Lung cancer is the most common malignancy in the United States and worldwide. In 2011, it is estimated that more than 221,000 people in the United States will be diagnosed with cancer of the lung and bronchus. For patients with early-stage disease, 5-year survival approaches only 50%. Recent advances using molecular, genetic, and proteomic profiling of lung tumors have enabled refining the prognosis for patients with non–small cell lung cancer. With targeted therapies, there is an opportunity to enhance long-term survival. This article discusses several key molecular markers used in the prognostication and treatment of non–small cell lung cancer.
With more than 1.2 million cases diagnosed annually, lung cancer is the leading cause of cancer mortality worldwide. The majority of lung cancer diagnoses are made at advanced stages (III-IV), where the mainstay of treatment is chemotherapy and/or radiation. For early-stage (I-II) lung cancer, surgery is the mainstay of treatment, sometimes in conjunction with adjuvant chemotherapy.
Clinicians optimally should prescribe a course of therapy that is tailored to individual patients and their comorbid conditions to provide best possible outcomes. If patients are considered medically operable, appropriate therapy should include surgical resection for patients with stage I, II, and selected IIIA disease. For the minority of patients with early-stage disease who are not suitable for or refuse surgery, tumor ablative strategies may be used as an alternative to surgery. Adjuvant therapy should be considered in patients with nodal metastasis (N1 and N2) and now for patients with stages Ib and IIa as well. This includes both traditional chemotherapeutic agents as well as molecular targeted agents. With recent advances in genetic, molecular, and proteomic profiling of lung tumors, clinicians can offer treatment that is tailored to individuals and their tumors, with the objective of maximizing long-term survival.
Currently, tumor stage is the most reliable prognostic indicator of long-term survival for patients diagnosed with lung cancer. Recently, the International Association for the Study of Lung Cancer analyzed 67,725 cases of non–small cell lung cancer (NSCLC) to further refine the prognostic accuracy of clinical and pathologic tumor stage. In recent years, however, several prognostic and predictive biomarkers for NSCLC have been identified. Prognostic biomarkers provide information regarding clinical outcomes regardless of therapy. In contrast, predictive biomarkers can be used to indicate potential responsiveness to a therapy or regimen; they can also serve as targets for molecular therapeutic agents. Rather than being either prognostic or predictive, some biomarkers fulfill both roles. This article discusses several key NSCLCs.
Individual genetic alterations
p53
Alterations in the p53 tumor suppressor gene are the most frequently found in human cancer; p53 mutations are found in more than half of all human malignancies. More than 90% of small cell lung cancers and up to 50% of NSCLCs harbor deletions or mutations of the p53 gene. The p53 network is quiet and senescent in the normal state. With cellular injury or stress, however, the p53 network is activated. Downstream effects of p53 activation include induction of apoptosis and DNA repair mechanisms as well as cell cycle regulation. Inactivation of p53 results in overall increased genomic instability and may be manifested as derangements of cell cycle regulation as well as diminished efficiency of DNA repair.
The role of p53 gene mutations and poor survival outcomes has been established. In a prospective study by Ahrendt and colleagues, p53 gene mutations were independently predictive of decreased survival in stage I tumors. Although missense mutations were not predictive of patient outcomes, mutations that were truncating, structural, or abolishing DNA contact were associated with poorer survival. The relationship between p53 mutational status and adverse survival outcomes has been corroborated by several other studies incorporating NSCLC samples from all tumor stages.
Immunohistochemical studies of p53 have been less consistent. In the largest studies examining p53 expression levels, some investigators have reported a correlation between abnormal p53 expression and poor prognosis; however, others report no statistically significant relationship. Despite the mixed evidence from immunohistochemical studies, however, most studies report an association between overexpression of p53 and poorer outcomes. Carbognani and colleagues examined the role of p53 status in long-term survival after surgery for lung adenocarcinoma. Using immunohistochemical analysis and a panel of several potential prognostic markers, p53 status was the only independent predictor of 10-year survival after resection. In another study, Tsao and colleagues observed that p53 protein overexpression was a predictor of both poor prognosis and shorter overall survival (OS). In addition, patients with tumors containing wild-type p53 had a survival benefit with adjuvant chemotherapy compared with those with functionally aberrant p53 status. Finally, a systematic review of 56 studies concluded that abnormal p53 status was associated with decreased OS in patients with NSCLC across all stages and in both squamous cell and adenocarcinoma histologies.
K-ras
The ras gene family members encode for cell membrane-associated G proteins, which mediate signal transduction for cellular proliferation. Up to 30% of NSCLCs harbor K-ras mutations. The most common mutation in NSCLC is a G→T transversion in codon 12. Activation of K-ras results in continuous transmission of growth signals to the nucleus secondary to constitutive activation. K-ras mutations are most commonly associated with tumors of adenocarcinoma histology and in patients with a history of tobacco use. Up to 15% of tumors in never smokers may harbor K-ras mutations; tumor mutations in these patients are often distinct from the G→T and G→C transversions seen in those from smokers. K-ras mutations are essentially mutually exclusive with EGFR mutations.
For patients with NSCLC, the prognostic significance of K-ras mutations is controversial. Some studies have reported worse prognosis, including decreased survival, in patients whose tumors had K-ras mutations. In a small study of patients with advanced NSCLC and K-ras mutant tumors, those treated with erlotinib (Tarceva) in addition to chemotherapy had worse outcomes than those with wild-type K-ras . Others have reported that tumors with K-ras mutations lack sensitivity to either gefitinib (Iressa) or erlotinib. Other studies, however, including a meta-analysis of 881 cases, have reported no significant association between K-ras mutation status and clinical outcomes.
Excision Repair Cross-Complementing 1
The excision repair cross-complementing group 1 (ERCC1) gene product is part of the nucleotide excision repair pathway that recognizes and removes cisplatin-induced DNA adducts. Nucleotide excision repair is important in DNA repair and is associated with resistance to chemotherapy with platinum-based agents. Clinically, NSCLC tumors with low ERCC1 expression may demonstrate resistance to cisplatin chemotherapy. In 2002, Lord and colleagues reported that patients with advanced NSCLC whose tumors had low ERCC1 expression had significantly longer OS than those with high ERCC1 expression tumors.
Other studies have confirmed the predictive value of ERCC1 expression. ERCC1 expression was present in 44% of tumors obtained from patients enrolled in the International Adjuvant Lung Cancer Trial. For patients in the trial who were randomized to adjuvant cisplatin-based chemotherapy, those with ERCC1-negative tumors had significantly prolonged survival relative to those who were observed (hazard ratio [HR] 0.65; 95% CI, 0.50–0.86; P = .002). There was no survival difference between the observation and chemotherapy for patients with ERCC1-positive tumors.
Furthermore, among those who did not receive adjuvant chemotherapy, patients with ERCC1-positive tumors had improved survival versus those with ERCC1-negative tumors (HR 0.66; 95% CI, 0.49–0.90; P = 0.009). Taken together, these results suggest that adjuvant cisplatin-based chemotherapy may benefit patients with ERCC1-negative tumors. Currently, several clinical trials are enrolling patients to further examine the benefit of customized chemotherapy based on ERCC1 status in early-stage (NCT00775385), resected (NCT00792701), and advanced NSCLC (NCT00499109 and NCT00736814).
Cell Cycle Regulatory Genes
Rb and p16
The retinoblastoma susceptibility gene (Rb), a tumor suppressor gene with a key role in human carcinogenesis, is inactivated in nearly 90% of small cell lung tumors and 20% to 30% of NSCLCs. Although most studies have reported no significant relationship between Rb and lung cancer survival, there seems to be an additive effect of concurrent abnormalities in the Rb and p53 pathways and it seems that these additive effects are predictive of patient prognosis in NSCLC. In a study by Burke and colleagues, certain combinations of abnormalities were negative predictors of survival: concurrent pRb-negative status and cyclin D1 overexpression; concurrent pRb-negative status, cyclin D1 overexpression, and p53 mutation; and concurrent cyclin D1 overexpression and p53 mutation.
The p16 INK4A gene is a tumor suppressor gene that encodes a cyclin-dependent kinase (CDK) inhibitor. p16 plays a prominent role in NSCLC; it is inactivated in 40% to 70% of NSCLCs. Under normal circumstances, p16 binds to the cyclin D/CDK4/6 complexes to inhibit phosphorylation of the Rb protein and therefore inhibits cell cycle progression at the G1→S phase. In a recent study of tumors from patients with stage IIIA NSCLC, the presence of both p16 and p21 proteins correlated with improved long-term survival.
Absent or dysfunctional p16 expression can result in unchecked progression through the cell cycle. There are several mechanisms of p16 inactivation, including epigenetic silencing by hypermethylation of the gene promoter CpG island in addition to point mutations or deletions. Alteration and inactivation of p16 have been associated with metastases, poor prognosis, and decreased OS in patients with NSCLC.
The cyclins, p21 WAF1/CIP1 and p27
Cyclin D1, cyclin E, cyclin B1 , p21 WAF1/CIP1 , and p27 are other cell cycle regulatory genes of interest in NSCLC. Up to 47% of NSCLC tumors demonstrate overexpression of cyclin D1; however, the prognostic effects of this overexpression are somewhat controversial. In some studies, favorable outcomes have been associated with overexpression of cyclin D1 . Other studies have reported lymph node metastasis, advanced pathologic stage, and shorter OS in association with this condition.
Similar results have been reported for cyclin E and cyclin B1 . High levels of cyclin E expression, present in up to 53% of NSCLCs, have been correlated with tumor invasion, unfavorable prognosis, and decreased patient survival. Overexpression of cyclin B1 has been linked to shorter survival and seems to occur more commonly in tumors of squamous histology.
p21 WAF1/CIP1 influences cell cycle progression at multiple sites, binding to several different cyclin/CDK complexes. Some investigators have reported a relationship between p21 expression and improved OS and relapse-free survival, whereas others have found none. p27 Kip1 interacts with both cyclin D1 and cyclin E to regulate the cell cycle. Several studies have used immunohistochemical techniques to determine p27 expression. Both overexpression and decreased levels of p27 have been correlated with poor prognosis in NSCLC.
Gene Arrays
The development and use of gene expression microarrays have facilitated the identification of specific gene signatures that correlate with specific clinical characteristics, such as smoking status and tumor histology. Some investigators have used gene expression profiles to predict nodal metastases as well as response to treatment. In a study of 37 NSCLCs, Kikuchi and colleagues used hierarchical clustering methods to establish a predictive scoring system based on the expression profiles of selected genes. With this system, 40 genes were identified whose expression profiles could be used to separate node-positive from node-negative adenocarcinomas.
Many studies have used gene expression arrays to predict overall prognosis and OS. One study used cDNA arrays to examine 39 NSCLC tumors. With unsupervised hierarchical clustering of a subset of 2899 genes, 2 groups were identified that differed significantly in disease-free survival. Similarly, Beer and colleagues examined 86 lung adenocarcinomas using oligonucleotide arrays (HuGeneFL). Using hierarchical clustering and other supervised analytical approaches, 3 clusters of tumors were identified. Significant relationships between clusters and tumor stage and differentiation were observed. Based on this information, a 50-gene risk index based on the top-50 survival-related genes was devised. Using this approach, the investigators were able to predict survival based on the risk index.
Further refinement of gene expression profiling has led to the development of predictive models using few genes. Applying an integrated approach to published gene expression data sets, Bianchi and colleagues described a 10-gene predictive model for OS in stage I lung adenocarcinoma. This model exhibited a prognostic accuracy of 75% validated in 2 independent cohorts.
Similarly, Chen and colleagues used gene expression arrays to develop a 5-gene model for prediction of relapse-free survival and OS in lung cancer. The model was subsequently validated in an independent cohort of 60 additional patients. Compared with those with a low-risk gene signature, patients with a high-risk gene signature had a significantly shorter median survival. When patients were stratified by stage, the model was predictive of survival; however, there was no correlation between gene signature and OS for patients with stage II disease. Further validation studies were performed on 86 tumors previously analyzed by another group. Patients whose tumors exhibited the high-risk gene signature had a significantly higher risk for death from any cause; results for survival trended toward significance.
Finally, Lau and colleagues described a 3-gene signature for predicting prognosis. This model was validated in 2 independent data sets from outside institutions. None of the models (described previously) has genes in common.
Tyrosine kinases and targeted therapies
Several targeted molecular therapies have been developed for the treatment of NSCLC. Specific targets include the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and anaplastic lymphoma kinase (ALK). Although some agents are approved for use by the US Food and Drug Administration, others are currently under investigation in clinical trials.
Epidermal Growth Factor Receptor
The EGFR family consists of a group of tyrosine kinases whose activation results in a cascade of downstream signals. These signals ultimately lead to enhanced cellular proliferation and angiogenesis and tumor cell mobility as well as diminshed apoptosis. Although rare in small cell lung cancer, EGFR overexpression is common in NSCLC, affecting up to 80% of tumors.
Gefitinib is a selective inhibitor of the EGFR tyrosine kinase with demonstrated clinical benefit in specific populations of patients with NSCLC. In the Iressa Survival Evaluation in Lung Cancer study, treatment with gefitinib as a second-line or third-line treatment did not improve survival in the overall population of patients with advanced NSCLC. There was demonstrated benefit, however, in preplanned subgroup analyses of patients of Asian origin and never-smokers.
EGFR mutation status can also be used to predict response to therapy with EGFR inhibitors. In a recent study of patients with advanced nonsquamous NSCLC, wild-type EGFR was a poor prognostic factor in patients receiving gefitinib therapy. Similarly, in the Iressa Pan-Asia Study, treatment with gefitinib was associated with improved progression-free survival (PFS) (HR 0.74; 95% CI, 0.65–0.85; P <.001). Among patients whose tumors harbored EGFR gene mutations, treatment with gefitinib was associated with improved PFS compared with carboplatin-paclitaxel (HR 0.48; 95% CI, −0.36–0.64; P <.001). For patients without EGFR mutations, however, PFS was significantly longer in patients treated with carboplatin-paclitaxel (HR for progression or death with gefitinib 2.85; 95% CI, 2.05–3.98; P <.001).
Erlotinib, another EGFR inhibitor, is currently used as second-line therapy for locally advanced or metastatic NSCLC. Compared with placebo, patients receiving erlotinib have improved tumor response as well as longer PFS and OS. A recent pooled analysis of more than 60 studies and 1800 patients was conducted to evaluate clinical outcomes in patients with EGFR mutations treated EGFR tyrosine kinase inhibitors (TKIs) versus conventional chemotherapy. Patients treated with gefitinib and erlotinib had longer PFS compared with those treated with chemotherapy ( P <.001).
Cetuximab (Erbitux) is a monoclonal antibody targeted against EGFR. These molecules can inhibit ligand binding and receptor activation, thereby inducing apoptosis of tumor cells. Several studies have demonstrated a survival benefit with the addition of cetuximab to standard chemotherapy regimens for patients with advanced NSCLC.
As with other TKIs, however, the efficacy of cetuximab has not been studied in early-stage NSCLC. In a small, randomized phase II study, patients with advanced NSCLC treated with cetuximab plus cisplatin/vinorelbine had improved median survival compared with those in the chemotherapy-alone group. These findings were validated in a larger, phase III randomized trial, in which patients given cisplatin/vinorelbine plus cetuximab survived longer than those in the control group (HR 0.871; 95% CI, 0.762–0.996). Another phase III study of cetuximab plus taxane/carboplatin chemotherapy, however, showed a favorable response rate in patients with advanced NSCLC but failed to demonstrate longer PFS.
Most studies of EGFR TKIs have focused on patients with advanced or recurrent lung cancer; few studies have investigated the use of these agents in the treatment of early-stage or resectable disease. Clinical trials are currently under way, however, to elucidate the role of these agents in conjunction with surgery for stage I-IIIA NSCLC (NCT00104728, NCT00049543, and NCT00324805).
Vascular Endothelial Growth Factor
Bevacizumab (Avastin) is a monoclonal antibody that targets VEGF-A. Its use has been shown to benefit patients with a variety of malignancies, including cancers of the colon, kidney, and brain. The presence of VEGF in NSCLC tumors is associated with poor prognosis and OS. The benefit of bevacizumab in NSCLC was demonstrated in a recent phase III study of 878 patients with advanced nonsquamous NSCLC. Patients were randomized to chemotherapy with carboplatin/paclitaxel alone versus chemotherapy with bevacizumab. Those who received bevacizumab in addition to chemotherapy had significantly improved response rates, PFS, and OS. Similarly, in the Avastin in Lung cancer trial, patients were randomized to receive bevacizumab or placebo in addition to chemotherapy with cisplatin/gemcitabine. Although OS was not different between the 2 groups, PFS was significantly prolonged with the addition of bevacizumab compared with placebo. The risk of progression or death at any time was reduced by 25% in the bevacizumab group (HR 0.75; 95% CI, 0.64–0.87; P = .0003).
A potential role of bevacizumab in the treatment of early-stage (IB-IIIA) lung cancer is under investigation in the Eastern Cooperative Oncology Group E1505 adjuvant therapy trial (NCT00324805). In this phase III study, patients with resected NSCLC are randomized to one of 4 adjuvant chemotherapy regimens, with or without bevacizumab. In addition to OS and disease-free survival, tissue and blood specimens are being collected to identify factors predictive of clinical outcomes.
Anaplastic Lymphoma Kinase
In 2007, Soda and colleagues identified the fusion gene of echinoderm microtubule-associated protein-like 4 (EML4) and ALK in a subset of NSCLCs. These EML4-ALK fusion products are present in 3% to 13% of NSCLCs. Perhaps more interesting is that they are mutually exclusive to tumors with EGFR mutations. Other clinical features associated with EML4-ALK fusions include younger age, male gender, light-smoking or never-smoking status, adenocarcinoma (specifically acinar) histology, and negative K-ras mutational status.
Crizotinib is an oral selective inhibitor of the ALK and MET tyrosine kinases. In recent studies, the use of crizotinib for patients with advanced ALK-positive NSCLC was associated with a clinical benefit, defined as tumor response plus stable disease. Currently, these agents are limited to use in patients with advanced NSCLC. Studies are being conducted, however, to evaluate the usefulness of these targeted molecular therapies. One study is investigating the use of crizotinib as standard therapy in patients with documented EML4-ALK mutations (NCT01154140); another is examining usefulness of crizotinib in combination with traditional chemotherapeutic agents in the neoadjuvant setting (NCT00924209).
Tyrosine kinases and targeted therapies
Several targeted molecular therapies have been developed for the treatment of NSCLC. Specific targets include the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and anaplastic lymphoma kinase (ALK). Although some agents are approved for use by the US Food and Drug Administration, others are currently under investigation in clinical trials.
Epidermal Growth Factor Receptor
The EGFR family consists of a group of tyrosine kinases whose activation results in a cascade of downstream signals. These signals ultimately lead to enhanced cellular proliferation and angiogenesis and tumor cell mobility as well as diminshed apoptosis. Although rare in small cell lung cancer, EGFR overexpression is common in NSCLC, affecting up to 80% of tumors.
Gefitinib is a selective inhibitor of the EGFR tyrosine kinase with demonstrated clinical benefit in specific populations of patients with NSCLC. In the Iressa Survival Evaluation in Lung Cancer study, treatment with gefitinib as a second-line or third-line treatment did not improve survival in the overall population of patients with advanced NSCLC. There was demonstrated benefit, however, in preplanned subgroup analyses of patients of Asian origin and never-smokers.
EGFR mutation status can also be used to predict response to therapy with EGFR inhibitors. In a recent study of patients with advanced nonsquamous NSCLC, wild-type EGFR was a poor prognostic factor in patients receiving gefitinib therapy. Similarly, in the Iressa Pan-Asia Study, treatment with gefitinib was associated with improved progression-free survival (PFS) (HR 0.74; 95% CI, 0.65–0.85; P <.001). Among patients whose tumors harbored EGFR gene mutations, treatment with gefitinib was associated with improved PFS compared with carboplatin-paclitaxel (HR 0.48; 95% CI, −0.36–0.64; P <.001). For patients without EGFR mutations, however, PFS was significantly longer in patients treated with carboplatin-paclitaxel (HR for progression or death with gefitinib 2.85; 95% CI, 2.05–3.98; P <.001).
Erlotinib, another EGFR inhibitor, is currently used as second-line therapy for locally advanced or metastatic NSCLC. Compared with placebo, patients receiving erlotinib have improved tumor response as well as longer PFS and OS. A recent pooled analysis of more than 60 studies and 1800 patients was conducted to evaluate clinical outcomes in patients with EGFR mutations treated EGFR tyrosine kinase inhibitors (TKIs) versus conventional chemotherapy. Patients treated with gefitinib and erlotinib had longer PFS compared with those treated with chemotherapy ( P <.001).
Cetuximab (Erbitux) is a monoclonal antibody targeted against EGFR. These molecules can inhibit ligand binding and receptor activation, thereby inducing apoptosis of tumor cells. Several studies have demonstrated a survival benefit with the addition of cetuximab to standard chemotherapy regimens for patients with advanced NSCLC.
As with other TKIs, however, the efficacy of cetuximab has not been studied in early-stage NSCLC. In a small, randomized phase II study, patients with advanced NSCLC treated with cetuximab plus cisplatin/vinorelbine had improved median survival compared with those in the chemotherapy-alone group. These findings were validated in a larger, phase III randomized trial, in which patients given cisplatin/vinorelbine plus cetuximab survived longer than those in the control group (HR 0.871; 95% CI, 0.762–0.996). Another phase III study of cetuximab plus taxane/carboplatin chemotherapy, however, showed a favorable response rate in patients with advanced NSCLC but failed to demonstrate longer PFS.
Most studies of EGFR TKIs have focused on patients with advanced or recurrent lung cancer; few studies have investigated the use of these agents in the treatment of early-stage or resectable disease. Clinical trials are currently under way, however, to elucidate the role of these agents in conjunction with surgery for stage I-IIIA NSCLC (NCT00104728, NCT00049543, and NCT00324805).
Vascular Endothelial Growth Factor
Bevacizumab (Avastin) is a monoclonal antibody that targets VEGF-A. Its use has been shown to benefit patients with a variety of malignancies, including cancers of the colon, kidney, and brain. The presence of VEGF in NSCLC tumors is associated with poor prognosis and OS. The benefit of bevacizumab in NSCLC was demonstrated in a recent phase III study of 878 patients with advanced nonsquamous NSCLC. Patients were randomized to chemotherapy with carboplatin/paclitaxel alone versus chemotherapy with bevacizumab. Those who received bevacizumab in addition to chemotherapy had significantly improved response rates, PFS, and OS. Similarly, in the Avastin in Lung cancer trial, patients were randomized to receive bevacizumab or placebo in addition to chemotherapy with cisplatin/gemcitabine. Although OS was not different between the 2 groups, PFS was significantly prolonged with the addition of bevacizumab compared with placebo. The risk of progression or death at any time was reduced by 25% in the bevacizumab group (HR 0.75; 95% CI, 0.64–0.87; P = .0003).
A potential role of bevacizumab in the treatment of early-stage (IB-IIIA) lung cancer is under investigation in the Eastern Cooperative Oncology Group E1505 adjuvant therapy trial (NCT00324805). In this phase III study, patients with resected NSCLC are randomized to one of 4 adjuvant chemotherapy regimens, with or without bevacizumab. In addition to OS and disease-free survival, tissue and blood specimens are being collected to identify factors predictive of clinical outcomes.
Anaplastic Lymphoma Kinase
In 2007, Soda and colleagues identified the fusion gene of echinoderm microtubule-associated protein-like 4 (EML4) and ALK in a subset of NSCLCs. These EML4-ALK fusion products are present in 3% to 13% of NSCLCs. Perhaps more interesting is that they are mutually exclusive to tumors with EGFR mutations. Other clinical features associated with EML4-ALK fusions include younger age, male gender, light-smoking or never-smoking status, adenocarcinoma (specifically acinar) histology, and negative K-ras mutational status.
Crizotinib is an oral selective inhibitor of the ALK and MET tyrosine kinases. In recent studies, the use of crizotinib for patients with advanced ALK-positive NSCLC was associated with a clinical benefit, defined as tumor response plus stable disease. Currently, these agents are limited to use in patients with advanced NSCLC. Studies are being conducted, however, to evaluate the usefulness of these targeted molecular therapies. One study is investigating the use of crizotinib as standard therapy in patients with documented EML4-ALK mutations (NCT01154140); another is examining usefulness of crizotinib in combination with traditional chemotherapeutic agents in the neoadjuvant setting (NCT00924209).
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