|Year : 2017 | Volume
| Issue : 1 | Page : 9-15
Genomic aberrations in non- small cell lung cancer and their impact on treatment outcome
Amrallah A Mohammed1, Hani El-Tanni2, Mohammed A Alsakkaf3, Ahmad A Mirza4, Tariq Al-Malki Atiah4, Arwa Al-Malki Atiah4
1 Department of Medical Oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt; Oncology Center, King Abdullah Medical City-Holy Capital, Makkah, Saudi Arabia
2 Oncology Center, King Abdullah Medical City-Holy Capital, Makkah, Saudi Arabia
3 Batterjee Medical College, Jeddah, Saudi Arabia
4 Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
|Date of Web Publication||16-May-2017|
Amrallah A Mohammed
Muzdallifa Streat, P.O. Box 57657, 21995 Mecca, Saudi Arabia
Source of Support: None, Conflict of Interest: None
The therapeutic options of nonsmall cell lung cancer (NSCLC) therapy has been changed since the first discovery of activating epidermal growth factor receptor (EGFR) mutations and the development of specific EGFR tyrosine kinase inhibitors, which resulted in the evolution of “personalized medicine.” There are a considerable number of genomic aberrations in NSCLC serving as potential predictive biomarkers and drug targets and still more. We summarized the molecular pathways, potential targets, and possible impact on disease outcome in NSCLC.
Keywords: Epidermal growth factor receptor, nonsmall cell lung cancer, oncogenes, targeted therapy, tyrosine kinase inhibitor
|How to cite this article:|
Mohammed AA, El-Tanni H, Alsakkaf MA, Mirza AA, Atiah TA, Atiah AA. Genomic aberrations in non- small cell lung cancer and their impact on treatment outcome. J Can Res Ther 2017;13:9-15
|How to cite this URL:|
Mohammed AA, El-Tanni H, Alsakkaf MA, Mirza AA, Atiah TA, Atiah AA. Genomic aberrations in non- small cell lung cancer and their impact on treatment outcome. J Can Res Ther [serial online] 2017 [cited 2017 Oct 21];13:9-15. Available from: http://www.cancerjournal.net/text.asp?2017/13/1/9/180605
| > Introduction|| |
Lung cancer is the leading cause of cancer-related mortality worldwide. The WHO divides lung cancer into two main classes based on its biology, therapy, and prognosis: Small cell lung cancer (SCLC) and non-SCLC (NSCLC). NSCLC accounts for more than 83% of all lung cancers cases; moreover, it is further characterized by two major types; nonsquamous cell carcinoma (non-SCC) including adenocarcinoma, large cell carcinoma, and other cell types; and SCC. Despite significant progress in the staging, diagnostic procedures, and therapeutic options, the overall 5-year survival is only 17.4% of all patients with lung cancer. This low survival rate is not only due to advanced stage and multiple comorbidities at the time of diagnosis but also due to intolerability to chemotherapies.
Known how cancer cells develop in NSCLC helps understanding how targeted therapy works. Targeted cancer therapies are drugs designed to interfere with specific molecules necessary for tumor growth and progression. Traditional chemotherapies usually kill rapidly dividing cells by interfering with cell division. A primary goal of targeted therapies is to fight cancer cells more precision and potentially fewer side effects. They sometimes work when chemotherapies do not. Nowadays, they are most often used for a significant subgroup of NSCLC patients, either alone or combined with chemotherapies.
Many genetic aberrations have been identified in NSCLC and lead to new classification based on their molecular subtypes. [Table 1] shows the frequency and type of gene alteration in NSCLC.
The most useful biomarkers for predicting the efficacy of targeted therapy in advanced NSCLC are somatic genome alterations known as “driver mutations.” These mutations occur in cancer cells within genes encoding for proteins critical to cell growth and survival. Many other recurrent molecular alterations have been identified in NSCLC that are much less essential to maintain the oncogenic phenotype and are often referred to as “passenger mutations.” Driver mutations are typically not found in the germline (noncancer) genome of the host and are usually mutually exclusive. [Figure 1]a and [Figure 1]b show an overview of molecular pathways and potential targets in NSCLC.
|Figure 1: Molecular pathways and potential targets in both adenocarcinoma (a) and squamous cell carcinoma (b). Adapted from Boolell et al.|
Click here to view
Multiple Phase 3 studies in advanced NSCLC showed the benefit of targeting an oncogenic driver versus standard first- or second-line chemotherapy. Given that the progression-free survival (PFS) benefit from the targeted therapy in these trials (range, 3.9–4.5 months) is longer than the historical overall survival (OS) benefit seen with either first-line platinum-based chemotherapy (1.5 months) or second-line docetaxel (2.4 months). In the general lung cancer population, it may seem as if everyone could agree that targeted therapy was the clear winner in terms of its impact on survival in lung cancer.,,
This aim of this review is to give an overview of the oncogenes known to be important in NSCLC pathogenesis and the impact of genomic aberrations on treatment outcome.
Epidermal growth factor receptor
Epidermal growth factor receptor (EGFR) is a transmembrane receptor with tyrosine kinase (RTK) activity on the intracellular domain. Upon binding of the ligand, various intracellular pathways are activated leading to promoting cell growth and motility. Based on the new adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society, Korean researchers identified EGFR mutations in 50.5% of surgically resected lung adenocarcinomas in their center. Mutations were associated with the micropapillary predominant subtype and the presence of the lepidic pattern.
The presence of EGFR exon 19 deletions or 21 exon L858R mutations is referred to as sensitizing EGFR mutations. EGFR inhibition is achieved through two main classes of drugs: Tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. Use of the EGFR-TKIs is limited to patients with adenocarcinomas who have known sensitizing EGFR mutations. The activity of the EGFR monoclonal antibody cetuximab seems to be independent of EGFR mutation status.
There are three generations of TKIs available, erlotinib and gefitinib are orally active first generation TKIs that are very tolerable by most patients and approved to be used in advanced NSCLC. Afatinib is the second generation TKIs that had Food and Drug Administration (FDA) for the first-line treatment of patients with metastatic NSCLC who sensitizing EGFR mutations. Based on preliminary data from multicenter, single arm Phase 2 clinical trials (AURA/AURA2), FDA had approved osimertinib; the third generation TKIs in patients with metastatic EGFR T790M mutation positive NSCLC.
An analysis of five clinical trials, (n = 223) with advanced NSCLC found that those with sensitizing EGFR mutations who received TKIs had a 67% response rate (RR) and OS of about 24 months. However, even among patients who are selected for specific treatments based on their somatic EGFR status profile, still lack of response to EGFR-targeted therapies in a significant portion of the patients. Resistance to EGFR inhibitors is acquired through multiple mechanisms, including the loss of the mutant protein, emergence of therapy-resistant EGFR mutant proteins, mesenchymal-epithelial transition (MET) amplification, and possibility of phenotypic transformation to small cell carcinoma. The presence of EGFR change has both prognostic and predictive implications. Both the BR.21 and Iressa Survival Evaluation in Lung Cancer trials demonstrated that patients with EGFR overexpression and increased EGFR gene copy number had a higher objective response rate (ORR) and extended survival when treated with EGFR-TKIs, compared with those with EGFR negative tumors.
On the other hand, the INTEREST trial of the second-line gefitinib versus docetaxel, the BMS099 trial of carboplatin/paclitaxel ± cetuximab, and the SATURN  trial of maintenance erlotinib versus placebo after platinum-based chemotherapy doublets, all failed to show differential outcomes; ORR, PFS, and OS, according to EGFR overexpression or gene copy number. Data also indicate that specific mutations have different effects on the efficacy of EGFR inhibitors. In retrospective and prospective analysis of patients with NSCLCs harboring typical EGFR exon 20 insertions, most displayed progressive disease in the cause of treatment with gefitinib or erlotinib or afatinib.
The 2011 American Society of Clinical Oncology provisional opinion on EGFR mutation testing recommended tumor testing for EGFR mutations in all patients with NSCLC for whom an EGFR TKI is being considered as the first-line therapy. However, the ESMO Guidelines specify that only patients with non-SCC NSCLC be assessed for EGFR mutations, patients with pure SCC NSCLC are unlikely to have sensitizing EGFR mutations.
BRAF mutations have been detected in a wide range of cancers although it is more common in melanoma. In NSCLC adenocarcinoma, BRAF mutations are found in 1–5%; half of them harboring the classical V600E mutation. They are mutually exclusive to EGFR and KRAS mutations and have been associated with decreased sensitivity to the EGFR TKIs. BRAF mutations have a powerful predictive marker and are evolving as a prognostic marker which can identify a subset of tumors that are sensitive to targeted therapies. Patients with V600E BRAF mutations had more aggressive tumor histotype, micropapillary features, and associated with shorter median disease-free survival and OS, while no prognostic impact was found for the non-V600E mutations. In addition, there are preclinical data, suggesting that BRAF mutations might predict sensitivity of NSCLC cells to MEK inhibitors which are supported by clinical response seen with MEK TKIs in BRAF mutated melanoma. Furthermore, synergistic activity for the combination of BRAF-and MEK-inhibition has been demonstrated.
KRAS is one of the first characterized oncogenes with activating mutations in codons 12 and 13 are detected in approximately 20–25% of lung adenocarcinoma and 4% of lung SCC. Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at a lower frequency in East Asian patient. Patients with KRAS mutations appear to have a shorter OS than patients with wild-type; therefore, KRAS mutations are prognostic biomarkers. KRAS mutational status is also predictive of lack of therapeutic efficacy with EGFR-TKIs; however, it does not appear to affect chemotherapeutic efficacy. No prospective trials have been conducted to demonstrate the potential value of testing for KRAS mutations and to tailor therapy accordingly. Nevertheless, despite the lack of definitive data demonstrating the benefit of KRAS mutation testing, the presence of mutations seems to be associated with primary resistance to EGFR-TKI therapy.
Anaplastic lymphoma kinase
Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) (a fusion gene consisting of portions of the EML4 gene and the ALK gene) was found in approximately in 3–7% of lung tumors harbor ALK, usually younger, nonsmokers, and adenocarcinoma histology. Based on Phase 3 trials, testing for ALK rearrangement is recommended in patients with metastatic NSCLC adenocarcinoma and the ALK inhibitor; crizotinib is recommended for ALK-positive patients. Clinically, the presence of EML4-ALK fusion gene is associated with EGFR TKI. Several ALK inhibitors have been approved for the treatment of lung adenocarcinoma. Retrospective studies have evaluated the activity of pemetrexed in ALK-fusion positive NSCLC compared with other molecular subtypes (KRAS, EGFR). Whether ALK fusion positive NSCLC is more sensitive to pemetrexed than an unselected NSCLC cohort is still a topic for more investigation.
The normal function of ROS in humans is yet unclear; however, the production of variant mutant forms of ROS is widely reported in NSCLC. Elevated ROS expression is observed in both early-and late-stage lung tumors, suggesting its role in initiation and development rather than progression. ROS1 rearrangement has been described in 0.7–1.7% of NSCLC patients. Usually, younger patients, never smokers, and adenocarcinoma. ROS1-rearangement is not only a predictive marker for response to crizotinib but also a prognostic molecular marker. Preclinical development of ROS1-specific kinase inhibitors is on-going.
Human epidermal growth factor receptor 2
In breast cancer, human epidermal growth factor receptor 2 (HER2) amplification occurs in about 20% of patients and is a predictive marker for anti-HER2 antibodies and TKIs. HER2 amplifications detected by FISH is found in 2–4% of NSCLC patients, commonly found in never smokers with adenocarcinoma histology. In a meta-analysis of forty published studies, HER2 overexpression was shown to be a marker of poor prognosis in NSCLC, in adenocarcinomas specifically, with primary resistance to the first generation EGFR TKIs. However, cells expressing the HER2 exon 20 mutations are sensitive to the irreversible dual EGFR and HER2 TKIs, lapatinib, neratinib, and afatinib. No prognostic value was found in SCC. Anti-HER2 therapies have not shown efficacy in HER2-amplified NSCLC. However, in a European cohort study, HER2 mutation positive adenocarcinoma has been shown to be responsive to HER2-targeted therapies with an ORR of 50% and a disease control rate of 83%. Afatinib, a TKI with activity against ERBB family members, is approved for EGFR mutation positive adenocarcinoma and has shown clinical activity in lung cancer patients harboring an HER2 mutation.
In NSCLC, PIK3 mutations and amplifications were detected in 2% and 12–17%, respectively. The fact that up to 70% of patients with a PIK3CA mutation harbor other coexisting mutations or rearrangements in other oncogenes supports the hypothesis that PIK3CA mutations are not oncogenic driver mutations per se in NSCLC. Chaft et al. reported that coexisting KRAS and PIK3CA mutations are associated with resistance to PI3K/AKT/mTOR inhibitors. Clinical trials with PI3K inhibitors as well as mTOR inhibitors are on-going.
In lung cancer, MET mutations are rarely detected and amplifications were found in around 2–5% of NSCLC, predominantly in adenocarcinoma. While their prevalence is low, their potential for causing disease progression is significant. MET amplification has been described as one potential mechanism of resistance toward EGFR inhibition in EGFR mutant lung adenocarcinoma. The ALK/ROS1 inhibitor crizotinib was originally developed as MET inhibitor. The clinical activity of crizotinib, in MET-amplified patients, has been demonstrated. Besides crizotinib, various other small-molecule MET inhibitors are being tested in NSCLC. However, to date, a predictive biomarker for MET inhibitor sensitivity remains to be defined.
Rearranged during transfection
Rearranged during transfection (RET) is an RTK and a known oncogene in thyroid cancer where translocations, as well as activating mutations, have been detected. In NSCLC, RET translocations can be detected in 1–2% of patients predominantly in light/never smokers, younger patients, and poorly differentiated adenocarcinoma. RET translocations seem to occur mutually exclusive from EGFR mutations, KRAS mutations, ALK, and ROS1 rearrangements. Alectinib is a potent inhibitor of ALK and has shown antitumor activity against RET positive NSCLC.
| > Other Genomic Aberrations|| |
Phosphatase and tensin homolog
Phosphatase and tensin homolog (PTEN) is a dual-specific lipid or protein phosphatase and acts as a tumor suppressor by negatively regulating PI3K/AKT pathway by dephosphorylating PIP3.
PTEN mutations occur in 4–8% of NSCLC and are more commonly detected in SCC and in patients with a smoking history. In preclinical studies, PTEN loss is associated with decreased sensitivity of EGFR mutant lung tumors to EGFR TKIs. Studies by Janku et al. showed that PTEN loss can be associated with increased PI3K/AKT/mTOR signaling and sensitivity to PI3K pathway inhibitors. Clinical trials investigating PI3K inhibitors in patients with PTEN deficiency are on-going.
Fibroblast growth factor receptor 1
Fibroblast growth factor receptor 1 (FGFR1) is a member of the FGFR family of RTK (FGFR1–4). FGFRs are transmembrane TK interfering with the RAS/RAF/MAPK and the PI3K/AKT signaling pathways and have been found to be deregulated in cancers either by amplifications, point mutations or translocations. FGFR amplifications have been detected in about 20% of SCC among former or current smokers and associated with a poor outcome. However, the negative prognostic impact of FGFR1 amplifications was not confirmed in a Caucasian patient cohort. Clinical trials with FGFR inhibitors are currently on-going.
MEK1, also known as MAP2K1, is a serine-threonine protein kinase which plays a pivotal role in the MAP kinase signaling pathway and hence plays an important role in many cellular processes. Somatic mutations in MEK1 have been found in approximately 1% of NSCLC, never smokers with lung adenocarcinoma not harboring other oncogenic driver aberrations. The presence of MEK1 mutation is associated with in vitro resistance to EGFR TKIs.
Discoidin domain receptor 2
Discoidin domain receptor 2 (DDR2) is an RTK involved in cell adhesion, migration, and proliferation. In NSCLC DDR2 mutations have been described with a frequency of nearly 4%. The ABL kinase inhibitors, imatinib, nilotinib, and dasatinib, inhibit the kinase activity of DDR2, making it a targetable molecular alteration seen in SCC of the lung.
| > Conclusions and Future Direction|| |
Although metastatic NSCLC is still an incurable disease and historically therapy for NSCLC was based on unselected treatment of all NSCLC patients with chemotherapy resulting in overall disappointing results, recent advantages in the understanding of the underlying molecular mechanisms have clearly improved the prognosis and quality of life for a substantial group of patients with advanced NSCLC. Molecular genetics analyses of lung acenocarcinoma have recently become the standard of care for treatment selection, and SCC is likely to follow similar clinical pathway. However, many molecularly targeted agents have not shown improvements in patient outcomes when tested in unselected patient populations. According to Govindan, the era of using molecularly targeted therapies in unselected populations is drawing to a close.
The most useful biomarkers for predicting the efficacy of targeted therapy in advanced NSCLC are somatic genome alterations known as “driver mutations.”
Mutations in EGFR, KRAS, and ALK are mutually exclusive in patients with NSCLC, and the presence of one mutation in lieu of another can influence response to targeted therapy. Therefore, testing for these mutations and tailoring therapy accordingly is widely accepted as a standard practice. Testing for activating EGFR mutations is recommended in all patients with advanced NSCLC adenocarcinoma to help determine whether an EGFR-TKI should be considered. Routine testing for KRAS mutations is not recommended but can be considered as a way to help determine whether a patient might be resistant to treatment with an EGFR-TKI. No clear guidelines suggest whether to test for EGFR T790M mutations in patients with acquired resistance to EGFR-TKIs because the clinical significance of mutation status relative to treatment continuation remains unknown. Regardless of current recommendations, any decision to test for genetic mutations should be individualized for each patient and should take into account considerations such as time factor, the availability and quality of the clinical laboratory, the cost, and lastly, the relative toxicities of alternative therapeutic options.
The report published by the Lung Cancer Mutation Consortium is a landmark study of the molecular mutations in patients with stage IV adenocarcinoma of the lung from 2009 to 2012. An actionable driver mutation was identified in 466 of 733 patients (64%). The most common driver mutations were KRAS (25%) followed by sensitizing EGFR (17%). The median survival of patients with a sensitizing mutation that was treated with a targeted therapy directed at the specific mutation was 3.5 years. Median survival was only 2.4 years in those with a sensitizing mutation who did not receive targeted therapy. This study demonstrates the feasibility and importance of performing mutation testing in patients with stage IV adenocarcinoma of the lung. Although this result is in highly selected patients, it clearly reflects the significant impact of progress in the molecular understanding and novel therapeutic options during the last decade in improving the outcome for a subgroup of NSCLC patients. However, we should not forget about the still larger subgroup of NSCLC patients not harboring an actionable genomic aberration. The improved results using targeted therapy in patients with these specific molecular abnormalities have led to an effort to identify other driver mutations and specific therapies appropriate for each driver mutation.
More research is urgently needed to detect novel potentially predictive biomarkers, more specific and more potent inhibitors of specific signaling pathways and overcome the potential resistance mechanisms in patients progressing during therapy with a targeted molecule. There is also still a large amount of work to be done with regards to the identification of the optimal sequences for the use of multiple inhibitors, potential combinations of targeted therapeutics with each other, with chemotherapy or with immunotherapeutic approaches, as well as the tolerability of these approaches, require further investigation. Further research into other methods of obtaining reliable information about the change in the biology of lung cancers on progression is needed. This could include circulating tumor DNA assays from peripheral blood or functional imaging-guided biopsies. SCCs of the lung, however, have not shown a great response to targeted agents until now. However, whenever possible; patients should be enrolled in formal clinical studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29.
Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, et al
. SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD. Available from: http://seer.cancer.gov/csr/1975_2012/
. [Last updated on 2015 Nov 18].
West L, Vidwans SJ, Campbell NP, Shrager J, Simon GR, Bueno R, et al.
A novel classification of lung cancer into molecular subtypes. PLoS One 2012;7:e31906.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, 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;13:239-46.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al.
Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34.
Kerr KM. Clinical relevance of the new IASLC/ERS/ATS adenocarcinoma classification. J Clin Pathol 2013;66:832-8.
Shim HS, Lee da H, Park EJ, Kim SH. Histopathologic characteristics of lung adenocarcinomas with epidermal growth factor receptor mutations in the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification. Arch Pathol Lab Med 2011;135:1329-34.
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al
. First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients with advanced ALK-positive nonsquamous non-small cell lung cancer: Results of a phase III study (PROFILE 1014). N Engl J Med 2014;371:2167-77.
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al.
First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: A phase-IV, open-label, single-arm study. Br J Cancer 2014;110:55-62.
Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al.
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527-37.
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al.
AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689-99.
Donington J, Ferguson M, Mazzone P, Handy J Jr., Schuchert M, Fernando H, et al.
American College of Chest Physicians and Society of Thoracic Surgeons consensus statement for evaluation and management for high-risk patients with stage I non-small cell lung cancer. Chest 2012;142:1620-35.
Mayo C, Bertran-Alamillo J, Molina-Vila MÁ Giménez-Capitán A, Costa C, Rosell R. Pharmacogenetics of EGFR in lung cancer: Perspectives and clinical applications. Pharmacogenomics 2012;13:789-802.
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al.
Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-7.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al.
Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.
Douillard JY, Kim E, Hirsh V, Mok T, Socinski M, Gervais R, et al
. Gefitinib (Iressa) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based chemotherapy: A randomized, open-label phase iii study (interest). J Thorac Oncol 2007;2:S305-6.
Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu LA, Horak CE, et al.
Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:918-27.
Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, et al.
Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521-9.
Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: Preclinical data and clinical implications. Lancet Oncol 2012;13:e23-31.
Keedy VL, Temin S, Somerfield MR, Beasley MB, Johnson DH, McShane LM, et al.
American Society of Clinical Oncology provisional clinical opinion: Epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol 2011;29:2121-7.
Kerr KM, Bubendorf L, Edelman MJ, Marchetti A, Mok T, Novello S, et al.
Second ESMO consensus conference on lung cancer: Pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol 2014;25:1681-90.
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;29:3574-9.
Joshi M, Rice SJ, Liu X, Miller B, Belani CP. Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer. PLoS One 2015;10:e0118210.
Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al.
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012;483:100-3.
Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, et al.
Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998-2006.
Brugger W, Triller N, Blasinska-Morawiec M, Curescu S, Sakalauskas R, Manikhas GM, et al.
Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 2011;29:4113-20.
Roberts PJ, Stinchcombe TE. KRAS mutation: Should we test for it, and does it matter? J Clin Oncol 2013;31:1112-21.
Sholl LM, Aisner DL, Varella-Garcia M, Berry LD, Dias-Santagata D, Wistuba II, et al.
Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: The lung cancer mutation consortium experience. J Thorac Oncol 2015;10:768-77.
Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, et al
. Effect of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls. Lancet Oncol 2011;12:1004-12.
Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al.
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94.
De Grève J, Teugels E, Geers C, Decoster L, Galdermans D, De Mey J, et al.
Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer 2012;76:123-7.
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;30:863-70.
Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, Berge EM, et al.
Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res 2012;18:4570-9.
Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, et al.
Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): Overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14:461-71.
Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al.
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27:4702-11.
Mazières J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, et al.
Lung cancer that harbors an HER2 mutation: Epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 2013;31:1997-2003.
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al.
Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26.
Chaft JE, Arcila ME, Paik PK, Lau C, Riely GJ, Pietanza MC, et al.
Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol Cancer Ther 2012;11:485-91.
Zhu CQ, Tsao MS. Prognostic markers in lung cancer: Is it ready for prime time? Transl Lung Cancer Res 2014;3:149-58.
Seo JS, Ju YS, Lee WC, Shin JY, Lee JK, Bleazard T, et al.
The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 2012;22:2109-19.
Ou SH, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW, et al.
Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo
MET amplification. J Thorac Oncol 2011;6:942-6.
Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, et al.
PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 2012;30:777-82.
Liao RG, Jung J, Tchaicha J, Wilkerson MD, Sivachenko A, Beauchamp EM, et al.
Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma. Cancer Res 2013;73:5195-205.
Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, et al.
Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 2013;19:1469-72.
Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, et al.
Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 2011;1:78-89.
Govindan R. Interesting biomarker to select ideal patients for epidermal growth factor receptor tyrosine kinase inhibitors: Yes, for EGFR mutation analysis, others, I pass. J Clin Oncol 2010;28:713-5.
Boolell V, Alamgeer M, Watkins DN, Ganju V. The evolution of therapies in non-small cell lung cancer. Cancers (Basel) 2015;7:1815-46.