Simultaneous Acquisition of T790M Mutation and SCLC Transformation during Targeted Therapy in EGFR-Mutated Lung Adenocarcinoma: A Rare Case Report

Introduction

Lung cancer is classified into 2 main types – small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) – which account for 15% and 85% of all cases, respectively, consisting mainly of adenocarcinoma and squamous cell carcinoma [1]. Adenocarcinomas are well known for their heterogeneous morphological aspects and diverse properties due to the discovery of driver mutations that may be required for promoting tumor growth [2]. The most common driver oncogene is the epidermal growth factor receptor (EGFR); mutations in its intracellular domain have been observed in 47% of cases [2]. The International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society classified histologically invasive adenocarcinomas as lepidic, papillary, micropapillary, and solid adenocarcinomas [2]. Although solid patterns have a low mutation rate in the EGFR gene, papillary and acinar patterns predict the presence of EGFR gene mutations [2]. EGFR mutations are significantly associated with female sex, non-smokers, Asians, and adenocarcinomas, and they predict response to EGFR tyrosine kinase inhibitors (TKI) [2,3]. EGFR-TKI is the standard of care in patients with lung cancer with sensitizing EGFR mutations (exon 19 deletion or L858R mutation) [4]. Several phase III studies have demonstrated the superiority of first-generation EGFR-TKIs (gefitinib, erlotinib) and second-generation EGFR-TKI (afatinib) to chemotherapy regarding progression-free survival and response rates [4]. However, the problem is acquired resistance, and various EGFR resistance mechanisms have been reported, with approximately half of cases showing T790M point mutations in resistance to EGFR-TKI [5]. In addition, 3–14% of NSCLC cases transform into small cell lung carcinoma (SCLC) during treatment [6,7]. It has been reported that Rb1, TP53, and PIK3CA mutations are often present, with a high response rate to platinum-etoposide and taxane-based anticancer drugs in patients with SCLC transformation. However, to date, treatment strategies have not been defined [8]. There have been a few reported cases with simultaneous resistance mechanisms: T790M point mutations and SCLC transformation [9,10]. This report presents a 66-year-old man with an initial presentation of stage IIA right-sided lung adenocarcinoma with EGFR gene exon 21 L858R mutation. Furthermore, approximately 4 years during receiving treatment with erlotinib, the patient developed stage IV SCLC and adenocarcinoma with EGFR exon 21 mutation L858R and exon 20 mutation T790M simultaneously.

Case Report

A 66-year-old man with a smoking history of 64 pack years was referred to the hospital due to a cough. The clinical course is shown in Figure 1. Chest computed tomography (CT) indicated a mass of 55×40 mm in the right lower lobe in March 2012 (Figure 1A). The patient received pneumonectomy plus nodal dissection (ND)2a for right hilar lung cancer in May 2012. The patient was diagnosed with EGFR exon21 L858R mutated positive exon20 T790M negative right lower lobe lung adenocarcinoma (acinar and solid components existed), pathological T2bN0M0 stage IIA, according to the seventh edition of the TNM Classification of Malignant Tumors (Figure 2A(i)). Immunostaining was performed on the adeno-carcinoma (Figure 2B). TTF-1 and CD56 exhibited positive nuclear staining on the tumor cells (Figure 2B(i, ii)). Both chromogranin A and synaptophysin were expressed negatively (Figure 2B(iii, iv)). The patient continued tegafur uracil for 2 years as adjuvant chemotherapy. Positron emission tomography (PET)-CT showed an accumulation in the right chest wall in February 2015 (Figure 1B). Recurrence due to pleural dissemination was determined, thereby erlotinib was started. The patient continued erlotinib for 52 months. PET-CT showed an accumulation in the right 6th and 7th ribs in March 2019 (Figure 1C). Chest wall tumor resection (right 6th and 7th ribs) was performed, and histopathological examination of the bone specimen revealed oval-shaped cells with large nuclei, showing 2 structures – a dense fenestrated structure on one side and a tubular arrangement on the other side (Figure 2A(ii)). Immunostaining revealed that TTF-1 was positive in the tubular and fenestrated structures, whereas CD56, Chromogranin A, and synaptophysin were positive in the fenestrated structures (Figure 2C). In other words, the fenestrated structure showed SCLC while tubular structures indicated adenocarcinoma. The World Health Organization (WHO) defines combined small cell lung cancer (C-SCLC) as SCLC with any other histology of NSCLC [11]. Therefore, the patient was diagnosed with C-SCLC. Genetic analysis of the adenocarcinoma acinar components revealed the presence of EGFR exon21 mutation L858R and EGFR exon20 mutation T790M positive. The patient was determined to have progression disease (PD) and received 4 cycles of second-line carboplatin and etoposide in June 2019. However, PET-CT indicated an accumulation in the right chest wall, and head magnetic resonance imaging (MRI) showed a high-signal nodule of 15×10 mm on T1 in the left occipital lobe in February 2020 (Figure 1D). Therefore, the patient was determined to have PD and further received stereo-tactic radiation and 14 cycles of third-line amrubicin. Chest CT showed a nodule of 15×10 mm in the left lower lobe in June 2021 (Figure 1E). The patient was determined to have PD and received 2 cycles of fourth-line irinotecan. A personality change was observed in the patient; he was then diagnosed with cancerous meninges and administered fifth-line treatment comprising Osimertinib and whole-brain irradiation (30 Gy/10 fractions) (Figure 1F). However, the patient was found to be unconscious, wherein continuing treatment was difficult. The patient continued Osimertinib for only 12 days and died in September 2021. Neuron-specific enolase (NSE) was within the normal range at the time of C-SCLC diagnosis but was elevated with subsequent disease progression. Changes in NSE were associated with the patient’s disease progression after initiation of chemotherapy (Figure 3).

Discussion

In our case, although SCLC transformation and T790M mutation were observed simultaneously after erlotinib resistance in EGFR-mutated lung adenocarcinoma, the patient was able to continue chemotherapy for 25 months. Re-biopsy played a key role.

The patient received long-term treatment with chemotherapy after transformation to SCLC. EGFR-TKIs are the standard treatment for adenocarcinomas with sensitizing EGFR mutations (exon 19 deletion or L858R mutation) [4]. However, the problem is acquired resistance, and various EGFR resistance mechanisms have been reported. T790M, MET, HER2 amplification, and transformation to SCLC have been previously reported as resistance mechanisms to EGFR-TKIs [7]. Only 2 cases involving 2 simultaneous resistance mechanisms (T790M and transformation to SCLC) have been reported [9,10]. Tables 1 and 2 present a summary of prior reports and our case. Osimertinib is effective in EGFR-mutated lung adenocarcinoma with T790M mutation, which is resistant to first- and second-generation EGFR-TKIs, and the median overall survival (OS) was reported to be 26.8 months [12]. Although no established therapy for transformed SCLC exists, Marcoux et al reported a large retrospective cohort of patients with EGFR mutation-positive SCLC-transformed lung cancer had a median survival from SCLC transformation of 10.9 months (95% CI, 8.0 to 13.7 months) and high response rate of 54% to cisplatin/carboplatin-etoposide after SCLC transformation [8]. Therefore, Case 1 and 2 were treated by simultaneously targeting the 2 resistance mechanisms, namely Osimertinib and chemotherapy. In contrast, in our case (Case 3), we diagnosed C-SCLC according to the WHO criteria and discussed the treatment options [9]. The optimal chemotherapy regimen for C-SCLC is yet to be identified [13]. However, while cisplatin/carboplatin-etoposide has shown efficacy in retrospective studies, EGFR-TKIs have only been used in a small number of C-SCLC cases with EGFR mutations [13]. In our case, NSE was correlated more with disease progression than carcino-embryonic antigen (CEA; a tumor marker of adenocarcinoma). Furthermore, treatment of SCLC, which defines the prognosis, is a priority. Osimertinib was used 5th line for all these reasons. In general, the efficacy of immune checkpoint inhibitor (ICI) monotherapy (PD-1 inhibitors), whether as first-line or back-line treatment, did not achieve the expected survival benefits [14,15]. Previous case reports showed the efficacy of ICI in combination with radiotherapy or chemotherapy [15,16]. Combination therapy with ICI may become a treatment option for C-SCLC in the future.

Chest wall tumor resection was performed in our case to secure specimen volume and lead to an accurate diagnosis. Performing a re-biopsy if possible and considering an appropriate treatment strategy in each case are necessary. Histology results have been reported to possibly differ depending on the organ that is biopsied [17]. Sonoda et al reported that EGFR mutation-positive lung cancers exhibit diverse acquired resistance [18].

The first hypothesis for this case is that type 2 alveolar epithelial cells are the common origin of both SCLC and EGFR mutation-positive adenocarcinoma, as shown by studies in mouse models [1]. EGFR-TKI and retinoblastoma susceptibility gene (RB1) inactivation can transform type 2 alveolar epithelial cells into SCLC, whereas the EGFR T790M mutation is thought to restore EGFR signaling and activate the pathway that leads to adenocarcinoma transformation [1]. These 2 mechanisms may have existed within the same tumor in our case. The second hypothesis is a possible combination of SCLC and NSCLC at initial presentation, and each histology was predominant due to the therapeutic agents. However, histology showed no prominent SCLC at initial presentation (Figure 2A, 2B).

Conclusions

EGFR-mutated lung adenocarcinoma treated with EGFR-TKI follows concurrent T790M mutation and SCLC transformation. However, long-term survival may be achieved with treatment for C-SCLC. Moreover, because EGFR mutation-positive lung cancers show a variety of acquired resistances, it is important to consider the treatment strategy by performing re-biopsy.