Is osimertinib resistant because it transformed into large-cell neuroendocrine cancer?

*It is only for medical professionals to read and reference to clarify the resistance mechanism of osimertinib, which is conducive to follow-up scientific treatment and management! Lung cancer is the cancer with the highest mortality rate in the world.
Among them, non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases.
Epidermal growth factor receptor (EGFR) is one of the common oncogenes in NSCLC.
EGFR mutations can be observed in 51.
4% of advanced NSCLC adenocarcinoma cases, while the mutation rate in the Caucasian population is about 20% [1]
.

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI), which can be used for the first-line treatment of advanced NSCLC with EGFR exon 19 deletion (19Del) or exon 21 L858R mutation.
It can also be used for first- and second-generation NSCLC.
Patients who carry the T790M mutation after being resistant to EGFR-TKI
.

About 50% of patients use first-generation and second-generation EGFR-TKI resistance because of the T790M mutation [2]
.

 Almost all patients will develop resistance when using EGFR-TKI treatment, and the exploration of the resistance mechanism of osimertinib has become a hot topic in clinical practice
.

EGFR-dependent drug resistance mechanisms (such as C797S mutation), alternative activation mechanisms (such as MET amplification) and histological transformation mechanisms (such as small cell transformation) have been reported with osimertinib treatment [3]
.

The Journal of Medical Case Reports reported a rare case of a patient with EGFR T790M mutation lung adenocarcinoma who transformed into large cell neuroendocrine carcinoma (LCNEC) after treatment with osimertinib [4], which provides another opportunity for the treatment of osimertinib resistance.
An idea
.

Case introduction: Osimertinib was treated with osimertinib after treatment, and pathological type conversion occurred after drug resistance.
In August 2016, a 64-year-old Asian man with a 46-year history of smoking was admitted to the hospital due to exertional dyspnea for 1 week
.

Examination revealed a mass in the middle lobe of the right lung, enlarged lymph nodes in the right hilar, bilateral lung nodules, and right pleural effusion with pleural nodules.
Nodules can be observed in the peritoneum, mesenteric and omentum
.

 A biopsy specimen was taken from the right middle lobe through the bronchus.
Histopathology showed adenocarcinoma; molecular analysis showed that carcinoembryonic antigen (CEA) was positive, synaptophysin was negative (Figure 1), and EGFR 19Del was positive
.

 Figure 1.
Histopathological results (ac Histopathological results of biopsy specimens: a.
hematoxylin and eosin staining, b.
CEA staining, c.
synaptophysin staining; df histology of pleural biopsy specimens: d.
Su Wood staining and eosin staining, e.
CEA staining, f.
synaptophysin staining
.

) The patient received afatinib as the first-line treatment and achieved partial remission (PR)
.

Seventeen months later, computed tomography (CT) showed that the primary lesion in the right middle lobe had progressed and newly transferred to the right pleura.
He received five cycles of carboplatin and pemetrexed (PEM) as the second-line treatment, and the disease was stable (SD )
.

A cycle of PEM maintenance treatment showed that the lesions of the right middle lobe and pleura were still progressing
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 Therefore, the patient received six cycles of docetaxel combined with afatinib treatment, and the efficacy evaluation showed that it was ineffective
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A liquid biopsy was then performed, which revealed the EGFR T790M mutation, and the patient was subsequently treated with osimertinib
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After maintaining the SD state for 4 months, the right pleural metastasis occurred and progressed rapidly
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A CT-guided pleural biopsy was performed, and LCNEC characterized by CEA positive and synaptic staining was confirmed by histological examination (Figure 1, df)
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 Genetic testing analysis showed that EGFR 19Del was positive but there was no T790M mutation.
Therefore, the patient received a combination therapy of carboplatin and etoposide (VP-16), and the patient's condition was stable for 3 months
.

After three cycles of carboplatin and VP-16 treatment, the disease progressed and the right pleural metastasis was changed to amrubicin (AMR) treatment.
One cycle later, the patient developed superior vena cava syndrome, 41 months after the first visit After death
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 Figure 2.
Case analysis of patient treatment history: tissue biopsy and genetic testing can provide solutions for EGFR-targeted drug resistance A rare case
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The pathogenesis of LCNEC transformation is similar to that of SCLC transformation.
The underlying mechanism leading to neuroendocrine differentiation may be the inactivation of retinoblastoma 1 (RB1) and tumor protein 53 (TP53)
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Inactivation of RB1 and TP53 was observed in EGFR mutant lung adenocarcinomas before and after transformation [5]
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 Re-biopsy plays a key role in studying the mechanism of EGFR TKI resistance, but previous studies reported that the re-biopsy rate is about 50% [6, 7]
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The reasons for not performing re-biopsy are the inability to perform re-biopsy (5%), deterioration of physical status (4%), and patient rejection (22%) [8]
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In this case, it is suggested that the conversion of pathological type to LCNEC is a potential mechanism of EGFR-TKI resistance, and the patient received chemotherapy after the pathological type conversion (Figure 3)
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At present, the treatment of NEC is mainly based on the chemotherapy regimen for SCLC
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 Figure 3.
The treatment process of patients with advanced EGFR-mutant NSCLC.
In summary, this article reports a case of EGFR T790M-positive adenocarcinoma transformed into LCNEC after treatment with osimertinib
.

The re-biopsy of the tumor after the disease has progressed helps to determine the mechanism of osimertinib resistance and guide the subsequent effective treatment
.

References: [1].
Shi Y, Au JS, Thongprasert S, et al.
A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER).
J Thorac Oncol .
2014;9: 154–62.
[2].
Jänne PA, Yang JC, Kim DW, et al.
AZD9291 in EGFR inhibitor-resistant nonsmall-cell lung cancer.
N Engl J Med.
2015;372:1689–99.
[3].
Minari R, Bordi P, Tiseo M.
Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance.
Transl Lung Cancer Res.
2016;5 :695–708.
[4].
Miyazaki S, Kuno Y, Hayai S, Teramachi R, Yamashita R, Saito Y, Higuchi K, Nara Y, Ikeda T.
An EGFR T790M-mutated lung adenocarcinoma undergoing large-cell neuroendocrine carcinoma transformation after osimertinib therapy: a case report.
J Med Case Rep.
2020 Aug 7;14(1):122.
doi: 10.
1186/s13256-020-02447-0.
PMID: 32762742; PMCID: PMC7412784.
[5].
Lee JK, Lee J, Kim S, et al.
Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas.
J Clin Oncol.
2017;35:3065–74.
[6].
Kawamura T, Kenmotsu H, Taira T, et al.
Rebiopsy for patients with nonsmall-cell lung cancer after epidermal growth factor receptor-tyrosine kinase inhibitor failure.
Cancer Sci.
2016;107:1001–5.
[7].
Ichihara E, Hotta K, Kubo T, et al.
Clinical significance of repeat rebiopsy in detecting the EGFR T790M secondary mutation in patients with non-small cell lung cancer.
Oncotarget.
2018;9:29525–31.
[8].
Zhou J, Zhao C, Zhao J, et al.
Re-biopsy and liquid biopsy for patients with non-small cell lung cancer after EGFR-tyrosine kinase inhibitor failure.
Thorac Cancer.
2019;10:957–65.
Approval number CN-80654 Expiration date 2021-12-31 *The materials are supported by AstraZeneca and are for reference only by medical professionals.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform