Conceived and designed the experiments: LEW SJV NPC RS JS. Performed the experiments: LEW SJV NPC RS JS. Analyzed the data: GRS RB GAO PAD. Contributed reagents/materials/analysis tools: LEW SJV NPC RS JS. Wrote the paper: LEW SJV NPC.
LEW, SJV, and JS are employees of CollabRx Inc. GO is on the Consulting/Advisory Boards of Genentech and Abraxis/Celgene and receives research funding from Genentech, Pfizer, Boehringer Ingelheim, Tragara, and Abraxis/Celgene. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. RS, NPC, GRS, PAD, and RB have no financial or competing interests to declare.
The remarkably heterogeneous nature of lung cancer has become more apparent over the last decade. In general, advanced lung cancer is an aggressive malignancy with a poor prognosis. The discovery of multiple molecular mechanisms underlying the development, progression, and prognosis of lung cancer, however, has created new opportunities for targeted therapy and improved outcome. In this paper, we define “molecular subtypes” of lung cancer based on specific actionable genetic aberrations. Each subtype is associated with molecular tests that define the subtype and drugs that may potentially treat it. We hope this paper will be a useful guide to clinicians and researchers alike by assisting in therapy decision making and acting as a platform for further study. In this new era of cancer treatment, the ‘one-size-fits-all’ paradigm is being forcibly pushed aside—allowing for more effective, personalized oncologic care to emerge.
Lung cancer kills more patients than any other malignancy in the world
We have previously developed a formal process for classifying a cancer - melanoma - into molecular subtypes
In light of the growing insight into the molecular mechanisms underlying lung cancer with the development of sophisticated molecular diagnostics and targeted therapies, we now extend the molecular subtyping approach to lung cancer. Similar to the previously described melanoma molecular disease model, the lung cancer molecular disease model consists of a set of actionable molecular subtypes and proposed practice guidelines for treating each subtype. In contrast to the melanoma model, there is a larger molecular heterogeneity that exists within lung cancer (see
There is significant cross-talk between these pathways and their downstream effectors, which we have classified into 6 pathways for simplicity to account for differences in treatment modalities. The additional 4 pathways are: EGFR (blue), KRAS (yellow), EML4-ALK (orange), and P53/BCL (purple). It is thought that the RAS/RAF/MEK/MAPK pathway may be constitutively activated by the EML4-ALK fusion oncogene
The online version contains additional in-depth information about relevant genes, genetic tests, pathways, drugs, targets, and clinical trials, all hyperlinked and organized in a Wikipedia-like format. Given the evolving state of knowledge, we anticipate this baseline model will need to be revised routinely with new clinical and scientific findings. Existing types are likely to be split into new subtypes corresponding to responders and non-responders, and new types are likely to be added to accommodate previously unseen tumor groups. Over time, this model will be defined with greater and greater specificity and linked to increasingly efficacious therapies.
Sub-type | Description | Pathway | Potentially relevant therapies | Relevant histological subtypes | Strength of evidence for clinical use* |
1.1 | EGFR sensitizing mutations | EGFR | TKIs & chemotherapy | Adenocarcinoma | High |
1.2 | EGFR resistance mutations including T790M | EGFR | Dual EGFR/HER2 TKI, c-MET inhibitors +/− 1st or 2nd generation EGFR TKIs, Hsp90 inhibitors, dual MET/VEGFR2 inhibitors, Chk1 inhibitors | Adenocarcinoma | High |
1.3 | VeriStrat proteomic signature | EGFR | TKIs & bevacizumab | Adenocarcinoma | High |
2.1 | K-ras mutations | K-ras | Dual MAPK & AKT/PI3K inhibitors, Hsp90 inhibitors | Adenocarcinoma | High |
3.1 | EML4-ALK | EML4-ALK | ALK inhibitors, Hsp90 inhibitors | Adenocarcinoma | High |
Sub-type | Description | Pathway | Potentially relevant therapies | Relevant histological subtypes | Strength of evidence for clinical use* |
4.1 | c-MET overexpression | c-MET | c-MET inhibitors, Dual Met/VEGFR2 inhibitors, ALK/MET inhibitors, c-MET monoclonal antibodies | Adenocarcinoma, small cell carcinoma, squamous | Medium |
4.2 | c-MET mutations | c-MET | c-MET inhibitors, dual Met/VEGFR2 inhibitors, ALK/MET inhibitors, c-MET monoclonal antibodies | Adenocarcinoma, squamous, large cell, small cell carcinoma | Low |
5.1 | PI3KCA amplification, mutations | AKT/PI3K | PI3K, AKT, mTOR inhibitors | Adenocarcinoma | Low |
5.2 | PTEN deletions/methylation | AKT/PI3K | PI3K, AKT, mTOR inhibitors | Adenocarcinoma | Low |
6.1 | VEGFR overexpression | VEGFR | VEGFR inhibitors | Small cell carcinoma | Low |
6.2 | Bcl-2 overexpression | P53/BCL | BCL-2 Inhibitors | Small cell carcinoma | Low |
7.1 | ROS1 translocation | ROS-1 | ROS1 inhibitors | Adenocarcinoma (1.5%) | Medium |
8.1 | Epigenetic alterations | HDAC inhibitors, epigenetic inhibitors with cytotoxic agents | - | Low | |
9.1 | IGF alterations | IGF | IGF1R monoclonal antibodies, IGF1R TKIs | Adenocarcinoma, Squamous, SCLC |
Subtype 1 harbors aberrations in the EGFR gene/pathway – a set of targetable mutations with commercially available inhibitors as well as newer agents on the horizon.
SUBTYPE 1.1 is characterized by mutations in the EGFR gene that make these tumors responsive to EGFR inhibitors. EGFR encodes a transmembrane receptor that is a member of the ErbB family of tyrosine kinases. EGFR is a cell surface protein that binds to epidermal growth factor and other growth factor ligands to become activated
EGFR has been shown to be dysregulated by various mechanisms in NSCLC, including overexpression, amplification or mutation
This subtype includes three classes of mutations: Class I mutations – exon 19 in-frame deletions (44% of all EGFR mutations), Class II - single amino acid changes (L858R 41%, G719 4%, other missense mutations 6%), Class III - exon 20 in-frame duplication/insertions (5%). Eighty-five percent of all EGFR activating mutations are Class I or L858R
NSCLC large cell and adenocarcinoma patients should be tested at diagnosis for EGFR mutations as those who exhibit such mutations benefit from EGFR inhibitors (e.g. erlotinib or gefitinib) in the first-line setting, as recommended by NCCN guidelines
Some additional trials for recurrent or advanced NSCLC are ongoing. These trials will test the efficacy of second-generation EGFR inhibitors or approved EGFR inhibitors (such as erlotinib) in combination with other inhibitor drugs such as MET/VEGFR2 inhibitors.
Subtype 1.2 is defined as NSCLC that harbors a T790M mutation in exon 20 of the EGFR gene. T790M mutations emerge in response to treatment with EGFR TKIs. The T790M mutation accounts for approximately 50% of cases in which acquired resistance to erlotinib or gefitinib occurs
EGFR TKIs (such as erlotinib or gefitinib) are selective inhibitors of EGFR's kinase domain that work by competing with ATP for binding at the ATP-binding site, thereby preventing autophosphorylation and activation. The T790M mutation affects the gatekeeper residue in the catalytic kinase domain and confers drug resistance by increasing EGFR's affinity for ATP – thus reducing the potency of the ATP-competitive kinase inhibitors
Interestingly, the development of a T790M mutation may actually confer a relatively improved survival, as tumors that acquire it appear to be less aggressive than tumors with EGFR TKI resistance due to other mechanisms
Several treatment modalities for addressing drug resistance due to the EGFR T790M mutation are currently being explored.
The first strategy employs second generation TKI's such as afatinib (BIBW2992) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and EGFR kinases. Preclinical data have demonstrated that afatinib is a potent irreversible inhibitor of EGFR/HER1/ErbB1 receptors including the T790M variant
While secondary mutations in EGFR are responsible for the majority of cases of acquired EGFR TKI resistance, activation of other pathways can also lead to resistance. For example, c-MET amplification has been observed in approximately 5%–20% of patients with acquired resistance to EGFR inhibitors. A second therapeutic strategy thus adds various drugs or antibodies capable of inhibiting c-MET (e.g. crizotinib, foretinib, ARQ 197, MetMAb) to first- (erlotinib) or second- (PF-00299804) generation EGFR-TKIs
A third approach involves inhibition of the molecular chaperone Hsp90 with Hsp90 inhibitors such as AUY922, and possibly ganetespib (STA9090). The molecular and cellular consequences of Hsp90 inhibition are not well defined, but some cancers increase levels of active Hsp90, utilizing Hsp90 to process mutant or misexpressed proteins
Some additional trials for recurrent or advanced NSCLC are ongoing. These trials will test the efficacy of various combination therapies including EGFR inhibitors, second- generation tyrosine kinase inhibitors, a dual MET/VEGFR2 inhibitor, a Chk1 inhibitor and more.
SUBTYPE 1.3 tumors are defined based on a proteomic signature called VeriStrat, which provides likely responsiveness to EGFR inhibitory therapies such as erlotinib in the absence of EGFR mutations.
VeriStrat utilizes mass spectrometry to evaluate tumor EGFR ligand levels and predict patient response and survival outcome to erlotinib and other EGFR inhibitors from serum samples
VeriStrat profiling is an approved serum analysis diagnostic tool for NSCLC patients who have tested negative for EGFR mutation since some patients with wildtype EGFR status may still benefit from erlotinib treatment regimens. Several recent studies have indicated that VeriStrat classification has significant power to predict response and survival to EGFR inhibitors for several cancer types
Patients with a “VeriStrat good” status are predicted to respond well to EGFR inhibitors and should pursue second- and third-line therapy for EGFR positive NSCLC as outlined by several reputable organizations including ASCO and the NCCN
As noted earlier, the dual EGFR and Her2 inhibitor BIBW 2992 is currently being tested in a phase 2 and 3 clinical trial to explore efficacy in patients with lung adenocarcinoma harboring wildtype EGFR
SUBTYPE 2.1 is characterized by mutations in the K-ras gene. K-ras belongs to a family of small GTPases that regulate cellular behavior in response to extracellular stimuli. Ras-regulated signal pathways control processes such as actin cytoskeletal integrity, proliferation, differentiation, cell adhesion, apoptosis, and cell migration via the MAPK and AKT/PI3K pathways
Ras has many isoforms of which K-ras and N-ras and the most relevant to human cancer and are estimated to be mutated in 20–30% of all cancers
Subtype 2.1 is the only subtype in this category and is characterized by mutations in K-ras. K-ras proteins possess intrinsic GTPase activity. Point mutations at codons 12, 13, or 60 in the K-ras oncogene lead to constitutive activation of K-ras protein via changes at the GTP binding domain which prevents the conversion of GTP to GDP
A meta-analysis that included 28 studies of NSCLC reported worse outcomes for patients with K-ras mutations, particularly those with adenocarcinoma histology
Despite the widespread impact of Ras mutations on cancer, Ras has not been successfully targeted therapeutically in NSCLC. However, several approaches are currently being tested in clinical trials. The first involves concurrently targeting the downstream MAPK and AKT/PI3K pathways
A second approach involves inhibition of the molecular chaperone Hsp90. As noted earlier, HSP90 inhibitors may block multiple signaling pathways that are functioning aberrantly in cancer cells
REOLYSIN is a proprietary formulation of human reovirus in development by Oncolytics Biotech Inc. for various cancers. REOLYSIN (Reovirus Serotype 3 - Dearing Strain) is a naturally occurring oncolytic virus that preferentially lyses cancer cells, specifically those that have upregulated RAS signaling. The preferential lysis of Ras activated cells and the non-pathogenic nature of the reovirus
The EML4-ALK oncogene is a relatively newly-discovered aberration in NSCLC with several targeted agents in active development, including crizotinib which was recently FDA-approved for this subtype
Subtype 3.1 is the only subtype in this category and it harbors the EML4-ALK fusion oncogene, a fusion between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK)
EML4-ALK NSCLC represents a unique subset of NSCLC patients for whom ALK inhibitors have high potential as a very effective therapeutic strategy
The Hsp90 inhibitor IPI-504 is currently in clinical trials to test its efficacy in lung cancer patients with ALK mutations. As noted earlier, HSP90 inhibitors may block multiple aberrantly functioning signaling pathways in cancer cells
Subtype 4 harbors aberrations in c-MET. c-MET is a proto-oncogene with important implications in NSCLC
SUBTYPE 4.1 is characterized by dysregulation of mesenchymal-epithelial transition factor receptor tyrosine kinase (noted as c-MET). c-MET is a proto-oncogene that encodes a tyrosine kinase membrane receptor known as hepatocyte growth factor receptor (HGFR)
c-MET overexpression has been observed in 67% of adenocarcinomas, 57% of large cell carcinomas, 57% of squamous cell carcinomas, and 25% of small cell lung cancers
The c-MET ligand HGF can also be overexpressed by tumor cells with moderate expression observed in 45% of lung cancer tumors
Finally, c-MET dysregulation may also occur through gene mutation. This aberration is clearly distinguishable from the others by gene sequencing
Subtype 4.2 is characterized by mutations of c-MET.
c-MET mutations have been observed in both NSCLC and small cell lung cancer. The prevalence of c-MET mutations is relatively low compared to the frequency of c-MET overexpression in lung cancer, but their potential for causing disease progression has been shown to be significant
Another aberration recently observed to positively correlate with c-MET mutation in NSCLC cell lines is mutation of the Casitas B-lineage lymphoma (c-CBL) gene
It should also be noted that MET mutations vary along ethnic and racial lines. One recent study found the highest frequency of c-MET mutations in East Asians. The N375S sema domain mutation was found to be the most frequent mutation overall, occurring more frequently in East Asians than Caucasians, and never in African-American samples
Several targeted therapies for the treatment of aberrant MET activity are currently in clinical testing. The first strategy employs direct MET inhibitors capable of interfering with c-MET signaling. Several - including ARQ 197, cabozantinib, and foretinib – are currently in phase 2 and 3 clinical trials.
A single-arm antibody directed against the extracellular domain of MET, called MetMAb, has been tested in a randomized phase II study in patients with previously treated NSCLC with erlotinib. In the intent-to-treat analysis, no benefit was seen with the addition of MetMAb to erlotinib compared to those treated with erlotinib alone. However, in those patients with “MET diagnostic-high” criteria on immunohistochemistry (a composite of intensity and extent of staining that was seen in approximately 50% of patients), there was improvement in progression-free and overall survival, leading to the initiation of a phase III study in this subset of patients
Two HGF antibodies that target the aberrant action of HGF are currently being tested in lung cancer patients. AMG-102 is a human monoclonal antibody that is in phase I and II clinical trials for NSCLC and several other cancers. Data from one trial in patients with advanced solid tumors suggests that AMG-102 is well tolerated and may inhibit tumor progression in some patients
Another strategy involves inhibition of the chaperone protein, Hsp90, which is required for c-MET protein (and other kinase) folding and stability
Subtype 5 harbors aberrations in the AKT/PI3K pathway. PI3K acts antagonistically with the lipid phosphatase, PTEN, to tip the balance between two signaling molecules, PIP2 and PIP3
Subtype 5.1 is characterized by aberrations in PI3K, a lipid kinase that regulates growth in the AKT/PI3K pathway. The PI3K protein family is divided into three classes and several subclasses based on primary structure, regulation, and in vitro lipid substrate specificity. Of these the Class Ia is the most studied, partly because of its role in cancer. These proteins are composed of a catalytic subunit known as p110 and a regulatory subunit known as p85. To date the PI3K is the only family member found to have somatic mutations in human cancer. These mutations occur predominantly in the helical or kinase domains of the alpha p110 catalytic subunit which is encoded by the PI3KCA gene
The PI3K/AKT pathway plays a key role in regulating mammalian cell proliferation and survival. Activating mutations in PI3KCA have been implicated in various cancers including melanoma, breast cancer, colorectal cancer and NSCLC. In lung cancer, PI3KCA gene amplification occurs at a much higher frequency than do activating mutations
There are three potential targets for therapeutic intervention in this pathway: AKT, PI3K, and mTOR. There are several drugs in clinical development against all three targets and a few drugs against mTOR that are currently approved for other cancer types.
Several phase I and II trials are currently ongoing targeting PI3K in NSCLC either alone or in combination with standard, cytotoxic chemotherapy. These agents include XL765 – which also inhibits mTOR – BKM120, and GDC-0941.
Phase I and II trials are currently recruiting that offer MK-2206 – an oral, potent, allosteric inhibitor of AKT – in combination with either erlotinib or gefitinib in advanced NSCLC.
Multiple phase I and II trials are recruiting patients for treatment of advanced NSCLC with mTOR inhibition either alone or in combination with chemotherapy or radiation therapy. These include agents such as everolimus, sirolimus, and temsirolimus as well as agents that have dual mTOR and PI3K activity such as XL-765.
Subtype 5.2 harbors inactivating mutations or deletions in PTEN, a lipid phosphatase that negatively regulates growth through the AKT/PI3K pathway, as noted above
Inactivation of PTEN is associated with a variety of cancers including glioblastoma, melanoma, prostate, breast, endometrial cancers, and NSCLC. Loss of the PTEN tumor suppressor results in tumorigenesis. PTEN mutations (in exons 5–8) have been observed in 8% of SCC and 1% of adenocarcinomas
Same as seen for Subtype 5.1.
This subtype is characterized by aberrations in the vascular endothelial growth factor (VEGF) pathway. The VEGF pathway regulates vascular angiogenesis. Tumors usurp this pathway to promote self survival and proliferation. Downstream of VEGF, B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic regulator protein that has been implicated in a number of cancers including SCLC. VEGF can promote the survival of tumor cells through the induction of Bcl-2 expression
SUBTYPE 6.1 is characterized by overexpression of vascular endothelial growth factor receptor (VEGFR). VEGFR is the receptor for vascular endothelial growth factor (VEGF), an important signaling protein involved in vasculogenesis and angiogenesis. Aberrations in the VEGFR pathway contribute to the rapid growth and high metabolic activity characteristic of SCLC and are associated with poor outcome for this cancer type
Current trials evaluating VEGFR inhibition in SCLC include the agents vandetanib and sunitinib, either in combination with cytotoxic chemotherapy or as maintenance therapy. To date, trials done in unselected patients have been disappointing. Future biomarker directed trials based upon serious biologic rational are needed to determine the true efficacy of these inhibitors in select patient groups.
Subtype 6.2 is characterized by aberrations in Bcl-2, a key inhibitor of cell apoptosis. The Bcl-2 family of proteins contains both pro- and anti-apoptotic members which regulate apoptosis via a delicate balance. The Bcl-2 pathway is activated in response to cellular stress such as growth factor deprivation, hypoxia, cell detachment or DNA damage via p53.
Several lines of evidence point to a key role of Bcl-2 in SCLC pathogenesis:
Bcl-2 has been reported to be up-regulated in 73%–90% of human SCLC tumors
Anti-sense suppression of Bcl-2 leads to decreased survival of SCLC cell lines and increased sensitivity to chemotherapy
Targeted inhibition of Bcl-2 using small molecule inhibitors killed SCLC cell lines treated in vitro and caused regression of established tumors in xenograft models (mice)
The SOE score for genetic testing for Bcl-2 aberrations in SCLC is currently ‘low’ since only data from pre-clinical models are available.
Several drugs that could provide therapeutic relief to this subtype of patients, including YM155, ABT-737, AT-101 and TW37, are in the early stages of development. The drug classes discussed here are also good candidates for targeted therapies for SCLC patients.
One anti-apoptotic agent, oblimersen, an anti-sense agent targeted at nuclear Bcl-2 has exhibited mixed results for SCLC. A small phase I study reported a promising response rate of 83% (10 of 12 evaluable patients) for oblimersen with paclitaxel in patients with chemorefractory relapsed SCLC, based on observations that Bcl2 family members contribute to paclitaxel resistance. A follow-up phase II study tested carboplatin and etoposide with or without oblimersen and the addition of oblimersen neither improved patient response rate nor survival
Phase I and II trials treating SCLC with Hedgehog inhibition alone or in combination with standard cytotoxic chemotherapy are currently ongoing. These agents include GDC-0449 and XL-139.
Picornaviruses are non-enveloped, positive-stranded RNA viruses with an icosahedral capsid. One particular picornavirus, Seneca Valley Virus-001, is a biologic agent which may have anti-neoplastic activity on its own. A phase II trial is currently ongoing in which patients with extensive-stage SCLC are randomized to Seneca Valley Virus-001 versus placebo after induction cytotoxic chemotherapy.
The recent discovery of ROS-1 mutations has shown that drugs such as crizotinib may have more activity than the already known inhibition of the EML4-ALK translocation and c-MET.
SUBTYPE 7.1 harbors the ROS-1 translocation. Patients with ROS-1 mutant tumors are characteristically young, non-smokers. The fusion gene has been observed predominantly in adenocarcinomas (∼1.5%) and is mutually exclusive with mutations in the EGFR, K-ras, and EML4-ALK genes
ROS1 NSCLC represents a unique subset of NSCLC patients for whom the c-MET/ALK inhibitor crizotinib has shown potential as a very effective therapeutic strategy. As noted earlier, the ALK inhibitors crizotinib and LDK378 are currently in development for EML4-ALK NSCLC though at present, only crizotinib has been shown to be effective in treating this small subset of patients with a ROS1 translocation
Subtype 8.1 involves epigenetic alterations. Epigenetics is the study of reversible changes to DNA and the nucleosome that affect expression of genes and can be pharmacologically manipulated. The earliest recognized of these changes was DNA methylation. In tumors, it was found that methylation at the 5 position of cytosines in the context of CpG islands (areas in the promoter of genes with a relative over-abundance of cytosine-guanine dinucleotides) led to decreased expression of affected genes, often tumor suppressor genes or other growth regulatory molecules. This process is complex and is controlled by DNA methyltransferase inhibitors, DNMT1, DNMT3a and DNMT3b. Hypermethylation of promoter regions in cancer, specifically lung cancer is an almost universal finding, with differences in different types of cancer
Control of gene expression is more complex such that in addition to DNA methylation, changes in the nucleosomal structure via post-translational modifications of histones, specifically methylation, acetylation, phosphorylation and sumoylation at the amino terminus of histone H3 and histone H4 can also lead to alterations of gene expression. The interplay between DNA methylation and histone post-translational modifications is complex, and includes histone methyltransferases and acetyltransferases as well as deacetylases. Typically, more heavily acetylated histone tails leads to a more “open” chromatin configuration and is more accessible to transcription factors and the basal transcriptional machinery. In vitro experiments have shown that histone deacetylase inhibitors (therefore leading to more heavily acetylated histones) leads to greater expression of target genes, and several HDAC inhibitors have been evaluated in clinical trials showing activity particularly in cutaneous T cell lymphoma
A number of trials have attempted to utilize epigenetic therapy including DNA methylation inhibitors, HDAC inhibitors, the combination of methylation inhibitors and HDAC inhibitors as well as epigenetic agents combined with standard cytotoxic agents. One of the great questions in epigenetic therapy is whether there are specific patients who are more likely to benefit from these therapeutic agents.
This subtype is characterized by aberrations in the insulin-like growth factor (IGF) axis. This axis involves two receptors (IGF1R and IGF2R), their ligands (IGF-1 and IGF-2), and multiple binding proteins. It is theorized that defects in the IGF axis are involved in the development of multiple malignancies, including NSCLC and SCLC
The IGF axis is important in normal cells for differentiation, metabolism, and growth with features of endocrine, paracrine, and autocrine control. Alterations in this pathway can lead to uninhibited proliferation, playing an important role in the development of neoplasia
There are several therapeutic approaches to inhibiting the IGF axis using monoclonal antibodies against the extracellular domain of IGF1R as well as small-molecule inhibitors of the intracellular tyrosine kinase domain of the same receptor
Multiple monoclonal antibodies have been investigated in the treatment of lung cancer. One such antibody, figitumumab, was shown to improve response rates in both adenocarcinoma and squamous cell histologies when combined with carboplatin and paclitaxel in a phase II trial
OSI-906 is a selective small molecule, dual kinase inhibitor of both IGF1R and the insulin receptor. A phase II clinical trial combining OSI-906 with erlotinib in NSCLC is currently recruiting patients
Lung cancer treatment has traditionally been viewed within the bounds of a ‘one-size-fits-all’ approach with the use of cytotoxic chemotherapy. With such poor outcomes, it is no wonder that a sense of nihilism has pervaded the management of these patients over the last half-century. During the past decade, however, research has shown that lung cancer is a molecularly-complex amalgam of diseases with specific derangements leading to vastly different outcomes and, more importantly, the chance to develop effective, targeted treatment
Currently, EGFR and K-ras mutational testing are already common practices for most community oncologists
This review has focused on the treatment of lung cancer based on the targeted treatment of single gene or pathway alterations. Some of these targets are actionable today. This is highlighted by the online lung cancer therapy finder application that can be accessed online (
The initial subtypes and associated practice guidelines defined here were identified by consensus of a panel of recognized lung cancer experts, and supported by detailed analysis of the peer-reviewed scientific literature. Subtypes are defined based on the status of key lung cancer genes/pathways and their combinations. Each subtype is defined by one key oncogene/tumor suppressor (such as EGFR for subtypes 1.1 to 1.3, and K-ras for subtype 2.1), either by itself or in combination with others that play a supportive role (such as EGFR activating mutations in exons 19 and 21 and the exon 20 resistance mutation T790M in the case of subtypes 1.1, 1.2, and 1.3).
We thank Dr. Michelle Turski for help with references, formatting, and organization of the manuscript, and Dr. George Lundberg for ongoing guidance and encouragement.