Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report
Aim: Classic activating mutations L858R and deletions in exon 19 (19del) in the gene for epidermal growth factor receptor (EGFR) are associated with sensitivity of the non-small cell lung cancer (NSCLC) to therapy with tyrosine kinase inhibitors (TKI). Insertions in EGFR exon 19 (19ins) are rare mut...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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irk-123456789-1379712018-06-18T03:12:50Z Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report Kozlov, V. Karpov, I. Kovalenko, S. Shamanin, V. Case report Aim: Classic activating mutations L858R and deletions in exon 19 (19del) in the gene for epidermal growth factor receptor (EGFR) are associated with sensitivity of the non-small cell lung cancer (NSCLC) to therapy with tyrosine kinase inhibitors (TKI). Insertions in EGFR exon 19 (19ins) are rare mutations in NSCLC; response of cases with 19ins to TKI is not well studied. Here we report a case of NSCLC with 19ins in a Russian patient who was treated with gefitinib. We also overview cases of 19ins reported in the literature. Case description: A 48 years old female Russian patient was diagnosed with adenocarcinoma of the lung (T3N2M1, stage IV). Mutation 19ins was detected in the tumor biopsy by fragment analysis and genotyped by Sanger sequencing as p.I744_K745insKIPVAI. Treatment with gefitinib (250 mg/day) resulted in clinical and radiological improvements scored as partial response that lasted 12 months. Conclusion: Treatment with gefitinib of lung adenocarcinoma that carries mutation EGFR 19ins can result in durable response. 2017 Article Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report / V. Kozlov, I. Karpov, S. Kovalenko, V. Shamani // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 155–156. — Бібліогр.: 7 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/137971 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Case report Case report Kozlov, V. Karpov, I. Kovalenko, S. Shamanin, V. Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report Experimental Oncology |
| description |
Aim: Classic activating mutations L858R and deletions in exon 19 (19del) in the gene for epidermal growth factor receptor (EGFR) are associated with sensitivity of the non-small cell lung cancer (NSCLC) to therapy with tyrosine kinase inhibitors (TKI). Insertions in EGFR exon 19 (19ins) are rare mutations in NSCLC; response of cases with 19ins to TKI is not well studied. Here we report a case of NSCLC with 19ins in a Russian patient who was treated with gefitinib. We also overview cases of 19ins reported in the literature. Case description: A 48 years old female Russian patient was diagnosed with adenocarcinoma of the lung (T3N2M1, stage IV). Mutation 19ins was detected in the tumor biopsy by fragment analysis and genotyped by Sanger sequencing as p.I744_K745insKIPVAI. Treatment with gefitinib (250 mg/day) resulted in clinical and radiological improvements scored as partial response that lasted 12 months. Conclusion: Treatment with gefitinib of lung adenocarcinoma that carries mutation EGFR 19ins can result in durable response. |
| format |
Article |
| author |
Kozlov, V. Karpov, I. Kovalenko, S. Shamanin, V. |
| author_facet |
Kozlov, V. Karpov, I. Kovalenko, S. Shamanin, V. |
| author_sort |
Kozlov, V. |
| title |
Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report |
| title_short |
Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report |
| title_full |
Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report |
| title_fullStr |
Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report |
| title_full_unstemmed |
Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report |
| title_sort |
adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2017 |
| topic_facet |
Case report |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/137971 |
| citation_txt |
Adenocarcinoma of the lung with rare insertion mutation in egfr exon 19 that had partial response to gefitinib: a case report / V. Kozlov, I. Karpov, S. Kovalenko, V. Shamani // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 155–156. — Бібліогр.: 7 назв. — англ. |
| series |
Experimental Oncology |
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| first_indexed |
2025-07-10T04:51:09Z |
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2025-07-10T04:51:09Z |
| _version_ |
1837234203066892288 |
| fulltext |
Experimental Oncology 39, 155–156, 2017 (June) 155
ADENOCARCINOMA OF THE LUNG WITH RARE INSERTION
MUTATION IN EGFR EXON 19 THAT HAD PARTIAL RESPONSE
TO GEFITINIB: A CASE REPORT
V. Kozlov1, I. Karpov2, S. Kovalenko2, 3, V. Shamanin2, 3, *
1Thoracic Department, Regional Cancer Hospital, Novosibirsk 630108, Russia
2BioLink Ltd, Novosibirsk 630055, Russia
3Institute of Molecular Biology and Biophysics, Novosibirsk 630117, Russia
Aim: Classic activating mutations L858R and deletions in exon 19 (19del) in the gene for epidermal growth factor receptor (EGFR)
are associated with sensitivity of the non-small cell lung cancer (NSCLC) to therapy with tyrosine kinase inhibitors (TKI). In-
sertions in EGFR exon 19 (19ins) are rare mutations in NSCLC; response of cases with 19ins to TKI is not well studied. Here
we report a case of NSCLC with 19ins in a Russian patient who was treated with gefitinib. We also overview cases of 19ins re-
ported in the literature. Case description: A 48 years old female Russian patient was diagnosed with adenocarcinoma of the lung
(T3N2M1, stage IV). Mutation 19ins was detected in the tumor biopsy by fragment analysis and genotyped by Sanger sequenc-
ing as p.I744_K745insKIPVAI. Treatment with gefitinib (250 mg/day) resulted in clinical and radiological improvements scored
as partial response that lasted 12 months. Conclusion: Treatment with gefitinib of lung adenocarcinoma that carries mutation EGFR
19ins can result in durable response.
Key Words: lung adenocarcinoma, EGFR, exon 19 insertion, gefitinib.
Some cases of non-small cell lung cancer (NSCLC)
carry activating mutations in the epidermal growth
factor receptor (EGFR) gene which are associated
with sensitivity of the tumor to tyrosine kinase in-
hibitors (TKI). Frequency of the mutations varies from
2 to 40% in different groups of patients and positively
correlates with adenocarcinoma histology, female
gender, non-smoker status and Asian ethnicity [1].
Most of activating mutations in EGFR gene (85–90%)
are small in-frame deletions in exon 19 (19del),
or missense mutation L858R. Insertions in EGFR exon
19 (19ins) are rare mutations which comprise about
1% among cases of NSCLC with mutant EGFR [2].
Due to the small number of patients response to TKI
of cases with 19ins is not well studied. Here we de-
scribe a case of NSCLC with 19ins in a Russian patient
that was treated with gefitinib.
CASE REPORT
Female Caucasian patient, 48 years old, non-
smoker, was diagnosed with lung cancer (T3N2M1,
stage IV). Major clinical symptoms were pronounced
dyspnea and cough with large amount of sputum
(up to 500 ml/day). Computed tomography (CT) scans
showed peripheral tumor of the right lung (Fig. 1, a).
Thoracoscopic biopsy of the right lung was performed
to verify morphological diagnosis. Biopsy of the tumor
had histology of adenocarcinoma.
Molecular tests of the DNA from FFPE tumor biopsy
did not find common mutations EGFR L858R or 19del.
The assays we used are based on allele-specific real-
time polymerase chain reaction (PCR) for mutation
L858R and wild-type blocking real-time PCR for 19del
(BioLink, Russia). Some rare deletions as well as inser-
tions in exon 19 are not included in the real-time PCR
assay, therefore we test for these mutations by frag-
ment analysis of the DNA after PCR with forward primer
5'-dGGTGAGAAAGTTAAAATTCCCGTCGC and reverse
primer 5'-dTCGAGGATTTCCTTGTTGGCTTTC. Frag-
ment analysis of the DNA detected insertion in EGFR
exon 19 (Fig. 2, a, case # 692). Sanger sequencing
of the DNA showed duplication of 18bp sequence
AAAATTCCCGTCGCTATC (c.2215_2232dup) that re-
sulted in mutation p.I744_K745insKIPVAI (Fig. 2, b).
During the first month after diagnosis the patient
had 1 course of chemotherapy (carboplatin AUC5, eto-
poside 120 mg/m2). After detection of the EGFR muta-
tion patient was switched to gefitinib (250 mg/day).
One month after treatment with gefitinib there was
pronounced improvement in clinical symptoms (mini-
mal dyspnea at physical exercise, rare cough with
small amount of sputum). Due to diffused infiltration
of the lung parenchyma and pleuritis it was not pos-
sible to select target on CT scans for evaluation of re-
sponse according to RECIST 1.1. Case was scored
as partial response based on clinical improvements
in patient performance from ECOG 2 to ECOG0-1 and
radiological improvements (dimi nished ground-glass
opacities and decreased amount of fluid in pleural
cavity on CT scans) after 2 months of treatment with
gefitinib (Fig. 1, b). CT scans were performed every
2 months. Radiological and clinical disease progres-
sion was revealed after 12 months of gefitinib treat-
ment. After that patient was switched to paclitaxel
(175 mg/m2) and due to lack of clinical response after
3 courses of paclitaxel the best available supportive
care was provided. Patient died 18 months after initia-
tion of treatment.
Submitted: March 1, 2017.
*Correspondence: E-mail: vladimir.shamanin@gmail.com
Abbreviasions used: CT — computed tomography; EGFR — epider-
mal growth factor receptor; NSCLC — non-small cell lung cancer;
TKI — tyrosine kinase inhibitors.
Exp Oncol 2017
39, 2, 155–156
CASE REPORT
156 Experimental Oncology 39, 155–156, 2017 (June)
Fig. 1. CT scans of chest before (a) and after 2 months of treat-
ment with gefitinib (b). Note large amount of fluid in pleural cavity
before treatment (arrow)
Fig. 2. Molecular analysis of a lung cancer case with insertion
in EGFR exon 19. (a) Fragment analysis of EGFR exon 19. Picture
of gel-electrophoresis of PCR DNA is shown with bands corre-
sponding to exon 19 wild-type (WT), deletion (arrow) and inser-
tion (arrow head). Lane 1 — 100bp DNA marker (M); lanes 2–5 —
DNA from FFPE tumor samples; lane 6 — blank (B); lane 7 — DNA
standard with 15bp deletion in exon 19 (p.E746_A750delELREA).
(b) Sanger sequencing of EGFR exon 19 in the tumor DNA # 692.
Duplicated 18bp sequence in the tumor DNA is underlined,
the insertion that resulted in mutation p.I744_K745insKIPVAI
is shown in a box
DISCUSSION
In our laboratory the single 19ins case was detected
among 421 patients with NSCLC that included also
37 cases of 19del and 33 cases of L858R (Table). In an-
other study of Russian patients with lung cancer 19ins
was detected in 4 cases in addition to 455 cases with
mutations 19del and L858R [3]. Frequency of 19ins
among EGFR mutant cases in Russia based on Iyevleva
et al. [3] and our study together was 5/530 (0.9%).
This frequency is similar to 8/601 (1.3%) of cases with
mutant EGFR in study in United States [2]. Interest-
ingly, 19ins comprised only 7/2581 (0.3%) of the lung
cancer cases in Asian patients with mutant EGFR [4,
5]. Much lower frequency of 19ins among Asian pa-
tients with mutant EGFR may be due to differences
between ethnic groups or between methods to detect
mutations in EGFR.
Table. Frequency of mutations EGFR L858R, 19del and 19ins in NSCLC
in different studies
Patients,
N (%)
EGFR+, N
(%)1
19del, N
(%)2
L858R, N
(%)2
19ins,
N (%)2
Coun-
try Reference
421
(100.0) 71 (16.9) 37 (52.1) 33 (46.5) 1 (1.4) Russia This study
2276
(100.0) 459 (20.2) 288 (62.7) 167 (36.4) 4 (0.9) Russia [3]
3026
(100.0) 601 (19.9) 347 (57.7) 246 (40.9) 8 (1.3) USA [2]
2018
(100.0) 860 (42.6) na na 3 (0.3) Hong
Kong [4]
3534
(100.0) 1721 (48.7) na na 4 (0.2) Taiwan [5]
Note: 1mutant EGFR cases as percent of all patients; 2percent of cases with
the mutation in comparison to all cases with mutant EGFR; na — not available.
Published data of response of lung cancers with
19ins to TKI (gefitinib, erlotinib or afatinib) includes
22 cases that were reviewed recently [5]. By searching
PubMed in addition to the cases reviewed by Lin et al.
[5] we found a report of Arabic female lung cancer
patient with 19ins responding to erlotinib [6]. Together
with our study total number of patients with 19ins
treated with TKI is limited to 24 cases would-wide.
Patients were predominantly female non-smokers
and most cases were sensitive to TKI. We observed
a case of lung adenocarcinoma (stage IV) with muta-
tion p.I744_K745insKIPVAI that had partial response
to gefitinib that lasted 12 months. Combined with data
from Iyevleva et al. [3] time to progression of Russian
patients (n = 4) with 19ins on gefitinib was on ave rage
9.3 months (range 5–12 months). For comparison,
Caucasion patients who had lung cancer with mutant
EGFR and were treated with gefitinib in the first-line
had progression free survival 9.7 months [7]. It ap-
pears that sensitivity of tumors with 19ins and dura-
tion of response to TKI is similar to classic mutations
in EGFR gene, however data on larger number of pa-
tients is needed.
In conclusion, our report contributes to small
number of cases in other studies indicating sensitivity
of the lung adenocarcinoma with insertions in exon
19 to thera py with TKI. The study also shows clinical
usefulness of fragment analysis of EGFR exon 19 in ad-
dition to real-time PCR assays that do not include
mutation 19ins.
ACKNOWLEDGMENTS
The work was supported by grant 15-14-10004 of Rus-
sian Scientific Foundation.
DISCLOSURE
The authors declare no conflict of interest.
REFERENCES
1. Mitsudomi T. Molecular epidemiology of lung cancer
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sertions: a new family of sensitizing EGFR mutations in lung
adenocarcinoma. Clin Cancer Res 2012; 18: 1790–7.
3. Iyevleva AG, Mitiushkina NV, Karaseva NA, et al.
Lung carcinomas with EGFR exon 19 insertions are sensitive
to gefitinib treatment. J Thorac Oncol 2014; 9: e31–3.
4. Chan AW, Tong JH, Lo SH, et al. An uncommon inser-
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gefitinib in Caucasian EGFR mutation-positive NSCLC pa-
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