Original Article
Frequency of actionable alterations in epidermal growth factor
receptor (EGFR) wild type non-small cell lung cancer: experience
of the Wide Catchment Area of Romagna (AVR)
Elisa Chiadini1, Matteo Canale1, Angelo Delmonte2, Claudio Dazzi3, Claudia Casanova3, Laura Capelli1,
Marita Mariotti 2, Maximilian Papi 4, Alessandro Gamboni 5, Maurizio Puccetti 6, Sara Bravaccini 1,
Alessandra Dubini7, Daniele Calistri1, Lucio Crinò2, Paola Ulivi1
1
Biosciences Laboratory, 2Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS,
Meldola, Italy; 3Medical Oncology Unit, S. Maria delle Croci Hospital, Ravenna, Italy; 4Oncology and Oncohematology Unit, Infermi Hospital,
Rimini, Italy; 5Medical Oncology Unit, Infermi Hospital, Faenza, Italy; 6Pathology Unit, S. Maria delle Croci Hospital, Ravenna, Italy; 7Pathology
Unit, Morgagni-Pierantoni Hospital, Forlì, Italy
Contributions: (I) Conception and design: P Ulivi; (II) Administrative support: None; (III) Provision of study materials or patients: M Puccetti,
A Dubini; (IV) Collection and assembly of data: A Delmonte, C Dazzi, C Casanova, M Mariotti, M Papi, A Gamboni; (V) Data analysis and
interpretation: P Ulivi; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Paola Ulivi. Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P.
Maroncelli 40, 47014 Meldola, Italy. Email: paola.ulivi@irst.emr.it.
Background: Molecular diagnostics for non-small cell lung cancer (NSCLC) has become the standard
of care for personalized treatment. Epidermal growth factor receptor (EGFR) mutation and EML4-ALK
translocation represent the two most important alterations in first-line treatment decision-making. However,
other potentially targetable alterations are also present.
Methods: One thousand consecutive NSCLC patients with EGFR wild type (wt) tumors diagnosed by
routine molecular analysis were considered. KRAS, BRAF, ERBB2, PIK3CA, NRAS, ALK, MAP2K1, RET and
DDR2 gene mutations were analyzed using the multiparametric Sequenom MassARRAY® platform. EML4ALK and ROS1 rearrangements were also assessed by fluorescent in situ hybridization. HER4 status was
determined by direct sequencing.
Results: Three hundred and forty-eight (34.8%), 31 (3.1%), 39 (4.4%), 14 (1.8%), 6 (0.7%), 16 (1.8%), 5
(0.6%) and 9 (0.9%) patients showed an alteration in KRAS, BRAF, ALK, ROS1, NRAS, PIK3CA, MAPK1/2
and HER2 genes, respectively. Of the 657 patients for whom all markers were determined, 318 (48%)
patients had at least one alteration. Eight patients showed overlapping mutations, 4 KRAS mutation/EML4ALK translocation, one KRAS mutation/ROS1 rearrangement, 2 KRAS/PIK3CA mutations, and one BRAF/
PIK3CA mutations.
Conclusions: About 50% of our patients had a potentially targetable alteration, confirming the usefulness
of a multiparametric approach for routine molecular diagnostics aimed at identifying potential therapeutic
targets.
Keywords: Non-small cell lung cancer (NSCLC); targeted therapy; epidermal growth factor receptor (EGFR);
multitarget analysis; Formalin-fixed paraffin-embedded samples (FFPE samples)
Submitted Apr 11, 2018. Accepted for publication Jun 15, 2018.
doi: 10.21037/jtd.2018.07.22
View this article at: http://dx.doi.org/10.21037/jtd.2018.07.22
© Journal of Thoracic Disease. All rights reserved.
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Journal of Thoracic Disease, Vol 10, No 8 August 2018
Introduction
Targeted therapy for non-small cell lung cancer (NSCLC)
has transformed the outcome of patients carrying specific
molecular alterations. In particular, epidermal growth
factor receptor tyrosine kinase inhibitors (EGFR-TKIs),
such as gefitinib, erlotinib or afatinib, and anti-ALK agents,
such as crizotinib, have changed the natural history of
adenocarcinoma patients carrying specific EGFR mutations
or EML4-ALK translocation/ROS1 rearrangements,
respectively (1-5). Other potentially targetable alterations
have been identified in lung cancer. Of these, BRAF and
HER2 mutations are present in about 3% and 2% of
patients with lung adenocarcinoma, respectively (6-8) and
represent possible targets for therapy using anti BRAF
(vemurafenib or dabrafenib) or anti-HER2 (trastuzumab,
dacomitinib, etc.) agents (8-11). Moreover, mesenchymalepithelial transition factor (MET) alterations (mutation or
amplification) would seem to identify a subset of patients
who are more likely to respond to crizotinib (12,13). In
addition, other potentially targetable alterations have been
found in several genes, including NTRK1, PIK3CA, HER4,
NRAS (6,14-18), and the frequency of these alterations
differs in different ethnicities. The number of clinical trials
aimed at analyzing the effect of targeted drugs specific
for these different alterations is thus expected to increase
enormously in the near future.
In the present study we evaluated a large Italian cohort
of NSCLC patients, all EGFR wild type (wt) according
to diagnostic molecular analysis, to verify the frequency
of potentially targetable alterations in relation to clinical
pathological characteristics of patients.
4859
samples, cytological FFPEs (cell blocks) or cytological
smears were available for molecular analysis. Biological
samples were evaluated and selected by AVR pathologists.
Tumor specimens comprising at least 50% tumor cells were
selected and underwent DNA extraction.
EML4-ALK and ROS1 determinations
Selected FFPE histological or cytological sections and
cytological samples were used to perform EML4-ALK and
ROS1 determinations. FISH assay was performed using a
break-apart ALK or ROS1 probe (Vysis LSI Dual Color,
Break Apart Rearrangement Probe; Abbott/Vysis, Illinois,
IL, USA. ALK and ROS1 rearrangements were scored as
positive when ≥15% of tumor cells displayed split signals
or isolated signals containing a kinase domain (red for ALK
and green for ROS1), as previously described (19,20). Slides
containing at least 50 tumor cells were considered evaluable
and were read independently by two experts blinded to the
patient’s history and histological findings.
Mutation analysis
Mutation analyses were centralized and performed in the
Biosciences Laboratory of IRST IRCCS. KRAS, BRAF,
ERBB2, PIK3CA, NRAS, ALK, MAP2K1, RET and DDR2
gene status was analyzed by Myriapod ®Lung Status kit
(Diatech Pharmacogenetics, Jesi, Italy) on MassARRAY®
(SEQUENOM® Inc., San Diego, CA, USA). Exons 18 to
23 of the HER4 gene were evaluated by direct sequencing.
Statistical analysis
Methods
Patients
We evaluated a cohort of 1,000 patients, all recruited
from the Wide Catchment Area of Romagna (AVR), with
histologically or cytologically confirmed advanced NSCLC
classified as EGFR wt by routine diagnostic molecular
analysis from January 2013 to December 2016. The clinical
pathological characteristics of patients are reported in
Table 1. The study was approved by our institutional Review
Board and all patients gave written informed consent.
Biological samples
Formalin-fixed paraffin-embedded (FFPE) histological
© Journal of Thoracic Disease. All rights reserved.
The chi-square test was used for group comparison of
variables.
Results
Frequency of gene alterations
KRAS, BRAF and HER2 determinations were performed in
the entire case series. Conversely, there was only sufficient
biological to perform NRAS, PIK3CA, MAP2K1, ALK, RET
and DDR2 mutation analysis in 901 patients, EML4-ALK
evaluation in 889 patients and ROS1 determinations in 733
patients. Overall, characterization of all 11 markers was
performed in 657 patients. HER4 mutation analysis was also
carried out in 450 cases. Three hundred and forty-eight
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Chiadini et al. Frequency of actionable alterations in EGFR wt NSCLC
Table 1 Relation between the Different Alterations and the Clinical Pathological Characteristics of Patients
Total No.
gene
mutations
Female
Male
P
<70
≥70
P
Never
Former
Current
P
KRAS
348
132 (37.9)
216 (62.1)
0.950
174 (50.0)
174 (50.0)
0.467
29 (11.1)
79 (30.2)
154 (58.8)
<0.001
BRAF
31
13 (41.9)
18 (58.1)
0.633
17 (54.8)
14 (45.2)
0.669
3 (15.0)
6 (30.0)
11 (55.0)
0.955
NRAS
6
4 (67.0)
2 (33.0)
0.204
6 (100.0)
–
0.032
–
2 (50.0)
2 (50.0)
0.656
PIK3CA
16
6 (37.5)
10 (62.5)
0.000
6 (37.5)
10 (62.5)
0.240
1 (10.0)
4 (40.0)
5 (50.0)
0.760
MAPK1/2
5
–
5 (100.0)
0.164
4 (80.0)
1 (20.0)
0.376
1 (20.0)
1 (20.0)
3 (60.0)
1.000
HER2
9
6 (66.7)
3 (33.3)
0.087
4 (44.0)
5 (56.0)
0.746
2 (40.0)
2 (40.0)
1 (20.0)
0.221
EML4-ALK
39
23 (59.0)
16 (41.0)
0.005
28 (71.8)
11 (28.2)
0.015
17 (51.5)
4 (12.1)
12 (36.4)
<0.001
ROS1
14
9 (64.3)
5 (35.7)
0.053
8 (57.1)
6 (42.9)
0.748
6 (66.7)
1 (11.1)
2 (22.2)
0.002
Gene
alteration
Gender (%)
Age, years (%)
Smoking habits* No. (%)
*, percentages refer to the total number of patients with smoking habits information available.
34.8%
51.9%
%
4.4
%
3.1
%
1.8
%
1.8 %
0.9 %
0.7
0.6%
KRAS
EML4-ALK
BRAF
ROS1
PIK3CA
HER2
NRAS
MAPK1/2
No oncogenic driving
Figure 1 Frequency of gene alterations in the entire case series of
EGFR wt patients.
(34.8%), 31 (3.1%), 39 (4.4%), 14 (1.8%), 6 (0.7%), 16
(1.8%), 5 (0.6%) and 9 (0.9%) patients showed an alteration
in KRAS, BRAF, ALK, ROS1, NRAS, PIK3CA, MAPK1/2
and HER2 genes, respectively (Figure 1). Of the 657 patients
in whom all the markers were determined, 318 (48%)
showed at least one alteration. The different mutations
found for each gene are shown in Figure 2. Eighty-four
percent of KRAS mutations were found at codon 12, the
majority (39%) being G12C alterations, while 10.3% of
mutations involved codon 13. Around half of all BRAF
mutations (54.8%) were V600E, whereas 45.2% were other
exon 15 alterations or exon 11 mutations. In particular, 2
(14%) of the mutated patients with no V600E alteration
harbored a different exon 15 mutation (D594G), while 12
(86%) showed an exon 11 alteration, 5 involving codon
466 (2 G466A, 2 G466E, one G466V) and 7 codon 469 (3
G469A, 1 G469E, 3 G469V). All NRAS mutations were
at codon 61 (3 Q61K, 2 Q61L and one Q61R), whereas
© Journal of Thoracic Disease. All rights reserved.
PIK3CA alterations were found in exon 9 (93.8%) in all
but one patient (exon 20). Of the 5 patients carrying a
MAPK1/2 mutation, 2 (40%) had a Q56P alteration whereas
3 (60%) showed a K57N substitution (Figure 2). Finally, all
HER2-mutated patients had an exon 20 insertion. The only
mutation found in HER4 gene was found in a former male
smoker and located in exon 19 (G735V). No alterations
were found in ALK, RET or DDR2 genes.
Eight patients showed overlapping mutations:
concomitant KRAS mutation and EML4-ALK translocation
(4 cases); KRAS mutation together with ROS1
rearrangement (1 case); concomitant KRAS and PIK3CA
mutation (2 cases); and concomitant BRAF and PIK3CA
mutation (1 case).
Gene alterations in relation to clinical pathological
characteristics of patients
The relation between the different alterations and the
clinical pathological characteristics of patients is reported
in Table 2. EML4-ALK translocation was significantly
correlated with gender, age and smoking habits (P=0.005,
P=0.015 and P<0.001, respectively) and was more frequent
in young, non-smoking females. ROS1 rearrangements
were significantly correlated with gender and smoking
habits (P=0.053 and P=0.002, respectively) but not with
age. Moreover, KRAS mutations were significantly more
common in current smokers (P<0.001), whereas NRAS
mutations were only found in patients <70 years of age
(P=0.032).
Of the 4 patients showing concomitant EML4-ALK
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KRAS
4861
KRAS
Other Cod 12
2.3% G13D
G12S
2.3%
2.3%
Q61H
4.9%
G12R
2.3%
BRAF
G469E
3.2%
G12D
12.4%
G12A
7.2%
G469V
9.7%
G469A
9.7%
G466V
3.2%
G12V
19.8%
G12C
39%
V600E
54.8%
G466E
6.5%
G466A
6.5%
D594G
6.5%
NRAS
PIK3CA
H1047R
E545Q 6%
6%
Q61R
17%
Q61L
33%
E542K
44%
Q61Q
50%
E454K
44%
MAPK1/2
Q56P
40%
Q57N
60%
Figure 2 Types of mutations found in the different genes.
translocations and KRAS mutations (3 of whom were
smokers), 2 were treated with first-line crizotinib and
second-line ceritinib. One patient harboring a G12D KRAS
mutation and with 70% fluorescent in situ hybridization
(FISH) positivity initially showed stable disease with
crizotinib but progressed after 5 cycles, and then again
obtained stable disease with ceritinib, relapsing after 4
treatment cycles. Another patient with a G13S KRAS
mutation and 50% FISH positivity obtained a partial
response with crizotinib lasting 6 treatment cycles and
another partial response with ceritinib lasting 3 cycles.
© Journal of Thoracic Disease. All rights reserved.
The only patient showing a concomitant KRAS mutation
(G12V) and ROS1 rearrangement was treated with secondline crizotinib but developed severe toxicity that led to
treatment suspension before the clinical response could be
evaluated.
Discussion
In the present study we report our results on a cohort of
1,000 consecutive NSCLC patients identified as EGFR wt
by routine diagnostic molecular analysis performed at our
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Chiadini et al. Frequency of actionable alterations in EGFR wt NSCLC
Table 2 Clinical pathological characteristics of analyzed samples
Variables
Overall
No. (%)
1,000
Age, years
>70
431 (43.0)
≤70
569 (57.0)
Gender
Male
622 (62.0)
Female
378 (38.0)
Smoking habits
Current
379 (37.9)
Former
239 (23.9)
Never
145 (14.5)
Missing
237 (23.7)
Histotype
ADC
793 (79.3)
PDC
178 (17.8)
Other
29 (2.9)
Type of sample
Histological
639 (64.0)
Cytological
361 (36.0)
ADC, adenocarcinoma; PDC, poorly differentiated carcinoma.
institute (IRST IRCCS). We demonstrated that about half
of all the EGFR wt patients carried a potentially targetable
gene alteration. The frequencies of alterations were as
follows: KRAS, 35%; EML4-ALK, 4.4%; BRAF, 3.1%;
ROS1, 0.7%; PIK3CA, 1.8; NRAS, 1.8%; MAPK1/2, 0.6%;
and HER2, 0.9%. Such findings are in agreement with
literature data (6,15,16,21). A slightly higher frequency
of KRAS mutations was observed, possibly attributable to
the fact that we considered a selected case series of EGFR
wt patients in whom KRAS mutations were more frequent
due to the mutual exclusivity of the 2 gene mutations. In
accordance with previous authors (22), we observed a higher
incidence of KRAS mutation and a high prevalence of G12C
alterations in current smokers.
With regard to BRAF mutation, we saw that almost half
of the mutated patients carried non-V600E alterations that
were predominantly located in exon 11 at codons 466 and
469. It is known that V600 alterations predict sensitivity to
© Journal of Thoracic Disease. All rights reserved.
anti-BRAF and anti-MEK combinations (23). Moreover,
recent evidence suggests that non-V600 alterations may
also be associated with sensitivity to such treatments (24).
These results suggest that about 3% of EGFR wt patients
could benefit from this type of targeted treatment.
In agreement with other studies (7), no associations
were observed between BRAF mutations and clinical
pathological characteristics of patients. Around 6% of our
patients harbored an EML4-ALK (4.4%) or ROS1 (1.8%)
rearrangement, the majority of whom were predominantly
young females who had never smoked, as described in other
studies (19,25).
Other alterations that are potential targets for treatment
are present in lung adenocarcinoma, e.g., 1.8% of our
patients carried a PIK3CA mutation. Although there are
still no drugs capable of inhibiting the growth of PIK3CA
mutated cells, such mutations would seem to confer
resistance to TKIs (26,27), making their determination of
clinical importance.
We observed a slightly lower percentage of HER2
mutations with respect to that described in the literature (28)
but similar (1.7%) to the findings of Mazières et al. (8). in a
large case series. However, the relatively low sensitivity of
the Sanger sequencing we used for the detection of HER2
mutations may partly explain our results. No significant
associations were found between HER2 mutation and
gender, age or smoking habits.
We also observed 8 patients with overlapping mutations,
4 of whom showed concomitant EML4-ALK and KRAS
alterations. Of these, 2 underwent treatment with anti-ALK
agents, one obtaining a partial response. In agreement with
other authors, we have already seen that the presence of a
KRAS mutation in patients with EML4-ALK translocation
can confer resistance to treatment with crizotinib (29,30).
Although the low number of double-mutated patients in our
study does not permit us to draw any definitive conclusions
about this, there were seem to be sufficient evidence to warrant
KRAS status being taken into consideration in EML4-ALK
translocated patients treated with anti-ALK agents.
In conclusion, although the frequency of single gene
alterations in our study was low, about half of the patients
with EGFR wt lung adenocarcinoma analyzed showed a
potentially targetable alteration. Anti-ALK agents have
already been approved for use as first-line treatment
of EML4-ALK-translocated tumors. However, larger,
randomized clinical trials are needed to verify the usefulness
of targeted agents in tumors harboring other specific
alterations.
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4863
Acknowledgements
The authors would like to thank Cristiano Verna for
editorial assistance.
10.
Footnote
Conflicts of Interest: The authors have no conflicts of interest
to declare.
11.
Ethical Statement: The study was approved by our
institutional Review Board (No. 675 of 3.09.2013) and all
patients gave written informed consent.
12.
References
13.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or
carboplatin-paclitaxel in pulmonary adenocarcinoma. N
Engl J Med 2009;361:947-57.
Rosell R, Carcereny E, Gervais R, et al. Erlotinib
versus standard chemotherapy as first-line treatment for
European patients with advanced EGFR mutation-positive
non-small-cell lung cancer (EURTAC): a multicentre,
open-label, randomised phase 3 trial. Lancet Oncol
2012;13:239-46.
Yang JC, Wu YL, Schuler M, et al. Afatinib versus
cisplatin-based chemotherapy for EGFR mutation-positive
lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6):
analysis of overall survival data from two randomised,
phase 3 trials. Lancet Oncol 2015;16:141-51.
Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib
versus chemotherapy in ALK-positive lung cancer. N Engl
J Med 2014;371:2167-77.
Mazières J, Zalcman G, Crinò L, et al. Crizotinib
therapy for advanced lung adenocarcinoma and a ROS1
rearrangement: results from the EUROS1 cohort. J Clin
Oncol 2015;33:992-9.
Kris MG, Johnson BE, Berry LD, et al. Using multiplexed
assays of oncogenic drivers in lung cancers to select
targeted drugs. JAMA 2014;311:1998-2006.
Chen D, Zhang LQ, Huang JF, et al. BRAF mutations
in patients with non-small cell lung cancer: a systematic
review and meta-analysis. PLoS One 2014;9:e101354.
Mazières J, Peters S, Lepage B, et al. Lung cancer
that harbors an HER2 mutation: epidemiologic
characteristics and therapeutic perspectives. J Clin
Oncol 2013;31:1997-2003.
Gautschi O, Milia J, Cabarrou B, et al. Targeted therapy
© Journal of Thoracic Disease. All rights reserved.
14.
15.
16.
17.
18.
19.
20.
21.
22.
for patients with BRAF-mutant lung cancer: results
from the european EURAF cohort. J Thorac Oncol
2015;10:1451-7.
Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib
in multiple nonmelanoma cancers with BRAF V600
mutations. N Engl J Med 2015;373:726-36.
Kris MG, Camidge DR, Giaccone G, et al. Targeting
HER2 aberrations as actionable drivers in lung cancers:
phase II trial of the pan-HER tyrosine kinase inhibitor
dacomitinib in patients with HER2-mutant or amplified
tumors. Ann Oncol 2015;26:1421-7.
Lu X, Peled N, Greer J, et al. MET Exon 14 mutation
encodes an actionable therapeutic target in lung
adenocarcinoma. Cancer Res 2017;77:4498-505.
Suryavanshi M, Shah A, Kumar D, et al. MET
amplification and response to MET inhibitors in stage IV
lung adenocarcinoma. Oncol Res Treat 2017;40:198-202.
Ding L, Getz G, Wheeler DA, et al. Somatic mutations
affect key pathways in lung adenocarcinoma. Nature
2008;455:1069-75.
Sholl LM, Aisner DL, Varella-Garcia M, et al. Multiinstitutional oncogenic driver mutation analysis in lung
adenocarcinoma: the Lung Cancer Mutation Consortium
experience. J Thorac Oncol 2015;10:768-77.
Yeung SF, Tong JH, Law PP, et al. Profiling of oncogenic
driver events in lung adenocarcinoma revealed MET
mutation as independent prognostic factor. J Thorac
Oncol 2015;10:1292-300.
Schrock AB, Frampton GM, Suh J, et al. Characterization
of 298 patients with lung cancer harboring MET exon 14
skipping alterations. J Thorac Oncol 2016;11:1493-1502.
Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and
drug-sensitive NTRK1 rearrangements in lung cancer.
Nat Med 2013;19:1469-72.
Bergethon K, Shaw AT, Ou SH, et al. ROS1
rearrangements define a unique molecular class of lung
cancers. J Clin Oncol 2012;30:863-70.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic
lymphoma kinase inhibition in non-small-cell lung cancer.
N Engl J Med 2010;363:1693-703.
Daoud A, Chu QS. Targeting novel but less common
driver mutations and chromosomal translocations in
advanced non-small cell lung cancer. Front Oncol
2017;7:222.
Chapman AM, Sun KY, Ruestow P, et al. Lung cancer
mutation profile of EGFR, ALK, and KRAS: meta-analysis
and comparison of never and ever smokers. Lung Cancer
2016;102:122-34.
jtd.amegroups.com
J Thorac Dis 2018;10(8):4858-4864
4864
23. Planchard D, Smit EF, Groen HJ, et al. Dabrafenib
plus trametinib in patients with previously untreated
BRAFV600E-mutant metastatic non-small-cell lung
cancer: an open-label, phase 2 trial. Lancet Oncol
2017;18:1307-16.
24. Noeparast A, Teugels E, Giron P, et al. Non-V600
BRAF mutations recurrently found in lung cancer
predict sensitivity to the combination of Trametinib and
Dabrafenib. Oncotarget 2016;8:60094-108.
25. Pillai RN, Ramalingam SS. The biology and clinical
features of non-small cell lung cancers with EML4-ALK
translocation. Curr Oncol Rep 2012;14:105-10.
26. Chen JY, Cheng YN, Han L, et al. Predictive value of K-ras
and PIK3CA in non-small cell lung cancer patients treated
with EGFR-TKIs: a systemic review and meta-analysis.
Cancer Biol Med 2015;12:126-39.
27. Wu SG, Chang YL, Yu CJ, et al. The Role of PIK3CA
Chiadini et al. Frequency of actionable alterations in EGFR wt NSCLC
mutations among lung adenocarcinoma patients with
primary and acquired resistance to EGFR tyrosine kinase
inhibition. Sci Rep 2016;6:35249.
28. Pillai RN, Behera M, Berry LD, et al. HER2 mutations
in lung adenocarcinomas: a report from the Lung Cancer
Mutation Consortium. Cancer 2017;123:4099-105.
29. Ulivi P, Chiadini E, Dazzi C, et al. Nonsquamous,
non-small-cell lung cancer patients who carry a double
mutation of EGFR, EML4-ALK or KRAS: frequency,
clinical-pathological characteristics, and response to
therapy. Clin Lung Cancer 2016;17:384-90.
30. Mengoli MC, Barbieri F, Bertolini F, et al. K-RAS
mutations indicating primary resistance to crizotinib in
ALK-rearranged adenocarcinomas of the lung: report
of two cases and review of the literature. Lung Cancer
2016;93:55-8.
Cite this article as: Chiadini E, Canale M, Delmonte A, Dazzi
C, Casanova C, Capelli L, Mariotti M, Papi M, Gamboni A,
Puccetti M, Bravaccini S, Dubini A, Calistri D, Crinò L, Ulivi
P. Frequency of actionable alterations in EGFR wild type nonsmall cell lung cancer: experience of the Wide Catchment Area
of Romagna (AVR). J Thorac Dis 2018;10(8):4858-4864. doi:
10.21037/jtd.2018.07.22
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J Thorac Dis 2018;10(8):4858-4864