Lung Cancer Biomarkers: Present Status and Future Developments [Archives of Pathology & Laboratory Medicine]
By Olsen, Randall J | |
Proquest LLC |
* The publication of the "Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline From the
(Arch Pathol Lab Med. 2013;137:1191--1198; doi: 10.5858/arpa.2013-0319-CR)
In
HISTORICAL PERSPECTIVE
For many years, lung cancer has been the leading cause of cancer deaths in the United States2 and worldwide.3 Most patients with lung cancer present with advanced disease, and conventional treatment options have been limited, resulting in an overall 5-year survival rate of only 10% to 15%, for many decades.4,5
Approximately 85% of lung cancers are non--small cell lung cancers (NSCLCs), traditionally divided into 3 major cell types: adenocarcinoma (approximately 50%), squa- mous cell carcinoma (approximately 35%), and large cell carcinoma (approximately 15%, although this is a dimin- ishing cell type category).6,7 About 70% of NSCLCs present with advanced disease not considered curable by surgical resection, either locally advanced (stage IIIB) or often with metastatic disease (stage IV). Clinical stage IIIB NSCLCs are associated with a 5-year survival rate of 7% and stage IV NSCLCs, with a 5-year survival rate of 2%.8 Conven- tional therapy for stage IV NSCLC is doublet chemother- apy that includes cisplatin or carboplatin. Affected patients may additionally receive radiation therapy. Of the patients with lung cancer who initially respond to first-line therapy, nearly all subsequently experience disease progression. These patients may receive second-line therapy, or possibly more lines of therapy, in an attempt to control their disease. Eventually, virtually all of these patients die from lung cancer as reflected in the statistics mentioned previously.9--16
Given the dismal prognosis and limited treatment options for patients with advanced-stage lung cancer, it is not surprising that the
The first generation of EGFR TKIs approved for treatment of advanced-stage lung cancer includes gefitinib (Iressa;
Subsequent studies have demonstrated that almost all of the EGFR mutations are in adenocarcinomas or NSCLCs with an adenocarcinoma component, including adenosqua- mous carcinoma and solid subtypes of adenocarcinoma initially misinterpreted histologically as squamous cell carcinomas but proven to be adenocarcinoma after further workup.1,24,25 Clinical evidence also demonstrated that EGFR mutation analysis was the most reliable method of determining which NSCLCs have EGFR mutations, and of predicting response to first-generation TKI therapy, as opposed to EGFR copy number detection by fluorescence in situ hybridization (FISH) or protein expression by immunohistochemistry (IHC).1,4,5,25--27
In 2007, translocation of the anaplastic lymphoma kinase gene (ALK) with echinoderm microtubule-associated pro- tein-like 4 gene (EML4) was first reported in pulmonary adenocarcinomas.28 Later studies29 showed that there were many variants of the EML4-ALK rearrangement in addition to ALK fusion with other partners. When clinical trials demonstrated that crizotinib therapy improved response rate and progression-free survival for patients with ad- vanced NSCLC with ALK rearrangements, the
THE CAP/IASLC/AMP GUIDELINE "MOLECULAR TESTING GUIDELINE FOR SELECTION OF LUNG CANCER PATIENTS FOR EGFR AND ALK TYROSINE KINASE INHIBITORS''
In the past several years, it became obvious that a subset of patients with lung cancer have responded to the first- generation TKI therapies. However, there were no uniform guidelines for performing biomarker testing to select patients for treatment that was based on an in-depth review and grading of evidence and that incorporated input and vetting across the relevant medical disciplines on a worldwide basis. Therefore, the CAP, IASLC, and AMP set out to create standardized international guidelines for lung cancer biomarker testing with input from multiple other stakeholders in an extended and exhaustive process as described in the opening sections of the guidelines.1 This work was conducted under the auspices of the CAP Pathology and Laboratory Quality Center.1
The CAP/IASLC/AMP guideline focuses on the lung cancer--predictive biomarkers corresponding to the first- generation EGFR TKIs (gefitinib and erlotinib) and ALK TKI (crizotinib), which are clinically validated and
A wide range of sample types, including cytology specimens, and fixatives (formalin-fixed paraffin-embedded, fresh, frozen, and alcohol) are allowable for biomarker testing. Mutation analysis, using a validated method with sufficient performance characteristics, is recommended for EGFR mutation testing. KRAS mutation testing is not recommended as a sole determinant of EGFR TKI therapy because most lung cancers that lack KRAS mutations also lack EGFR mutations. FISH assay using dual-labeled break- apart probes is recommended for ALK translocation testing. Carefully validated ALK IHC can be used as a screening method to select specimens for ALK FISH testing. The reader is referred to the published guideline for additional details and the complete recommendations, suggestions, and expert consensus opinions.1
UNRESOLVED ISSUES, CAVEATS, AND FUTURE OBJECTIVES
The results of clinical trials with first-generation TKIs and the release of the CAP/IASLC/AMP "Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors'' have offered much promise and generated considerable excitement among patients, their families, their physicians, and the media.1 Looking forward, there are multiple unresolved issues, caveats, and future objectives that must be addressed:
1. The original clinical trials of first-generation EGFR and ALK TKIs were performed with patients with advanced- stage lung cancer and, therefore, the approvals are for patients with stage IIIB and IV lung cancer. Since many patients with earlier-stage lung cancer later have lung cancer recurrence, and many ultimately die from their disease, this raises the question of whether or not predictive biomarker testing should be done in these earlier-stage lung cancers, either to have the data for treatment when recurrence occurs or to use as an adjuvant therapy during initial treatment.1
2. EGFR mutations are identified in only approximately 15% of NSCLCs in white persons in
3. Virtually all NSCLCs develop acquired resistance to first- generation EGFR TKIs or crizotinib after a period of initial response that may last for months. This acquired or secondary resistance results from secondary mutations in the EGFR or ALK gene or to a variety of other mechanisms.1,25 Second-line or third-line therapies for these patients might include second-generation TKIs or drugs directed at other actionable targets.34,35
4. EGFR mutations and ALK rearrangements are found in pulmonary adenocarcinomas, including adenosquamous carcinomas and other variants, but are found uncom- monly, if at all, in pure squamous cell carcinomas or pure small cell carcinomas.4,5,24,26,27,36 Therefore, targeted therapies and corresponding biomarkers are needed for lung cancer cell types other than adenocarcinoma.25
5. Investigations into targeted therapy of lung cancer stem cells may provide a novel alternative to treating these patients.37
6. New technologies are altering the paradigm for predic- tive biomarker testing.1,25
7. Reimbursement for predictive biomarker testing is an important issue if testing is going to be done and, especially, if it is going to be done on a reflex basis.1
THERAPY IN EARLY-STAGE LUNG CANCER
Only approximately 30% of NSCLCs are diagnosed in an early stage (stage I, II, or IIIA) with limited disease. Most affected patients are treated with surgical resection and may also receive adjuvant therapy based on various proto- cols.16,38,39 However, despite treatment during early stage, a large percentage of these patients will nevertheless have relapse, with disease progressing to an advanced stage, and they will eventually die from their lung cancer (5-year survival rate by clinical stage is 50% for stage IA, 43% for stage IB, 36% for stage IIA, 25% for stage IIB, and 19% for stage IIIA).8
Since most patients with early-stage lung cancer will eventually have relapse with disease progression, the CAP/ IASLC/AMP guideline encourages EGFR and ALK testing of lung cancers at the time of diagnosis for patients presenting with stage I, II, or III disease.1 Alternatively, if testing is not performed in these early-stage cancers, the guidelines encourage the retaining of cancer tissue for future biomarker testing should the patient's condition progress to an advanced stage.1
Biomarker testing of the lung cancer tissue may provide a basis for TKI therapy when the patient's condition progresses to an advanced stage. It may also form the basis for TKI therapy as an adjuvant therapy at the time of initial diagnosis and treatment in the early stage.1 Several studies40--42 are investigating the use of first-generation EGFR TKIs as adjuvant therapy in early-stage lung cancers, including the RADIANT and SELECT trials.
MOLECULAR TARGETED THERAPIES UNDER INVESTIGATION
Cetuximab (Erbitux;
Patients receiving first-generation EGFR TKIs eventually develop acquired resistance to their drug. Second-genera- tion EGFR TKIs are under investigation as additional lines of therapy when acquired resistance develops or as a potentially more effective first-line therapy. These drugs are ERBB family blockers and, compared to first-generation EGFR TKIs, they typically exhibit higher affinity for the target, irreversible binding, and inhibition of more than 1 target in the ERBB family of receptors. In addition, some of the second-generation drugs may also bind to EGFR receptors with mutations of acquired resistance to the first-generation EGFR TKIs.53--56
Three of these ERBB family blockers under investigation are afatinib (BIBW2992; Boehringer Ingelheim, Ingelheim,
Some TKIs inhibit more than 1 kinase. Crizotinib, currently used for ALKþ adenocarcinomas, is a prime example. In addition to ALK, crizotinib inhibits ROS1, MET, and RON.59,60 ROS1 translocations occur in 1% to 2% of NSCLCs, with several different fusion partners reported. Approval of crizotinib for treatment of ROS1þ adenocarci- nomas is generally expected in the not too distant future.60,61
There are multiple other potentially druggable targets with corresponding predictive biomarkers in lung adeno- carcinomas, including in the signaling pathways down- stream of the ERRB receptors. Other drugs undergoing clinical trials include (1) the mammalian target of rapamycin (mTOR) inhibitor everolimus, the phosphoinositide-3 ki- nase (PI3K) and mTOR inhibitor BEZ235, the PI3K inhibitors GDC-0941 and XL147, and the AKT inhibitor MK-220662--65; (2) inhibitors and antibodies for c-MET and its ligand, hepatocyte growth factor66; tivantinib as second- line therapy in patients with advanced nonsquamous NSCLC in the MARQUEE (Met Inhibitor ARQ 197 plus Erlotinib versus Erlotinib plus placebo in NSCLC) trial67,68; the JAK (Janus kinase) inhibitors enzastaurin and AZD1480 and the
KRAS is the most frequently mutated oncogene in lung adenocarcinomas, occurring in about 30% of cases, mostly in smokers. There are currently no direct inhibitors of KRAS, although there are inhibitors of targets downstream to KRAS.79
Cetuximab in combination with first-line platinum-based chemotherapy has been reported to improve overall survival for patients with lung squamous cell carcinomas that have high total EGFR expression by IHC (score of 200 or more) using the Dako pharmDx kit, compared to chemotherapy alone.48--52
Potential targets for squamous cell carcinoma under investigation include members of the PI3K pathway, the fibroblast growth factor receptor, and the discoidin domain receptor.80--83 Potential drugs under investigation for small cell lung cancer include the mTOR inhibitors everolimus and temsirolimus.84--86
MOLECULAR TARGETING OF LUNG CANCER STEM CELLS
Stem cells in lung cancer have been postulated for more than 3 decades,87 and in the last decade they have been increasingly examined for the presence of possible diagnos- tic and therapeutic benefits. Lung cancer stem cells have specific characteristics of all stem cells, including chemore- sistance and radioresistance, the ability to self-renew, the ability to produce a large number of multilineage progeny, and slow proliferation.88,89 Postchemoradiotherapy expres- sion of lung cancer stem cell markers correlates with poor prognosis in patients with lung cancer.88 Research is continuing to clarity the critical role lung cancer stem cells play in metastases, drug resistance, and tumor regenera- tion.37 The predominant use of mouse models, as well as lung cancer stem cells' slow cycling and asymmetric cell division, make their identification difficult; and studies of potential treatments targeting lung cancer stem cells are all the more challenging.37 Identification of molecular targets for effective lung cancer stem cell therapy requires the differentiation of lung cancer stem cells from normal multipotent stem cells. This differentiation might be accomplished by using magnetic bead isolation or flow cytometry to identify unique cell type markers.90
Treatment regimens for cancers have traditionally as- sumed that all cancer cells have equal malignant potential, so the concept that cancers are driven by cancer stem cells has significant clinical implications.91 Researchers are now actively seeking therapies that target stem cells, and cancer stem cell inhibitory mechanisms, such as blocking stem cell factor, antagonists of ABCG2 pumping activity, and Notch inhibitors, are becoming increasingly studied.91 Hedgehog, Wng, and Notch pathways have been found to be critical to stem cell regulation, and might provide appropriate therapy targets.37 The Hedgehog signaling pathway is essential for determining whether a cell undergoes self-renewal or differentiation.92 Wnt signaling is necessary for embryogen- esis and homeostatic maintenance of adult tissues, and its activation has been shown to significantly enhance lung cancer proliferation, migration, colony formation, and drug resistance.37,92 Approximately one-third of lung cancers have an activated Notch pathway, and its presence has been shown to indicate a significantly worse prognosis in patients who concomitantly lack TP53 mutations.37 Studies of lung cancer stem cell--targeted therapy based on these pathways is ongoing.92 Ongoing studies of potential lung cancer stem cell--targeted therapies are also ongoing. For example, a study showing significantly increased Rac1 guanosine triphosphatase activity in lung cancer cells that have undergone epithelial-mesenchymal transition suggests that targeting Rac1 might provide a more effective lung cancer therapy by eliminating cancer stem cell subpopulations and by blocking non--cancer stem cell to cancer stem cell transition and eliminating cancer stem cell subpopula- tions.93 It has also been suggested that ALDH1A1þ lung cancer stem cells may cause EGFR TKI resistance.94 Also, another study95 suggests that an existing phenothiazine-like antipsychotic drug, trifluoperazine, has the ability to down- regulate cancer stem cell markers CD44 and CD133 and as such might possess anti--lung cancer stem cell properties. Finally, the concept of a single lung cancer stem cell has been complicated by the possibility of an associated mesenchymal stem cell that might play a role in lung cancer tumorigenesis and progression by producing or maintaining a cancer-permissive microenvironment.96
ADVANCES IN NEXT-GENERATION TECHNOLOGY
Before the debut of benchtop next-generation sequencing instruments, clinical laboratories had limited options for identifying the presence or absence of gene mutations in tumors. Many molecular pathologists developed tests using traditional technologies, such as pyrosequencing,
Several next-generation sequencing platforms are com- mercially available. The technologies vary in the type of DNA molecule used as a sequencing template, the chemistry underlying the sequencing reaction, and the amount of sequence data generated per run. The instru- ments most commonly used in clinical laboratories are the 454 GS Junior (454 Life Sciences, Roche,
Although still in its infancy as a diagnostic tool, whole genome sequencing has the potential to truly personalize patient care. Importantly, the long-sought
Inasmuch as a molecular diagnostics laboratory can generate tremendous amounts of data by using next-generation sequencing, information management and interpretation is a significant challenge. Given the magnitude of the human genome (approximately 3 billion base pairs encoding approx- imately 20 000 genes), some investigative pathologists are now building bioinformatics and statistics support into their clinical laboratories. However, before genomics can be performed as a routine test, automated bioinformatics pipelines and analysis algorithms must be developed. Currently, whole genome sequence data cannot be interpreted within a time frame that is optimal for patient care. Furthermore, the functional conse- quence of many gene polymorphisms remains unknown. Molecular pathogenesis researchers must investigate all common gene alterations, defining which are driver mutations and which are bystander mutations. Coordinated efforts to generate a comprehensive reference human genome sequence and cancer genome database (http://cancergenome.nih.gov, http://cancercommons.org, and http://icgc.org; each accessed
ADVANCES IN BIOMARKER IMMUNOHISTOCHEMISTRY
Traditional EGFR IHC detects total EGFR protein expression, but does not differentiate between wild type and mutations so it is not recommended as a basis for selecting patients for EGFR TKI therapy.98 Investigations have examined antibodies to proteins associated with the 2 primary mutations, which represent 90% of EGFR mutations that are associated with response to first-generation EGFR TKIs. These antibodies may be useful in screening for most EGFR mutations but will not detect the less frequent EGFR mutations.113--115
As discussed previously, total EGFR protein expression by IHC may be the predictive biomarker used if cetuximab is approved for lung cancer therapy. High expression with EGFR IHC (score of 200 or more) using the Dako pharmDx kit correlated with increased overall survival for patients with lung cancer-specifically, adenocarcinoma and squa- mous cell carcinoma-receiving first-line platinum-based chemotherapy plus cetuximab compared to chemotherapy alone.48--50 The EGFR expression scoring system has already been validated for this particular setting.51,52
Immunohistochemistry does not demonstrate ALK expres- sion in most tissues that lack an ALK fusion gene. When an ALK fusion gene is present, IHC usually reveals increased ALK expressions. Well-known examples include lymphoma and inflammatory myofibroblastic tumor. Probably because of the relatively low expression of ALK protein in lung cancers with ALK translocations, false-negative IHC results have been observed in lung cancers that were shown to have ALK fusion genes by other methods.1,25,116 Several procedures have been used to enhance the sensitivity of IHC for ALKþ lung cancers, but ALK antibodies that are highly specific and sensitive to ALK expression in lung cancers have been developed. While ALK expression is known to correlate with ALK transloca- tions with these antibodies, clinical trials validating ALK IHC as a predictive biomarker for patient outcomes with crizotinib therapy have not been performed.1,25,116--120 The CAP/IASLC/ AMP guidelines note that screening for ALK translocations with the new sensitive ALK antibodies may potentially be used to identify lung cancers that should then have ALK translocations confirmed with FISH.1
PAYMENT FOR PREDICTIVE BIOMARKER TESTS AND THE FUTURE OF TARGETED THERAPY
A common and important, but as yet unanswered, question is how pathologists and laboratories will be paid for performing lung cancer biomarker tests. Many oncolo- gists and patients are now requesting biomarker testing and, in some hospitals, reflex testing has been implemented as a policy. The number of requests is expected to increase and the addition of new biomarkers for which testing may be done is also expected to increase. For patients with lung cancer with a very bleak prognosis, for their families, and for their oncologists, it is difficult to put any price on potential additional months of life, particularly based on taking a pill without the significant inconveniences and side effects of chemotherapy, even if ultimately there is relapse. Currently, pathologists and laboratories have the option of billing
Whether, under what circumstances, and to what extent
CONCLUSION
The advent of predictive biomarker testing on tissue samples for targeted therapy has forever altered the role of the pathologist in the management of patients with lung cancer. The role of the pathologist in biomarker testing, including very direct participation with IHC, has potential to grow. Patients with lung cancer and their families are now more aware of who pathologists are and the critical role that they have in their health care. New tests, new test technologies, and overall advances in precision medicine will likely improve the cost to benefit ratio for biomarker testing which, along with the powerful desire from patients and physicians to improve survival and quality of life, suggest that predictive biomarker testing will expand as a routine component of cancer care.
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Accepted for publication
From the
The authors have no relevant financial interest in the products or companies described in this article.
Presented at the New Frontiers in Pathology: An Update for Practicing Pathologists meeting;
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Copyright: | (c) 2013 College of American Pathologists |
Wordcount: | 8515 |
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