BRONCHIOLOALVEOLAR LUNG CANCER and TARCEVA

( keywords, BAC, Tarceva, lung cancer, BAC, epidermal growth factor receptor, Iressa, non-smoker's lung cancer, EGFR, BAC,  tarceva. bonchoalveolar cancer, treatment, second mutation,BAC, bronchioalveolar cancer  Tarceva and lung cancer, treatment for lung cancer, EGFR, epidermal growth factor, egfr antibody, egfr inhibitor,

1.0 OVERVIEW  AND CATEGORIZATION

Bronchioloalveolar lung cancer (BAC) is a type of adenocarcinoma, part of the overall category non-small lung cancer.  Traditionally the same treatment was provided to various types of non-small lung cancer.   In recent years scientists have discovered a group of BAC patients respond particularly well to epidermal growth factor inhibitors which includes the drugs Tarceva and Iressa.  See Tarceva and lung cancer   One recent study found a modest 22% overall response to the drug Tarceva but "four of five responders ... had a classic epidermal growth factor receptor tyrosine kinase mutation."  Giaccone (5).  Another study of Iressa found modest responses and that "all responders were women and/or nonsmokers with adenocarcinoma or bronchoalveolar carcinoma."

1.01 What is BAC

Bronchioloalveolar carcinoma (BAC) arises in the microscopic terminal bronchiolar and alveolar regions of the lung.   The diagnosis of BAC is generally made from a surgical specimen.  BAC represents 2 to 5% of all lung carcinoma (LC), though that percentage appears to be rising.   Garfield (13). 

1.01 Smoking History and Categorization

There is increasing evidence tying BAC type with smoking history.  There appear to be be two types of BAC, one involving non-smokers with EGFR positive status, and the other smokers who are EGFR negative:

"We demonstrated that EGFR mutations were linked to female sex, absence of smoking, late age at diagnosis, and adenocarcinoma (ADC) with bronchioloalveolar (BAC) features. Moreover, in invasive ADC with BAC component, microdissection assays showed that mutations were retrieved in both tumor subtypes suggesting that EGFR mutations appear early in lung carcinogenesis.... KRAS mutations correlated with smoking, younger age at diagnosis, and ADC subtype regardless of BAC differentiation. These results suggest the existence of distinct carcinogenesis pathways both leading to disruption of EGF regulation and targeted either by tobacco carcinogens or by unidentified toxic. ." Distinct Pathways (6)   

Non-mucinous "BAC is associated with smoking, whereas those with mucinous BAC (M-BAC) tend to be nonsmokers." Garfield (13).

1.1  BAC TREATMENT FOR EGFR POSITIVE NONSMOKERS 

1.11 Lynch and other studies. 

One important and relatively new treatment for lung cancer is a group of drugs targeting the epidermal growth factor receptor (EGFR).  "The epidermal growth factor receptor (EGFR), a member of the HER or Erb-B family of type I receptor tyrosine kinases, is implicated in the development and progression of cancer and is expressed in many human epithelial malignancies, including NSCLC.  Several small molecules have been synthesized to inhibit the tyrosine kinase domain of EGFR including gefitinib (Iressa; AstraZeneca ) and erlotinib (Tarceva; Roche Pharmaceuticals."   

The findings were not obvious or easily uncovered.  Initial studies looked at levels of EGFR expression disease and response, but the findings were inconclusive.  From the initial clinical trials of Iressa, scientists did notice that non-smokers and patients with adenocarcinoma and subtype BAC were among those who responded.  But why?  Lynch then did a groundbreaking study in Boston and painstakingly examined minute portions of genes called exons in smokers, non-smokers, and drug-responders and found the following,. "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."  Lynch (3).   The seven patients who responded had the mutation, while the eight who fail to respond did not.   The findings of this and some followup studies can be summarized:  

1) a relatively small percentage of patients have mutations in the binding portion of the EGFR.  These were primarily non-smokers and to a lesser extent, light former smokers.  These patients predominantly have adenocarcinoma or BAC, a subtype of adenocarcinima.  

2) when those patients are treated with Tarceva or Iressa, a substantial number had responses. (response defined as reduction of one half of tumor volume). This accords with cell biology, these two drugs attack the tyrosine kinase binding area where the mutations are located.  In contrast, most of the other patients, smokers, those with other types of lung cancer, did not respond and had at best stabilized disease.  (response medically is dimunition of at least 50% of tumor volume).  A few patients with the mutation even had complete responses in subsequently studies, though complete response were almost unheard of for those without the mutation. 

3) the BAC or adenocarcinoma patients who responded appear appear to have tumors that are EGFR driven and are again largely non-smokers.  They likely have limited genetic damage due to smoking and fewer genetic mutations than smokers who may have multiple areas of genetic damage. 

4) cell testing is now used to determine which patients have the mutation.

Here are some subsequent studies replicating and amplifying Lynch's findings.   

" To ascertain whether mutations within the TK domain of EGFR are associated with sensitivity to the TKI, gefitinib (Iressa), we performed mutational profiling of exons 18-24 of EGFR in tumors from 10 patients who demonstrated a partial response or marked clinical improvement when treated with the drug as a single-agent at the Memorial Sloan-Kettering Cancer Center....  Seven tumors (70%) had mutations, six of which had in-frame nucleotide deletions in exon 19 that occur adjacent to K745 encoded by nucleotides 2233-2235.  Seven of the patients who responded to Iressa had defects in the exons 18-24 area, where EGFR binding occurs (and where Iressa prevents binding), the same area discussed in the Lynch study.  Most of the patients were not smokers.  "Nine of 12 (75%) mutation-positive tumors in this study had adenocarcinoma histology and were derived from never smokers." (4). 

This makes sense.  Since non-smokers have limited exposure to carcinogens, their tumors are more likely the product of a single defect, rather than multiple ones as in other lung tumors.  "Of 139 patients, 21 (15% ), experienced a partial radiographic response. Variables identified as significant in univariate analysis included adenocarcinoma versus other NSCLC (19% v 0% ), adenocarcinoma with bronchioloalveolar features versus other adenocarcinomas (38% v 14%;), never smoker status versus former/current (36% v 8%;), and Karnofsky performance status > or =80% versus < or =70% (22% v 8%; ). " Miller (1).  The response for BAC patients was two and a half time that of other patients. 

1.12 Who are EGFR Positive

Generally EGFR positive patients are non-smokers, with a few light former  smokers.  " Interestingly, among the four tumors with the L858R mutation, three (specimens 65, 98, and 134) arose in patients with a limited exposure to cigarette smoking: all three had smoked 1 pack per day for 9 years (9 "pack years") and had quit at least 30 years before surgery. Specimen 5 was resected from an individual with a 14 pack-year history who quit 1 month before surgery. " (4) 

Nonetheless some studies have found smokers with the mutation.  Testing may make sense  for almost all patients with BAC to confirm the existence or absence of the mutation. 

1.13. Comparison to Chemotherapy  

The results are striking when compared with conventional chemotherapy.  Most studies have found that response rates with Tarceva among EGFR positive patients substantially exceed response rates from conventional chemotherapy.  Chemotherapy studies show a response rate in the 20-25% range, while EGFR patients frequently have response rates exceeding 50% sometimes reaching an astounding 75%.  .  Chang (2).    This would suggest Tarceva should become initial or first-line treatment for EGFR positive BAC patients, either alone or combined with chemotherapy.  While no one can doubt the response rates among EGFR positive non-smokers are substantially higher than conventional chemotherapy, it is not yet the acknowledged standard.

While the studies have dealt with response rates, they have not addressed survival.  While logically response should translate into increased survival that has not been conclusively shown.  Additionally, there is the unfortunate occurrence of a second Iressa-resistant mutation, arising after treatment.  Scientists need to develop a drug to combat the second mutation and/or show that even with its existence, Tarceva and Iressa increase survival.     

1.2 CONFRONTING SECOND MUTATIONS 

       1.21 The Problem of  Drug Resistance 

Patients with EGFR damages will frequently initially respond but the tumor recurs.  Scientists have found that a second EGFR pathway develops following initially successful therapy with Tarceva or Iressa. 

"Although these targeted therapies are initially effective in this subset of patients, the drugs eventually stop working, and the tumors begin to grow again. We call this acquired or secondary resistance," said Vincent A. Miller, MD, a thoracic oncologist at MSKCC and one of the study's two lead authors. "This is different from primary resistance, which means that the drugs never work at all," Dr. Miller said. The study involved six patients who had received treatment with gefitinib or erlotinib and who later developed acquired resistance. Researchers studied samples taken from the patients' tumors at different times before and during treatment. All of the tumors had the kinds of mutations in the EGFR gene that were previously associated with responsiveness to these drugs. But, in three of the six patients, they found that tumors that grew despite continued therapy had an additional mutation in the EGFR gene, strongly implying that the second mutation was the cause of drug resistance. Further biochemical studies showed that this second EGFR mutation, which was the same in all three tumors, could confer resistance to the EGFR mutants normally sensitive to these drugs. "It is especially interesting that the mutation we found is strictly analogous to a mutation that makes other kinds of tumors resistant to another targeted therapy, imatinib mesylate (Gleevec®)," said Harold Varmus, President of MSKCC and senior author of the study. "Acquired resistance to Gleevec is a well-known problem, and understanding its molecular causes has led to the design of other drugs that overcome that resistance,"  Why Some Cancers Stop Responding (62) .

These findings have been duplicated in several recent studies.  Pao (68). Yokoyama (65).

       1.22 Location of  Second Mutation at  T790M

Pao (68) writes, "We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. "  This appears to be a mutation the tumor develops in response to the administration of Tarceva or Iressa and the mutation is not found in other lung tissue or the patient's tissue before the use of Tarceva or Iressa.  How does the second mutatation work:

Panel A shows the crystallographically determined binding of erlotinib to wild-type EGFR, whereas Panel B shows how the T790M mutation leads to steric hindrance of erlotinib binding owing to the presence of the bulkier methionine side chain (orange) in the ATP-kinase–binding pocket.... This second mutation replaced threonine with methionine at position 790 (T790M) in the catalytic cleft of the EGFR tyrosine kinase domain, thereby preventing  the access of gefitinib to the gefitinib-binding site while preserving the kinase activity of the ligand after ligand stimulation. Thus, the oncogenic function of the mutated EGFR was retained, but the ability of gefitinib or erlotinib to bind to the receptor by a second mutation was lost.

Further cell study confirmed the resistance of lung cancer cells carrying the T790m mutation to Tarceva or Iressa (gefitinib)- "all four constructs carrying the T790M amino acid substitution demonstrated high-level resistance, with persistent generation of phosphorylated EGFR at concentrations of gefitinib as high as 2 µM."
Kobayashi (72)

   1.23 Addressing The Second Mutation 

The development of the second mutation allows EGFR signalling and cell duplication.    The doctor should theoretically have an easier task with a patient who initially responded to Tarceva but has now developed the second mutation.   First, testing to confirm the mutation makes sense.  Additionally pan-inhibitors can be considered for this subgroup.     

"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  While this may not be a valid alternative for many patients, it may make sense for patients whose cancers have been shown to be associated with EGFR."  Kubayashi (71)  

"Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation."

1.3  THE EPIDERMAL GROWTH FACTOR PATHWAY   

1.31   Cell Signaling  and a Basic Model of Cancer

The human body has a complex system of signaling between cells and duplication of genes is a normal part of this process.  Duplication of genes is necessary for growth, repair of damaged cells and other functions.    Proteins called growth factors signal other cells to initiate replication.  Malfunctions in these growth factors are a part of cancer, as growth factors prompt excessive duplication.  A separate type of gene called a tumor suppressor gene regulates and restricts growth, sending signals to stop duplication or initiate apoptosis, an orderly system of  cell death.    A basic model of cancer suggests it is is a product of abnormal growth factors prompting duplication of cells and the failure of tumor suppresor genes to properly regulate them.  

A sophisticated model suggests cancer represents a complex system of many growth factors, multiple tumor suppresor genes, and damage to other cellular regulators.   As we enter the 21st century we are learning that both models may be correct for different types of cancers- there are simple cancers with limited and identifiable growth factor abnormalities with complex ones like lung cancer have numerous contributing factors.  In the 60's and 70th, we learned that cancers acted differently depending upon their site; today we know that lung cancer involves multiples types cancers, some of which respond  differently to treatment than others.   We now look to one important growth factor, (EGF) and its treatments.  

1.32  Epidermal Growth Factor                             

Epidermal Growth Factor (EGF) plays a role in normal human development helping to repair damaged tissue and develop lungs in fetuses.  Klein (49).   When glands associated with the epidermal growth factor were removed from pregnant mice, scientists found increased mortality and reduction of milk production.  Britannica (36).   EGF is expressed in many tumors.  To initiate cell reproduction, a growth factor links with an associated receptor, like a lock and key.  EGF links with EGFR, the epidermal growth factor receptor.   

1.32 Epidermal Growth Factor Receptor

In recent months, the receptor rather than the growth factor itself has become the target of new drugs.  "The epidermal growth factor receptor (EGFR) signaling pathway is one of the most important pathways that regulate growth, survival, proliferation, and differentiation in mammalian 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) .  See also (Baselga 24).   
   

1.33  Structure of EGFR

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.  Dowell (71).

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. 

1.34 Expression of Epidermal Growth Factor and Lung Cancer

"The high level of expression of the EGFR on non small cell lung cancer (NSCLC) and the important role of EGFR in signal transudation make it potentially an excellent target for antibody directed therapy." Zhonghua (20).   One report found overexpression of EGF in 50% of lung adenocarcinomas, while another study found EGFR expression in 94 of 169 (56%) non small cell cases. Pass (3), Cox (4)

1.4 EPIDERMAL GROWTH FACTORS COMBINED WITH CHEMOTHERAPY AND RADIATION

1.41 Clinical Trials Using Iressa and Chemotherapy

Two large scale clinical trials found Iressa did not improve the effects of chemotherapy.  (50).  The well-publicized clinical trial compared patients who took chemotherapy and Iressa with those who took chemotherapy alone.  

1.5 DIFFERENT MEASUREMENTS FOR EGFR

1.51 Harvard EGFR Study and Tyrosine Kinase

The classic and it appears most important test is ascertaining mutations in the tyrosine kinase portion of the EGFR.  "Reports have instead turned attention to specific missense mutations and deletions in the tyrosine kinase domain of the EGFR gene, which are highly associated with gefitinib response."   This is the Harvard EGFR test, a specialized test.    Here is one summary of some important tests. Johnson (9)

We see Takano found an astounding 82% response rate amount EGFR positive patients. Takano (10).  In contrast, the response rates were below 12% in those lacking the mutation. Survival rates were substantially more in the EGFR positive group.  2 EGFR positive patients (not shown) had complete responses in the Takano study, while none outside the group did. 

        1.511 Location of Deletions - Exon 19

"We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months; P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion." Jackman (11)

1.52 Gene Copy Number (FISH)

While the Harvard EGFR test seems to be the most reliable indicator of response, other measurements are possible.  Indeed, studies have found some sporadic response amoung EGFR negative patients, and a greater number of stabilized disease.  Takano found EGFR copy number to be another independent predictor of gefitinib sensitivity. It is noteworthy that an increased EGFR copy number was observed in two of the three responders with wild-type EGFR, and was significantly associated with a longer TTP among patients with wild-type EGFR." Takano (10)

Hirsch writes,

"the low frequency of these mutations (four of 81 standard EGFR test) in United States lung cancer patients who are current or former smokers, and the results of the BR21 study described above, suggest that a substantial subset of patients without these mutations also derive a survival benefit. Furthermore, although these activating mutations identify patients with high response rates, they cannot account for the high stable disease rates, reported to occur in approximately 30% of NSCLC patients treated with gefitinib.  Increased EGFR gene copy number detected by fluorescence in situ hybridization (FISH) is associated with a poor prognosis in NSCLC, similar to the assessment of HER2 by FISH in breast cancer patients.  Moreover, among patients with breast cancer, FISH is reported to be a more reliable predictor of treatment benefit with the HER2 inhibitor trastuzumab (Herceptin; Genentech, San Francisco, CA) than is protein expression by IHC, especially in the patients with intermediate protein expression (2+)^.   We have previously evaluated EGFR gene copy number in a cohort of 102 NSCLC patients treated with gefitinib and found high copy number or gene amplification in approximately 30% and a significant correlation between gene EGFR gene status and outcome  "  (Hirsch (8). 

            1.521 Efficacy of Fish

While direct measurement of EGFR mutations in the tyrosine kinase seems to be a reliable indicator of response, the figures on Fish are less clear.  Hirsch's study found a correlation: 

"This study demonstrates that increased EGFR gene copy number detected by FISH is associated with improved survival after gefitinib therapy in patients with advanced-stage BAC and adenocarcinoma with BAC features, a subset of NSCLC that may serve as a model for study of EGFR pathways because of its underlying biologic characteristics.³¹ In the current study, approximately one third of the patients had increased EGFR gene copy number, and these patients also had a trend for higher response rates and a longer time to progression after gefitinib therapy."  (Hirsch 8).  "Dr Hirsch and colleagues have provided data on the impact of EGFR copy number assessed by FISH on a subset of 81 patients from a trial of 136 patients with BAC treated with gefitinib on a Southwest Oncology Group trial.  This study showed that patients with EGFR FISH-positive tumors have two-fold increases in their partial response rate, median progression-free survival, and overall survival than those with FISH-negative tumors." Johnson (9). 

On the other hand, a recent study found no correlation between gene copy number, response or survival in patients previously treated with chemotherapy.

            1.522 Applicability to Smokers

Fish still appears less accurate than the Harvard EGFR test.  As pointed out, the Harvard test targets only a small percentage of patients, primarily non-smokers.  Outside this group, Fish may provide some guidance about when Tarceva would be useful for smokers. Smokers may want to take the Fish test.

References

1. Miller, Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer, J Clin Oncol. 2004 Mar 15;22(6):1103-9.

2. Chang, Successful treatment of multifocal bronchioloalveolar cell carcinoma with ZD1839 (Iressa) in two patients, J Formos Med Assoc. 2003 Jun;102(6):407-11.

3. Lynch, Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib, Volume 350:2129-2139, May 20, 2004 (full text available online) http://content.nejm.org/cgi/content/full/350/21/2129

4. 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, http://www.pnas.org/cgi/content/full/101/36/13306 

5. Giaccone, Erlotinib for Frontline Treatment of Advanced Non-Small Cell Lung Cancer: a Phase II Study.Clin Cancer Res. 2006 Oct 15;12(20):6049-55

6. Epidermal growth factor receptor mutation in lung cancer are linked to bronchioloalveolar differentiation. Am J Surg Pathol. 2006 Oct;30(10).

7. Reck, Gefitinib Monotherapy in Chemotherapy-Naive Patients with Inoperable Stage III/IV Non-Small-Cell Lung Cancer, Clin Lung Cancer. 2006 May;7(6):406-11

8. Hirsch,  Increased Epidermal Growth Factor Receptor Gene Copy Number Detected by Fluorescence In Situ Hybridization Associates With Increased Sensitivity to Gefitinib in Patients With Bronchioloalveolar Carcinoma Subtypes: A Southwest Oncology Group Study, Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 6838-6845

9. Johnson, Selecting Patients for Epidermal Growth Factor Receptor Inhibitor Treatment: A FISH Story or a Tale of Mutations? Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 6813-6816.

10. Takano, Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non–Small-Cell Lung Cancer, Volume 23, Number 28, Ocotber 1, 2005, Journal of Clinical Oncology. 

11. Jackman, Exon 19 Deletion Mutations of Epidermal Growth Factor Receptor Are Associated with Prolonged Survival in Non–Small Cell Lung Cancer Patients Treated with Gefitinib or Erlotinib, Clinical Cancer Research Vol. 12, 3908-3914, July 1, 2006

12. Dziadziuszko,  Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non-small-cell lung cancer patients treated with chemotherapy.Ann Oncol. 2006 Nov 2;

13.  Garfield, The Bronchioloalveolar Carcinoma and Peripheral Adenocarcinoma Spectrum of Diseases, Journal of Thoracic Oncology: Vol. 1(4) May 2006pp 344-359


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