NON-SMOKER'S LUNG CANCER OVERVIEW 

keywords, non-smoker's lung cancer, Tarceva, EGFR inhibitor, ALK mutation, non-smoker lung cancer, treatment, 

1. Incidence 

Non-smoker's lung cancer has increased in recent years, and some estimate 10% of lung cancers involve non-smokers.  They are typically non-small cell lung cancers and specifically, adenocarcinoma or broncioloalveolar cancers (BAC).  Cancer involves mutations of genes and there are multiple genes thought to be generally involved with cancer and lung cancer.  However, two distinct genes appear to have particular importance with non-smoker's lung cancer, the epidermal growth factor receptor (EGFR), and ALK fusion.  Patients who have particular mutations of these genes are called positive, such as EGFR positive.  Targeted drugs show an impressive response of about 60% for these patients.  Indeed scientists would be close to a cure were it not for the resistance phenomenon.   This page is divided into two sections, the first dealing with EGFR, and the second dealing with ALK. 

2. The Role of the Epidermal Growth Factor Receptor

About a decade  ago, a drug called Iressa was developed and showed modest success.  However, some patients seemed to be doing particular well.   A ground-breaking study by Lynch found that the patients who responded had a mutation in a particular gene called the epidermal growth factor receptor (EGFR).   

"Most patients with non–small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown.  Mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib (Iressa) responsive lung cancer, as compared with none of the seven patients with no response.  Conclusions A subgroup of patients with non–small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib."  Lynch (1) 

Thus, there were two groups: an EGFR positive group with the mutation who frequently showed significant response, and another group, EGFR negative which did not have this initial response.   Further examination showed that the EGFR positive group was typically comprised of non-smokers or very slight smokers who had quit (less than 10 pack years, years smoked x packs per day).  Pao first confirmed the findings about response.  "25 of 31 (81%) tumors from individuals experiencing partial responses or marked clinical improvement while taking gefitinib or erlotinib (Tarceva) contain mutations in the EGFR TK domain. By contrast, none of 29 specimens from patients refractory to these agents had such mutations."  Pao (2).  Most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime (“never smokers”).   Subsequent studies would confirm that most who respond are EGFR positive, and that the EGFR positive group is primarily comprised of non-smokers and light former smokers. 

3. What is EGFR 

The human body has a complex system of signaling between cells with gene duplication a normal part of this process.  Duplication is necessary for growth, repair of damaged cells and other functions.   Proteins signal other cells to initiate replication but mutation and malfunction in these growth factors are a part of cancer, as these growth factors prompt excessive and uncontrolled duplication.  The EGFR signaling pathway helps regulate growth, survival, proliferation, and differentiation in our cells.

“The epidermal growth factor receptor (EGFR) autocrine pathway contributes to a number of processes important to cancer development and progression, including cell proliferation, apoptosis, angiogenesis, and metastatic spread. The critical role the EGFR plays in cancer has led to an extensive search for selective inhibitors of the EGFR signaling pathway. .. The most promising strategies in clinical development include monoclonal antibodies to prevent ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity to inhibit autophosphorylation and downstream intracellular signaling."  Tartora (2), See also FDA (1) .     

The receptor  has two basic parts.   The first part of the receptor is called the extracellular ligand-binding domain.  There it receives a signal from the growth factor and a process called ligand binding occurs.  Once binding occurs, a signal is sent to the second part of the receptor called the tyrosine kinase domain.  There a process called autophosphorylation occurs.   A chemical change occurs and signals are sent to other cells.   In cancer, these signals are abnormal, and thus other cells are told to duplicate are perform other aberrant functions.  "The tyrosine kinase activity of phosphorylated EGFR in cancer cells results in the phosphorylation of downstream proteins that incite cell proliferation, invasion, metastasis, and inhibition of apoptosis.  

Cancer drugs can work in two basic ways, they can try to prevent binding at the ligand-binding domain,  or prevent autophosphorylation in the tyrosine kinase.  The fact that there are two separate functions means that drugs may later be combined.  Cells both give and receive signals.  A particular growth factor is involved both by receiving abnormal signals from other cells and giving them.    

4. Response Rates with EGFR Drugs 
 
Studies over the next 5 years confirmed and amplified the basic findings in Lynch and Pao's research.   Iressa was the first EGFR drug, but Tarceva was believed more potent.  Studies found response rates of about 60% for Iressa and Tarceva for EGFR positive patients, more than double the response rate of conventional chemotherapy.    

5. EGFR Testing for Non-Smokers 

Studies found that most, not all, non-smokers were EGFR positive, and that most, but not all smokers were EGFR negative.   Lynch's group originated testing, and commercial tests are now available, to confirm the patient's EGFR status.   Samples could be secured by biopsy, possibly in a less intrusive bronchoscope, and test are being conducted for even less intrusive means of gathering genetic material. 

6. Resistance after Initial Response 

Tarceva has been a promising drug for EGFR positive patients, with many initial responses, and even some complete responses.   Sadly, the cancer has been just as creative as the scientists.  Many patients have developed resistance and the Tarceva no longer becomes effective.  Two specific mutations have been identified as the causes of resistance:  T 790M and MET.  Strategies involve testing and identifying the mutation and developing other methods of attacking EGFR, including drugs called pan-inhibitors.

7. T790M Mutation    

One cause of resistance to Tarceva is a mutation at T790M.   It appears as but a single change, a threonine-to-methionine substitution at amino acid position 790 (T790M)  "Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M.  Threonine 790 is the “gatekeeper” residue, an important determinant of inhibitor specificity in the ATP binding pocket." 

        A. T790M Testing

Testing makes sense, first determine the cause of the mutation, and secondly, use a drug showing promise with that mutation.  T790M testing is now being marketed. Maheswaran (4).   "The DxS T790M Mutation Test Kit (T790M Kit) is intended for the detection of the T790M somatic mutation in the EGFR gene. The T790M kit detects the presence of a mutant thymidine base in a background of normal cytosine bases at position 2369 (3) of the EGFR gene."

8. MET Mutation 

A second cause of resistance is the MET mutation or oncogene. 

9. Strategies for Combating Tarceva Resistance 

   A. Pan-inhibitors 

Research is ongoing.  Pan-inhibitors are showing some success in cell studies in suppressing T790 resistance. Sharma explains:

 "one of the main challenges in the treatment of NSCLC is to design inhibitors that can overcome the steric interference to drug binding conferred by the T790M mutation... Previous studies from our laboratory have shown that the irreversible dual EGFR and ERBB2 inhibitors, HKI-272 (Ref. 136) and HKI-357 (Ref. 37), as well as the irreversible EGFR inhibitor EKB-569 (Ref. 137) were all able to overcome gefitinib resistance owing to T790M in cis with an L858R mutation in EGFR. Sharma (5)

"Pan  inhibitors permanently and irreversibly stop certain functioning of EGFR.   Initial cell studies have indicated these stronger inhibitors can work against the resistant cells with the mutation.  To determine whether the T790M mutation leads to resistance to EGFR inhibitors that have different molecular structures and mechanisms, we screened four commercially available EGFR inhibitors (AG1478, cetuximab, erlotinib, and CL-387,785) using cells that were transiently transfected with the delL747–S752 construct and the delL747–S752+ T790M construct. We consistently found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, strongly inhibited EGF-induced phosphorylation  

Its success in human studies has been debatable.  There have been several trials but none sufficient impressive to move towards FDA approval.  Many of these studies did not deal solely with T790M but a variety of patients. 

While the initial studies were promising, subsequent studies indicate a combined approach utilizing the pan-inhibitor and another drug, Erbitux, may be necessary.  Attempt to hinder the initial binding and stop the phosphylation is the idea.  Here are some of the pan-inhibitors that are being tested.

  B. HKI 272

One cell study found pan-inhibitor HKI 272 effective with tumor cells in a laboratory setting, though subsequent studies have not confirmed that promise.   Ji (1)

C. BMS 690514

Only cell studies are available.  "BMS-690514, a novel panHER/vascular endothelial growth factor receptor (VEGFR) inhibitor described here, exerted antiproliferative and proapoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation."  Again, this type of study is only preliminary.

D. Cause of Resistance

The latest studies suggest a combination approach.   A recent study showed promise for a combination of Cetuximab (Erbitux) and Lapatanib (Tykerp), 

"In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. We observed that T790M lung cancer cells were resistant to gefitinib, and Stat3 was persistently activated in the resistant cells. A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC."

Both Erbitux and Lapatanib are FDA approved drugs, though not specifically approved for this purpose.  They can be prescribed off label if a physician chooses.

11. ALK Mutation

Summary

A new drug is showing impressive results with a group of lung cancer patients.  The drug Crizotinib showed an impressive response rate of close to 60% of patients with an ALK gene abnormality. Those with the mutation were primarily adenocarcinoma patients.  Testing of adenocarcinoma patients for the mutation would appear sensible since the response rate for patients with the mutation is significantly exceeds that of conventional treatment.   

1. Treatment Rationale

The newest cancer treatments focus on identifying a specific gene believed to be responsible for the particular tumor's creation.  With research, increasing number of differences and distinctive characteristics are identified.  For example, the EGFR gene has been identified as the culprit in EGFR positive lung cancers leading to a response rate of about 60% far exceeding conventional chemotherapy.  Another gene called ALK has been identified with similar results.  An article in the New England Journal of Medicine reports a response rate of 57% for selected patients with ALK mutations using the drug Crizotinib,  That greatly exceeds the about 20% response of standard chemotherapy, and here are some features from this important study. 

2. What is ALK

ALK stands for Anaplastic Lymphoma Kinase.  Originally associated with lymphoma.  “EML4-ALK is a fusion-type protein tyrosine kinase that is generated in human non-small-cell lung cancer as a result of a recurrent chromosome inversion, Soda (4).  Chromosomal translocations and gene fusions play an important role in the initiation of tumorigenesis.  Here, chromosomal rearrangements interrupt the ALK gene and fuse it with another gene result in the creation of an oncogenic, ALK fusion genes.

We have found a novel fusion product between the echinoderm microtubule- associated protein-like4 (EML4) and the anaplastic lymphoma kinase (ALK) in  non-small cell lung cancers (NSCLCs). Tumors featuring EML4-ALK fusion     constitute one subtype of NSCLC that might be highly sensitive to ALK  inhibitors. Inamura (10) 

Translocation of ALK can result in fusion with the neighbouring gene, EML4, in

cancer cells. The fused genes then encode a fusion protein in which the intracellular tyrosine kinase domain of the ALK receptor is constitutively active.

While translocations are seen in cancer, scientists associated them with hematological tumors and have only recently investigated their significance with solid tumors such as lung.  Lin, (11)  

            A. Mechanism of Action of ALK

Several studies showed that cell lines with ALK rearrangements underwent cell cycle arrest and apoptosis when treated with ALK-selective inhibitors.  Lin (11). 

            B. Location of Translocation

There are two different locations of the fusion mirroring the various locations seen in the EGFR mutation.  Wong writes, “there were 2 cases each of variants 1 and 2 with fusion

points at EML4 exons 13 and 20, respectively, one tumor, yielded a novel fusion transcript that was sequenced characterized as fusion of EML4 exon 18, and designated

variant 5.”  

It is a  tyrosine kinase.  Tyrosine kinases have been increasingly associated with cancer and identified for targets for research.   Tyrosine kinases are typically associated with cancer involve a mutated gene.  This malfunction involves a fuses gene.  The discovery of a small inversion of chromosome 2p in a significant proportion of non-small-cell lung cancer patients is therefore of potential importance. The inversion gives rise to a fusion protein comprising portions of a protein known as EML4 and the anaplastic lymphoma kinase, ALK.   

            C. Association with Other Cancers

ALK belongs to the insulin receptor subfamily of receptor  tyrosine kinases. Aberrant ALK activity has recently been shown to be present in anaplastic large cell lymphoma, as

well as in solid tumors.  Zhang (14)

3. Crizotinib

A response rate of close to 60% was reported with Crizotinib for patients with the ALK mutation.   This response rate is very similar to the response rate for Tarceva with EGFR positive patients.  It appears that if the malfunctioning gene can be identified and appropriate treatment prescribed, impressive response rates can be seen. 

4. Animal and Cell Studies

Impressive results were found in cell and animal studies.  In one study, mice developed  adenocarcinoma nodules in several weeks.  Inhibition of EML4-ALK activity with a small-molecule drug induced rapid death of the tumor cells.  Soda (4).  Ttumors in the lungs of the transgenic mice changed to bullae or cysts after treatment with the ALK inhibitor, as revealed by CT scanning and pathology.  Soda (4)

5. Prevalence of the ALK Mutation  

The studies have shown differing percentages of the table indicates with an average of about 6%.  Inamura found only 5 of 149, Kwak found, while Lin found 12 of 106 or 11%.    Study methods varied.     

6.  Adenocarcinoma  

Kwak’s study found "predominantly" adenocarcinoma patients with the mutation.  Article at 1696.   Another article found adenocarcinoma patients almost exclusively.   "Eighteen of the 19 EML4-ALK tumors were adenocarcinomas." 

Sakiri found all adenocarcinomas in his study of cells from bronchosopy.    Sakari (7)

            A. Types of Adenocarcinomas

7. Squamous  Cell Cancers

Kwak found one squamous cell patient with the mutation.   Inamura found none in 48 tumor cells sampled in his study (Inamura (10).  The possibility of squamous patients having the mutation appears small but not nonexistent.  If a squamous cell patient asked, is there anything else that can be done, even if is a 1/100 chance, perhaps the physician should mention testing. 

8. Large Cell and other types

Kwak categorizes tumors as adenocarcinoma, squamous cell carcinoma, and other.  She found two classified as other. Kwak (1).  In contrast, Inamura found no positive samples among 3 large cell and 21 small cell tumor samples. 

2. Smokers and non-smokers 

Most of the patients were non-smokers or light former smokers.  See also Soda, Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer, Nature 448, 561-566 (August 2, 2007). However, the study found "five patients had a history of more than 10 packyears including three who had smoked for at least 35 packyears."  One could not exclude smokers and testing may make sense for these group.    

10. Age

Younger patients were more likely to have the mutation

11.  EGFR and ALK

EGFR is the other prominent tyrosine kinase.  However, the groups appear to be different. 

The patient population harbouring EGFR mutations did not overlap

with that harbouring the EML4–ALK fusion gene, showing that

EML4–ALK-positive cancer is a novel subclass within NSCLC. Soda (2)

12. Testing for the ALK Fusion Mutation

The studies provide a strong argument for testing adenocarcinoma patients.  Whether  insurance will cover this, whether surgical tissue is needed, the ease and cost of testing,

are open questions. 

            A. Commercial entities performing testing

A company called Response Genetics advertises an ALK test.    www.responsegenetics.com  Another study suggests that routine laboratory testing may be able to detect the mutation:

            Low levels of ALK protein expression is a characteristic feature of ALK-   rearranged lung adenocarcinomas.  A novel, highly sensitive IHC assay   reliably detects lung adenocarcinomas with ALK rearrangements and obviates the       need for fluorescence in situ hybridization analysis for the majority of cases, and   therefore could be routinely applicable in clinical practice to detect lung cancers           that may be responsive to ALK inhibitors.  Knutsen (6) 

            B. Tissue or sample needed

Generally a tissue is secured through a biopsy which is a surgical procedure carrying some risk and some discomfort.  Studies are looking at less intrusive alternatives, For example, one study looked at obtaining EGFR mutation results from pleural fluid which would be more easily obtained.  

Knutsen suggests standard testing may be able to detect the mutation.  (3)    

13. Insurance Coverage

A powerful argument can be made for use of Crizotinib for ALK positive adenocarcinoma patients,  The impressive  response data together with other material on tyrosine kinase (Hirsch 9) presents a powerful argument for use with this subgroup.  Consistent with that, a reasonable argument can be made for testing adenocarcinoma patients. 

6. Crizotinib’s Use for ALK negative patients  

Whether Tarceva, an anti-EGFR drug is effective with EGFR negative patients has been debated here and elsewhere.  There may be similar discussion of Crizitonib, and whether this gene plays any role in patients without the ALK rearrangements. 

7. Approval and Standards

The manufacturer is apparently seeking expedited FDA approval of the drug.  Unfortunately standard practices and standard of care can lag as studies are examined.  Patients may want to look at testing, clinical trials and other alternatives. 

4. Drugs Other Thank Crizotinib

Other drugs may be developed to target the ALK mutation.  It appears Crizotinib is the only anti-ALK drug to have had a successful clinical trial.  

8. Use of Crizotinib with ALK Negative Patients

The primary focus of this new drug, and the area of impressive response is with ALK positive patients.  Interestingly , even with ALK positive patients there was a large group, 33%  for which stabile disease, but no response was reported.  Similarly with Tarceva for EGFR negative patient, the drug is justified for relieving disease and stabilizing disease.  Are the 1/3 of ALK positive patients who did not respond but apparently derived some benefit, comparable to the EGFR negative group.   

References

1. Kwak, Anaplastic Lymphoma Kinase Inhibition in Non-Small Cell Lung Cancer, Oct 28, 2010,

2. Soda, Identification of the transforming EML4–ALK fusion gene in non-small-cell

lung cancer ,  Nature, Aug. 2, 2007

3. Kimura, EGFR mutation status in tumour-derived DNA from pleural effusion fluid is a practical basis for predicting the response to gefitinib, British Journal of Cancer (2006) 95, 1390–1395.

4. Soda, A mouse model for EML4-ALK-positive lung cancer, PNAS December 16, 2008 vol. 105 no. 50 19893-19897.

5. Nelson, ALK Inhibitors: Possible New Treatment for Lung Cancer, medscape.com.

6.  Knutsen, A Novel, Highly Sensitive Antibody Allows for the Routine Detection of ALK-Rearranged Lung Adenocarcinomas by Standard Immunohistochemistry, ical Cancer Research March 2010 16; 1561

7. Sakari, EML4-ALK Fusion Gene Assessment Using Metastatic Lymph Node Samples Obtained by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration, Clinical Cancer Research October 2010 16; 4938

8. Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK, Journal of Clinical Oncology, August 10, 2009. 

9. Hirsch, The Tissue Is the Issue: Personalized Medicine for Non-Small Cell Lung Cancer, Clinical Cancer Research October 2010 16; 4909

10. Inamura, EML4-ALK Fusion Is Linked to Histological Characteristics in a Subset of Lung Cancers,  Journal of Thoracic Oncology, January 2008 - Volume 3 - Issue 1 - pp 13-17

11. Lin,  Exon Array Profiling Detects EML4-ALK Fusion in Breast,

Colorectal, and Non–Small Cell Lung Cancers, Mol Cancer Res 2009;7(9). September 2009

12. Wong, The EML4-ALK Fusion Gene Is Involved in Various Histologic Types

of Lung Cancers From Nonsmokers With Wild-type EGFR and KRAS,

13. Martelli, EML4-ALK Rearrangement in Non-Small Cell Lung Cancer and Non-Tumor Lung Tissues, American Journal of Pathology. 2009, 174:661-670.

14. Zhang, Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with

ALK expression, Molecular Cancer 2010,

15. Misudomi, Clinico-pathologic features of lung cancer with EML4-ALK translocation, Journal of Clinical Oncology, Vol 28, No 15_suppl (May 20 Supplement), 2010

References

keywords, non-smoker's lung cancer, Tarceva, EGFR inhibitor, Iressa, non-smoker lung cancer, treatment,

1. Lynch, Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib, Vol 350: 2129-2139  May 20, 2004  

2.  Pao, EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib, Proceeding National Academy of Science, NAS September 7, 2004 , vol. 101, no. 36 13306-13311. www.pnas.org.

3. Yun, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, PNAS February 12, 2008 vol. 105 no. 6 2070-2075

4. Maheswaran, Detection of Mutations in EGFR in Circulating Lung-Cancer Cells, Volume 359:366-377,
July 24, 2008  Number 4 New Eng J Med

Our book Lung Cancer and Mesothelioma (2009) is now entering its second edition.  This site contains excerpts from chapters in the Book along with articles from various sources dealing with: new treatments, gene therapy, caregiver support, insurance issues and legal questions.   

EGFR INHIBITORS TARCEVA AND IRESSA 

Tarceva and lung cancer Analysis of Tarceva, Iressa and epidermal growth factor inhibitors. Also see Iressa 
BAC and Iressa. (Discusses results with Iressa and BAC for non-smokers)
EGFR  cell test   (Review of cell tests to determine which tumors are EGFR positive and therefore responsive to Tarceva. 
Non-smoker's lung cancer (review of treatment for non-smoker's lung cancer and recent research).
HKI 272 treatment
Newsletter Overview of EGFR inhibitors
T790 mutations and pan inhibitors

keywords, EGFR, non-smoker's lung cancer, Tarceva, EGFR inhibitor, Iressa, non-smoker lung cancer, treatment,

keywords, non-smoker's lung cancer, Tarceva, EGFR inhibitor, Iressa, non-smoker lung cancer, treatment,