Gefitinib response of erlotinib-refractory lung cancer involving meninges - Role of EGFR mutation

Abstract

A 70-year-old Japanese-American woman who had never smoked was diagnosed with stage IV non-small-cell lung cancer with rib metastases. She had previously been well and she had no family history of malignancy. While receiving treatment with erlotinib, an epidermal growth factor receptor small-molecule inhibitor, she progressed and developed new brain metastases. She failed further chemotherapy treatments and subsequently developed extensive symptomatic leptomeningeal carcinomatosis associated with diplopia, hemiparesis, weight loss, and incontinence.
Chest X-ray, head and chest CT scan, R2 lymph-node biopsy, histopathology, immunohistochemistry, MRI of head and spine, lumbar puncture, laser microdissection and EGFR genomic DNA sequencing of the R2 lymph node and cerebrospinal fluid tumor cells.
Erlotinib-refractory stage IV lung adenocarcinoma and end-stage symptomatic leptomeningeal metastases with a novel double L858R + E884K somatic mutation of the EGFR.
Carboplatin, paclitaxel and erlotinib, whole-brain radiotherapy, temozolomide with and without irinotecan, and gefitinib.

Full text

CASE STUDY
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Gefitinib response of erlotinib-refractory lung
cancer involving meninges—role of EGFR mutation
Nicholas W Choong†, Sascha Dietrich†, Tanguy Y Seiwert, Maria S Tretiakova, Vidya Nallasura,
Gareth C Davies, Stanley Lipkowitz, Aliya N Husain, Ravi Salgia and Patrick C Ma*
This article offers the opportunity to earn one
Category 1 credit toward the AMA Physician’s
Recognition Award.
THE CASE
A 70-year-old Japanese-American woman,
who had never smoked, was diagnosed with
T2N2M1 stage IV non-small-cell lung cancer
(NSCLC) with rib metastases in April 2002.
She had initially presented to her primary-
care physician in December 2001 with a cough
of several months’ duration. She lost 3.6 kg
over 6 months and weighed 41 kg at presenta-
tion. She was otherwise healthy with no family
history of malignancy. A chest X-ray performed
in February 2002 showed a right hilar mass.
In March 2002, a chest CT confirmed a right
middle lobe mass, measuring 5 × 6 cm, and
enlarged hilar and mediastinal lymph nodes. A
bone scan 8 days later showed multiple rib meta-
static foci. The patient underwent bronchoscopy
and mediastinoscopy in April 2002, and biop-
sies of two involved R2 lymph nodes confirmed
adenocarcinoma (Figure 1A). Histopathologic
and immunohistochemical examination of
this biopsy specimen revealed strong positive
staining for cytokeratin 7 and thyroid tran-
scription factor-1 (data not shown). Epidermal
growth factor receptor (EGFR) expression
was strongly positive and predominantly
membranous (Figure 1A, inset).
The patient was immediately referred to the
chest oncology clinic of a large cancer center in
the US midwest. Her physical examination and
laboratory findings were unremarkable. She
was enrolled in a phase III clinical trial and
received first-line treatment with carboplatin
(area under the curve 6) and paclitaxel
(200 mg/ m2 every 3 weeks). She was also rand-
omized to receive concurrent erlotinib (150 mg
daily).1 She completed six cycles of this therapy
and attained a maximal tumor reduction of
42%. After 11 months of single-agent erlotinib
and disease stabilization, however, she
developed ataxia and leg weakness. An
Background A 70-year-old Japanese–American woman who had never smoked
was diagnosed with stage IV non-small-cell lung cancer with rib metastases. She
had previously been well and she had no family history of malignancy. While
receiving treatment with erlotinib, an epidermal growth factor receptor small-
molecule inhibitor, she progressed and developed new brain metastases. She
failed further chemotherapy treatments and subsequently developed extensive
symptomatic leptomeningeal carcinomatosis associated with diplopia,
hemiparesis, weight loss, and incontinence.
Investigations Chest X-ray, head and chest CT scan, R2 lymph-node
biopsy, histopathology, immunohistochemistry, MRI of head and
spine, lumbar puncture, laser microdissection and EGFR genomic DNA
sequencing of the R2 lymph node and cerebrospinal fluid tumor cells.
Diagnosis Erlotinib-refractory stage IV lung adenocarcinoma and
end-stage symptomatic leptomeningeal metastases with a novel double
L858R + E884K somatic mutation of the EGFR.
Management Carboplatin, paclitaxel and erlotinib, whole-brain
radiotherapy, temozolomide with and without irinotecan, and gefitinib.
KEYWORDS epidermal growth factor receptor, leptomeningeal
carcinomatosis, lung cancer, mutation, small-molecule inhibitor
CME
NW Choong and TY Seiwert are Fellows in the Section of Hematology–Oncology,
MS Tretiakova is a research pathologist in the Department of Pathology,
V Nallasura is a senior research assistant in the Aerodigestive Tract Translational
Research Laboratories, AN Husain is Professor of Pathology, and R Salgia is
Associate Professor of Medicine and Director of the Thoracic Oncology Research
Program at the Pritzker School of Medicine, all at the University of Chicago,
Chicago, IL, USA. S Dietrich is a final year medical student and PhD candidate
from the University of Jena, Germany, and an elective research fellow in the
Thoracic Oncology Research program at the University of Chicago, Chicago, IL,
USA. GC Davies is a visiting Fellow, and S Lipkowitz is an investigator in the
Laboratory of Cellular and Molecular Biology at the National Cancer Institute,
Bethesda, MD, USA. PC Ma is Assistant Professor of Medicine and clinician–
scientist in the Thoracic Oncology Program, Case Western Reserve University and
Case Comprehensive Cancer Center, Cleveland, OH, USA.
Correspondence
*Division of Hematology–Oncology, Case School of Medicine, Case Western Reserve University,
University Hospitals of Cleveland and Ireland Cancer Center, Case Comprehensive Cancer Center,
Wolstein Research Building WRB 2-123, 10900 Euclid Avenue, Cleveland, OH 44106, USA
patrick.ma@case.edu
†Both authors contributed equally to this work
Received 23 October 2005 Accepted 16 November 2005
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doi:10.1038/ncponc0400
SUMMARY
50 NATURE CLINICAL PRACTICE ONCOLOGY JANUARY 2006 VOL 3 NO 1
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investigative head CT scan showed new
multiple brain metastases in her right cere-
bellum and left parietal lobe. Erlotinib was
stopped, and in November 2003 the patient
underwent standard whole-brain radiation
therapy. Thereafter, she was enrolled in a phase
II trial of combination oral temozolomide
(75 mg/m2 daily on days 1–15) and intravenous
irinotecan (100 mg/m2 on days 8 and 15 in a
21-day cycle); this therapy was not tolerated,
and was dis continued after one cycle because
of severe diarrhea and dehydration. The patient
then remained clinically stable, off chemo-
therapy, until August 2004 when she developed
new-onset hemiparesis associated with radic-
ular pain in her left leg, left-gaze diplopia, and
incontinence of the bowel and bladder. She
became wheelchair-bound as a result of
I II III
TT
F
Forward Forward
Reverse
Involved R2 lymph node
G L858R A K
TTGGGCTGGCCAAAC TGGCAT TGGAATC
A L E884K S I
AA T T
A
B
C
TT
F
Metastatic CSF tumor cells
G L858R A K
TTGGGCTGGCCAAAC TGGCAT TGGAATC
A L E884K S I
AA T T
TT
F
Wild-type EGFR (CSF leukocytes)
G L858 A K
TTGGGCTGGCCAAAC TGGCAT TGGAATC
A L E884 S I
AA T T
Forward Forward
Forward Forward
Reverse
Reverse Reverse
Reverse Reverse
Figure 1 Lung adenocarcinoma tumor cells and EGFR somatic mutations. (A) Hematoxylin and eosin staining of lung
adenocarcinoma in the involved mediastinal R2 lymph node at time of diagnosis, demonstrating the typical acinar pattern of
glandular differentiation (upper panel). Intense EGFR staining of the adenocarcinoma tumor cells (inset). Laser microdissection of the
tumor cells in the lymph node is shown (lower panels) with digital micrographs taken before (I, left), during (II, middle) and after (III,
right) the UV laser firing. Magnification ×200. (B) Cerebrospinal fluid (CSF) with non-small-cell lung cancer tumor cell (black arrow)
and normal leukocyte (arrow outline) identified. Magnification ×400. (C) Chromatogram of the EGFR DNA sequencing, showing
missense mutations L858R (CTG→CGG, heterozygous) in exon 21 and E884K (GAA→AAA, heterozygous) in exon 22 seen in the
involved R2 lymph node (top panel) and also in the metastatic CSF tumor cells (middle panel). Wild-type EGFR sequence seen in
normal leukocytes isolated from CSF (bottom panel) is shown as a control, and confirms the somatic nature of L858R and E884K
mutations. Presence of the two mutations was confirmed in both tumor samples by reamplification and sequencing in both sense
(Forward) and antisense (Reverse) directions.
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weakness in her left leg (quadriceps strength
grade 1/5). CT scan showed that her brain
metastases and pulmonary disease (Figure 2A)
burdens were unchanged, with no mass effect
and little interval progression since her last
completed therapies. Brain MRI in August 2004
showed postradiation therapy changes in the
peri ventricular white matter. There were subtle
areas of leptomeningeal enhancement in the
posterior fossa suggestive of leptomeningeal
carcinomatosis. Spine MRI ruled out the possi-
bility of spinal-cord compression, but revealed
extensive spinal leptomeningeal metastases
with multiple well-demarcated intrathecal
isointense masses that demonstrated intense
enhancement with contrast administration,
consistent with drop metastases. The disease
was predominantly localized to the lumbar
region surrounding the cauda equina, and was
shown to have worsened on the MRI in October
2004 (Figure 3A,B), despite two cycles of
single-agent oral temozolomide (150 mg/m2 on
days 1–5 in a 28-day cycle). The patient had
declined lumbar puncture and intrathecal
chemotherapy.
Gefitinib (250 mg daily) was initiated in
October 2004, and the patient experienced
significant symptom improvement within
3 weeks. She started gaining weight, the pain in
her leg improved, she was able to move her left
leg and her diplopia also improved. The patient
then received follow-up consultations in the
clinic every 1–2 months. After 6 weeks on gefit-
inib, she was able to ambulate with walker assist-
ance, her diplopia and incontinence completely
resolved, and muscle strength in her left quad-
riceps improved to grade 4/5. Brain and spine
MRI showed a dramatic decrease in meningeal
ABC
Figure 2 Response to gefitinib in the primary tumor and thoracic involved lymph nodes. CT scan of the
chest (A) prior to gefitinib, (B) 2 months after starting gefitinib, and (C) 4.5 months after starting gefitinib,
demonstrating reduction in the size of the involved lymph node (white arrow) and the right middle lobe
tumor (arrow outline).
ABCD
Figure 3 Response to gefitinib in extensive leptomeningeal carcinomatosis. MRI scan of the lower
thoracic and lumbar spine (A,B) prior to starting gefitinib, and (C,D) 2 months after gefitinib monotherapy,
demonstrating a dramatic reduction in the number and enhancement of leptomeningeal metastases (solid
white arrows), correlating with the positive clinical response.
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enhancement and nodular tumor mass burden
(Figure 3C,D) after only 6 weeks of gefitinib
therapy. Analysis of cerebrospinal fluid (CSF)
confirmed the presence of residual metastatic
NSCLC cells (Table 1; Figure 1B). Her right
middle lobe mass had decreased from 2.2 cm to
1.5 cm in the short axis over the first 2 months,
and it continued to respond on subsequent
evaluations. Hilar and media stinal lymph nodes
showed a similar response (Figure 2A–C).
At a follow-up visit 4 months after starting
gefitinib, the patient’s neuro logical exami-
nation showed further improvement, and
she was ambulating independently with a
walker. Six months after starting gefitinib,
her ECOG (Eastern Cooperative Oncology
Group) performance status improved from 4
to 2. No significant adverse effects—specifically
diarrhea, rash, or interstitial pneumonitis—
were reported. Unfortunately, 8 months after
initiating gefitinib, the patient had a witnessed
food aspiration with resultant acute respiratory
distress. She died of aspiration pneumonia in
June 2005, 7 days after hospital admission.
DISCUSSION OF DIAGNOSIS
Multifocal seeding of the arachnoid membrane
and pia mater by metastatic tumor cells is known
as leptomeningeal carcinomatosis. Brain paren-
chymal metastases occur in 30% of NSCLC
patients, while leptomeningeal carcinomatosis
occurs in only 5%.2 Leptomeningeal carcinoma-
tosis carries a devastating prognosis and often
represents a terminal event,3 with a median
survival of 1.8 months in NSCLC, even with
active treatment.4 As improved therapies have
created a trend towards prolonged survival, the
incidence of this advanced complication is likely
to increase. Leptomeningeal carcinomatosis
commonly presents with cranial nerve palsies,
mental changes, stroke-like symptoms, cerebellar
signs, and, less commonly, autonomic distur-
bances. The condition can be readily diagnosed
by MRI and lumbar puncture with CSF analysis.
Radiographic studies may show subarachnoid
masses, diffuse meningeal contrast enhance-
ment, or hydrocephalus without a mass lesion.2
The presence of malignant cells in the CSF is
considered the gold standard in the diagnosis
of leptomeningeal carcinomatosis.3 Mutations
within the EGFR tyrosine kinase domain,
particularly L858R (exon 21) and exon 19 short
in-frame deletions, have been associated with the
response to EGFR-targeted therapy (gefitinib and
erlotinib).5–7 Therefore, in this case, genomic
analysis of EGFR was performed on both the
original pretreatment tumor biopsy and also on
tumor cells found in the CSF.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for leptomeningeal
carcinomatosis includes various chronic states
of meningitis and acute spinal-cord compres-
sion. Careful CSF examination and MRI should
be performed to distinguish these conditions.
TREATMENT AND MANAGEMENT
The standard treatment for leptomeningeal
carcinomatosis is intrathecal chemotherapy
(methotrexate, liposomal cytarabine, and thio-
peta) and neuroaxis radiation therapy. The effi-
cacy of systemic chemotherapy is usually limited
because tumor cells in the CSF are protected by
the blood–brain barrier. Radiotherapy is indi-
cated for bulky disease, as intrathecal chemo-
therapy can be limited by diffusion to 2–3 mm
penetration into tumor nodules. A recent study
favors liposomal cytarabine over methotrexate as
the drug of choice.3 Moreover, potential impair-
ment of CSF circulation in patients might result
in uneven distribution of intra thecal chemo-
therapeutics within the sub arachnoid space.
Aggressive approaches such as those described
carry significant toxicity,3 and result in reversal
or palliation of neurological symptoms in only
a minority of patients.4 The patient in this case
study was previously treated with erlotinib
in combination with carboplatin/paclitaxel
(TRIBUTE trial)1 with subsequent progressive
central nervous system (CNS) metastases when
receiving erlotinib. The TRIBUTE trial did not
show any statistically significant survival benefit
of adding erlotinib to standard chemotherapy.
Table 1 Laboratory analysis of the patient’s cerebrospinal fluid.
Test Result
Glucose (normal range: 2.2–4.4 mM 3.2 mM
Protein (normal range: 0.15–0.45 g/l) 0.57 g/l
Lactate dehydrogenase
(normal range: 0–26 U/l)
46 U/l
Red blood cell count (normally, there
are no red blood cells in the CSF)
12,017/μl
White cell count (normal range: 0–5/μl) 33/μl (neutrophils 58%, lymphocytes
26%, monocytes 9%, tumor cells 4%)
Cytology Positive (non-small-cell carcinoma)
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The clinical response resulting from use of the
alternative anti-EGFR quinazoline inhibitors
in the setting of progressive CNS disease has
not been previously described. In this case, the
role of gefitinib at the time of the patient’s lepto-
meningeal disease progression was unclear, in
light of her previous erlotinib failure. As a result
of the minimal adverse effect profile of the EGFR
tyrosine kinase inhibitor (TKI), gefitinib was
initiated instead of hospice referral, after fully
informed discussion of the limited treatment
options. A prompt and striking response was
Erlotinib inhibition Gefitinib inhibition
IB: p-EGFR [Y1068] IB: p-EGFR [Y1068]
ErbB1
ErbB2
ErbB3
ErbB1: VP IKWMALES I LHR IYTHQSDVWSY
ErbB2: VP IKWMALES I LRRRFTHQSDVWSY
ErbB3: VP IKWMALES I HFGKYTHQSDVWSY
E884K (GAA>AAA)
Amino acid alignment
CLUSTAL W (1.82) mulitiple sequence alignment
GTGCCTATCAAGTGGATGGCATTGGAATCAATTTTACACAGAATCTATACCCACCAGAGT 60
GTGCCCATCAAGTGGATGGCGCTGGAGTCCATTCTCCGCCGGCGGTTCACCCACCAGAGT 60
ACTCCAATTAAGTGGATGGCCCTTGAGAGTATCCACTTTGGGAAATACACACACCAGAGT 60
** ** *********** * ** ** * * ** *********
ErbB1
ErbB2
ErbB3
GATGTCTGGAGCTACG 76
GATGTGTGGAGTTATG 76
GATGTCTGGAGCTATG 76
***** ***** ** *
IB: β-actin
U 0.01 0.1 1 5 U 0.01 0.1 1 5 U 0.01 0.1 1 5 U 0.01 0.1 1 5 μM U 0.01 0.1 1 5 U 0.01 0.1 1 5 U 0.01 0.1 1 5 U 0.01 0.1 1 5 μM
IB: β-actin
WT L858R E884K L858R + E884K WT L858R E884K L858R + E884K
A
CD
B
80–
60–
40–
20–
0–
Erlotinib Gefitinib
Percent phospho-EGFR level of untreated control
L858R
L858R + E884K
Figure 4 EGFR mutations and differential effects on the sensitivity of the receptor towards inhibition by erlotinib and gefitinib. COS-
7 cells transiently transfected with EGFR plasmid constructs (wild-type, L858R, E884K, and L858R + E884K [created by site-directed
mutagenesis as previously described16]) were treated with increasing concentrations of either (A) erlotinib or (B) gefitinib, in the
presence of EGF (100 ng/ml, 30 min). Whole cell lysates were collected after EGF stimulation, separated on 7.5% SDS-PAGE and
electrotransferred onto nitrocellulose membrane for immunoblotting. The membrane was probed with an antibody against phospho-
EGFR [pY1068] (upper panel) and β-actin (lower panel) as a loading control. Equivalent receptor expression was also confirmed
with an anti-EGFR immunoblot (see Supplementary Figure 1 online). Two separate immunoblotting experiments were used for
quantitative analysis of the phospho-EGFR signal intensity. U, cells untreated with TKI; WT, wild-type. (C) Percentage (%) phospho-
EGFR signal level compared with the untreated control (100%) plotted for EGFRL858R-COS-7and EGFRL858R + E884K-COS-7 cell lines
treated with either of the two EGFR TKIs at 0.1 μM. The EGF-stimulated phospho-EGFR activation of L858R mutation is modulated
by the E884K mutation differentially with erlotinib (resistant) and gefitinib (sensitizing) as shown here at the in vitro concentration
of 0.1 μM. The percentage phospho-EGFR signal level (%) relative to untreated control (100%) was shown for both the L858R and
L858R + E884K mutations to illustrate how E884K differentially modulates the sensitizing effect of L858R on the receptor towards the
two different inhibitors. (D) Multiple sequence alignment performed by the CLUSTAL W alignment program for exon 22 of ErbB1, 2,
and 3 of the ErbB receptor family. The black arrow shows the conserved nucleotide G that was mutated in our patient’s tumor EGFR
gene and the arrow outline and bold text shows the conserved amino acid residue glutamic acid, E884. The methods are further
described in the Supplementary methods section; please go to the article online for details. *Conserved nucleotides among the
three sequences; IB, immunoblot.
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seen with gefitinib, resulting in a significant
reduction in the burden of leptomeningeal
carcinomatosis with corresponding improve-
ment in quality of life and performance status.
Interestingly, this response was not associated
with any toxicity. Notably, the patient was not
receiving any medications that might change
the serum levels of the EGFR inhibitors, such as
CYP3A4 inducers or inhibitors. Although studies
have reported good and prolonged responses
of brain metastases to gefitinib,8–10 successful
treatment of leptomeningeal metastasis has not
been reported. Furthermore, in patients who
have a response to gefitinib or erlotinib in their
primary tumor, brain and leptomeninges are
often sites of treatment failure.11 This report is
the first, to the authors’ knowledge, to describe
the response of lepto meningeal carcinoma-
tosis and extracranial disease to gefitinib after
erlotinib failure.
In the era of molecular-targeted therapy,
treatment options are often dependent on the
molecular and genetic profile of the tumor cells.
In this case, approximately 300 tumor cells from
the R2 lymph node were laser micro dissected
for genomic DNA extraction (Figure 1A,
I–III) and sequenced for the entire EGFR gene
(exons 1–28). Two EGFR missense mutations
within the tyrosine kinase domain were identi-
fied. Both mutations were present in the initial
pretreatment R2 lymph-node biopsy and in the
malignant cells from the CSF (four tumor cells
isolated by laser microdissection) (Figure 1C).
The first somatic mutation was L858R (exon
21, heterozygous), where leucine was substi-
tuted by arginine. The second mutation was a
novel E884K mutation (exon 22, heterozygous),
where glutamic acid was substituted by lysine.
The wild-type EGFR sequence was identified
in the patient’s CSF leukocytes (Figure 1B,C),
thereby confirming the somatic nature of the
mutations. We also identified two single nucle-
otide polymorphisms, Q787Q and T903T (data
not shown).
WT L858R T790M E884K L858R+
E884K
S S++ R+++ R++ R+
S
Erlotinib
Gefitinib S++ R+++ S++
Class I Class IIIClass II
S+++
EGFR
WT
EGFR
L858R
EGFR
T790M
EGFR
E884K
EGFR
L858R+E884K
Figure 5 Summary of EGFR mutations and their effects on sensitivity and resistance towards inhibition
by EGFR small molecule inhibitors. The known somatic missense mutations of EGFR and their effects on
sensitivity and resistance towards erlotinib or gefitinib inhibition are shown schematically. L858R sensitizes
the receptor to both inhibitors to a similar extent, and more than the wild-type receptor. T790M is the
recently reported resistant mutation against both EGFR inhibitors. E884K gives the receptor a sensitizing
effect towards gefitinib, while rendering it more resistant to erlotinib. The double mutation L858R + E884K
also sensitizes the receptor to gefitinib inhibition, with a synergistic effect when compared with E884K
alone, and confers resistance to erlotinib. Of note, the most sensitizing mutation towards gefitinib inhibition
is EGFRL858R + E884K, identified in this patient. Hence, the effects of EGFR mutations on TKIs can be divided
into: Class I, sensitizing responses; Class II, resistant responses; and Class III, differential responses.
S, sensitive; R, resistant.
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In order to further delineate the correla-
tion of EGFR mutational status and inhibitor
responsiveness, we performed in vitro trans-
fection studies in COS-7 cells using expres-
sion vectors containing wild-type (EGFRWT),
EGFRL858R, EGFRE884K, and EGFRL858R + E884K
constructs (Figure 4A,B). The L858R muta-
tion sensitized the receptor to both erlotinib
and gefitinib inhibition. Interestingly, we also
found that the EGFRE884K mutation alone
decreased the sensitivity of the receptor to
erlotinib inhibition compared with both wild-
type and L858R (Figure 4A). E884K abrogated
the sensitizing effect of the L858R mutation
towards erlotinib inhibition (Figure 4C). The
relative erlotinib resistance is dose-dependent;
this dose dependency appeared to be overcome
by increasing the dose to ≥1 μM. Conversely,
EGFRE884K and EGFRL858R + E884K were both
found to increase the gefitinib-sensitivity of
the mutated receptor to a greater extent than
EGFRWT (Figure 4B). Most interestingly, when
the two gefitinib-sensitizing mutations—L858R
and E884K—coexisted, they synergistically
sensitized the receptor to gefitinib inhibition,
with dramatic inhibition of phospho-EGFR
seen at 0.1 μM (Figure 4B,C). This double
mutant form is more sensitive to gefitinib inhi-
bition than either L858R or E884K alone. In
summary, while the E884K mutation increases
sensitivity of the EGFR to gefitinib inhibition,
it reduces sensitivity of the receptor to erlotinib
inhibition (Figure 4C).
Residue E884 is conserved in members of the
EGF receptor family (Figure 4D), and it is unclear
how common the mutation E884K is among
the NSCLC patient population. Whether or not
there are racial differences in the frequency of
this mutation has yet to be determined. Recent
sequencing studies, in which most known muta-
tions were identified, only sequenced the EGFR
gene from exons 18–21.12,13 Since the E884K
mutation is present in exon 22, it would not
have been identified. Among Asians, a high
frequency of EGFR tyrosine kinase mutations
in adeno carcinomas have been identified—55%
in Taiwan13 and 49% in Japan.12 It has been
reported that double missense mutations of the
EGFR often involve L858R.5–7
This case report demonstrates that, according
to molecular profiling, it is possible to achieve
a meaningful response from an EGFR TKI,
even in the setting of a terminal condition such
as extensive leptomeningeal metastases. To the
authors’ knowledge, this differential response
between erlotinib and gefitinib, mediated
by the EGFR mutation E884K, has not been
reported before. The T790M mutation of
the EGFR has recently been shown to confer
resistance to both gefitinib and erlotinib.14,15
This case provides new evidence to expand the
spectrum of the effects of EGFR mutations on
small-molecule inhibitors (Figure 5).
CONCLUSION
To the authors’ knowledge, this is the first case
to describe a striking response to gefitinib in a
patient with leptomeningeal metastases and
erlotinib-refractory lung adenocarcinoma. The
case shows that some EGFR mutations can
modulate differential responses to erlotinib and
gefitinib. Eventually, molecular and mutational
profiling of lung tumors might help to predict
differential response to TKIs and could guide
the selection of optimal therapeutics. Patients
with lepto meningeal metastases represent a
unique subgroup of patients with advanced
disease, who might still benefit from individual-
ized targeted therapy with small molecule TKIs
selected based on the patient’s mutational profile.
Further biochemical and functional assays are
needed to better understand the alteration of cell
signaling that is mediated by these mutations.
Furthermore, structural studies such as X-ray
crystallography of the novel mutant receptor
EGFRL858R + E884K are warranted, to elucidate
the structural mechanism behind the differen-
tial responses towards the inhibitors conferred
by these mutations.
Supplementary information
is available on the
Nature Clinical Practice Oncology website.
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Acknowledgments
S Dietrich is supported by
a Boehringer Ingelheim
Foundation Research
Fellowship, Germany.
TY Seiwert is supported by
a CALGB research grant
award. GC Davies
and S Lipkowitz are
supported by the Intramural
Research Program of
the NIH, National Cancer
Institute, Center for Cancer
Research. R Salgia is
supported by NIH/NCI-R01
award, American Cancer
Society Award (National), and
Institutional Cancer Research
Awards from the University of
Chicago Cancer Center with
the American Cancer Society
and the V-Foundation.
PC Ma is supported by
NIH/NCI-K08 award, the
American Association
for Cancer Research–
AstraZeneca–Cancer
Prevention and Treatment
Translational Lung Cancer
Research Fellowship, and
American Cancer Society
(Illinois Division)-LUNGevity
Foundation Lung Cancer
Treatment Research Award.
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©2006

CASE STUDY
JANUARY 2006 VOL 3 NO 1 CHOONG ET AL. NATURE CLINICAL PRACTICE ONCOLOGY 57
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Competing interests
The authors declared
they have no competing
interests.
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©2006