patient population. Am J Clin Pathol. 2011;135(5):783-789.
(35.) Aisner DL, Deshpande C, Baloch Z, et al. Evaluation of EGFR mutation status in cytology specimens: an institutional experience [published online ahead of print November 18, 2011]. Diagn Cytopathol. doi:10.1002/dc.21851.
(36.) BrunoP, MariottaS, Ricci A, et al. Reliability of direct sequencing of EGFR: comparison between cytological and histological samples from the same patient. Anticancer Res. 2011;31(12):4207-4210.
(37.) Gil-Bazo I, Castanon E, Fusco JP. EGFR mutation testing in nonsmall cell lung cancer patients by using cytology specimens: when the tissue is no longer the issue. Cancer Cytopathol. 2011;119(5):354.
(38.) Navani N, Brown JM, Nankivell M, et al. Suitability of endobronchial ultrasound-guided transbronchial needle aspiration specimens for subtyping and genotyping of non-small cell lungcancer: amulticenter study of 774 patients. Am JRespir Crit Care Med. 2012;185(12):1316-1322.
(39.) D'Angelo SP, Park B, Azzoli CG, et al. Reflex testing of resected stage I through III lung adenocarcinomas for EGFR and KRAS mutation: reporton initial experienceand clinical utility at a single center. J Thorac Cardiovasc Surg. 2011; 141(2):476-480.
(40.) Mino-Kenudson M, Mark EJ. Reflex testing for epidermal growth factor receptor mutation and anaplastic lymphoma kinase fluorescence in situ hybridization in non-small cell lung cancer. Arch Pathol Lab Med. 2011; 135(5):655-664.
(41.) Bell DW, Lynch TJ, Haserlat SM, et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005;23(31):8081-8092.
(42.) Cappuzzo F. EGFR FISH versus mutation: different tests, different end points. Lung Cancer. 2008;60(2):160-165.
(43.) Hirsch FR, Varella-Garcia M, Dziadziuszko R, et al. Fluorescence in situ hybridization subgroup analysis of TRIBUTE, a phase III trial of erlotinib plus carboplatin and paclitaxel in non-small cell lung cancer. Clin Cancer Res. 2008; 14(19):6317-6323.
(44.) Pirker R, Herth FJ, Kerr KM, et al. Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop. JThorac Oncol. 2010;5(10):1706-1713.
(45.) Brevet M, Arcila M, Ladanyi M. Assessment of EGFR mutation status in lung adenocarcinoma by immunohistochemistry using antibodies specific to the two major forms of mutant EGFR. J Mol Diagn. 2010;12(2):169-176.
(46.) Hasanovic A, Ang D, Moreira AL, Zakowski MF. Use of mutation specific antibodies to detect EGFR status in small biopsy and cytology specimens of lung adenocarcinoma. Lung Cancer. 2012;77(2):299-305.
(47.) Yu J, Kane S, Wu J, et al. Mutation-specific antibodies for the detection of EGFR mutations in non-small-cell lung cancer. Clin Cancer Res. 2009;15(9): 3023-3028.
(48.) Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci. 2007;98(12): 1817-1824.
(49.) Suda K, Tomizawa K, Mitsudomi T. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Metastasis Rev. 2010;29(1):49-60.
(50.) Reinersman JM, Johnson ML, RielyGJ, et al. Frequency of EGFR and KRAS mutations in lung adenocarcinomas in African Americans. J Thorac Oncol. 2011; 6(1):28-31.
(51.) Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277-300.
(52.) Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10-29.
(53.) Eng C. The evolving role of monoclonal antibodies in colorectal cancer: early presumptions and impact on clinical trial development. Oncologist. 2010; 15(1):73-84.
(54.) Mehra R, Cohen RB, Burtness BA. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol. 2008;6(10):742-750.
(55.) Moon C, Chae YK, Lee J. Targeting epidermal growth factor receptor in head and neck cancer: lessons learned from cetuximab. Exp Biol Med (Maywood). 2010;235(8):907-920.
(56.) Vincenzi B, Zoccoli A, Pantano F, Venditti O, Galluzzo S. Cetuximab: from bench to bedside. Curr Cancer Drug Targets. 2010;10(1):80-95.
(57.) Wong SF. Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther. 2005;27(6):684-694.
(58.) Cagle PT, Myers J. Precision medicine for lung cancer: role of the surgical pathologist. Arch Pathol Lab Med. 2012;136(10):1186-1189.
Philip T. Cagle, MD; Randall J. Olsen, MD, PhD
Accepted for publication November 2, 2012.
Published as an Early Online Release December 31, 2012.
From the Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston, Texas, and the Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Philip T. Cagle, MD, Department of Pathology & Genomic Medicine, The Methodist Hospital, 6565 Fannin Street, Main Bldg, Room 227, Houston, TX 77030 (e-mail: pcagle@tmhs. org).
|Printer friendly Cite/link Email Feedback|
|Author:||Cagle, Philip T.; Olsen, Randall J.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Sep 1, 2013|
|Previous Article:||Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs.|
|Next Article:||Eltrombopag and serum of a different Hue.|