CHAPTER 29: NON-SMOKER’S LUNG CANCER
keywords, cancer lung non-smoker, Tarceva, non-smoker's lung cancer,
why do non-smokers get lung cancer, .
29.1 CHARACTERISTICS AND DISTINGUISHING FEATURES
While lung cancer is usually associated with smoking, an estimated 10% of cancer
patients have no smoking history. Recent studies show their non-smoker's
has several distinct characteristics:
1) EGFR (epidermal
growth factor receptor) plays a critical role in the developement of their
tumors. Many non-smokers are likely to be EGFR positive.
2) EGFR positive
patients show signficant response rates to Tarceva. Response rates
(elimination of at least one half the tumor) are in the 60% range, almost triple
the 20-25% response rate of conventional chemotherapy. Many EGFR positive
patients will show impressive initial response rates to Tarceva with the drug
even sometimes eliminating multi[ple areas of metastasis. Whether used alone,
with chemotherapy or following chemotherapy, Tarceva should be considered as a
part of the drug regimen.
3) Many EGFR
positive non-smokers will show impressive initial response rates but experience
remission. One culprit appears to be the T790M mutation. Newer
pan-inhibitors like HKI 272, CI 1033 are showing success in combating T790 in
cell studies with human trials ongoing. Since they are not showing
tremendous success outside the EGFR positive patient area, interest has slowed,
and the patient may have to search for clincial trials. See Engelman,
PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer
Models with EGFR and ERBB2 Mutations that Are Resistant to
Gefitinib, Cancer Research 67, 11924-11932, December 15, 2007
29.11 Areas of Genetic Damage
The initial research found non-smokers with lung cancer have damage to the
tyrosine kinase area of the epidermal growth factor receptor (EGFR).
Lynch's seminal study found that this damage predicted response to Iressa, and
was found almost exclusively in non-smokers and light former smokers. Lynch (1).
"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. (Iressa) 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). Eight of nine patients who
responded to Iressa had specific identifiable tyrosine kinase damage.
These results can be contrasted with smokers' lung cancer. After
finding mutations in exons 19 and 21 of the EGFR in the non-smokers who
responded to Iressa, Lynch then tested samples from other lung tumors.
"We sequenced exons 19 and 21 in a total of 95 primary tumors and 108
cancer-derived cell lines, representing diverse tumor types. No
mutations were detected, suggesting that only a subgroup of cancers,
in which EGFR signaling may play a critical role in tumorigenesis,
harbor EGFR mutations. Lynch (1). Subsequent studies
replicated Lynch's findings. Pao (4).
With an identifiable genetic component prompting growth, non-smoker's lung cancer
may be easier to treat. Rather than threading the way through
multiple growth factors and tumor suppressor
genes, we may have only a few areas to address.
29.12 Adenocarcinoma and Bronchioloalveolar Lung Cancer
These non-smokers generally have adenocarcinoma and bronchioloalveolar lung
cancer (BAC). Lynch (1).
29.13 Iressa (Gefitinib) and Epidermal Growth Factor Inhibitors
Iressa suppresses chemical reactions leading to cancerous signaling in the
tyrosine kinase part of the epidermal growth factor receptor.
"Gefitinib targets the ATP cleft within the tyrosine kinase epidermal
growth factor receptor (EGFR), which is overexpressed in 40 to 80
percent of non–small-cell lung cancers and many other epithelial
cancers." Lynch (1)
Iressa and Tareva are
drugs designed for the BAC or adenocarcinoma egfr tyrosine kinase driven lung
cancer many non-smokers have. “Patients with non–small-cell lung cancer who had
striking responses to gefitinib had somatic mutations in the EGFR gene that
would indicate the essential role of the EGFR signaling pathway in the tumor.”
Lynch (1). "Gefitinib (Iressa) and erlotinib (Tarceva) induce dramatic
clinical responses in cases of non-small cell lung cancers (NSCLCs) harboring
activating mutations in the EGF receptor (EGFR)." Many of the responders to Iressa are nonsmokers with BAC or
29.14 Implications for Treatment
Smoking history should be a part of medical history and be considered in
formulating treatment plans. We are at the point of contouring treatment plans
depending upon the type of disease, smoking history, cell studies, and other
29.15 Brain Metastases and Iressa
Some recent studies have suggested that Iressa alone can provide relief to nsclc
patients with cranial metastases. Ishida (5). One study testing Iressa reported,
“A disease control rate of 46% (objective response rate 8.7%) and 1-year
survival of 29% were documented. Histology (adenocarcinoma) and a
"never-smoking" history were predictive of response. “ Iressa is being tested as
first line treatment, with chemotherapy, or after chemotherapy for patients with
29.2 DEALING WITH ACQUIRED DRUG RESISTANCE
29.21 The Problem
Some tumors respond to chemotherapy but after a period the therapy stops
working. The phenenomenon is sometimes called MDR or multi-drug
resistance. The tumor basically acquire a mechanism to evade the
cell-killing chacteristics of chemotherapy or receive other signals contrary to
A similar phenomenon occurs with Iressa and Tarceva :
"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. Tumor cells from a sixth patient with a drug-sensitive EGFR
mutation whose tumor progressed on adjuvant gefitinib after complete resection
also contained the T790M mutation. This mutation was not detected in untreated
tumor samples. Moreover, no tumors with acquired resistance had KRAS
mutations, which have been associated with primary resistance to these drugs.
Biochemical analyses of transfected cells and growth inhibition studies with
lung cancer cell lines demonstrate that the T790M mutation confers resistance to
EGFR mutants usually sensitive to either gefitinib or erlotinib." Pao (11)
"Gefitinib and erlotinib induce dramatic clinical responses in cases
of non-small cell lung cancers (NSCLCs) harboring activating
mutations in the EGF receptor (EGFR) (, which is targeted by these
competitive inhibitors of ATP binding . The effectiveness of these
tyrosine kinase inhibitors may result both from alterations in the
ATP cleft associated with these mutations, which lead to enhanced
inhibition of the mutant kinase by these drugs, and from biological
dependence of these cancer cells on the increased survival signals transduced by the mutant receptors, a phenomenon described as
“oncogene addiction”. Although therapeutic responses to both
gefitinib and erlotinib can persist for as long as 2–3 years, the
mean duration of response in most cases of NSCLC is only 6–8 months
." Kwak (7)
29.211 T790 Mutation
The T790 mutation apparently develop in response to Iressa treatment
and allows cancer type signalling and resistance to the drug.
"the T790M mutation confers drug resistance not just to
wild-type EGFR but also to mutant EGFRs associated with
clinical responsiveness to EGFR tyrosine kinase
inhibitors . Our results further demonstrate that an
analogous mechanism of acquired resistance exists for
imatinib and EGFR tyrosine kinase inhibitors
despite the fact that the various agents target
different kinases in distinct diseases.... The T790
mutation appears In tumors from patients not treated
with either gefitinib or erlotinib, the 2369 C→T
mutation (T790M) appears to be extremely rare. We have
not identified this mutation in 155 tumors (see above),
and among nearly 1,300 lung cancers in which analysis of
EGFR exons 18 to 21 has been performed."
There are a variety of possible approaches.
Initially a drug that could target T790M specifically is
possible, but does not appear to be available.
See Ihle (12)
We look below at two approaches with drugs available or
in clinical trials.
29.22 Erb-2 Inhibitors
Complimenting Iressa with other EGFR inhibitors is one approach. EGFR
is part of the ERB family, and is also known as Erb1. Drugs have targeted
ERb2, and signalling occurs between Erb1 and Erb2. Herceptin is a
well-known drug used principally for breast cancer which inhibits ERB2.
Henson (8). Kwak (7) explains, "Knockdown of ERBB2 in NCI-H1650 and
its gefitinib-resistant derivatives also caused loss of viability suggesting a
role for EGFR–ERBB2 heterodimers in transducing essential survival signals in
tumor cells harboring
EGFR mutations. "
29.23 Irreversible Inhibitors
Like most gene associated with cancer, Erb1 has a role in normal tissue
functioning. Drugs like Iressa and Tarceva have relatively limited side
effects and are reversible upon cessation of treatment. A more
dramatic approach is to permanently suppress functioning of EGFR. This
approach makes sense if it appears EGFR is playing a significant role in the
cancer, and Iressa or Tarceva have stopped working on a patient with
advanced life-threatening metastatic cancer. Kwak's cell study indicates
the effectiveness of such drugs:
"Inhibition of EGFR alone by an irreversible inhibitor seems to be
sufficient to induce apoptosis (cell death) in gefitinib resistant cells, as
demonstrated by the effectiveness of EKB-569, which primarily targets EGFR....
Both HKI-357 and HKI-272 were considerably more
effective than gefitinib in suppressing ligand-induced EGFR autophosphorylation
and its downstream signaling, as determined
by AKT and MAPK phosphorylation (Fig. 4A). Similarly, all three irreversible
inhibitors suppressed proliferation
in this cell line under conditions where it is resistant to gefitinib (Fig. 4B).
Thus, irreversible ERBB inhibitors seem to
be effective in cells harboring the T790M EGFR as well as in cells with altered
trafficking of the wild-type receptor. " Kwak (7) See Rabintran (9)
for prior studies with HKI 272.
A clinical trial will be testing the drug. Wyeth (10).
keywords, cancer lung non-smoker, non-smoker's lung cancer,
why do non-smokers get lung cancer, non-smoker's lung cancer, non-smoker's lung
29.31 Harvard EGFR Test
Lynch provided the initial research on EGFR at Harvard and Massachusetts
General Hospital, and helped formulate a test which detects the EGFR damage
which predicts response to Iressa and Tarceva:
"The Harvard Medical School - Partners HealthCare Center for Genetics and
Genomics (HPCGG) has begun to offer a test that gives doctors a valuable new
tool to guide the treatment of certain lung cancers.
The test – known as EGFR Kinase Domain Sequencing – was developed in
cooperation with the pathology laboratories of Brigham and Women’s Hospital and
Massachusetts General Hospital, and detects mutations in a critical part of the
gene called epidermal growth factor receptor (EGFR). The gene mutation is
present in a subset of non-small cell lung cancers, most commonly
adenocarcinomas and bronchoalveolar carcinomas arising in nonsmokers. When the
mutation is present, it is associated with a response to the anti-cancer drug
Iressa (gefitinib). Iressa works by blocking the function of the mutant EGFR
protein that these cancer cells need to survive and proliferate.
Last April, two teams of investigators – one led by Thomas Lynch, MD, and Daniel
Haber, MD, PhD, at Massachusetts General Hospital, and one by Bruce Johnson, MD,
William Sellers, MD, and Matthew Meyerson, MD, PhD, at the Dana-Farber Cancer
Institute – discovered the molecular marker that identifies lung cancer patients
whose tumors will respond to Iressa. Until then, doctors had been unable to
understand why Iressa caused tumors to shrink significantly in only 13.6 percent
of patients, even though some of those responses were rapid and dramatic. The
discovery of the EGFR mutation provided the answer.
Now, less than six months after the gene mutation discovery, the HPCGG
Laboratory has prepared a molecular test to screen lung cancer tumors for the
mutation. The test, which takes approximately two weeks to complete, involves
extracting DNA from a tumor tissue sample. The test is significant because it
gives doctors the information they need to decide which patients may benefit
from Iressa at the earliest possible time, within weeks of diagnosis."
29.32 Cost and Insurance
The test costs approximately 850. A reasonable argument can be made
that this amount should be covered by insurance, where a physician prescribed
Many insurers have particular laboratories. However, because this is a
new test, few will have comparable facilities.
The test is useful to both include and exclude patients. The value of
Iressa or Tarceva outside the target group is at best debatable. There is
little reliable evidence to show its benefits outside this group. A few
studies have found people outside the target group who may benefit, and there
was some evidence of disease stabilization even in those that do not response.
29.4 EGFR SCIENCE
29.41 Location of EGFR
Recent studies indicate the importance of identifying specific areas of
genetic damage in cancer. Scientists have created a genetic map
identifying specific locations for genes. EGFR is located at
That means it is located on chromosome 7,
29.42 Family of Genes
EGFR is part of the ERB family of tyrosine kinase receptors. EGFR is
also called Erb1. The family comprises Erb1, Erb2 (responsive to
Herceptin), Erb3, and Erb 4.
Growth factors initiate their process by binding to and activating
cell-surface receptors with tyrosine kinases. EGFR is a receptor comprised of three basic parts: extracellular region, ligand-binding
region, and tyrosine kinase.
29.431 Extracellular Ligand Binding Domain of the EGFR
The title is descriptive; this is a portion of the EGFR which lies outside
the tyrosine kinase region. Here is where binding occurs, where the growth
factor meets the receptor.
29.432 Tyrosine Kinase Region
Once binding occurs a signal is sent to the tyrosine kinase. The
binding of growth factors (GFs) to receptor tyrosine kinases (RTKs) activates
RTK activity and initiates the formation of several protein complexes
The receptors’ intrinsic tyrosine kinase activity phosphorylates tyrosine
amino acid residues in both receptors
It then signals other genes.
29.44 Function of EGFR
This receptors plays a role in the control of cellular activities
including cell division, differentiation, and migration. "The epidermal
growth factor receptor (EGFR) is a cell surface receptor that directs the
initiation of processes such as growth, proliferation, apoptosis, adhesion,
migration, and differentiation, when it is activated by specific growth factors.
Overexpression, or increased abundance, of EGFR has been reported in numerous
29.45 Role in Cancer
Overexpression or dysregulation of the EGFR family members has
been implicated in a variety of human cancers. Klein 16, Genetic Map 14.
29.46 Associated Growth Factors
It would be easy to say that EGFR links with its associated growth factor
Epidermal Growth Factor. However, when it links with EGF it is also linked
with Transforming Growth Factor, and potentially others.
Cox-2 has been associated with carcinogenic processes and EGF is linked with
keywords, cancer lung non-smoker, non-smoker's lung cancer,
why do non-smokers get lung cancer, non-smoker's lung cancer.
1. 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).
2. 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.
3. Chang, Successful treatment of multifocal bronchioloalveolar cell carcinoma
with ZD1839 (Iressa) in two patients, J Formos Med Assoc. 2003
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. www,pnas.org.
5. Ishida, Gefitinib as a first line of therapy in non-small cell lung cancer
with brain metastases, Intern Med. 2004 Aug;43(8):718-20
6. Haringhuizen, Gefitinib as a last treatment option for non-small-cell lung
cancer: durable disease control in a subset of patients, Ann Oncol. 2004
7. Kwak, Irreversible inhibitors of the EGF receptor may circumvent acquired
resistance to gefitinib, Proc Natl Acad Sci U S A. 2005 May 24; 102(21):
7665–7670 (full-text available online).
8. Henson, Herceptin Sensitizes ErbB2–Overexpressing Cells to Apoptosis by
Reducing Antiapoptotic Mcl-1 Expression Clinical Cancer Research Vol. 12,
845-853, February 2006
9. Rabintran, Antitumor Activity of HKI-272, an Orally Active, Irreversible
Inhibitor of the HER-2 Tyrosine Kinase Cancer Research 64, 3958-3965,
June 1, 2004
10. Wyeth Laboratories, Study Evaluating the Safety of HKI-272 in Subjects With
Advanced Non-Small Cell Lung Cancer, ClinicalTrials.gov Identifier: NCT00266877
11. Pao, Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib
Is Associated with a Second Mutation in the EGFR Kinase Domain, PLoS Med. 2005
March; 2(3): e73.
12. Ihle, The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes
resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549
human non–small cell lung cancer xenografts Mol Cancer Ther. 2005;4:1349-1357
13. ww.FDA.gov Food and Drug Administration Center for Drug Evaluation and
Research Oncologic Drugs Advisory Committee Meeting- Iressa March 4, 2005
14. OMIM Genetic Map,
16. Klein, A structure-based model for ligand binding and dimerization of
EGF receptors, PNAS | January 27, 2004 | vol. 101 | no. 4 | 929-934
17. Ludwig Institute for Cancer Research www.licr.org/D_programs/d2a1a_EGFR.php
Comments or questions about this article are welcome. Email
keywords, cancer lung non-smoker, epidermal growth factor
inhibitor, non-smoker's lung cancer,
Iressa, Tarceva, why do non-smokers get lung cancer, resistance and Iressa,
Tarceva and lung cancer, treatment
resistance and non-smoker's lung cancer.
Above is an expanded version of portions of our book dealing with lung cancer.
(Please note that the author is not a doctor)
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