Cancer Genetics 

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Cancer Genetics
journal homepage: www.elsevier.com/locate/cancergen
Case Report
Late recurrence of lung adenocarcinoma harboring EGFR exon 20
insertion (A763_Y764insFQEA) mutation successfully treated with
osimertinib
Kei Kunimasaa,g,∗
, Kazumi Nishinoa
, Yoji Kukita b
, Shingo Matsumotoc
, Hayato Kawachi a
,
Takahisa Kawamuraa
, Takako Inouea
, Motohiro Tamiyaa
, Keiichiro Honma d,
Naotoshi Sugimotoe,g
, Tomoyuki Yamasakif,g
, Fumio Imamura e,g
, Koichi Gotoc
,
Toru Kumagai a
a Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae Chuoku, Osaka 541-8567, Osaka, Japan b Laboratory of Genomic Pathology, Osaka International Cancer Institute, Osaka, Japan c Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan d Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka, Japan e Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan f Department of Endocrinology/Metabolism Internal Medicine, Clinical Examination, Osaka International Cancer Institute, Osaka, Japan g Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan
a r t i c l e i n f o
Article history:
Received 26 December 2020
Revised 19 March 2021
Accepted 6 April 2021
Keywords:
EGFR
Ex.20 insertion mutation
EGFR-A763_Y764insFQEA
Osimertinib
Late recurrence
a b s t r a c t
The EGFR-A763_Y764insFQEA is a unique mutation among EGFR exon 20 insertion mutations in that it
is associated with sensitivity to conventional EGFR-tyrosine kinase inhibitors. This mutation, which was
not initially covered by conventional reverse transcription polymerase chain reaction (RT-PCR) genotyp￾ing method, has only been detected in clinical practice when a next-generation sequencing (NGS)-based
cancer panel is implemented. We present the case of a female patient with recurrent lung adenocar￾cinoma from a lung tumor resected 10 years earlier. Sequential single-gene investigations and the On￾comineTM Comprehensive Assay (ver.3) analysis of the recurrent tumor did not reveal any targetable
driver mutations. However, the second NGS analysis with the OncoGuideTM NCC oncopanel found the
EGFR-A763_Y764insFQEA mutation after tumor progression with carcinomatous lymphangiomatosis and
multiple brain metastases. Osimertinib treatment improved her condition immediately. The identical
EGFR-A763_Y764insFQEA mutation was detected in the tumor resected 10 years earlier. Based on this
common mutation the patient was diagnosed with late recurrence of lung cancer harboring the EGFR￾A763_Y764insFQEA mutation. The OncoGuideTM NCC oncopanel covered whole exons of the EGFR gene
and was able to detect this mutation. In the present clinical practice, the EGFR-A763_Y764insFQEA mu￾tation is the only treatable mutation among EGFR Ex.20 insertion mutations. We need to understand the
gene mutation profile identified by each panel and consider reexamining them for this mutation.
© 2021 Elsevier Inc. All rights reserved.
Introduction
EGFR exon (Ex.) 20 insertion mutations are rare among EGFR
mutations in lung cancer, accounting for approximately 10% of such
alterations [1,2]. Unlike activating major EGFR mutations includ￾ing Ex.19 deletion and Ex.21 L858R mutations, they are reported
to result in primary resistance to clinically available EGFR-TKIs
(tyrosine kinase inhibitors) including gefitinib, erlotinib, afatinib,
∗ Corresponding author.
E-mail address: [email protected] (K. Kunimasa).
and osimertinib [3]. However, EGFR-A763_Y764insFQEA, which re￾sults in the identical amino acid sequence to that with EGFR￾D761_E762insEAFQ and is one of the EGFR Ex.20 insertion muta￾tions, is associated with sensitivity to conventional EGFR-TKIs, as
opposed to other EGFR Ex.20 insertion mutations [3,4]. The in￾serted FQEA sequence changes the register of the C-helix toward
its N-terminus resulting in structural and kinetic alterations that
more closely resemble those of the two activating major EGFR mu￾tations, which are sensitive to EGFR-TKIs [3,5].
Although there have been reports of clinical cases with the
EGFR-A763_Y764insFQEA mutation showing sensitivity to EGFR￾TKIs [3], this mutation has not been detected in a clinical setting

https://doi.org/10.1016/j.cancergen.2021.04.001

2210-7762/© 2021 Elsevier Inc. All rights reserved.
K. Kunimasa, K. Nishino, Y. Kukita et al. Cancer Genetics 256–257 (2021) 57–61
Fig. 1. Chest CT findings and images of resected lung tumors of the primary and recurrent tumors. A chest plain CT image of the primary lung cancer 10 years earlier (A)
and a macroscopic image of the resected tumor (B) are provided. A chest plain CT image of the recurrent multiple scattered nodules is shown; white arrowheads indicate
tumors (C) and (D): a pathological image of the resected recurrent nodules is provided. (E) Sanger DNA sequence chromatogram of EGFR A763_Y765insFQEA (c.2284-
5_2290dup) showing forward and reverse sequencing. Black arrows show low amplitude waves indicating mutant waves. Filled arrow heads () indicate normal control
peaks and unfilled () arrow heads indicate shifted peaks by inserted base pairs (TCCAGGAAGCCT in forward sequencing).
[6]. Further, the present EGFR detection tests based on reverse tran￾scription polymerase chain reaction (RT-PCR) assays were not de￾signed to target this mutation [6,7]. Recently, cancer gene panel
testing using next generation sequencing (NGS) has been imple￾mented in clinical practice, which enables sequencing of whole
exons of the EGFR gene, and this mutation has been successfully
found.
We present a case of lung adenocarcinoma harboring the EGFR
Ex.20 insertion mutation (EGFR-A763_Y764insFQEA) that recurred
10 years after surgery with multiple lung metastases. The mutation
had not been detected by either an RT-PCR-based EGFR detection
test or the Oncomine Comprehensive Assay (ver. 3) and later was
successfully detected by a second NGS analysis with the OncoGu￾ideTM NCC oncopanel that covered whole exons of the EGFR gene.
The detection of the mutation led to successful treatment with os￾imertinib. Although there have already been reports of lung cancer
patients harboring EGFR-A763_Y764insFQEA mutation treated with
EGFR-TKIs including osimertinib [1–4,6],there are no other reports
of late recurrence of lung cancer harboring this mutation, and thus,
this case might represent a new biological aspect of lung cancer.
Case presentation
A 70-year-old, never-smoker woman was diagnosed with
cT1bN0M0 lung adenocarcinoma and treated with right upper
lobectomy 10 years earlier (Fig. 1A,B). A histopathological analysis
of the resected specimen resulted in the diagnosis of pT1bN1M0.
She was further treated with a combination of cisplatin and vi￾norelbine for four cycles as adjuvant chemotherapy. After that,
she was followed-up with periodic imaging at the outpatient de￾partment; 10 years later, bilateral multiple lung micronodules ap￾peared (Fig. 1C), and a wedge resection was performed for the le￾sion. The histopathological analysis revealed the recurrence of lung
adenocarcinoma (Fig. 1D). Sequential single-gene investigations of
the recurrent tumor showed no activating major EGFR mutations
[7], BRAF V600E mutations, or ALK and ROS1 fusions in the sam￾ple, and the PD-L1 tumor proportion score was 0%. Furthermore, a
cancer gene panel analysis for the recurrent tumor using the On￾comineTM Comprehensive Assay (OCA) (ver.3) (Thermo Fisher Sci￾entific, Massachusetts, USA) in the lung cancer genomic screening
project for individualized medicine (LC-SCRUM) [8] also identified
no targetable driver oncogenic alterations in 2018.
For her metastatic lung adenocarcinoma, she was treated with
combination of pemetrexed (500 mg/m2) and carboplatin (430 mg,
AUC (the area under the concentration-time curve);5) plus pem￾brolizumab (200 mg/body) as the first-line chemotherapy. After
four cycles of the combination regimen, she received four addi￾tional cycles of pemetrexed and pembrolizumab therapy until her
tumor progressed. The progression free survival (PFS) of the combi￾nation immunotherapy was approximately one year. The response
to the first line treatment was assessed as partial response (PR)
based on Response Evaluation Criteria in Solid Tumors (RECIST
v1.1) criteria [9]. Immune checkpoint inhibitor-associated primary
adrenal insufficiency (Grade (Gr).2 based on Common Terminol￾ogy Criteria for Adverse Events (CTCAE v5.0)) was observed dur￾ing the first line treatment. Five cycles of ramucirumab plus doc￾etaxel for the second-line chemotherapy were administered follow￾ing vinorelbine monotherapy as the third-line chemotherapy. The
PFS of the second-line and third-line treatment was approximately
6 months and 2 months, respectively. The responses to the second
and third line treatments were assessed as stable disease (SD) and
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K. Kunimasa, K. Nishino, Y. Kukita et al. Cancer Genetics 256–257 (2021) 57–61
Fig. 2. Chest plain CT and enhanced brain MRI images before and after osimertinib treatment. Chest plain CT images before osimertinib treatment showed an irregular,
nodular, or smooth, peribronchovascular fissure and interlobular septal thickening (A). An enhanced brain MRI before osimertinib treatment showed multiple enhanced
nodules in the brain (B). Each tumor lesion was shown by yellow arrow heads. After a 1-month osimertinib treatment, abnormal chest plain CT findings and multiple
nodules in the brain disappeared (C,D). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
progressive disease (PD), respectively [9]. Alopecia of Gr.2 (CTCAE)
and neutropenia of Gr.3 (CTCAE) were observed as adverse events
in the second-line treatment. No major adverse events were ob￾served in the third-line treatment. During the third-line treatment,
her recurrent tumor was re-genotyped using the OncoGuideTM
NCC oncopanel (Sysmex Corporation, Kobe, Japan) [10]. The exam￾ination revealed an EGFR exon 20 insertion (A763_Y764insFQEA)
mutation. By the time the result was available, the third-line treat￾ment had failed, resulting in the development of carcinomatous
lymphangiomatosis and multiple brain metastases (Fig. 2A,B). Her
performance status rapidly deteriorated to Gr. 3. As soon as the
Ex.20 insertion mutation was detected, treatment was switched to
osimertinib (80 mg once daily), and 1 month after the start of ad￾ministration, the carcinomatous lymphangiomatosis and multiple
brain metastases disappeared (Fig. 2C,D) and her performance sta￾tus immediately improved to Gr 0. The toxicity of osimertinib was
only dry skin (Gr.2), and there were no other major adverse events.
The response to osimertinib was assessed as PR [9]. Six months
after the administration of osimertinib, the patient relapsed into
dizziness and nausea and enhanced brain MRI showed recurrence
of carcinomatous meningitis and multiple brain metastases. The
combination of erlotinib (150 mg once daily) and bevacizumab
(15 mg/kg) was introduced as the following fifth line treatment af￾ter osimertinib failure.
To examine whether the lung cancer resected 10 years ear￾lier had the same Ex.20 insertion mutation, we sequenced it us￾ing our primers (forward primer: CATGCGTCTTCACCTGGAA, reverse
primer: GCATGAGCTGCGTGATGA) specific for the mutation. The se￾quence revealed the identical Ex.20 insertion mutation in the old
specimen (Fig. 1E). Based on the common mutation and diffuse
scattered nodules in both lung fields at the time of recurrence, the
patient was diagnosed with late recurrence of lung cancer harbor￾ing the EGFR-A763_Y764insFQEA mutation.
Discussion
The EGFR exon 20 insertion (A763_Y764insFQEA) mutation is
structurally different from other EGFR Ex.20 insertion mutations,
and due to its structure, currently available EGFR-TKIs were re￾ported to be effective [3,4,6]. However, this mutation has not been
generally included in RT-PCR-based assays for EGFR mutations con￾ducted in clinical practice, and it remained unidentified without
NGS analysis. In Japan, NGS analysis up-front treatment is not al￾lowed under the medical insurance system, and the mutation was
finally detected in this case at an advanced stage of treatment. The
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K. Kunimasa, K. Nishino, Y. Kukita et al. Cancer Genetics 256–257 (2021) 57–61
carcinomatous lymphangiomatosis and multiple brain metastases
led to a decrease in her PS into 3, but the successful osimertinib
treatment saved her from death.
In fact, before the NGS analysis using the OncoGuideTM NCC
oncopanel that identified the EGFR-A763_Y764insFQEA mutation,
she had been subjected to another NGS analysis using the OCA
(ver.3) at LC-SCRUM Japan as a clinical study, but the panel did
not cover that variant at the time of analysis in 2018. The OncoGu￾ideTM NCC oncopanel [10] covers whole exons of the EGFR gene,
which enables it to detect all mutations in this gene, including
the EGFR-A763_Y764insFQEA mutation. OCA (ver.3) covers 161 of
the most relevant cancer driver genes, including increased kinase
domain coverage and a representation of genes involved in DNA
repair. Of the 161 covered genes, 48 are subject to full-length se￾quencing, but EGFR is not included among these [6]. In addition to
the currently approved cancer gene panels, new cancer gene pan￾els are expected to enter the clinical setting and we need to know
which genes are covered by each panel and whether the muta￾tions that they detect are hot spots only or comprise full-length
regions. Mutation variants covered by both RT-PCR-based and NGS
tests are occasionally modified based on accumulating clinical data.
Accordingly, we must apply new information when we use these
mutation search assays. Manufacturers should also ensure that any
changes to the sensitivity of NGS panels or variants searched are
communicated to clinical practice.
The present case had undergone surgical treatment for lung
adenocarcinoma of the right upper lobe 10 years before. The same
EGFR-A763_Y764insFQEA mutation was detected from the resected
specimen by using direct sequencing. Furthermore, micronodular
scattered shadows were observed in both lung fields, and the dis￾tribution and nature of these shadows were considered to be a late
recurrence of lung cancer. Miliary lung metastases from lung ade￾nocarcinoma with EGFR Ex.20 insertion mutations other than the
EGFR-A763_Y764insFQEA mutation have been reported [11]. In the
present case as well, the scattered nodules in the lung fields at the
time of recurrence were similar to those of miliary lung metas￾tases. There have been no reports of late recurrence of lung adeno￾carcinoma harboring the EGFR-A763_Y764insFQEA mutation. The
biologic and clinical characteristics of lung adenocarcinoma harbor￾ing this mutation must thus be verified through case accumulation.
The development of new TKIs that are effective against EGFR
Ex.20 insertion mutations, for which conventional EGFR-TKIs are
not effective, is ongoing on clinical trials. These drugs will soon
be used in clinical practice, and the EGFR Ex.20 insertion muta￾tions are targetable driver mutations that can be detected. Unlike
variants such as the Exon.19 deletion, among Ex.20 insertion muta￾tions, the EGFR-A763_Y764insFQEA alteration is structurally differ￾ent from other Ex.20 insertion mutations and is unique in that it
results in sensitivity to conventional EGFR-TKIs. Other Ex.20 inser￾tion mutations other than the EGFR-A763_Y764insFQEA mutation
involving the insertion of amino acid residues into the loop follow￾ing C-helix region form the crystallographic asymmetric unit ar￾ranged in a continuous chain of asymmetric dimer interactions in
which the C lobe of one molecule interacts with the N lobe of the
next by the inserted amino acid residues [3]. This interaction me￾diates EGFR activation by ligand-induced dimerization, which leads
to active conformation of the EGFR kinase [12]. On the other hand,
the inserted four amino acid residues into just C terminal to A763
in the EGFR-A763_Y764insFQEA mutation shifts the register of the
C-helix toward its N terminus, resulting in altering the length of
the C loop length and I759A replacement [3]. The I759A alteration
adjacent to L858R and L861Q leads to catalytic activation in a re￾lated manner [13]. These structural and enzyme kinetic alterations
more closely resemble the major activating L858R and Ex.19 dele￾tion mutations than other Ex.20 insertion mutations [3].
In vitro analysis indicated that new TKIs for the EGFR Ex.20
insertion mutations under development have a lower 50% in￾hibitory concentration value than the conventional TKI for the
EGFR-A763_Y764insFQEA mutation, suggesting that the upcoming
EGFR-TKIs could be more effective for this mutation [14]. Pozio￾tinib is a covalent, irreversible inhibitor of EGFR and HER2, which
is the most advanced clinical candidate of compounds with the ca￾pacity to target Ex.20 insertion mutations [15]. A phase 2 trial for
poziotinib in lung cancer patients harboring Ex.20 insertion mu￾tations confirmed that 64% response rate was achieved in 11 pa￾tients [5]. TAK-788 (mobocertinib) is another covalent, irreversible
inhibitor designed to selectively target the Ex.20 insertion muta￾tions of EGFR and HER2 [5,16]. In a phase 1/2 study of mobocer￾tinib, 14 out of 26 lung cancer patients (54%) harboring Ex.20 in￾sertion mutations had a PR [16]. In addition, the development of
TAS6417, a nobel EGFR-TKI with a unique scaffold fitting into the
ATP-binding site of the EGFR hinge region, is advanced as a drug
targeting for Ex.20 insertion mutations [17].
In conclusion, we present a case of late recurrence of
lung adenocarcinoma harboring the EGFR exon 20 insertion
(A763_Y764insFQEA) mutation after right upper lobectomy for
lung adenocarcinoma 10 years earlier. There are no effective
EGFR-TKIs for all EGFR Ex.20 insertion mutations in clinical prac￾tice, but conventional EGFR-TKIs are effective against the EGFR￾A763_Y764insFQEA mutation. In present clinical practice, the
EGFR-A763_Y764insFQEA mutation is the only treatable mutation
among EGFR Ex.20 insertion mutations. However, it is not covered
by the conventional RT-PCR-based assay. It is possible that some
cases, determined not to have an EGFR mutation in a previous
search, have the EGFR-A763_Y764insFQEA mutation. Furthermore,
even if NGS analysis has been performed, it is possible that the
EGFR-A763_Y764insFQEA mutation was not covered, and it is nec￾essary to understand the genes that are covered by each panel.
Declaration of Competing Interest
Dr. Kunimasa reports personal fees from Novartis Pharma and
Chugai Pharmaceutical Co. outside the submitted work; Dr. Nishino
reports personal fees from Boehringer Ingelheim, personal fees
from Chugai Pharma, personal fees from AstraZeneca, personal
fees from MSD, outside the submitted work; Dr. Matsumoto re￾ports grants from Chugai Pharma, Novartis, Lilly, Merck Serono,
and MSD, personal fees from AstraZeneca, Chugai Pharma, Novar￾tis, Pfizer outside the submitted work; Dr. Kawachi reports per￾sonal fee from Chugai Pharmaceutical Co. outside the submitted
work; Dr. Tamiya reports personal fees from Chugai Pharmaceuti￾cal, personal fees from AstraZeneca, personal fees from Pfizer Japan
Inc., personal fees from Boehringer-Ingelheim, outside the submit￾ted work; Dr. Imamura reports personal fees from Chugai Pharma￾ceutical, personal fees from AstraZeneca, personal fees from Pfizer
Japan Inc., personal fees from Boehringer-Ingelheim, outside the
submitted work; Dr. Goto reports grants from AstraZeneca, Bristol￾Myers Squibb, Chugai, and Ono, during the conduct of the study;
grants from AbbVie, Astellas, Boehringer Ingelheim, Daiichisankyo,
Eisai, Kyowa Hakko Kirin, Ignyta, Janssen, Life Technologies, Lilly,
Loxo Oncology, Merck Serono, MSD, Novartis, Oxonc, Pfizer, SRL,
Sumitomo Dainippon, Sysmex Corporation, RIKEN GENESIS, Roche,
Taiho, Takeda, personal fees from AbbVie, AstraZeneca, Boehringer
Ingelheim, Bristol-Myers Squibb, Chugai, Daiichisankyo, Life Tech￾nologies, Lilly, Ono, Merck Serono, MSD, Nippon Kayaku, Novartis,
Pfizer, RIKEN GENESIS, Roche, SRL, Taiho, Takeda, outside the sub￾mitted work; Dr. Kumagai reports grants and personal fees from
Ono Pharmaceutical, grants and personal fees from MSD, grants
and personal fees from Chugai Pharmaceutical, grants and personal
fees from AstraZeneca, grants from Takeda Pharmaceutical Com￾pany, personal fees from Taiho Pharmaceutical Co., personal fees
60
K. Kunimasa, K. Nishino, Y. Kukita et al. Cancer Genetics 256–257 (2021) 57–61
from Merck Serono Co., grants and personal fees from Pfizer Japan
Inc., personal fees from Novartis Pharma, personal fees from Eli
Lilly Japan, outside the submitted work; other authors have no
conflict of interest.
Ethical approval
Informed consent was obtained from the present case.
Funding
This study was supported by The Japan Society for the Pro￾motion of Science (JSPS) (Grant no. JP19K176974) KAKENHI Early￾Career Scientists (K.K) and Takeda Science Foundation (K.K).
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