The n e w e ng l a n d j o u r na l
case records of the massachusetts general hospital
From the Center for Thoracic Cancers
(A.T.S.) and the Departments of Gastro-
enterology (D.G.F.), Radiology (S.R.D.),
and Pathology (A.J.I.), Massachusetts
General Hospital; and the Departments
of Medicine (A.T.S., D.G.F.), Radiology
(S.R.D.), and Pathology (A.J.I.), Harvard
Medical School — both in Boston.
N Engl J Med 2011;365:158-67.
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158
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of m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor
Case 21-2011: A 31-Year-Old Man
with ALK-Positive Adenocarcinoma of the Lung
Alice T. Shaw, M.D., Ph.D., David G. Forcione, M.D., Subba R. Digumarthy, M.D.,
and A. John Iafrate, M.D., Ph.D.
Pr e sen tat ion of C a se
A 31-year-old man was seen in the outpatient cancer center at this hospital because of
dysphagia and a mediastinal mass.
The patient had been well until approximately 3 months before this evaluation,
when progressive difficulty swallowing (solid foods but not liquids) developed that
was occasionally associated with choking and regurgitation. On examination by his
primary care physician 6 weeks before this evaluation, the patient’s blood pressure
was 140/90 mm Hg, and the remainder of the examination was normal. A course of
omeprazole was prescribed. Symptoms persisted, and 4 weeks later, a barium-swallow
examination performed at another hospital showed narrowing of the distal third of
the esophagus, which was thought to be caused by extrinsic compression. Computed
tomography (CT) of the chest, abdomen, and pelvis was performed after the admin-
istration of oral and intravenous nonionic contrast medium. The images revealed a
heterogeneous soft-tissue mass (4.0 cm in diameter) adjacent to the distal esophagus,
gastrohepatic and subcarinal lymphadenopathy (including nodes up to 2.5 cm in di-
ameter), and numerous nodules (<1 cm in diameter) in the right lung. The patient was
referred to the cancer center at this hospital.
At presentation, the patient reported that the dysphagia had not worsened, and he
was not aware of having lost weight. He also reported a morning cough (but no per-
sistent coughing or difficulty breathing) and severe anxiety about his current medical
problem. There was no odynophagia, nausea, vomiting, diarrhea, anorexia, or fatigue.
He had had a history of intermittent heartburn for several years, asthma in child-
hood, and three episodes of palpitations of unknown cause. His only medication was
zolpidem, and he had no known allergies. He lived with his wife and child, worked in
a technical field, and was physically active, participating in sports and working out
regularly. He drank alcohol, had a history of smoking (10 pack-years) but had stopped
2 years earlier, and did not use illicit drugs. A maternal aunt had an unknown type
of cancer.
On examination, the patient was anxious and pacing but in no acute distress; the
weight was 82.7 kg and the height 175 cm; the vital signs, oxygen saturation, and
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 case records of the massachusetts gener al hospital
remainder of the physical examination were nor-
mal. The level of carcinoembryonic antigen was
6.5 ng per milliliter (reference range, <3.4) and
that of human chorionic gonadotropin 1.2 IU per
liter (reference range, <0.7). The complete blood
count was normal, as were serum measurements
of electrolytes, calcium, phosphorus, magnesium,
glucose, total protein, albumin, globulin, alkaline
phosphatase, lactate dehydrogenase, and alpha-
fetoprotein and tests of coagulation and kidney
and liver function.
A diagnostic procedure was performed, and
management decisions were made.
Differ en t i a l Di agnosis
Dr. Alice T. Shaw: I cared for this patient and am
aware of the diagnosis. May we review the imaging
studies?
Dr. Subba R. Digumarthy: The barium-swallow ex-
amination performed at the other hospital shows
narrowing and deviation of the distal esophagus
to the left. The mucosa appears smooth, and the
proximal esophagus is dilated (Fig. 1A). These
findings are most likely the result of a mass lo-
cated outside the esophagus. Combined positron-
emission tomographic (PET) and CT scans at ini-
tial staging, obtained after the administration of
18F-fluorodeoxyglucose (18F-FDG), reveal a large,
metabolically active paraesophageal mass of lymph
nodes (Fig. 1B) and enlarged subcarinal lymph
nodes (Fig. 1C). There was increased uptake of
18F-FDG in the lymph nodes, multiple scattered
lung nodules, a focus of 18F-FDG uptake in the T1
vertebra (without a corresponding lesion on CT),
and a sclerotic bone lesion in the L4 vertebra, all
findings suggestive of metastases.
Dr. David G. Forcione: An upper endoscopy and
an endoscopic ultrasound examination were per-
formed. Endoscopic examination of the esophagus
showed that the mucosa was normal and intact
(Fig. 2A). However, as the endoscope advanced
toward the gastroesophageal junction, we observed
substantial luminal narrowing, most likely from
extrinsic compression. The lumen was not com-
pletely obstructed, and we were able to pass the
endoscope into the stomach and duodenum, which
appeared normal. We then performed upper endo-
scopic ultrasonography with a linear echoendo-
scope at 5 MHz. Adjacent to the esophagus we
observed a large, hypoechoic irregular mass with
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some internal heterogeneity and shadowing (Fig.
2B). To further characterize the mass, we per-
formed sonoelastography, an ultrasound-based
imaging technique for measuring tissue elastic-
ity with the use of vibration. This revealed a blue-
green overlay, which indicates firm and most
likely neoplastic tissue (Fig. 2C). A biopsy specimen
of this lesion was obtained by transesophageal
fine-needle aspiration. Endoscopic ultrasonogra-
phy also revealed upper abdominal lymphadenopa-
thy, with a well-defined, hypoechoic lymph node
(20 mm in diameter) in the paragastric fat. A bi-
opsy specimen of this node was obtained by fine-
needle aspiration in a transgastric fashion (Fig.
2D), and all specimens were submitted for path-
ological evaluation.
Dr. Shaw: This 31-year-old man presented with
severe dysphagia and was found to have a medi-
astinal mass that was causing extrinsic compres-
sion of the distal esophagus. On the basis of only
his symptoms, the differential diagnosis is broad
and includes both benign and malignant disorders
of the esophagus and mediastinum. However, the
results of imaging studies indicate the presence
of an advanced malignant tumor. Because of the
normal appearance of his esophageal mucosa on
esophagogastroduodenoscopy, a typical invasive
esophageal cancer such as esophageal adenocar-
cinoma is highly unlikely. An esophageal adeno-
carcinoma that arises in the submucosal layer or
an adenoid cystic carcinoma of the esophagus
would be compatible with the endoscopic find-
ings, but neither is common. An advanced non–
small-cell lung cancer (NSCLC) could present in
this manner, with extensive mediastinal lymph-
adenopathy, although the absence of a dominant
parenchymal lung lesion is unusual. Because of
the patient’s young age and male sex, germ-cell
tumors or lymphomas would be more likely than
either esophageal or lung cancer. However, the
levels of germ-cell tumor markers were only mini-
mally elevated, and testicular examination and
testicular ultrasound studies were negative. The
presence of pulmonary nodules and the absence
of systemic symptoms argued against lymphoma.
Finally, we also considered the possibility of a car-
cinoma of an unknown primary site, with metas-
tases to mediastinal and abdominal lymph nodes,
lung, and bone. Pathological examination of tis-
sue from the biopsy specimens was needed to
provide a definitive diagnosis.
159
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

Figure 1. Imaging Studies at Diagnosis.

A barium-swallow examination (Panel A) shows narrowing of the distal esophagus and deviation to the left (arrow).
The mucosa appears normal. Axial images from a chest CT show enlarged paraesophageal lymph nodes (Panel B,
arrow) and enlarged subcarinal lymph nodes (Panel C, arrow).

Dr . A l ice T. Sh aw ’s Di agnosis pressed cytokeratin (CK) 7 and thyroid transcrip-

Metastatic carcinoma.
Pathol o gic a l Discussion
Dr. A. John Iafrate: Examination of a biopsy specimen
from the patient’s mediastinal mass revealed a
malignant neoplasm with glandular differentia-
tion and prominent cells containing abundant
intracellular mucin and eccentrically located nuclei
(i.e., signet-ring cells) (Fig. 3A). Signet-ring cells
are common in gastric adenocarcinoma but less
common in esophageal and primary lung adeno-
carcinomas. Immunohistochemical analysis was
performed and revealed that the tumor cells ex-
tion factor 1 (TTF1) and did not express CK20 or
the gastrointestinal marker CDX2 (Fig. 3B). To-
gether, these data indicate a primary lung adeno-
carcinoma with metastasis to the mediastinum.
Discussion of M a nagemen t
Diagnostic evaluation
Dr. Shaw: The first step in the management of this
patient’s newly diagnosed metastatic lung adeno-
carcinoma was genetic profiling of the tumor.
Lung cancer has traditionally been classified ac-
cording to histologic subtype, with the two ma-
jor categories being small-cell lung cancer and
NSCLC; NSCLC is subclassified as adenocarci-

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 case records of the massachusetts gener al hospital

A B

C D

Figure 2. Upper Endoscopic and Endoscopic Ultrasound Images.

Esophagogastroduodenoscopy (Panel A) reveals normal squamous mucosa in association with a long, smooth ste-
nosis of the distal esophagus (arrows point to a compressed lumen). An endoscopic ultrasound image (Panel B)
shows a large, heterogeneous, hypoechoic, solid mediastinal mass (circumscribed) compressing the esophagus.
Sonoelastography produced the pseudocolor image (Panel C, left), which reveals a blue-green overlay, correspond-
ing to firm tissue (reduced elasticity and high tissue resistance). These features are seen most often in neoplastic
tissue. On the right is the corresponding endoscopic ultrasound image of the mass. A lobulated, hypoechoic para-
gastric lymph node (20 mm in diameter) was identified by endosonography (Panel D) and was sampled with a
25-gauge needle (arrow) with the use of a transgastric approach.

noma, squamous-cell carcinoma, or large-cell (ALK). Activation of oncogenic kinases such as

carcinoma. These distinctions are important for
selecting among standard cytotoxic chemothera-
peutic regimens.
However, there is increasing awareness that
lung cancers can also be classified according to
the presence of specific genetic alterations. Just
over half of all cases of lung adenocarcinomas
can be defined by a known genetic abnormality or
oncogenic driver (Fig. 4). The most common are
activated mutant forms of KRAS and epidermal
growth factor receptor (EGFR), although there
are many others that define smaller subgroups
of disease, such as mutant BRAF and fusion on-
cogenes involving anaplastic lymphoma kinase
EGFR and ALK leads to dependency of the tumor
cells on the activated kinase (often called onco-
gene addiction) and sensitivity to the correspond-
ing kinase inhibitor. Thus, identifying the under-
lying genetic abnormality can be important to a
patient’s care, since this information may sug-
gest the use of targeted therapeutic agents that
are more effective and less toxic than standard
chemotherapeutic regimens.
The most important genetic test to perform in
a patient, such as this one, with a new diagnosis
of metastatic lung adenocarcinoma, is testing for
EGFR mutations. Most patients with EGFR-mutant
lung cancer have never smoked or are light smok-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 3. Pathological and Molecular Genetic Analysis.

A photomicrograph of the patient’s tumor (Panel A, hematoxylin and eosin) shows adenocarcinoma with signet-ring
cells (i.e., cells containing abundant intracellular mucin and eccentrically located nuclei). Immunohistochemical
staining for thyroid transcription factor 1 (TTF1) (Panel B, diaminobenzidine) highlights the expression of TTF1 in
the nuclei of tumor cells, a feature that is consistent with adenocarcinoma of pulmonary origin. A fluorescence in
situ hybridization (FISH) assay of tumor cells performed with the use of a break-apart probe (Panel C) reveals re-
arrangement of the gene encoding anaplastic lymphoma kinase (ALK). The green probe hybridizes to the region
immediately 5′ to ALK, and the red probe hybridizes to the 3′ region. Isolated red probe signals (arrow) indicate a
chromosomal rearrangement involving ALK. Close apposition of red and green probe signals indicates an intact
wild-type copy of ALK (arrowhead). Immunohistochemical analysis of ALK protein (Panel D, diaminobenzidine)
shows that ALK is weakly expressed in tumor cells.

ers (defined as 10 pack-years or less), as this pa-
tient had been; unlike this patient, they are more
often female and of Asian descent. These tumors
respond markedly to the administration of EGFR
tyrosine kinase inhibitors, such as gefitinib and
erlotinib,1,2 which is now a standard regimen for
patients with advanced, EGFR-mutant lung can-
cer. Recently, several large, randomized trials
were conducted to address the role of EGFR tyro-
sine kinase inhibitors in the first-line treatment
of patients with advanced NSCLC.3-5 In the Ires-
sa Pan-Asia Study (ClinicalTrials.gov number,
NCT00322452),3 patients with a new diagnosis
of metastatic lung adenocarcinoma with an EGFR
mutation had a higher response rate to gefitinib
than to standard chemotherapy, as well as pro-
longed progression-free survival and a better qual-
ity of life. In contrast, in those patients without
an EGFR mutation, gefitinib was clearly inferior
to chemotherapy, in terms of both response rate
and progression-free survival. These and other
findings have led to our current practice of ge-
notyping lung tumors at the time of diagnosis,
before the initiation of systemic treatment. Pa-

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 case records of the massachusetts gener al hospital
tients who have lung tumors with activating mu-
tations in EGFR are treated with EGFR tyrosine
kinase inhibitors such as erlotinib, whereas pa-
tients with wild-type EGFR are offered standard
first-line cytotoxic chemotherapy, typically a plat-
inum-based regimen. To determine whether this
patient should receive an upfront EGFR tyrosine
kinase inhibitor or standard first-line chemo-
therapy, we submitted the tumor tissue to the
molecular pathology laboratory for comprehen-
sive genetic profiling.
Pathol o gic a l Discussion
Dr. Iafrate: Molecular genetic studies are becom-
ing increasingly important for the diagnosis and
management of epithelial cancers. This patient’s
tumor tissue was analyzed for a panel of more than
100 recurrent mutations with the use of a multi-
plex mutation screening assay (SNaPshot Multiplex
System, Applied Biosystems) that includes the com-
mon EGFR, KRAS, and BRAF mutations, among oth-
ers.6 This analysis is currently part of our routine
pathological assessment of lung cancers and re-
lies on the use of DNA extracted from archived,
formalin-fixed, paraffin-embedded tumor mate-
rial. An important prerequisite for genetic testing
is sufficient tumor tissue for performing the mo-
lecular analysis. At our institution, pathologists
are careful to preserve lung cancer tumor speci-
mens for these studies and will, for example, pre-
pare cell blocks from all cytologic samples, as was
done in this case.
In addition to the SNaPshot screening assay,
fluorescence in situ hybridization (FISH) was per-
formed to assess for chromosomal rearrangement
of ALK. ALK gene rearrangements were first dis-
covered in anaplastic large-cell lymphoma7 and in
2007 were reported in a small proportion of pa-
tients with NSCLC.8 In NSCLC, the predominant
ALK rearrangement results from a small inversion
within chromosome 2p, leading to fusion of a
portion of the EML4 gene with exons 20 through
29 of ALK. The resulting EML4–ALK fusion gene
encodes a potent oncogenic fusion kinase. To iden-
tify EML4–ALK and other ALK rearrangements, we
perform a FISH assay, with the use of a break-
apart probe, on formalin-fixed, paraffin-embedded
tumors.9
This patient’s tumor was negative for all mu-
tations, including EGFR and KRAS mutations, ac-
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KRAS
EGFR
PIK3CA
ALK
HER2
BRAF
AKT
NRAS
MET
ROS
Unknown
Figure 4. Genetic Abnormalities in Adenocarcinomas of the Lung.
The pie chart depicts the approximate frequency of each oncogenic altera-
tion. Results are based on the screening of 650 lung adenocarcinomas at
Massachusetts General Hospital. The genotyping platform detects activat-
ing mutations in KRAS, EGFR, PI3K, HER2, BRAF, AKT, and NRAS. In addi-
tion, fluorescence in situ hybridization is used to identify chromosomal re-
arrangements involving ALK or ROS and gene amplification of c-MET. In
nearly half of lung adenocarcinomas, no genetic abnormality can be identi-
fied by these methods.
cording to SNaPshot mutational analysis. Howev-
er, a FISH assay for ALK gene rearrangement was
positive (Fig. 3C). To confirm ALK positivity in this
case, we performed immunohistochemical analy-
sis with the use of an ALK-specific antibody. Since
ALK is not expressed in normal lung tissue, the
detection of ALK by immunohistochemical anal-
ysis strongly supports the presence of ALK re­
arrangement (Fig. 3D). Immunohistochemical
analysis with currently available commercial anti-
bodies has not yet been shown to be sufficiently
sensitive or specific to replace FISH as the screen-
ing test for ALK rearrangement.
Discussion of M a nagemen t
Clinical Features of ALK-positive NSCLC
Dr. Shaw: This patient has several key clinical fea-
tures associated with ALK rearrangement in lung
cancer. The prevalence of ALK rearrangement in
unselected patients with NSCLC is only 3 to 4%,
but ALK rearrangements are more common in pa-
tients who have never smoked or who, like this
patient, have a history of light smoking.9-14 At our
163
 The n e w e ng l a n d j o u r na l
institution, we find that approximately 15% of
patients with NSCLC who have never smoked or
who have a history of light smoking are ALK-pos-
itive, and of patients with ALK-positive lung can-
cer, more than 90% have never smoked or are
light smokers. These data suggest that ALK re­
arrangement defines a distinct subgroup of lung
cancer that is not related to smoking. In gener-
al, and as seen in this case, the ALK-positive sub-
group does not overlap with the EGFR mutant
subgroup9,10,12-16; patients typically have either
EGFR mutation or ALK rearrangement, but not
both. A second important feature of this case is
the patient’s young age — he was 31 years of age
at diagnosis. On average, patients with ALK re­
arrangement are 10 to 15 years younger than
those without ALK rearrangement, with a median
age of about 50 years.9,10,12,14,17 Finally, ALK rear-
rangement is associated with adenocarcinoma
rather than squamous-cell carcinoma. This patient
had not only adenocarcinoma but also abundant
signet-ring cells, which have been associated with
ALK rearrangement in non-Asian patients.9,18
Management of ALK-positive NSCLC
In this patient with advanced NSCLC, identifica-
tion of ALK rearrangement is important for two
reasons. First, because his tumor is ALK-positive
and is not positive for EGFR mutation, the patient
is not a candidate for first-line treatment with
erlotinib. Furthermore, should the patient have a
relapse, erlotinib most likely will not be part of
additional therapy because of data suggesting that
patients with ALK-positive tumors do not benefit
from EGFR tyrosine kinase inhibitors.9 Second,
oral, small-molecule inhibitors targeting ALK are
clinically available. The first of these — crizotinib
— has shown marked antitumor activity in ALK-
positive NSCLC.19 In a phase 1 trial involving
82 patients with advanced, ALK-positive NSCLC
(NCT00585195), the overall response rate to crizo-
tinib was 57%, with an estimated probability of
6-month progression-free survival of 72%19; this
contrasts with response rates of 10% and pro-
gression-free survival of less than 3 months for
standard single-agent chemotherapies.20,21 Crizo-
tinib has been shown to have relatively mild side
effects, including nausea, vomiting, diarrhea, pe-
ripheral edema, constipation, and visual changes.19
Thus, unlike the majority of patients with NSCLC,
this patient has the additional therapeutic option
of a safe, highly effective, targeted agent.
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of m e dic i n e
At this time, patients with ALK-positive lung
cancer can receive crizotinib only if they are par-
ticipants in a clinical trial. To be eligible for the
PROFILE 1007 trial (NCT00932893) — a global,
randomized phase 3 registration trial comparing
crizotinib with standard chemotherapy (single-
agent pemetrexed or docetaxel) — patients must
have advanced ALK-positive lung cancer, and the
cancer must have progressed after one previous
platinum-based chemotherapy regimen. The pri-
mary end point is progression-free survival. Study
patients who have a relapse while they are receiv-
ing standard chemotherapy will be eligible for a
companion phase 2 trial named PROFILE 1005
(NCT00932451), in which all patients receive crizo-
tinib. In the United States, PROFILE 1007 enroll-
ment has recently closed, but PROFILE 1005 re-
mains open. In addition, for newly diagnosed,
previously untreated patients with advanced ALK-
positive NSCLC, a phase 3 trial of first-line treat-
ment with crizotinib as compared with combina-
tion chemotherapy (with standard platinum and
pemetrexed) opened in May 2011 and is actively
recruiting patients (NCT01154140). The original
phase 1 trial (NCT00585195) also remains open
for ALK-positive patients who do not meet the eli-
gibility requirements for the phase 2 and phase 3
trials.
At the time of this patient’s presentation, there
was no clinical trial for patients with newly diag-
nosed, previously untreated ALK-positive NSCLC.
Therefore, he was treated with first-line, platinum-
based combination chemotherapy (cisplatin, peme-
trexed, and bevacizumab). A pemetrexed regimen
was selected because the patient had an adeno-
carcinoma, and first-line pemetrexed-based che-
motherapy has been shown to have efficacy in
non–squamous-cell lung cancer.22 His swallowing
improved, but he struggled with side effects, in-
cluding fatigue and anorexia. CT scans after four
cycles of chemotherapy showed a mixed response,
with improvement in the lymphadenopathy but
worsening bone disease. The patient then enrolled
in a clinical trial of crizotinib. Within 5 weeks after
starting crizotinib, the patient had complete reso-
lution of the dysphagia and his energy improved
dramatically.
Dr. Digumarthy: CT images of the chest were
obtained before and after 12 weeks of treatment
with crizotinib. After treatment, a decrease can be
seen in the size of the paraesophageal lymph-node
mass, the subcarinal lymph nodes (Fig. 5A and 5B),
 case records of the massachusetts gener al hospital

A B

C D

Figure 5. Imaging Studies after Crizotinib Treatment.

Axial images from CT of the chest (at the same levels shown in Fig. 1B and 1C), obtained 12 weeks after the start of
crizotinib therapy, show that paraesophageal lymphadenopathy (Panel A, arrow) and subcarinal lymphadenopathy
(Panel B, arrow) are decreased as compared with the lymphadenopathy seen before therapy (Fig. 1B and 1C, arrows).
Bone scans, obtained after the administration of technetium-99m–labeled methylene diphosphonate, show radio-
tracer uptake in the metastases in the T1 and L4 vertebrae and the right femur before crizotinib therapy (Panel C,
arrows) and 12 weeks after crizotinib therapy (Panel D, arrows); the uptake is decreased after therapy.

and the lung nodules. This response meets the
criteria for a partial response, as defined by guide-
lines for evaluating the response to treatment in
solid tumors.23 In addition, bone scans obtained
before and after treatment with crizotinib show
improvement in the T1 and L4 metastases after
treatment (Fig. 5C and 5D).
Dr. Shaw: The patient continues crizotinib ther-
apy 9 months after the diagnosis, with no side
effects and no symptoms of the disease. The bone
lesions at T1 and L4 are no longer detectable on
bone scanning, and CT images show an estimated
40% reduction in the size of the lesions in the
chest.
Dr. Nancy Lee Harris (Pathology): Are there any
questions?

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Dr. Bruce Chabner (Hematology–Oncology): What
is Pfizer going to do about a diagnostic biomarker
test for commercialization of this drug?
Dr. Shaw: For the submission to the Food and
Drug Administration (FDA), Pfizer is partnering
with Abbott Molecular to develop a companion
diagnostic FISH assay. To be eligible for the
PROFILE trials, all patients must submit a tissue
sample to a central laboratory, and testing with
this FISH assay must show ALK positivity. If the
central laboratory testing performed for the
PROFILE trials shows equivalency to the FISH as-
say used in the phase 1 trial, the FISH assay will
be FDA-approved as a companion diagnostic assay.
Dr. Harris: Dr. Iafrate’s point that we need
enough tissue to do this type of molecular pro-
filing is important to remember, especially for
oncologists as they talk to their patients and for
practitioners who are performing diagnostic bi-
opsies. It definitely can be worthwhile to perform
a core or excisional biopsy to get some actual
tissue, in addition to the fine-needle aspiration,
which yields only suspended cells.
Dr. Chabner: How widely have you screened
other cancers for ALK rearrangements?
Dr. Iafrate: We have looked at many different
types of tumors, such as other tumors with the
morphologic features of signet-ring cells (e.g.,
breast and colon cancers), and found a very low
incidence (<1%) of these translocations.
Dr. Harris: What is known about the normal
function of ALK, and what pathway is being in-
terrupted?
Dr. Shaw: ALK is a receptor tyrosine kinase in
the insulin receptor superfamily. Its precise func-
tion is not well understood, but it is believed to
have a role in the developing nervous system. In
the adult, there is little to no expression of ALK
in most tissues, which most likely explains the
extremely favorable side-effect profile associated
with crizotinib.
A nat omic a l Di agnosis
Adenocarcinoma of the lung (non–small-cell lung
cancer), with anaplastic lymphoma kinase (ALK)
gene rearrangement.
This case was discussed at the Massachusetts General Hospi-
tal Cancer Center Grand Rounds.
Dr. Shaw reports receiving consulting fees from Pfizer, Ariad,
Chugai, and Millennium; and Dr. Iafrate, consulting fees from
Pfizer and Abbott Molecular. No other potential conflict of inter-
est relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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