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Fall 2014
VOLUME 27, ISSUE 1
Editorial: Personalized Medicine in Lung
Cancer - The Time is Now
Mike R. Sung, B.Sc.
Natasha B. Leighl, MD, MMSc, FRCPC
Mike R. Sung
Mr. Sung is a young graduate
who is spending the year at the
Princess Margaret Cancer
Centre working with the lung
cancer research team, he
wishes to pursue a career in
medicine.
Dr. Natasha Leighl
Dr. Leighl is an Associate
Professor at the Department of
Medicine at the University of
Toronto as well as a Medical
Oncologist with the Division of
Medical Oncology, Princess
Margaret Cancer Centre.
The discovery of genomic abnormalities that drive
progression of lung cancer has resulted in recognition of
new lung cancer subtypes, and the development of new
treatments that target these subtypes. Cheema et al.
provide an exciting overview of current and future
personalized lung cancer treatment pathways (1). EGFR
TKIs in EGFR-mutant lung carcinoma and ALK inhibitors in
ALK-rearranged lung carcinoma yield superior outcomes
compared to standard chemotherapy, with dramatic
Volume 27, Issue 1
An official publication of the Ontario Thoracic Society,
a medical section of the Ontario Lung Association
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Ontario Thoracic Reviews Editorial Board, 2014-2015
Dr. Christopher Li (Co-Editor)
Dr. Mark Soth (Co-Editor)
Dr. Robert Hyland (Editor Emeritus)
Dr. Thomas Kovesi (Chair, OTS)
Ms. Hélène Michaud (Chair, OLA)
Mr. George Habib (President and CEO, OLA)
Dr. Hedy Ginzberg (Medical Director, OTS)
Ms. Jeanne Castellanos (OTS Administrator)
Ms. Pam Richards (Health Sciences Librarian)
Ontario Thoracic Society Executive Committee, 2014-2015
Dr. Thomas Kovesi (Chair)
Dr. George Chandry (Chair Elect)
Dr. Michael Fitzpatrick (OTS/OLA Board Representative)
Dr. Shawn Aaron (Research Advisory Committee Chair)
Dr. Marcel Tunks (2015 Better Breathing Conference Chair)
Dr. Dhenuka K. Radhakrishnan
Dr. Virjanand Naraine
Dr. Eric Hentschel
Dr. Onofre Moran
Dr. Frank Vincent Ritacca
Dr. Khalil Sivjee
Dr. John Granton
Dr. Helen Ramsdale (OMA Representative)
Dr. Chris Li (Program Director Rep)
Dr. Sharon Dell (Pediatric Rep)
Dr. Jade Coyne (Resident Representative)
Dr. Hedy Ginzberg (OTS Medical Director)
Ms. Jeanne Castellanos (OTS Administrator)
Mission Statement
To Promote Respiratory Health through
Medical Research and Education
Fall 2014 Ontario Thoracic Review
Page 1 of 10
efficacy and improved tolerability (2,3). But within one to
two years, even patients responding to these new
therapies
will
develop
resistance.
Growing
understanding of the molecular basis of resistance has
led to our ability to target resistance mutations after
initial treatment failure, like the EGFR T790M mutation
or one of several ALK resistance mutations (4). Today’s
lung cancer patient may be able to avoid chemotherapy
for longer than ever before, moving from one targeted
therapy to another. Additional oncogenic drivers in lung
cancer with active targeted therapies have been
identified, including ROS-1 translocations (5), BRAF
mutations, HER2 insertion mutations, MET amplification,
RET translocations and more (4). Even for patients
without oncogenic driver mutations in their lung cancer,
there is progress. Immune-based therapies targeting the
programmed cell death protein-1 (PD-1) pathway may
provide new opportunities for targeting lung cancer.
Response rates range from 17-24% with prolonged
response duration, and mild toxicity profile for most
patients (6). But there are important challenges as we
move forward. Cheema et al. highlight the challenges of
diagnostic sampling and pathology (1). It is critical that
our respirology and radiology colleagues understand that
today’s lung cancer diagnosis requires more than just a
few cells. Larger tissue samples are needed for molecular
diagnostics, such as cytology or biopsy samples with at
least 30% tumour cellularity (7). Some techniques are
less likely to yield sufficient samples, such as
bronchoalveolar lavage, and likely should not be the
primary method of diagnosing suspected lung cancer.
Routine feedback should be available from pathologists
about adequacy of samples for diagnostic and molecular
testing. In the pathology laboratory, lung cancer tissue
must be prioritized for molecular testing (8,9). This may
include minimizing unnecessary sectioning and extensive
immunohistochemistry panels. Once the diagnosis of
lung cancer with an adenocarcinoma component has
been made, initiation of molecular testing by
pathologists should occur within three days, and results
should be available to clinicians within five to ten days
(8,9). As targeted therapy for resistance mutations
becomes available, more patients will be referred for
repeat tumour biopsies in the setting of disease
progression. The difficulty in obtaining repeat biopsies –
lack of system capacity and patient safety concerns - has
led to the evaluation of circulating biomarkers, including
circulating tumor cells (CTC) and cell free tumor DNA
(cfDNA), as methods of less invasive sampling for
molecular testing (10). While promising, these assays are
not yet available for routine use. Treatment access is also
a challenge. Provinces have required randomized trials
Volume 27, Issue 1
before funding targeted therapies in standard practice.
But does each new treatment require randomized data?
For example, crizotinib demonstrates similar activity in
ROS-1-rearranged lung cancer, (about 1% of cases), as it
does in ALK-rearranged lung cancer, where early phase
and randomized trials demonstrate superiority over
chemotherapy (3,5). Must we really repeat these trials in
ROS-1 positive patients? How can we move targeted
therapies into standard care faster, and how can we
make them more affordable? With current pricing of
novel agents crizotinib (~$10,000/month) and ceritinib
(~$13,500/month), drug cost will be an important
consideration in accessing personalized medicine in lung
cancer (11,12). In this new era of lung cancer
therapeutics, optimal diagnostic sampling and molecular
testing is a cornerstone. Our ability to ensure that
Canadians with lung cancer can access the best possible
treatment and outcomes begins with our colleagues in
respirology, radiology, surgery and pathology who make
that initial diagnosis.
REFERENCES:
1. Cheema PK, Raphael S, Burkes RL. Personalized Approach to Systemic
Therapy in Advanced Non Small Cell Lung Cancer – One Size Does Not Fit
All. Ontario Thoracic Review (in press)
2. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N,
Sunpaweravong P, Han BH, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y,
Yang JJ, Chewaskulyong B, Jiang HY, Duffield EL, Watkins CL, Armour AA,
Fukuoka M. Gefitinib or Carboplatin–Paclitaxel in Pulmonary
Adenocarcinoma. N Engl J Med 2009; 361(10):947-957.
3. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T,
Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O’Byrne KJ, MoroSibilot D, Camdige DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A,
Wilner KD, Janne PA. Crizotinib versus chemotherapy in advanced ALKpositive lung cancer. N Engl J Med. 2013; 368(25):2385-94.
4. Korpanty GJ, Graham DM, Vincent MD, Leighl NB. Biomarkers That
Currently Affect Clinical Practice in Lung Cancer: EGFR, ALK, MET, ROS-1,
and KRAS. Front Oncol. 2014; 4: 204.
5. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ,
Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan
W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark
JW, Iafrate AJ. Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer.
N Engl J Med. 2014 Sep 27 [Epub ahead of print].
6. Brahmer JR, Pardoll DM. Immune Checkpoint Inhibitors: Making
Immunotherapy a Reality for the Treatment of Lung Cancer. Cancer
Immunology Research. 2013 1(2):85-91.
7. Shiau CJ, Babwah JP, da Cunha Santos G, Sykes JR, Boerner SL, Geddie
WR, Leighl NB, Wei C, KamelReid S, Hwang DM, Tsao MS. Sample features
associated with success rates in population-based EGFR mutation testing.
J Thorac Oncol 2014; 9(7):947-56.
8. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G,
Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M.
Molecular testing guideline for selection of lung cancer patients for EGFR
and ALK tyrosine kinase inhibitors: guideline from the College of
American Pathologists, International Association for the Study of Lung
Cancer, and Association for Molecular Pathology. J Thorac oncol 2013;
8(7):823-59.
9. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M,
Ramalingam SS, West H, Whitlock S, Somerfield MR. Molecular Testing
Fall 2014 Ontario Thoracic Review
Page 2 of 10
for Selection of Patients with Lung Cancer for Epidermal Growth Factor
Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors:
American Society of Clinical Oncology Endorsement of the College of
American Pathologists/International Society for the Study of Lung
Cancer/Association of Molecular Pathologists Guideline. J Clin Oncol 2014
Oct 13 [Epub ahead of print].
10. Esposito A, Bardelli A, Criscitiello C, Colombo N, Gelao L, Fumagalli L,
Minchella I, Locatelli M, Goldhirsch A, Curigliano G. Monitoring tumorderived cell-free DNA in patients with solid tumors: clinical perspectives
and research opportunities. Cancer Treat Rev 2014; 40(5):648-55.
11. Djalalov S, Beca J, Hoch JS, Krahn M, Tsao MS, Cutz JC, Leighl NB. Cost
effectiveness of EML4-ALK fusion testing and first-line crizotinib
treatment for patients with advanced ALK-positive non-smallcell lung
cancer. J Clin Oncol 2014;32(10):1012-9.
12. Leighl NB, Beca JM, Tsao MS, Hoch JS. Reply to C.G. Azzoli et al and C.
Chouaid et al. J Clin Oncol 2014 Sep 8 [Epub ahead of print].
Funding acknowledgements – Princess Margaret Cancer Foundation OSI
Pharmaceuticals Chair in New cancer Drug Development; Grant funding
from the Ontario Institute of Cancer Research/Cancer Care Ontario
Health Services Research Program
Feature Article: Personalized Approach to
Systemic Therapy in Advanced Non Small
Cell Lung Cancer - One Size Does Not Fit All
Parneet K. Cheema, Simon Raphael and
Ronald L. Burkes
Dr. Parneet K. Cheema,
HBSc, MD, MBiotech,
FRCPC
Dr. Cheema is a Medical
Oncologist, Sunnybrook
Odette Cancer Centre.
Her professional
Interests: Thoracic,
Gastrointestinal and
Skin Malignancies
Dr. Simon Raphael, M.Ed.,
M.D., FRCPC
Associate Professor at the
University of Toronto. Chief
Pathologist and Director of
Laboratories, North York
General Hospital
Department of Laboratory
Medicine
Volume 27, Issue 1
Dr. Ronald Burkes, MD,
FRCPC
Dr. Burkes is a Medical
Oncologist at Mount
Sinai Hospital, Princess
Margaret Cancer
Center/University
Health Network and a
Professor of Medicine
at the University of
Toronto. His personal
interests include:
Sports, Reading and
Travelling
Introduction
Non-small-cell lung (NSCLC) remains the leading cause of
cancer-related deaths globally for both men and
women.1,2 It is estimated that in 2012 there were
25,600 new cases and 20,100 deaths associated with
NSCLC in Canada with an incidence and mortality rate of
54/100,000 and 42/100,000 population, respectively.3
The most important risk factor for developing lung
cancer remains tobacco use, accounting for an estimated
86% of lung cancer cases in high-income countries like
Canada and the median age at diagnosis is 70.4,5 The
prognosis of NSCLC remains poor with 5 year survival
rates across all stages being only 16% with a majority of
patients presenting with advanced incurable stage
disease.6 If left untreated, patients with advanced
incurable NSCLC have a median survival after diagnosis
of 4-5 months.7 The goal of systemic therapy in this
setting is to prolong survival and improve quality of life
(QoL) by treating cancer related symptoms.
Traditionally NSCLC was thought of as 3 predominant
histological subtypes; adenocarcinoma, squamous cell
and large cell carcinoma and was treated as a "one-sizefits-all" therapeutic approach using cytotoxic
chemotherapy.8,9 We now recognize that within these
subtypes of NSCLC exists a collection of discrete
malignancies with distinct molecular aberrations that
drive carcinogenesis and result in different outcomes
and responses to therapies.8,9 Several biomarkers have
emerged as predictive of response to targeted therapies
in advanced NSCLC, including the epidermal growth
factor receptor (EGFR) and Echinoderm microtubule
associated protein like-4/anaplastic lymphoma kinase
(ALK) rearrangement.10,11
Fall 2014 Ontario Thoracic Review
Page 3 of 10
Personalized Chemotherapy
Palliative chemotherapy with a platinum based doublet
(in combination with vinorelbine, gemcitabine,
pemetrexed or taxane) has been the cornerstone of
treatment for patients with advanced stage NSCLC and
has resulted in a modest increase in prolonging survival
and associated QoL.12 In treatment naïve patients
platinum doublets offer response rates of 25% and a
median survival of 8-11 months. Although a majority of
patients will experience disease progression at a median
of 4 months.13,14 Platinum doublet chemotherapy is also
accompanied by significant toxicity and due to advanced
age, poor performance status and/or co-morbidities
many patients do not receive treatment.5, 15
NSCLC histology has become an important factor to
select optimal chemotherapy for a patient with advanced
NSCLC. The chemotherapy agent pemetrexed has
become a preferential drug for patients with nonsquamous NSCLC due to randomized trials showing
favourable responses and survival with better tolerability
than older chemotherapy agents.13, 16,17 Cisplatinpemetrexed has been shown to be modestly superior to
cisplatin-gemcitabine in non-squamous NSCLC, and has
become the preferred platinum-doublet for this subtype
of patients if they do not have an activating EGFR
mutation or an ALK rearrangement [Figure 1].
Conversely, in patients with squamous cell carcinoma
subtype, pemetrexed is associated with inferior
outcomes compared to older chemotherapy regimens,
highlighting the importance of reporting the subtype of
NSCLC to be able to offer personalized chemotherapy.
The pathology report stating NSCLC “not otherwise
specified” is no longer acceptable.
EGFR mutation positive advanced NSCLC
In 2004, two pivotal studies revealed that the presence
of somatic activating mutations in the kinase domain of
EGFR of NSCLC tumours, particularly small in frame
deletions in exon 19 (deletion 19) and the L858R
missense mutation in exon 21 (L858R) which accounts
for 90% of EGFR mutations, strongly correlated with
increased responsiveness to EGFR tyrosine kinase
inhibitors (TKIs).18,19
EGFR activating mutations are generally limited to nonsquamous histology and mutually exclusive to other
oncogenic driver mutations including ALK
rearrangements and KRAS (KRAS has been shown to be
associated with poor prognosis but no effective targeted
therapies to this biomarker have been demonstrated to
date).20 The rate of EGFR mutations in the general
Volume 27, Issue 1
NSCLC adenocarcinoma population is 12% and in a
subset of patients this rate can be as high as 60%.10,20
These mutations are more common in never smokers,
those of east Asian ethnicity, and females.20
The first clinical study to demonstrate the correlation of
EGFR mutations and optimal systemic therapy in
advanced NSCLC was the IPASS study.10 This phase III trial
evaluated the EGFR TKI gefitinib versus standard
chemotherapy (carboplatin/paclitaxel) in treatment
naïve patients. The study enrolled patients with known
clinical characteristics that are associated with
harbouring the EGFR mutation (adenocarcinoma
subtype, Asian decent, non smokers). In patients with
tumours harbouring EGFR mutations and treated with
gefitinib, response rates and delaying cancer progression
were significantly improved compared to chemotherapy
(HR 0.48, 95% CI 0.36-0.64, p<0.001). Subsequently,
numerous randomized phase III studies of EGFR TKIs in
EGFR mutation positive advanced NSCLC patients with
erlotinib, gefitinib or afatinib have reported high
response rates of up to 50% - 70% and compared to
chemotherapy offer a significant improvement in
delaying disease progression (median progression free
survival is 9 - 11 months with EGFR TKIs), improved
tolerability and health related QoL compared with
platinum-based doublet chemotherapy.21-25 However,
these trials demonstrated no difference in prolonging
survival most likely because of the high proportion of
patients in the chemotherapy arms of these trials that
were treated with EGFR TKIs after study completion (65%
- 95% crossover rates; one pivotal study with erlotinib
included crossover in the study design). The median
survival among advanced NSCLC patients in these trials
ranged from 18.6 to 39 months, compared to
chemotherapy trials of 8 to 11 months, reflecting the
improved prognosis of EGFR mutated NSCLC patients
treated with EGFR TKIs.
Conversely, advanced NSCLC patients that do not have
tumours that harbour activating EGFR mutations have
improved outcomes with chemotherapy opposed to
EGFR TKIs. In the IPASS study, despite patients having
clinical characteristics that are associated with
harbouring the EGFR mutation, those patients without
an EGFR mutation had a delay in disease progression and
improved response rate with chemotherapy compared
to the EGFR TKI. This supports the fact that the presence
of the EGFR mutation predicts efficacy to EGFR TKIs as
opposed to just clinical characteristics. In fact in the
IPASS study which consists of a highly selected
population likely to harbor an EGFR mutation 40% of
Fall 2014 Ontario Thoracic Review
Page 4 of 10
patients did not demonstrate one. Also, the IPASS study
was preceded by the TORCH study that evaluated the
EGFR TKI erlotinib versus chemotherapy in treatment
naïve patients with advanced NSCLC in an unselected
patient population (defined as EGFR mutation unknown).
In this patient population chemotherapy was associated
with superior outcomes compared to the EGFR TKI.26
Based on the aforementioned data, optimal treatment
for advanced NSCLC follows a personalized approach in
which an EGFR TKI with erlotinib, gefitinib or afatinib is
now standard first-line treatment for patients with
advanced NSCLC whose tumours harbour activating
EGFR mutations, and chemotherapy is standard first-line
therapy for advanced EGFR negative NSCLC patients
[Figure 1].27
EGFR TKIs have a very different side effect profile
compared to standard chemotherapy and are generally
better tolerated. 10, 21-25 The most frequent side effects
are a result of inhibition of systemic wild type EGFR,
which includes acneaform rash, stomatitis, paronychia
and diarrhea. The life threatening risk of these agents is
interstitial pneumonitis, fortunately reported in only 1% 3% of patients.10, 21-25 Dosing of the EGFR TKIs is also
more convenient with once a day oral dosing as opposed
to regular clinic visits to the cancer centre which is
required for intravenous chemotherapy. Because of this
side effect profile and ease of administration, EGFR TKIs
offer an effective systemic therapy option for most
patients with an EGFR mutation, including elderly
patients or patients with multiple comorbidities that may
not be candidates for chemotherapy.
ALK positive advanced NSCLC
The ALK gene rearrangement has been found in 2% - 7%
of NSCLC patients with adenocarcinoma, with
approximately 400-500 ALK positive advanced NSCLC
cases occurring each year in Canada.28 There is a higher
prevalence in young patients (median age 49 - 59), never
smokers and may be more likely in men.29, 30 In an
enriched population of non smoker adenocarcinoma
NSCLC the rate is 12%.30 Without targeted therapy, ALK
positive NSCLC may have a less favourable prognosis and
appears to be associated with more advanced disease
stage compared with patients with ALK negative
tumours.29,31
Crizotinib, an oral ALK selective inhibitor is currently the
only approved ALK inhibitor by Health Canada and is
indicated as monotherapy in patients with ALK positive
Volume 27, Issue 1
advanced (not amenable to curative therapy) or
metastatic NSCLC. Following a platinum doublet
crizotinib delayed cancer progression to a median of 7.7
months compared to 3.0 months among those patients
who received chemotherapy (HR 0.49, 95% CI 0.37-0.64;
p<0.0001). The overall response rate was also
significantly higher in those treated with crizotinib (65%
vs 20%; p<0.0001)11. Crizotinib is also associated with
high response rates (57%) in heavily pretreated
advanced ALK positive NSCLC patients and compared to
historical controls it appears to prolong survival.32, 33
Although patients with advanced ALK positive NSCLC
could be offered crizotinib in the treatment naïve
setting, in Ontario drug reimbursement for crizotinib is
currently limited to patients who have previously been
treated with a platinum doublet which reflects the
patient population studied in the phase III clinical trial.27
However, this may change once the phase III trial of
crizotinib versus chemotherapy in treatment naïve ALK
positive advanced NSCLC is reported.
Crizotinib has also shown efficacy in a phase I/II trial in
advanced NSCLC patients with tumours that harbour a
ROS1 gene rearrangement with reported response rates
of 54%.34 The ROS1 rearrangement is found in
approximately 1% of all NSCLC patients. Similar to ALK
positive NSCLC, ROS1 gene rearrangement is more
commonly found in NSCLC tumours of young, non
smokers with adenocarcinoma subtype.35 Due to the
rarity of this mutation, it is unlikely that a phase III trial
will be conducted, thus crizotinib is a valid targeted
therapy option for this patient population.
Similar to the EGFR inhibitors, ALK inhibitors such as
crizotinib are oral agents with a tolerable safety profile.
Common side effects are visual disturbances,
gastrointestinal side effects as well as a transaminitis.11
Future developments
Ultimately, tumours harboring EGFR activating mutations
or ALK gene rearrangements treated with the
appropriate targeted therapies develop resistance.
Currently the standard of care is to treat with
chemotherapy after failure of the targeted therapy.
However, there are a plethora of new targeted agents
that are currently in development to target this resistant
population. The most common mechanism of resistance
to EGFR TKIs in EGFR mutated NSCLC is the development
of a second mutation in the EGFR, the T790M
‘gatekeeper’ mutation, which is found in approximately
60% of patients with acquired resistance.36 Targeted
Fall 2014 Ontario Thoracic Review
Page 5 of 10
agents to the T790M mutation are currently in phase I/II
studies and have reported high response rates of up to
67% in this resistant population.37,38 Also, preliminary
results with second generation ALK inhibitors after
failure of crizotinib have reported response rates of 50%
- 60%.39,40 As well these second generation ALK
inhibitors appear to cross the blood brain barrier and
may be effective in treating brain metastases.
Currently approved targeted agents and newer
chemotherapy agents such as pemetrexed are generally
limited to adenocarcinoma subtype. However, there are
ongoing studies looking for driver mutations in
squamous cell carcinoma.41 One of the new targets in
NSCLC is hepatic growth factor/cMET overexpression
which is found in approximately 25% - 75% of NSCLC
including both adenocarcinoma and squamous cell
histologies.42 cMET overexpression is associated with a
poor prognosis and is also a mechanism of acquired
resistance to EGFR TKIs. There appears to be a synergistic
effect of cMET activation and EGFR. MET inhibitors are
currently in clinical trials.42,43,44
Other driver mutations that have been identified include,
but are not limited to, FGFR1, PIK2CA, PTEN, HER2, and
BRAF mutations. The impact of these mutations and
response to matching targeted therapies will need to be
validated in future clinical trials.41 The Lung Cancer
Mutation Consortium presented data recently that found
that two thirds of NSCLC patients have an oncogenic
driver and those patients with these drivers have been
shown to live longer if they receive the corresponding
targeted agent.45
The Importance of Tissue
Testing for EGFR and ALK mutations requires paraffinembedded tissues whether obtained by thin needle
biopsies in cytologic samples or traditional core biopsies.
Insuring this tissue is available requires co-operation of
the physician obtaining the sample (usually an
interventional radiologist) as well as the pathologist.
Both have to adapt their practice patterns to obtain the
necessary information regarding EGFR and ALK
mutations for the treating oncologist.
for these purposes. In the pathology lab cytology
technologists should use all material for cell blocks
rather than cytospin preparations as the latter cannot be
used for molecular testing.
Specimens are usually very small and there is significant
patient morbidity incurred to obtain them, therefore the
tissue should be used in the most effective manner.
Pathologists must minimize the use of immunostains to
diagnose these specimens and save as much tissue
possible for mutation analysis. The number and type of
immunostains must be the minimum to determine that
the lesion is non-small cell primary lung carcinoma and
to distinguish squamous carcinoma from
adenocarcinoma. Each case is judged on its clinical and
histologic context but for what appears to be a
straightforward lung adenocarcinoma TTF1 is useful to
support primary adenocarcinoma while p63 will be
negative in these cases.46
Mutational analysis can be performed on primary
tumours or on metastases including effusions as long as
a cell block is created. The only tissue often unsuitable
for analysis are those that have been decalcified such as
bone biopsies. If a bone lesion is the only appropriate
target for a biopsy, advising the interventional radiologist
to target a soft tissue component will improve the
success of mutational testing.
From time of initiation of EGFR and ALK testing to time of
reporting results, this takes a median of 18 +/- 9.7 days
(range: 15 - 26 days).47 Patients with advanced NSCLC are
often quite symptomatic from their disease, thus the
weeks required to report EGFR and ALK results creates a
barrier for medical oncologists to offer personalized
medicine. Pathologists can play a crucial role in reducing
this turnaround time by ordering EGFR and ALK testing
once the diagnosis of NSCLC non-squamous subtype is
made. A majority of patients with NSCLC present with
advanced stage disease, therefore a significant number
of patients would benefit from having their EGFR and
ALK mutation results known at the time of first
consultation with a medical oncologist. Also, given the
poor prognosis of NSCLC across all stages, a significant
number of patients with earlier stage disease will
progress to advanced disease in which EGFR and ALK
mutation results will eventually guide their therapy. This
supports the notion to test all tumour samples for EGFR
and ALK mutations at time of diagnosis of non-squamous
NSCLC irrespective of stage, a term coined “reflex
testing”.
For the radiologist the number of smears prepared
should be minimized to allow most of the specimen to be
placed in the “rinse” for preparation of a cell block. A
cell block is a centrifuged button of tissue embedded in
paraffin in the cytology laboratory. These may be used
for EGFR and ALK testing while smears cannot be used
Volume 27, Issue 1
Fall 2014 Ontario Thoracic Review
Page 6 of 10
There has been some exploration of searching for
mutations in plasma using highly sensitive molecular
techniques. Although these methods appear less
sensitive than tissue assays they may be used in the
future to monitor therapy, or in selected patients where
a biopsy is not possible.48, 49
Summary
Over the last decade the treatment of advanced
incurable NSCLC has evolved considerably and a
personalized approach to treatment is now a reality.
There are effective therapies for advanced NSCLC that
are beyond chemotherapy and offer a tolerable safety
profile. Given that the median age of patients with
NSCLC is 70, patients are often elderly with a poor
performance status or have multiple comorbidities which
makes them ineligible for chemotherapy. However, they
may be eligible for a targeted therapy assuming they
have the appropriate target.
It is important for physicians involved in the diagnosis
and treatment of lung cancer to be aware that
maximizing tissue yield for histologic subtyping and
molecular testing is essential to be able to offer patients
a personalized treatment approach. Furthermore,
clinical trials in advanced NSCLC routinely include
biomarker analysis and a tissue sample is often required
for eligibility. Testing all patients with advanced NSCLC
adenocarcinoma subtype for EGFR mutations and ALK
gene rearrangements is now the standard of care.27
Relying on patient demographics to select patients for
EGFR and ALK testing (i.e. non smokers) would miss
eligible patients for potentially effective targeted
therapies or the corollary is true in that one might select
patients who do not harbor a mutation thus exposing
them to an ineffective treatment.
This is an exciting time to be involved in the care of
patients with NSCLC as we are just at the tip of the
iceberg for personalized systemic therapies. With
increasing knowledge of the genomic landscape of NSCLC
it is expected that further driver mutations will be
identified and the development of matching targeted
therapies will continue to grow.
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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D.
Global cancer statistics. CA Cancer J Clin. 2011; 61(2):69-90.
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Cancer Care Ontario. Cancer Fact: Lung cancer is the
leading cause of cancer death among Ontario women
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[internet]. Toronto, Cancer Care Ontario; 2012 January.
[cited 2014 March 03] Available from:
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Canadian Cancer Society's Steering Committee on Cancer
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Toronto: Canadian Cancer Society; 2012 May. [cited 2014
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and the Comparative Risk Assessment collaborating group
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Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J
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24. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B,
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Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J,
Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M,
Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D,
Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo
R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia
V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal
A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A,
Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA,
Taron M, Paz-Ares L; Spanish Lung Cancer Group in
collaboration with Groupe Français de PneumoCancérologie and Associazione Italiana Oncologia Toracica.
Erlotinib versus standard chemotherapy as first-line
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T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J,
Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V,
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plus pemetrexed in patients with metastatic lung
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31 (27): 3327-3334
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da Cunha Santos G, Piccirillo MC, Di Maio M, Morabito A,
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30. Koh Y, Kim DW, Kim TM, Lee SH, Jeon YK, Chung DH, Kim
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Ontario Lung Health Action Plan
Calling for an Ontario Lung Health Action Plan
In the Spring/Summer 2014 edition of the Ontario
Thoracic Review, we told you about our efforts to create
a comprehensive Ontario Lung Health Action Plan.
Of the four chronic diseases responsible for eight out of
10 deaths (cancers, cardiovascular diseases, lung disease
and diabetes), lung disease is the only one without a
dedicated province-wide strategy.
If we don’t act quickly to stem the rising tide of lung
disease in Ontario, the economic impact will reach a
staggering $300 billion within the next 30 years.
The time is approaching when Ontario simply will not be
able to afford the high cost of treating people with lung
disease.
With a comprehensive and coordinated Ontario Lung
Health Action Plan, however, we can prevent lung
disease, improve patient outcomes and reduce costs.
Over the past several months, OLA has continued to
work with experts, patients, other health-care
organizations and government to make lung health a
priority in this province. The consultation session and
reception at Queen’s Park on November 25 are the next
major steps in developing a comprehensive plan for the
province.
Jeff Yurek, MPP for Elgin-Middlesex-London, is
sponsoring this private member’s bill designed to make
the province’s schools safe for children with asthma.
The Bill is named in memory of Ryan Gibbons, who died
in the fall of 2012 after suffering an asthma attack at
school.
To learn more about Ryan’s Law, please
visit: www.passryanslaw.com.
We are also urging all members of provincial parliament
to support Bill 11, the Radon Awareness and Prevention
Act. The legislation provides for creation of an Ontario
Radon Registry and will reduce radon levels in dwellings
and workplaces.
Radon is a colourless, odourless gas that is produced
from the natural breakdown of uranium in the ground.
Radon can enter a home through tiny openings in floors
and foundations and build up to dangerous levels. Longterm exposure to radon is the second leading cause of
lung cancer in Canada.
In September, we were pleased to join partners from
Health Canada, the Canadian Association of Radon
Scientists and Technologists (CARST), and a very special
guest, Canada's most famous contractor Mike Holmes, to
help a Niagara Falls couple install a radon mitigation
system in their contaminated home.
You can review the Global TV News coverage of the
event here: www.globalnews.ca/news/1571387/whyyou-should-test-your-home-for-radon-gas.
To learn more or to support our advocacy efforts please
contact Chris Yaccato, Provincial Manager, Government
Relations and Public Affairs, at: [email protected].
With your support the OLA will be better positioned to
help Ontarians breathe with ease.
Because when you can’t breathe, nothing else matters.™
Our advocacy efforts, however, don’t stop there. The
OLA is also supporting other critical pieces of provincial
legislation which align with the overall goals of the
Action Plan.
Currently, we are working to secure passage of Bill 20,
Ryan’s Law.
Volume 27, Issue 1
Fall 2014 Ontario Thoracic Review
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