Potential therapeutic option for EGFR-mutant small cell lung cancer transformation: a case report and literature review

Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is rare and is associated with poor prognosis. However, the standard treatment protocols for patients with SCLC transformation remain unknown. Here, we report the case of a patient with advanced EGFR exon 19 deletion (19del) NSCLC who underwent SCLC transformation during targeted therapy. Biopsies and genetic testing were performed to adjust treatment regimens accordingly. The patient responded favorably to a combined treatment regimen comprising etoposide plus cisplatin chemotherapy and adebrelimab plus osimertinib. This case highlights the critical importance of acknowledging tumor heterogeneity in clinical decision-making and identifying potentially effective treatment options for patients with SCLC transformation. Additionally, we reviewed cases of the transformation of NSCLC to SCLC from 2017 to 2023.


Introduction
The management of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) is a critical area of investigation in the field of oncology.NSCLC, which accounts for 80-85% of all lung cancers, plays a significant role in targeted therapy (1,2).EGFR exon 19 deletion (19del) is a common genetic alteration observed in patients with advanced NSCLC (3).When treated with EGFR-tyrosine kinase inhibitor (TKI), some EGFR-mutated NSCLC patients may undergo rare pathological transformations to SCLC (4), which is an important mechanism for resistance to EGFR-TKI treatment.Several studies have reported that NSCLC-derived SCLCs exhibit clinical features similar to primary SCLCs (5).However, for patients who undergo transformation from NSCLC to SCLC, chemotherapy provides only short-term effectiveness and leads to poor prognosis, with a median overall survival (OS) of less than 1 year (6).Therefore, the timely identification and development of effective treatment strategies are crucial.Although SCLC transformation in NSCLC patients has been documented in the literature (Table 1), there is no clear consensus on the optimal treatment regimen for these patients.
Here, we describe the case of a patient with advanced NSCLC with EGFR 19del who underwent pathological transformation from NSCLC to SCLC.Repeated biopsies and next-generation sequencing (NGS) tests, along with clinical disease evolution, have underscored tumor heterogeneity.These findings indicate that multimodal treatment, including chemotherapy, targeted therapy, and immunotherapy, may be a viable therapeutic strategy for this specific patient group.

Case presentation Diagnosis and initial treatment response
A 68-year-old female was admitted to the hospital on July 12, 2021, because of cough and expectoration for 2 months.The patient had no history of smoking or cancer history.Contrast-enhanced chest computed tomography (CT) revealed a mass in the upper lobe of the left lung, along with multiple small nodules in both lower lobes and enlarged mediastinal and hilar lymph nodes.Moreover, pleural thickening and pleural effusion were observed (Figure 1A).Biopsy of the enlarged lesion in the left upper lobe (LUL) revealed poorly differentiated adenocarcinoma of the lung (Figure 2A).14gene panel testing identified an EGFR 19del mutation (Table 2).The patient was diagnosed with stage IV lung adenocarcinoma with EGFR 19del.The patient achieved partial response (PR) after firstline treatment with osimertinib (Figure 1B).Progression-free survival (PFS) after the first-line treatment was 24 months.

Subsequent treatment regimen and treatment response
The patient declined the therapeutic option of chemotherapy and instead opted for second-line treatment with a combination of anlotinib and aumolertinib.However, 4 months later, follow-up enhanced CT and neck ultrasonography revealed PD of the LUL lesion (Figure 1D) and shrinkage of the cervical lymph nodes (Figure 3B).Therefore, the regimen was changed to etoposide plus cisplatin (EP) chemotherapy plus adebrelimab.Following two cycles of EP chemotherapy combined with immunotherapy, the primary lesion located in the LUL exhibited a significant reduction in size (Figure 1E), while enlargement of the right cervical lymph node was observed (Figures 3C, D).Fine-needle aspiration biopsy of the right cervical lymph node was performed to determine the underlying reasons for the inconsistent response in distinct lesions.Pathological examination revealed poorly differentiated adenocarcinoma originating in the lung (Figure 2C).IHC staining demonstrated TTF-1 (+), napsin A (+), CK7 (+), synaptophysin (-), CD56 (-), and CgA (-).1012-gene panel testing revealed multiple gene mutations, including EGFR 19del, TP53 missense mutation, RB1 truncating mutation, NDM4 amplification, and a TMB of 11 mt/Mb (Table 2).Considering the heterogeneity of lung cancer, we introduced osimertinib in addition to the existing chemotherapy and immunotherapy regimens from the third cycle onward.After two cycles of combined treatment, both the primary LUL lesion and metastatic lesion in the cervical lymph nodes showed a notable decrease (Figures 1F, 3E, F).Until the last follow-up in February 2024, no deaths occurred and the followup time was 32 months.The flowchart of the treatment process is shown in Figure 4.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and the Declaration of Helsinki (as revised in 2013).Written informed consent was obtained from the patient for publication of the case report and accompanying images.A copy of the written consent form is available for review by the journal's editorial office.

Discussion
For advanced NSCLC patients with EGFR mutation, the first-line treatment option is EGFR-TKIs, including gefitinib, erlotinib, afatinib, osimertinib, anlotinib, and aumolertinib (34).However, single-agent targeted therapies for NSCLC frequently fail because of the development of acquired drug resistance.Transformation into SCLC represents a rare mechanism of resistance to EGFR-TKIs in advanced lung adenocarcinoma harboring EGFR mutations, accounting for approximately 5-15% of resistance etiologies (35,36).However, the precise mechanisms underlying this transformation remain unknown.The potential mechanisms of SCLC transformation include epithelialto-mesenchymal transition (EMT); mutations that affect TP53, RB1, and PIK3CA; and acquired EGFR mutations (35,37,38).Patients with a triple-positive mutation profile of EGFR, TP53, and RB1 exhibited a 6-fold augmented susceptibility to SCLC conversion compared with patients without mutations in TP53 and RB1 (39,40).Few cases of SCLC transformation have been reported in patients receiving immunotherapy, such as programmed death-1 inhibitors (41).
Patients with EGFR-mutated NSCLC who underwent transformation to SCLC exhibited a significantly unfavorable prognosis in terms of survival.A study involving 39 patients reported an average survival duration of merely 6 months after SCLC conversion (42).An analysis of 67 patients revealed a median OS of 10.9 months after SCLC transformation (43).These data imply that timely recognition and efficient intervention play crucial roles in the management of patients undergoing SCLC transformation.Due to the lack of established treatment guidelines for patients undergoing SCLC transformation, current therapeutic approaches  are based on retrospective studies and case reports (6).Platinum and etoposide-based chemotherapy remains the standard treatment for patients with SCLC transformation, with the median disease control time of approximately 3 months.A real-world study included 29 patients who developed SCLC transformation following EGFR-targeted therapy.The analysis indicated that compared to chemotherapy alone, the combination of chemotherapy and targeted therapy improved objective response rates and PFS, although it did not significantly extend OS.Antiangiogenic therapy and local radiotherapy can prolong OS after transformation (44).A multicenter study involving 32 patients with EGFR-mutant NSCLC who experienced SCLC transformation after targeted therapy revealed that the most commonly used chemotherapy regimen post-transformation was etoposide combined with platinum (n=27), with a median PFS of 3.5 months.Additionally, 3 patients received irinotecan combined with platinum, achieving a median PFS of 7.6 months.Five patients were treated with anlotinib, and the anlotinib group showed a median PFS of 6.2 months (45).Although data suggest that irinotecan combined with platinum and anlotinib may yield better survival outcomes, the limited sample size makes this conclusion less convincing.Furthermore, a case report compared the outcomes of two patients with EGFR-mutant NSCLC who underwent SCLC transformation and received different treatment regimens.One patient received the EP regimen alone posttransformation, achieving a PFS of only 3 months.The other patient received erlotinib combined with the EP regimen, followed by long-term maintenance therapy with erlotinib and oral etoposide, ultimately achieving a PFS of 8 months (46).However, to date, there have been no reports on combined use of chemotherapy, targeted therapy, and immunotherapy for patients with SCLC transformation.In this case, the patient developed PD that transformed into SCLC after 24 months of osimertinib treatment.Further PD occurred following the dual-targeted therapy.Subsequent EP chemotherapy and immunotherapy led to a reduction in the size of the primary lesion and enlargement of   (40).In our case, re-biopsy following disease progression on EGFR-TKIs revealed concurrent EGFR, RB1, and TP53 mutations.Unfortunately, due to the lack of comprehensive genetic analysis at the initial NSCLC diagnosis, only a 14-gene panel was performed, missing critical baseline information on TP53 and RB1 gene status.This underscores the importance of re-biopsy in EGFR/RB1/TP53-mutant lung adenocarcinoma, particularly in patients with poor response to EGFR-TKIs.
In a comprehensive systematic review by Roca et al., 39 patients who underwent SCLC transformation between 2006 and 2016 were systematically evaluated (42).To delve deep into the demographic characteristics, therapeutic interventions, and prognoses of patients experiencing SCLC transformation, we reviewed 33 cases of SCLC transformation from 2017 to 2023 and summarized their genetic mutations, treatment modalities, and patient outcomes in Table 1.Among the 33 reported cases, the majority were of Asian ethnicity and demonstrated a pronounced association with poor prognoses, frequently accompanied by central nervous system metastases.Notably, 13 out of 33 patients (39%) presented with central nervous system metastasis.Observational data suggest that male patients (66%) may be more likely to undergo SCLC transformation.What's more, among the 33 cases, the majority of patients had either an unmentioned family history or no family history, and the patient presented in this case had no history of cancer.It was worth noting that 63% were smokers and 18% were non-smokers, suggesting that smoking may have a potential impact on transformation to SCLC.Disparities in the implementation of personalized medicine across different countries and regions underscore variations in treatment standards and medication accessibility, potentially impacting treatment efficacy and patient survival rates.For instance, Asian populations may prioritize the utilization of the EGFR-TKIs, while Western countries may prioritize the utilization of immunotherapy.EGFR, ALK, and TP53 mutations are commonly observed in patients undergoing SCLC transformation.Among them, EGFR mutations were reported in 13 cases (39%), including 8 cases with EGFR 19 del (62%) and 3 case with EGFR exon 21 L858R (23%).Therefore, we speculate that SCLC transformation is more likely to occur in patients with EGFR mutation and subsequent resistance to targeted therapy.
Surgical specimens were unattainable in patients with unresectable NSCLC at the initial diagnosis.The presence of two histological components could not be definitively excluded because of the inherent limitations of the existing examination methods and techniques.This highlights the importance of obtaining an ample number of tissue specimens from patients with advanced lung cancer to mitigate misdiagnoses resulting from limited sampling.
Despite multiple reported cases of SCLC transformation, treatment strategies remain inadequately explored.In our case report, we document the successful use of EP chemotherapy in combination with adebrelimab and osimertinib for the first time in the management of advanced SCLC transformation.Encouragingly, imaging results indicate a favorable therapeutic response.Nevertheless, the precise molecular mechanism underlying this transformation remains elusive, and consensus treatment guidelines are lacking.Future work should focus on unraveling the molecular mechanisms of this transformation and conducting prospective studies to establish evidence-based treatment protocols.

Conclusions
SCLC transformation is a rare but crucial cause of acquired EGFR-TKI resistance.It is essential to conduct repeated biopsies and employ NGS and IHC tests to identify alterations in histological types.We found that the combination of EP chemotherapy plus adebrelimab and osimertinib had a significant therapeutic effect in patients with NSCLC pathological transformed to SCLC.The multimodal treatment approach involving chemotherapy, targeted therapy and immunotherapy may be a promising strategy for this distinct patient cohort.

FIGURE 1 Chest
FIGURE 1 Chest CT scans at different time points.The red arrow indicates primary lesion in the left upper lobe of the lung.(A) Chest CT scan of baseline.(B) Chest CT scan of best response PR after first-line treatment with Osimertinib.(C) Chest CT scan showing progression after 24 months of Osimertinib.(D) Chest CT scan showing progression after 4 months of Anlotinib and Aumolertinib.(E) Chest CT scan showing reduction in the LUL lesion after 2 cycles of EP chemotherapy plus Adebrelimab.(F) Chest CT scan showing regression in the LUL lesion after fourth-line treatment with Osimertinib in addition to the existing chemotherapy and immunotherapy regimen.CT, computed tomography; PR, partial response; LUL, left upper lobe; EP, etoposide plus cisplatin.

FIGURE 2 HE
FIGURE 2 HE and IHC staining of the tumor at different time points.All pictures were taken at a 200-fold magnification using a light microscope.(A) Biopsy specimen of LUL revealed poorly differentiated lung adenocarcinoma with HE staining.(B) The second biopsy of LUL revealed mixed histology of adenocarcinoma and SCLC with HE and IHC staining for TTF-1 and Syn.(C) The third biopsy of the right cervical lymph node revealed poorly differentiated adenocarcinoma with HE and IHC staining for TTF-1 and Syn.HE, hematoxylin and eosin; IHC, immunohistochemistry; LUL, left upper lobe; SCLC, small cell lung cancer; TTF-1, thyroid transcription factor-1; Syn, synaptophysin.

FIGURE 3
FIGURE 3The ultrasound features of cervical lymph nodes at different time points.(A) After 24 months of Osimertinib, enlarged lymph nodes were observed in the IV region of the right neck, with a maximum size of 2.3 × 1.7 cm.(B) Following dual-targeted therapy, a previously enlarged lymph node in the IV region of the right neck reduced to 0.5 × 0.5 cm.(C, D) After 2 cycles of EP chemotherapy plus Adebrelimab, increased and enlarged lymph nodes were detected in the right neck IV area, with the largest measuring 1.9 × 1.6 cm and 1.3 × 0.9 cm.(E, F) With the addition of Osimertinib to the existing chemotherapy and immunotherapy regimen, the enlarged lymph nodes in the right neck IV area measured 1.6 × 1.3 cm and 1.1 × 0.8 cm.

TABLE 1
Summary of cases of small cell lung cancer transformed from non-small cell lung cancer (2017 to 2023).

TABLE 2
Overview of patient's multiple next-generation sequencing results.