Impacts of co-mutations in oligometastatic and oligoprogressive non-small cell lung cancer with EGFR/ALK mutations—a narrative review of the current literature

Introduction

Non-small cell lung cancer (NSCLC) comprises approximately 80% of all lung cancers worldwide and is one of the leading causes of cancer-related mortality (1). Approximately 40% of NSCLC patients present with metastatic disease. With the advent of targeted therapies and immunotherapy, patients with advanced NSCLC can expect improved survival outcomes compared to those with non-mutation-driven NSCLC. Unfortunately, as these systemic treatments are typically palliative rather than curative, most cancers eventually progress (2).

An emerging focus in improving outcomes for NSCLC is recognizing oligometastatic NSCLC as a distinct disease entity. Oligometastatic NSCLC can be described as an intermediate metastatic state, indicating an early stage in the spread of cancer with limited metastatic potential. The term oligometastasis was first proposed in 1995 by Hellman and Weichselbaum (3). This stage describes a clinically significant condition characterized by limited metastatic burden in one or a few organs, while the generally accepted number of metastatic lesions is 1 to 5 (4). Moreover, more sensitive staging imaging modalities, such as positron emission tomography-computed tomography (PET-CT), have gained clinical importance in defining oligometastatic disease (5). In comparison to more disseminated metastatic states, oligometastatic disease appears to follow an indolent course, with better prognosis, and may therefore be considered for radical multimodality treatment. Systemic treatment combined with stereotactic ablative radiotherapy (SABR), resection of metastatic lesion or thermal ablation can achieve long-term survival in terms of progression-free survival (PFS) and overall survival (OS) rates in oligo­metastatic NSCLC (6-8).

When addressing oligometastases, clinical efforts traditionally focus on the size and number of metastatic lesions (9). However, mutational burden has received relatively little clinical attention. Clinicians should determine whether a radical treatment approach needs adjustment based on the presence of co-mutations. This consideration becomes particularly significant in oligometastatic NSCLC patients who possess actionable mutations, such as those in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes. In a prospective phase 2 trial assessing SABR in stage IV NSCLC patients with ≤5 lesions, of the 47 participants, somatic genetic alterations (EGFR/ALK) were detected in 44.7%, with EGFR exon 19 deletions being the most prevalent in 38.3% of the cohort (10).

In metastatic NSCLC, including oligometastatic cases, patients undergo comprehensive mutational analyses, such as next-generation sequencing (NGS) from tissue or plasma or whole-exome sequencing (WES). When applied to oligometastatic NSCLC, this approach provides detailed information on mutational burden and potential targetable co-mutations in EGFR/ALK-mutated NSCLC and is not significantly different from strategies used in disseminated metastatic NSCLC. While the efficacy of local treatments like radiotherapy and surgical resection combined with systemic therapy is well-studied in oncogene-addicted oligometastatic NSCLC (6,7,11), now is an optimal time to explore how co-mutations influence the management of oligometastatic NSCLC with EGFR or ALK mutations and identify opportunities for further enhancing clinical outcomes.

In this review, we discuss the impact of co-mutations on oligometastatic NSCLC patients with targetable alterations undergoing targeted therapy. Among various oligometastatic categories (12), our primary discussion will focus on synchronous oligometastatic disease and oligoprogressive NSCLC in patients with targetable mutations. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1121/rc).

Methods

The authors conducted an electronic literature search to identify relevant publications available in PubMed and ClinicalTrials.gov (search in November 2024). The search was restricted to articles in the English language. In addition to peer-reviewed manuscripts, conference abstracts were also included in this review. The titles and abstracts of the search results were screened, and irrelevant publications were excluded based on the authors’ evaluation following established criteria.

Only the pertinent manuscripts were further examined for their full content to extract relevant information. However, since this is intended as a narrative review, a systematic literature search was not conducted, and the included literature reflects the authors’ preferences. The literature reviewed for this manuscript covers the period from 2008 to 2024 (Table 1). J.U.L., J.L., and C.K.P. independently screened the studies for inclusion. In cases of disagreement, consensus was reached through discussion.

Current treatment of synchronous oligometastatic NSCLC with targetable mutations

Existing research on managing oligometastatic NSCLC with actionable mutations is mostly retrospective and from single institutions. However, several key prospective studies and current guidelines provide necessary insights.

In a randomized trial involving patients with common EGFR mutations, the efficacy of a first-generation tyrosine kinase inhibitor (TKI) alone was compared with a regimen combining stereotactic body radiation therapy (SBRT) to both the primary tumor and all metastatic lesions followed by TKI therapy (13). The phase II ATOM study evaluated the effectiveness of local ablative therapy (LAT) in oligoresidual patients undergoing EGFR-TKI treatment. Preemptive LAT significantly decreased the progression risk [hazard ratio (HR) 0.41, P=0.0097]. Nonetheless, enrollment was halted prematurely due to sluggish accrual, possibly because of heterogeneity in oligometastatic cases and a shift in clinical practice and oligometastatic criteria (14).

In the SINDAS phase III randomized controlled trial (RCT), 133 patients with oligometastatic lung adenocarcinoma harboring an EGFR mutation received radiotherapy to all metastases and the primary tumor/involved regional lymphatics alongside first-generation EGFR-TKIs. This combination significantly enhanced median progression-free survival (mPFS) and overall survival (mOS), with mPFS at 20.2 versus 12.5 months and mOS at 25.5 versus 17.4 months, both showing HR of 0.68 with high statistical significance (P<0.001), but the exclusion of patients with brain metastases (BM) limits the applicability of the results to broader clinical practice challenging (13). Nevertheless, several retrospective studies have shown that the use of consolidative LAT, such as SBRT or surgery, to treat metastatic sites in patients with EGFR-mutant oligometastatic NSCLC during ongoing EGFR-TKI therapy results in improvements in both PFS and OS (15-17). Not only have early-generation TKIs demonstrated efficacy when combined with localized radiotherapy in oligometastatic NSCLC, but later-generation TKIs, such as osimertinib, have also shown positive results (18,19).

Current guidelines from major medical societies generally recommend integrating local treatment with targeted therapy for managing oligometastatic NSCLC that harbor actionable mutations. ASTRO/ESTRO Clinical Practice Guidelines recommend administering optimal systemic therapy including targeted therapy for metastatic disease for at least three months to evaluate response and treatment tolerance before considering definitive local therapy. This systemic approach is to ensure eligibility for local treatment of oligometastatic disease by assessing the potential for complete response or progression during the initial treatment period (20). Recent recommendations by the EORTC-ESTRO OligoCare consortium advise combining EGFR or ALK inhibitors with SBRT for eligible patients without reducing the radiation dose (21). The 2023 European Society for Medical Oncology (ESMO) guidelines, despite a lack of extensive prospective data, recommend integrating LAT with systemic treatment for oncogene-addicted synchronous oligometastatic and oligoprogressive NSCLC (22). The National Comprehensive Cancer Network (NCCN) guideline recommends integrating local treatment with EGFR or ALK inhibitors (23).

Ongoing studies involving patients with oligometastatic NSCLC and actionable mutations are expected to yield results that will enhance clinical strategies (Table 2).

In the OMEGA study (NCT03827577), among the four subgroups classified based on targetable mutations and PD-L1 expression, patients with either EGFR, ALK, or ROS1 mutations were categorized separately as one group. Meanwhile, the phase II NORTHSTAR trial (NCT03410043) aims to evaluate the efficacy of initial osimertinib treatment, with consideration for adding local consolidative radiotherapy or surgical resection in patients diagnosed with stage IIIB-IV EGFR-mutant NSCLC following 6–12 weeks of induction with osimertinib (24,32,35). While earlier research primarily assessed the efficacy of combining local and systemic treatments, current studies are expanding their scope to include detailed treatment strategies such as the sequencing and timing of local and systemic interventions, and the identification of biomarkers (36-38).

Management of oligoprogressive oncogene‑driven NSCLC

While the related literature predominantly focuses on synchronous oligometastatic diseases, oligoprogressive disease frequently encountered in oncogene-addicted NSCLC requires a separate approach. Oligoprogression is characterized as the emergence of metachronous oligometastatic disease during active systemic treatment, predominantly seen in patients with oncogene-driven NSCLC undergoing targeted therapy. This concept defines a subset of metastatic disease where limited sites progress while the primary tumor and other metastases remain controlled under ongoing systemic treatment (39). In EGFR-mutant NSCLC, patients are more likely to show oligoprogressive progression patterns rather than systemic patterns (72% vs. 28%), as shown in a real-world data analysis of patients undergoing osimertinib treatment (40).

In a study by Weickhardt et al., disease control benefit was noted in patients with EGFR and ALK-positive NSCLC undergoing oligoprogression during ongoing targeted therapy. Of 51 patients, 49% (25 patients) received local therapy in addition to continuous crizotinib or erlotinib. Among those experiencing progression after the local therapy, the post-local therapy PFS was 6.2 months (41). Qiu et al. performed a retrospective study on 46 patients with oligoprogression, showing that EGFR mutation type, local treatment site, and the interval from progression to local treatment were independent prognostic factors. They demonstrated a median OS of 14 months, significantly longer than the 7 months (P=0.0009) observed in control group patients who did not receive local treatment (42). Patients with NSCLC harboring EGFR or ALK mutations have a higher incidence of BM at baseline compared to wild-type patients (43,44), highlighting the need for a special focus on BM. In a retrospective Swiss cohort study, 50 EGFR T790M-positive NSCLC patients were treated with osimertinib, revealing that 17% experienced brain progression, with 83% of these cases classified as oligoprogression (40). Another study analyzing 61 ALK/ROS1/RET-rearranged lung adenocarcinomas showed that local therapy (radiotherapy, surgery, and percutaneous thermal ablation) for progression on ALK, ROS1, or RET TKIs was associated with significant prolongation of continued TKI therapy beyond progression (45).

In cases of oligoprogression in NSCLC with EGFR mutations, several management strategies can be selected based on tumor burden, patient conditions, and characteristics of the available treatment modalities. For polymetastatic NSCLC with targetable mutations, clinical decision-making regarding the switch in systemic treatment modalities at the time of progression after prior targeted therapy is more straightforward when actionable co-mutations are identified, either through tissue-based or circulating markers, as mechanisms of acquired resistance (46-49). However, for oligoprogressive NSCLC patients, this decision should be more personalized, as discontinuing targeted therapy too early may prematurely remove future treatment options. Specifically, localized treatment, such as SBRT for an oligoprogressive lesion, can be a viable option.

One strategy is to continue existing systemic treatments, such as EGFR-TKIs, even after oligoprogression. This consideration is based on the possibility for tumor flare-ups, which are observed in approximately 20% of patients following the abrupt discontinuation of previously administered TKIs (50). The current NCCN guidelines recommend continuing first-line treatment and definitive local therapy for asymptomatic progressive lesions in patients with limited progression while on osimertinib or amivantamab-vmjw plus lazertinib in EGFR-mutant NSCLC (51). Different strategies combine first-line EGFR-TKIs in patients with chemotherapy or with another targeted agent (52). Acquiring tissue at the time of progression can be beneficial for optimal clinical decision-making in oligoprogressive NSCLC with EGFR mutations. Choudhury et al. demonstrated that patients treated with TKIs who underwent post-progression tissue-based genomic analysis to identify acquired resistance mechanisms had improved survival outcomes with subsequent treatments (53). For appropriate candidates, surgical resection of oligoprogressive lesions may be advantageous as it not only provides abundant tissue samples for precise pathological examination but also reduces tumor burden (54).

Genetic alterations and intertumoral heterogeneity in oligometastatic NSCLC

Data of oligometastatic NSCLC specifically with targetable mutations are scarce, but a number of previous studies have examined genetic alterations associated with oligometastatic NSCLC. The co-mutations should be considered in relation to other disease statuses, with resectable or locally advanced NSCLC indicating a disease burden smaller than oligometastasis, and polymetastatic NSCLC indicating a larger burden. Comparing genetic alterations among early-stage, oligometastatic, and polymetastatic NSCLC would be clinically significant in understanding disease progression and treatment implications. However, more real-data analyses based on in-depth pathological samples are essential for further validation. Nevertheless, recent studies provide some insights into the co-mutations of oligometastatic diseases.

Werner et al. reported that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were the most prevalent genetic alterations in primary tumors, with variations such as G12C, G12V, G13C, G12A, and Q61H, listed in order of frequency. Other notable genetic alterations observed included EGFR mutations, CDK4 amplifications, NRAS mutation, amplifications of EGFR, ERBB2, PIK3CA, and an EML4-ALK fusion (55).

In a study by Liao et al., oligometastatic (n=77) and polymetastatic (n=21) NSCLC cases were compared for genetic alterations using NGS. Mutations in ERBB2, ALK, MLL4, PIK3CB, and TOP2A were significantly less frequent in the oligometastatic group compared to polymetastatic patients. Additionally, EGFR and Kelch-like ECH-associated protein 1 (KEAP1) alterations were found to be mutually exclusive in the oligometastatic group; however, this finding is specific to this study and is limited by the small sample size. They further found that mutations in high-frequency genes among oligometastatic patients included TP53 (64%), EGFR (56%), and others such as CDKN2A and KRAS, linked to critical pathways like p53, RTK/RAS, PI3K-Akt, and cell cycle regulation (56).

While oligometastatic NSCLC comprises multiple tumor sites, discrepancies in genetic alterations between primary tumors and metastatic sites can be observed. This intertumoral heterogeneity can be an obstacle in the effective treatment of oligometastatic NSCLC (57). However, few studies have specifically evaluated intertumoral heterogeneity between primary tumor and metastatic samples in oligometastatic NSCLC. Werner et al. (55) retrospectively analyzed genetic alterations in oligometastatic NSCLC by examining primary tumors and BM from 46 patients. While most primary tumor alterations (93.5%) were preserved in BM, about 34.8% of BMs showed additional oncogenic mutations, especially MYC amplifications found only in metastatic sites.

Intertumoral heterogeneity, marked by additional genetic alterations of metastatic sites, is an independent predictor of reduced OS in patients with oligometastatic NSCLC and synchronous or metachronous BM (55). Song et al. examined treatment-naïve lung cancer patients with oligometastatic BM for genetic alterations in primary and metastatic tumors. The most frequent mutations in primary tumors included EGFR (44%) and TP53 (40%), while BM showed a similar profile with minor differences including slightly higher co-mutations of EGFR and TP53. RNA Binding Motif Protein 10 (RBM10), a tumor suppressor gene involved in RNA splicing regulation, was more frequently observed in primary tumors. The analysis revealed only minor differences in genetic mutations between primary tumors and their corresponding metastases (58).

Future studies with sufficiently large, molecularly stratified analyses are needed to determine whether specific genetic alterations influence the response to localized therapies such as SBRT or combinatorial approaches in oligometastatic NSCLC. Identifying such associations could enhance personalized treatment strategies and improve patient outcomes.

Impact of co-mutations on management of oligometastatic NSCLC with targetable mutations

It is crucial for clinicians to consider information about co-mutations in oligometastatic NSCLC with targetable mutations, focusing on prognosis prediction and treatment strategy planning. The approach may vary depending on the type of oligometastasis (synchronous or oligoprogressive) and previous treatments received.

In a prospective study focusing on the surgical resection of oligopersistent NSCLC, where the majority of participants exhibited EGFR mutations, WES of tumors identified resistant clones in some patients. Importantly, patients without detected acquired resistance mutations in their tumor tissues demonstrated more favorable prognosis compared to those with such mutations [HR =3.67, 95% confidence interval (CI): 0.92–14.7, P=0.006] (59).

Although not all patients enrolled were oligometastatic, in a retrospective analysis of EGFR mutant NSCLC patients who underwent SBRT combined with TKI treatment, liquid NGS at baseline and at the time of progression indicated the presence of T790M mutations in 64.3% (18/28) of patients, followed by TP53 mutations in 28.6% (8/28), and BRAF mutations in 3.6% (60). These findings suggest that the genetic alteration landscape in patients eligible for local treatment closely mirrors that of individuals undergoing TKI therapy for advanced EGFR-mutant NSCLC (61).

Earlier studies often did not focus on co-mutations in EGFR/ALK-mutated oligometastatic NSCLC. However, ongoing studies are expected to more clearly show the impact of co-mutations on treatment outcomes (24,32,62), as they incorporate more comprehensive genetic analyses, including NGS.

Role of lung resection in detection of co-mutations

For synchronous oligometastatic NSCLC patients with actionable mutations, systemic targeted therapy is based on targetable mutations identified at the time of diagnosis. For patients with oligoprogressive NSCLC, when rebiopsy samples are available at the time of oligoprogression, the mutational profile is crucial for guiding subsequent treatment decisions, particularly information related to acquired resistance. In this context, obtaining an adequate biopsy sample after the initiation of first-line TKI treatment can significantly facilitate decisions regarding further therapeutic options. In this regard, lung resection is a clinical option to consider.

Lung resection following initial nonoperative management for initially unresectable NSCLC that later becomes resectable is a treatment option increasingly under consideration in oligometastatic NSCLC (63-65). Dunne et al. observed that 22% of patients underwent surgery for oligoprogressive disease and 38% for local control of oligometastatic disease; their study found that patients with stage IV NSCLC who underwent salvage lung resection had better OS compared to those who did not undergo surgery (66). In a study by Joosten et al., where 28 patients underwent surgery for an oligoprogressive lesion, it was shown that resecting oligoprogressive lesions after systemic treatment is a feasible option in NSCLC, yielding favorable outcomes post-resection (67). Besides improving prognosis in appropriate surgical candidates, resecting lung lesions also enables the detection of co-mutations using adequate sample amounts. For instance, a retrospective analysis involving 33 EGFR mutant NSCLC patients who underwent salvage surgery after EGFR-TKI treatment showed that 11 of the 33 patients had a T790M mutation in the resected sample (63). In another retrospective analysis of 29 salvage surgery cases following prior EGFR-TKI treatment, the majority of patients had M1b and oligometastatic M1c disease, possibly representing oligopersistent or oligoresidual cases. Resected lung samples showed a variety of co-mutations, including the T790M mutation and mutations in the APC, CTNNB1, PIK3CA, and PTEN genes (68).

However, a multidisciplinary discussion should precede surgical intervention to ensure that patients who are operable and have resectable target lesions undergo surgery, thereby avoiding unnecessary surgery-related adverse outcomes.

Impact of co-mutations on radiosensitivity of oligometastatic NSCLC with targetable mutations

Radiotherapy primarily induces tumor cell death by causing DNA damage. However, tumor cells respond by activating checkpoint signaling and DNA repair mechanisms. While the DNA damage response (DDR) typically initiates programmed cell death, co-mutations, intertumor heterogeneity, and the surrounding microenvironment allow cancer cells to evade death and develop resistance to radiation (69). For example, mutant EGFR can activate various downstream pathways including RAS/ERK, MAPK, JNK, or mTOR leading to tumor cell proliferation and anti-apoptosis (70). This acquired radioresistance is a key factor in treatment failure and recurrences.

Radiotherapy plays a central role in the management of oligometastatic NSCLC with targetable mutations, and predicting sensitivity to the treatment can be crucial for improving patient outcomes. Certain genetic alterations can impact radiosensitivity. For instance, KRAS mutations are associated with radioresistance (71,72), an association supported in several real-world data analyses (73,74). In a small SBRT case series, KRAS mutation was associated with cancer-specific survival in early-stage NSCLC (72). Mutations in other genes such as KEAP1 (75,76), and TP53 are also known to be correlated with radioresistance in NSCLC (77,78). In an analysis of patients who underwent SBRT for stage I lung adenocarcinoma, MET-amplification was associated with worse regional and distant disease control (74). While certain genetic alterations are associated with decreased responses to radiotherapy, future studies are needed to determine whether radiotherapy methods or dose adjustments can help overcome this resistance in oligometastatic NSCLC.

Combining radiotherapy with targeted therapy may improve radiosensitivity in oncogene-addicted oligometastatic NSCLC. Several preclinical studies have shown that combining TKI, anti-EGFR antibody and other oncogenic molecular inhibitors can help overcome radioresistance (79,80). Potential synergistic effects from combining targeted therapy and radiotherapy may be more pronounced in oncogene-addicted NSCLC. However, clinicians should exercise caution when combining high-dose radiotherapy with targeted therapy, as the risk of radiation pneumonitis may increase (81). In patients with identifiable risk factors such as severe pre-existing lung diseases, withholding systemic therapy during radiotherapy can be considered to mitigate this risk (82).

An important question for clinicians to consider is whether the radiotherapy approach should vary based on co-mutations detected. In an analysis of 580 patients with 1,487 BM who underwent radiotherapy, genomic alterations identified through NGS revealed that mutations in 11 genes (ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, and MDM4) and 2 genes (FBXW7 and AURKA) were linked to decreased or increased risk of local recurrence, respectively. Although patients with EGFR/ALK-altered NSCLC comprised only a subset of the study population, these results suggest that genetic alterations are clinically significant for predicting radiotherapy failure (83). For patients with aggressive genomic profiles, studies validating whether more intensive local treatment for BM is necessary should be performed.

Role of liquid biopsy

Liquid biopsy, a minimally invasive diagnostic platform, was examined for its potential role as a prognostic biomarker in oligometastatic NSCLC by detecting oncogenic mutations and predicting disease courses (84,85). The detection of circulating tumor DNA (ctDNA) and its burden has been analyzed in oligometastatic NSCLC using both single-point and serial measurements. In patients with oligometastatic NSCLC, the presence of a driver alteration in ctDNA has been linked to reduced PFS (HR 2.62, 95% CI: 1.27–5.43, P=0.009) after receiving consolidative radiation therapy, regardless of mutation status (37). In a multi-institutional cohort study involving 1,487 patients with oligometastatic NSCLC, analyses of 1,880 liquid biopsies revealed a 20% detection rate of ctDNA before radiotherapy. Patients with undetectable ctDNA prior to radiation therapy exhibited significantly improved PFS (P=0.004) and OS (P=0.030). Pre-radiation ctDNA maximum variant allele frequency (VAF) and ctDNA mutational burden were independently inversely correlated with PFS and OS (86). Cell-free DNA genetic alterations detected include EGFR, KRAS, ERBB2, MET, BRAF, ALK, ROS1, and RET, listed in order of frequency. Liquid biopsy, though minimally invasive, can aid in identifying patients with oligometastatic NSCLC who may benefit from more aggressive local treatment. With advancements in assay sensitivity, particularly in the detection of minimal residual disease (MRD), the prognostic and predictive value of liquid biopsy as a biomarker continues to evolve.

Changes in ctDNA status before and after local treatment can serve as prognostic indicators. In a prospective observational study by Fu et al., perioperative ctDNA levels were monitored in patients, primarily with oligopersistent disease, who underwent surgical resection of residual lesions following initial systemic therapy. Of the 68 patients studied, EGFR mutations were present in 64.7% of cases. Preoperative ctDNA negativity was a significant predictor of improved outcomes (HR =3.42, P=0.001). Moreover, patients who maintained or shifted to a ctDNA-negative status one month after surgery experienced better survival compared to those who remained ctDNA-positive, with hazard ratios of 3.22 for maintaining negativity and 4.57 for transitioning to negativity (59).

Future perspectives

Future research should focus on identifying the optimal treatment strategy for oligometastatic NSCLC, including the best sequencing approach and patient selection criteria.

While detecting co-mutations is becoming increasingly clinically significant and detection techniques are advancing rapidly, this is particularly important for oligometastatic NSCLC with targetable mutations. As more patient data accumulates from ongoing studies, treatment strategies will continue to evolve. Additionally, whether certain genetic alterations are associated with treatment outcomes specifically in oligometastatic NSCLC should be closely investigated so that the findings can be reflected in treatment guidelines. Furthermore, it will be clinically significant to determine how genetic alterations contribute to differentiating oligometastatic from polymetastatic NSCLC. Moreover, biomarker-driven treatment decisions, including ctDNA monitoring, could help refine therapy selection and improve patient outcomes.

Conclusions

Oligometastatic disease remains an evolving field, and a consensus on the optimal treatment approach has yet to be established. In oligometastatic NSCLC with targetable mutations, active management combining systemic treatment and local therapy can improve clinical outcomes. Accounting for co-mutations is important to enhance personalized treatment, and when possible obtaining sufficient pathological samples may help clinicians to create better treatment plans.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1121/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1121/prf

Funding: This research was supported by the Nano & Material Technology Development Program through the National Research Foundation of Korea (NRF) funded by Ministry of Science and ICT (RS-2024-00403376).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1121/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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