Abstract
Predictive biomarkers are valuable in predicting drug response, and their significance increased with the development of targeted therapies in the past decade. In contrast, prognostic biomarkers may allow patients’ risk stratification in relation to specific outcome, usually in the absence of any treatment. The prognostic value of many biomarkers is controversial and mostly reflects differences in study methodologies, patient population, and interpretations. Prognostic biomarkers in lung cancer highly depend on tumor histology. For example, many predictive biomarkers in adenocarcinomas also have prognostic significance. Despite recent biomarker discoveries in squamous cell carcinomas, no well-defined prognostic biomarkers have been established. This chapter will briefly review some of the most important prognostic biomarkers in non-small cell lung carcinoma, primarily adenocarcinoma.
Access provided by CONRICYT-eBooks. Download chapter PDF
Similar content being viewed by others
Keywords
ALK
The prognostic significance of ALK rearrangement in lung adenocarcinoma is controversial. The European Thoracic Oncology Platform Lungscape project has demonstrated better overall survival (OS) in patients with surgically resected lung adenocarcinoma whose tumors were considered ALK positive either by ALK immunohistochemistry or ALK FISH [1]. In contrast, study in Asian patients, never smokers, with ALK-positive surgically resected lung adenocarcinoma showed worse disease-free survival (DFS) [2]. This sharp difference could be related to the different ethnicity of study population. The prognostic role of ALK was also reported in patients with advanced NSCLC who were not candidate for surgical treatment. Patients with ALK-positive NSCLC showed improved survival after radiotherapy for brain metastases compared with EGFR, KRAS, or wild-type tumors. The median OS for ALK-positive patients was 26.3 months, while patients with EGFR, KRAS, or wild-type tumors showed 13.6, 5.7, and 5.5 months of OS, respectively [3]. Subsequent treatment with targeted therapy resulted in further improvement in OS.
BRAF
In contrast to other tumors, non-V600E BRAF mutations represent almost 50% of all BRAF mutations in lung cancer. The prognostic significance of BRAF mutations in lung cancer is still uncertain, because of the limited data. BRAF mutations may coexist with other mutations such as mutations in EGFR, KRAS, and PIK3CA genes. It has been shown that patients with these coexistent mutations have shorter OS than patients with BRAF mutations only [4]. Most of the published studies failed to show any prognostic significance of BRAF in NSCLC [5,6,7,8].
EGFR
To date, the prognostic value of EGFR mutations in NSCLC is controversial. Several studies have shown longer survival in surgically treated patients with EGFR-mutated lung carcinomas when compared to EGFR wild type, regardless of subsequent treatments [9,10,11,12]. Other studies and meta-analysis showed no prognostic value of EGFR status in surgically treated lung carcinomas [13,14,15,16].
Recently published updates on LUX-Lung3 and LUX-Lung6 trials showed that patients with exon 19 deletion treated with afatinib have a better OS when compared to platinum-chemotherapy subgroup [17]. It has been known from prior retrospective studies and a meta-analysis that all of the EGFR-TKIs are more active in patients with exon 19 deletions than in L858R mutations, but the LUX-Lung studies were the only ones that prospectively showed an OS benefit [18, 19].
The T790M mutations most frequently occur in patients who initially responded to EGFR-TKI treatment but may also occur in EGFR-TKI-naïve patients. The prognostic significance seems to be different depending on the EGFR-TKI treatment status. It has been suggested that patients with pretreatment T790M have shorter PFS when treated with EGFR-TKIs [20,21,22]. However, other studies showed potential positive prognostic value in post-TKI setting [23, 24].
KRAS
Many retrospective studies reported correlation between KRAS mutations and a poor overall survival in patients with resected NSCLC [25]. A meta-analysis of more than 53 retrospective studies identified KRAS mutations as a negative prognostic factor [26, 27]. However, a recent pooled analysis including four trials comparing platinum-based adjuvant chemotherapy to observation in early-stage resected NSCLC has shown that KRAS mutation status is not significantly prognostic [28].
References
Blackhall FH, Peters S, Bubendorf L, Dafni U, Kerr KM, Hager H, et al. Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: results from the European thoracic oncology platform lungscape project. J Clin Oncol. 2014;32(25):2780–7.
Kim MH, Shim HS, Kang DR, Jung JY, Lee CY, Kim DJ, et al. Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma. Lung Cancer. 2014;83(3):389–95.
Mak KS, Gainor JF, Niemierko A, Oh KS, Willers H, Choi NC, et al. Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non-small cell lung cancer treated with radiotherapy for brain metastases. Neuro-Oncology. 2015;17(2):296–302.
Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29(26):3574–9.
Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013;19(16):4532–40.
Paik PK, Arcila ME, Fara M, Sima CS, Miller VA, Kris MG, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29(15):2046–51.
Kinno T, Tsuta K, Shiraishi K, Mizukami T, Suzuki M, Yoshida A, et al. Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations. Ann Oncol. 2014;25(1):138–42.
Villaruz LC, Socinski MA, Abberbock S, Berry LD, Johnson BE, Kwiatkowski DJ, et al. Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the lung cancer mutation consortium. Cancer. 2015;121(3):448–56.
D'Angelo SP, Janjigian YY, Ahye N, Riely GJ, Chaft JE, Sima CS, et al. Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol. 2012;7(12):1815–22.
Kosaka T, Yatabe Y, Onozato R, Kuwano H, Mitsudomi T. 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(1):22–9.
Jeon JH, Kang CH, Kim HS, Seong YW, Park IK, Kim YT. Prognostic and predictive role of epidermal growth factor receptor mutation in recurrent pulmonary adenocarcinoma after curative resection. Eur J Cardiothorac Surg. 2015;47(3):556–62.
Lee YJ, Park IK, Park MS, Choi HJ, Cho BC, Chung KY, 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(12):1647–54.
Liu WS, Zhao LJ, Pang QS, Yuan ZY, Li B, Wang P. Prognostic value of epidermal growth factor receptor mutations in resected lung adenocarcinomas. Med Oncol. 2014;31(1):771.
Lim KH, Huang MJ, Liu HC, Kuo HT, Tzen CY, Hsieh RK. Lack of prognostic value of EGFR mutations in primary resected non-small cell lung cancer. Med Oncol. 2007;24(4):388–93.
Marks JL, Broderick S, Zhou Q, Chitale D, Li AR, Zakowski MF, et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol. 2008;3(2):111–6.
Zhang Z, Wang T, Zhang J, Cai X, Pan C, Long Y, et al. Prognostic value of epidermal growth factor receptor mutations in resected non-small cell lung cancer: a systematic review with meta-analysis. PLoS One. 2014;9(8):e106053.
Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, 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(2):141–51.
Zhang Y, Sheng J, Kang S, Fang W, Yan Y, Hu Z, et al. Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis. PLoS One. 2014;9(9):e107161.
Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12(13):3908–14.
Rosell R, Molina MA, Costa C, Simonetti S, Gimenez-Capitan A, Bertran-Alamillo J, et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin Cancer Res. 2011;17(5):1160–8.
Su KY, Chen HY, Li KC, Kuo ML, Yang JC, Chan WK, et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol. 2012;30(4):433–40.
Ding D, Yu Y, Li Z, Niu X, Lu S. The predictive role of pretreatment epidermal growth factor receptor T790M mutation on the progression-free survival of tyrosine-kinase inhibitor-treated non-small cell lung cancer patients: a meta-analysis. Onco Targets Ther. 2014;7:387–93.
Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17(6):1616–22.
Li W, Ren S, Li J, Li A, Fan L, Li X, et al. T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients. Lung Cancer. 2014;84(3):295–300.
Slebos RJ, Kibbelaar RE, Dalesio O, Kooistra A, Stam J, Meijer CJ, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med. 1990;323(9):561–5.
Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer. 2005;92(1):131–9.
Meng D, Yuan M, Li X, Chen L, Yang J, Zhao X, et al. Prognostic value of K-RAS mutations in patients with non-small cell lung cancer: a systematic review with meta-analysis. Lung Cancer. 2013;81(1):1–10.
Shepherd FA, Domerg C, Hainaut P, Janne PA, Pignon JP, Graziano S, 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(17):2173–81.
Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863–70.
Dimou A, Non L, Chae YK, Tester WJ, Syrigos KN. MET gene copy number predicts worse overall survival in patients with non-small cell lung cancer (NSCLC); a systematic review and meta-analysis. PLoS One. 2014;9(9):e107677.
Guo B, Cen H, Tan X, Liu W, Ke Q. Prognostic value of MET gene copy number and protein expression in patients with surgically resected non-small cell lung cancer: a meta-analysis of published literatures. PLoS One. 2014;9(6):e99399.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this chapter
Cite this chapter
Dacic, S. (2018). Prognostic Biomarkers in Lung Cancer. In: Cagle, P., et al. Precision Molecular Pathology of Lung Cancer. Molecular Pathology Library. Springer, Cham. https://doi.org/10.1007/978-3-319-62941-4_18
Download citation
DOI: https://doi.org/10.1007/978-3-319-62941-4_18
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-62940-7
Online ISBN: 978-3-319-62941-4
eBook Packages: MedicineMedicine (R0)