Personalization of lung cancer treatment requires predictive biomarkers that have been validated by correlation between tumor features and outcomes after therapy. Several mutations have been identified in the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC). Mutations in this gene are considered an important predictor of response to EGFR tyrosine kinase inhibitors (TKIs) with 70–80% of NSCLC patients receiving substantial beneﬁts from this targeted therapy (1). The EGFR mutation is both a predictive and prognostic factor of EGFR-TKI therapy outcome (1,2). Testing for these mutations in all patients with recurrent or metastatic lung adenocarcinoma is therefore recommended for standard practice.
Several studies have reported that EGFR mutations have an impact on prognosis after surgical resection of NSCLCs (3,4). Izar et al. demonstrated that the mutation status of EGFR can serve as an independent prognostic marker associated with decreased recurrence and improved progression-free survival and overall survival (OS) in patients with stage I lung adenocarcinoma (3). This study was restricted to patients who had no adjuvant or neoadjuvant systemic therapy administered and focused solely on the postoperative prognostic differences among different genotypes. On the other hand, Kosaka et al. reported that the significant prognostic impact of EGFR mutations was lost after adjusting for other confounding prognostic factors (4). Several other studies in the literature corroborate this finding (5,6). Additionally, EGFR mutation status and the use of EGFR-TKI therapy particularly affected the postoperative recurrence survival (PRS), which is survival after disease recurrence, among patients who underwent surgical resection for lung cancers (7). The results could also affect OS in general.
Exon 19 deletion (Ex19) and the L858R point mutation in exon 21 (Ex21) of EGFR comprise approximately 90% of all EGFR mutation positive lung adenocarcinomas (8) and are strongly associated with robust responses to EGFR-TKI. Patients with Ex19 advanced NSCLC have consistently shown improved outcomes with afatinib vs. chemotherapy compared with those with Ex21 NSCLC (9). The cause for these differences in response to EGFR-TKIs among EGFR mutation subtypes is not known. However, another trial that demonstrated survival curves of patients with Ex19 and Ex21 advanced NSCLC showed no statistically significant differences between afatinib or gefitinib and the EGFR mutation subtypes (10).
In the study by Isaka et al. published in the Annals of Thoracic Surgery, the authors demonstrated that different EGFR mutation subtypes were associated with different prognoses among patients with surgically resected pathologic N1-N2 lung adenocarcinoma (11). This meaningful work showed that patients with Ex19 displayed statistically significant better 5-year disease-free survival (DFS) rate (38.8%) than those with Ex21 (11.8%, P=0.001). In this study, pathologic N status (N1 or N2) or pathologic stage (stage II or III) were determined to not be statistically informative prognostic factors for DFS using multivariate analysis (HR 1.71; P=0.353, or HR 0.75; P=0.627, respectively). Additionally, patients with Ex21 tumors displayed a significantly higher prevalence of pN2 (70.7%) than those with Ex19 tumors (45.5%, P=0.014). However, in this case, the EGFR mutation subtype was a prognostic factor for DFS using multivariate analysis (HR 2.25; 95% CI, 1.21–4.20, P=0.011). Therefore, they hypothesized that tumors with Ex19 might possess lower proliferative potential, making them more susceptible to cell death than those tumors with Ex21.
Meanwhile, two conflicting in vivo assessments have been reported. Carey et al. showed that the growth rate of the NR6-EGFR del [746-752] cell line was more aggressive in vivo than the NR6-EGFR L858R cell line (12). This data might support the results and hypothesis of Isaka’s study. However, Politi et al. demonstrated that lung tumors from EGFR L858R expressing mice developed faster and exhibited a preponderance of lepidic growth with a more aggressive nature compared with lung tumors derived from EGFR del [L747-S752] expressing mice. It is to be noted that both EGFR mutation subtypes promoted lung adenocarcinomas with lepidic growth features in transgenic mice (13).
Table 1 summarizes ten studies that reported a relationship between EGFR mutation subtypes and prognosis (4,5,11,14-21). In focusing on the association between DFS or recurrence and EGFR mutation subtype, Liu et al. also reported that patients with Stage I-IIIA lung adenocarcinoma harboring Ex19 had a better DFS rate than those with Ex21 (P=0.056) (14). Conversely, Okamoto et al. demonstrated that patients with Stage I-III lung adenocarcinoma harboring Ex21 showed statistically significant better DFS than those with Ex19 (P=0.027), and that the EGFR mutation subtype was a potential prognostic factor for DFS (HR 0.41, P=0.067) (17). In the study reported by Nishi et al., whose institution was the same as Isaka et al., the DFS rate of Stage IB lung adenocarcinoma harboring Ex21 was better than that of Ex19 (P=0.008), with no differences in DFS observed among patients with stage IA adenocarcinoma (P=0.681) (16). Furthermore, several other groups reported there to be no significant differences of DFS between tumors with Ex19 and those with Ex21 (19,20).
Possibilities for the discrepancies in survival might be due to clinicopathological factors, studies containing small cohorts of patients, or selection bias in the examination of EGFR mutation analysis. For instance, Isaka et al. determined the EGFR mutation status in their cohort and identified mutations in 72.9% of 277 patients with pN1–2, and EGFR mutation status was also examined for not all of the patients in other studies. Moreover, it might be necessary to interpret that DFS were affected by death from other cause as well as lung cancer recurrence or death and by follow-up assessment schedule after operation.
The current study demonstrated the association between EGFR mutation subtype and prognosis, especially DFS among patients with pN1–N2 lung adenocarcinoma. This study could provide additional evidence to support EGFR mutation analysis for surgically resected lung adenocarcinoma. Large prospective and multicenter studies with appropriate EGFR mutation detection methods are warranted to validate the prognostic effect of EGFR mutation subtypes.
Funding: This work was supported by the Grant-in-Aid for Scientific Research, Japan Society for the Promotion of Science (24592104), Ministry of Education, Culture, Sports, Science and Technology, Japan.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009;361:947-57. [Crossref] [PubMed]
- Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900-9. [Crossref] [PubMed]
- Izar B, Sequist L, Lee M, et al. The impact of EGFR mutation status on outcomes in patients with resected stage I non-small cell lung cancers. Ann Thorac Surg 2013;96:962-8. [Crossref] [PubMed]
- Kosaka T, Yatabe Y, Onozato R, et al. Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma. J Thorac Oncol 2009;4:22-9. [Crossref] [PubMed]
- 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;3:111-6. [Crossref] [PubMed]
- Kim YT, Seong YW, Jung YJ, et al. The presence of mutations in epidermal growth factor receptor gene is not a prognostic factor for long-term outcome after surgical resection of non-small-cell lung cancer. J Thorac Oncol 2013;8:171-8. [Crossref] [PubMed]
- Kudo Y, Shimada Y, Saji H, et al. Prognostic Factors for Survival After Recurrence in Patients With Completely Resected Lung Adenocarcinoma: Important Roles of Epidermal Growth Factor Receptor Mutation Status and the Current Staging System. Clin Lung Cancer 2015;16:e213-21. [Crossref] [PubMed]
- Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006;118:257-62. [Crossref] [PubMed]
- Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015;16:141-51. [Crossref] [PubMed]
- Paz-Ares L, Tan EH, O'Byrne K, et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol 2017. [Epub ahead of print]. [Crossref]
- Isaka T, Nakayama H, Yokose T, et al. Epidermal Growth Factor Receptor Mutations and Prognosis in Pathologic N1-N2 Pulmonary Adenocarcinoma. Ann Thorac Surg 2016;102:1821-8. [Crossref] [PubMed]
- Carey KD, Garton AJ, Romero MS, et al. Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res 2006;66:8163-71. [Crossref]
- Politi K, Zakowski MF, Fan PD, et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 2006;20:1496-510. [Crossref] [PubMed]
- Liu WS, Zhao LJ, Pang QS, et al. Prognostic value of epidermal growth factor receptor mutations in resected lung adenocarcinomas. Med Oncol 2014;31:771. [Crossref] [PubMed]
- Lee YJ, Park IK, Park MS, et al. Activating mutations within the EGFR kinase domain: a molecular predictor of disease-free survival in resected pulmonary adenocarcinoma. J Cancer Res Clin Oncol 2009;135:1647-54. [Crossref] [PubMed]
- Nishii T, Yokose T, Miyagi Y, et al. Prognostic value of EGFR mutations in surgically resected pathological stage I lung adenocarcinoma. Asia Pac J Clin Oncol 2016. [Epub ahead of print]. [Crossref] [PubMed]
- Okamoto T, Kitahara H, Shimamatsu S, et al. Prognostic Impact of EGFR Driver Mutations on Postoperative Disease Recurrence in Lung Adenocarcinoma. Anticancer Res 2016;36:3057-63. [PubMed]
- Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339-46. [Crossref] [PubMed]
- Nose N, Sugio K, Oyama T, et al. Association between estrogen receptor-beta expression and epidermal growth factor receptor mutation in the postoperative prognosis of adenocarcinoma of the lung. J Clin Oncol 2009;27:411-7. [Crossref] [PubMed]
- Jin Y, Chen M, Yu X. Differences among lesions with exon 19, exon 21 EGFR mutations and wild types in surgically resected non-small cell lung cancer. Sci Rep 2016;6:31636. [Crossref] [PubMed]
- Sugio K, Uramoto H, Ono K, et al. Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking. Br J Cancer 2006;94:896-903. [Crossref] [PubMed]