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Respir Med Case Rep
Respir Med Case Rep
Respiratory Medicine Case Reports
2213-0071
Elsevier

S2213-0071(24)00117-5
10.1016/j.rmcr.2024.102094
102094
Case Report
Case report of a patient with stage IV lung adenocarcinoma and uncommon/compound EGFR mutations who responded to afatinib
Hirokawa Hisanori hirokawa@dokkyomed.ac.jp
a1
Hirata Hirokuni hirokuni@dokkyomed.ac.jp
a⁎1
Azuma Hayase a-hayase@dokkyomed.ac.jp
a
Sugitate Kei sugitate@dokkyomed.ac.jp
a
Soda Sayo s-s-sayo@dokkyomed.ac.jp
b
Matsushima Jun jmatsu@dokkyomed.ac.jp
c
Fukushima Yasutsugu y-fuku@dokkyomed.ac.jp
a
a Department of Respiratory Medicine and Clinical Immunology, Dokkyo Medical University, Saitama Medical Center, 2-1-50 Minamikoshigaya, Koshigaya, Saitama, 343-0845, Japan
b Department of Respiratory Medicine and Clinical Immunology, Dokkyo Medical University, 880 Kitakobayashi, Shimotusga-gun, Tochigi, 321-0293, Japan
c Department of Pathology, Dokkyo Medical University, Saitama Medical Center, 2-1-50 Minamikoshigaya, Koshigaya, Saitama, 343-0845, Japan
⁎ Corresponding author. hirokuni@dokkyomed.ac.jp
1 H.Hirokawa and H.Hirata contributed equally to this work.

22 8 2024
2024
22 8 2024
51 10209416 3 2024
19 7 2024
17 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
There is no established treatment for lung adenocarcinoma with uncommon/compound epidermal growth factor receptor (EGFR) mutations. We report a case of a 73-year-old man with stage IVB lung adenocarcinoma harboring E709G and L861Q EGFR mutations. After 2 months of afatinib treatment, significant tumor shrinkage was observed, and the patient's condition remained stable for 1 year. This case highlights the potential effectiveness of afatinib for treating rare stage IV lung adenocarcinoma with these specific EGFR mutations.

Keywords

Case report
Lung adenocarcinoma
E709G
L861Q
EGFR
Uncommon/compound mutation
afatinib
Abbreviations

EGFR epidermal growth factor receptor

EGFR-TKI EGFR–tyrosine kinase inhibitor

CT computed tomography

PET-CT positron emission tomography–computed tomography

CEA carcinoembryonic antigen

ORR overall response rate

IC50 half maximal inhibitory concentration
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pmc1 Introduction

The standard treatment recommended for stage IV non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations is a tyrosine kinase inhibitor (TKI), which is a molecularly targeted drug [1]. Over 80 % of patients with EGFR mutations (excluding T790M) are positive for exon 19 deletion or exon 21 L858R mutation, both of which are common mutations [2]. Osimertinib, a third-generation EGFR-TKI, is suggested to be an effective treatment for these common mutations [3]. There are also many uncommon mutations, including exon 18 E709X, exon 18 G719X, exon 20 S768I, and exon 21 L861X [4]. Afatinib, a second-generation EGFR-TKI, has been reported to be effective for some uncommon mutations, but its effect on many others remains unclear [5]. In addition, the clinical effectiveness of EGFR-TKI in patients with compound uncommon mutations is less clear. Here, we present a case of a patient with rare stage IV lung adenocarcinoma and the uncommon/compound EGFR mutations E709G and L861Q in whom afatinib administration resulted in tumor shrinkage and stabilization.

2 Case report

The patient was a 73-year-old man. Chest computed tomography (CT) (Fig. 1a: lung window; Fig. 1b: mediastinal window) performed during a regular health checkup revealed a 3.3-cm tumor shadow and mediastinal lymphadenopathy. As a result, he was referred to our respiratory and allergy ward with suspected lung cancer. The patient's medical history included endocrine therapy for prostate cancer for the past 3 years. His prostate-specific antigen levels were stable and within the normal range at the time of hospitalization. He had a Brinkman index of 500. Tumor markers were as follows: carcinoembryonic antigen (CEA) 93.9 ng/mL, CYFRA 4.7 ng/mL, sialyl Lewis-x antigen (SLX) 110 U/mL, squamous cell carcinoma antigen 1.0 ng/mL, pro-gastrin-releasing peptide (ProGRP) 44.7 pg/mL, neuron-specific enolase 11.1 ng/mL, and soluble interleukin-2 receptor 585 U/mL.Fig. 1 Imaging and pathological findings before treatment.

a. Chest computed tomography (CT) (lung window) at the initial visit. The arrow shows a tumor with a maximum diameter of 3.3 cm in the superior lobe of the right lung.

b. Chest CT showing the (mediastinal window) at the initial visit. The arrow shows swelling of the mediastinal lymph node (#4R) (short axis 1.7 cm, long axis 2.0 cm)

c. Hematoxylin and eosin stains from the histopathological analysis of lung tissue obtained from the right S3 tumor. Adenocarcinoma, consisting of cuboidal atypical epithelium with a relatively high NC ratio growing in tubular and papillary form, is visible. Magnification is 10 × and 20 × with objective lens.

d. The result of positron emission tomography–computed tomography. Increased uptake is visible in the tumor shadow in the superior lobe of the right lung, cervical vertebrae (C5 and C6), a lumbar vertebra (L3), the pelvis, the right hilum, the subcarinal space. And multiple lymph nodes on the right side of the trachea, suggesting lung adenocarcinoma with multiple bone and lymph node metastases.

Fig. 1

During bronchoscopy, a transbronchial tumor biopsy was taken from the bronchus 3 region of the right superior lobe, and adenocarcinoma was histologically diagnosed (Fig. 1c). Positron emission tomography-computed tomography (PET-CT) (Fig. 1d) revealed increased uptake in the tumor shadow in the superior lobe of the right lung, cervical vertebrae (C5 and C6), a lumbar vertebra (L3), the pelvis, the right hilum, the subcarinal space, and multiple lymph nodes on the right side of the trachea. This suggested lung adenocarcinoma with multiple bone and lymph node metastases, and it was staged as cT2aN2M1c OSS Stage ⅣB according to the World Health Organization classification [6]. His performance status according to Eastern Cooperative Oncology Group [7] was grade 3. Programmed cell death-ligand 1 expression in the lung cancer tissue was 55 %. Analysis of 46 cancer-driver gene variants performed using the Oncomine Dx Target Test Multi-CDx System (analysis performed by SRL, Inc., Tokyo, Japan) revealed the presence of the uncommon/compound mutations E709G and L861Q; the test was negative for all other mutations. Consequently, the patient was hospitalized and EGFR-TKI treatment was initiated.

On day 1 of hospitalization, palliative radiation of 8 Gy as a single fraction was performed for the C5–C6 vertebral metastases. Subsequently, administration of anti-RANKL (receptor activator for nuclear factor-kappaB ligand) antibody preparations was initiated. The clinical course is shown in Fig. 2. Afatinib has previously been reported to be effective in some double EGFR mutations including L861Q [8,9]. In our case, afatinib 40 mg/day was administered from day 2 but was temporarily halted at day 14 due to diarrhea and loss of appetite. Chest CT performed on day 15 showed shrinkage of the tumor shadow and mediastinal lymph node, and the gastrointestinal symptoms improved. Therefore, on day 21, administration of afatinib was resumed at 20 mg/day every other day with no apparent adverse effects, and the patient was discharged on day 37. Two months later, the afatinib regime was changed to 20 mg/day every day. CEA values fluctuated between 20 and 50 ng/mL. Although we could not perform chest CT because of the patient's poor general condition due to bone metastasis and other problems, radiography performed 1 year and 2 months after resuming afatinib showed no tumor enlargement (Fig. 3). However, 2 months later, the patient developed aspiration pneumonia and died. After resuming administration of afatinib, the patient continued taking the drug orally for a total duration of approximately 1 year and 4 months. Informed consent was obtained from the patient's wife for publication of this case report.Fig. 2 Clinical course, including diagnosis, treatment, follow-up, and death. The day before admission for afatinib treatment was defined as day 0. On day −6, the patient was finally diagnosed with stage IV lung adenocarcinoma harboring E709G and L861Q mutations. D, day; Yr, year; Mo, month.

Fig. 2

Fig. 3 Imaging findings showing effects of treatment with afatinib.

a. Chest CT on day 15 of hospitalization (lung window). The maximum diameter of tumor in the superior lobe of the right lung was 2.3 cm

b. Chest CT on day 15 of hospitalization (mediastinal window). Mediastinal lymphadenopathy has improved compared with the image taken on the initial visit (short axis 1.1 cm, long axis 1.3 cm).

c. Plain chest X-ray taken before afatinib administration and at 1 year and 2 months after resuming afatinib administration.

Fig. 3

3 Discussion

We reported a case of a 73-year-old man with stage IVB lung adenocarcinoma harboring E709G and L861Q EGFR mutations. After 2 months of afatinib treatment, significant tumor shrinkage was observed, and the patient's condition remained stable for 1 year.

However, the follow-up period was relatively short, which limits the understanding of the long-term efficacy and safety of afatinib in this patient population. Furthermore, because of the patient's poor general condition, follow-up chest CT scans were not performed, limiting the ability to fully assess the long-term tumor response and progression. Afatinib 40 mg/day caused gastrointestinal symptoms, which may have led to a further decline in activities of daily living (ADL) and shortened survival time. On the other hand, if the patient had not taken afatinib, it is highly likely that his survival time would have been even shorter due to cancer progression. Continued administration of afatinib at 20 mg per day instead of 40 mg per day may have prevented further declines in ADLs, inhibited cancer progression, and led to relatively long-term survival. When side effects occur, including gastrointestinal symptoms as in this case, it is important to take measures to prevent worsening of ADLs and ensure long-term survival. This means options such as pausing, stopping, or reducing current medications must be carefully considered in order to choose the approach that is best for the patient's quality of life.

As of May 2016, around 16,000 cases of EGFR mutations have been registered in the COSMIC (Catalogue Of Somatic Mutations In Cancer) database. There were 594 non-small cell lung cancer EGFR mutations, of which 93 % were concentrated in exons 18–21 [10]. A large-scale meta-analysis conducted in 2015 (muMAPII: a global EGFR mutMAP) revealed that 45 % of adenocarcinomas in the Japanese population involve EGFR mutations, which is higher than in Western populations [11]. EGFR mutations are classified into common mutations, exon 20 insertion mutations, and uncommon mutations [11]. EGFR-activating mutations (common mutations)—specifically exon 19 deletion and L858R mutation—account for 44.8 % and 39.8 % of all reported cases, respectively, while exon 20 insertion mutations account for 5.8%–12 % of cases [10]. Uncommon mutations include the exon 18 codon 719-point mutation (G719X), E709X, exon 18 deletions, exon 19 insertions, S768I, and exon 21 L861Q [10]. Meanwhile, E709G-positive cases and L861Q account for just 0.3 % 0.9 % of all EGFR mutations (excluding T790M), respectively, reflecting the rarity of these uncommon mutations [10]. Our case had both uncommon and compound mutations, making it extremely rare. Compound mutations are thought to arise from intratumor heterogeneity, in which several preexisting minor mutations become detectable as the tumor grows [12]. Of the EGFR mutations, L861Q single mutation responds to first-generation EGFR-TKIs with an overall response rate (ORR) of 39 %, and to afatinib, a second-generation EGFR-TKI, with an ORR of 56 % [10]. Moreover, afatinib has a high affinity to this mutation, with an in vitro half maximal inhibitory concentration (IC50) of 0.5 nM, whereas osimertinib, a third-generation EGFR-TKI, has an IC50 of 9 nM [10]. For the single E709G mutation, there has been no clear clinical report on the effectiveness of EGFR-TKIs. In general, compound mutations have a poor prognosis [12], which might be due to the different affinities of EGFR-TKIs to each EGFR mutation. Furthermore, co-existing mutations may have an additive impact on the tertiary structure of EGFR, which might underlie the relevance of compound mutations in acquired resistance [12]. In our case, the tumor shrinkage observed from the short-term administration of afatinib may be attributable to its action against either the L861Q or E709G mutation, or to both. In vitro studies using cell lines have shown the binding affinity of afatinib to mutant proteins based on analysis of the three-dimensional structure of mutated EGFR protein [9]. In our case, a possible reason why afatinib was effective against the compound mutation is that afatinib was able to bind to the protein of L861Q and/or the E709G mutation.

In conclusion, this case highlights the potential of afatinib as a treatment option for patients with stage IV lung adenocarcinoma harboring E709G and L861Q mutations. Further studies are needed to confirm these findings and explore the underlying mechanisms of the TKI treatment effect and resistance in such rare mutations.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Hisanori Hirokawa: Writing – original draft. Hirokuni Hirata: Writing – original draft, Investigation. Hayase Azuma: Data curation. Kei Sugitate: Visualization, Data curation. Sayo Soda: Writing – review & editing. Jun Matsushima: Writing – review & editing, Visualization. Yasutsugu Fukushima: Writing – review & editing.

Declaration of competing interest

The authors declare that they have no conflicts of interest.
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