
==== Front
J Cancer Res Clin Oncol
J Cancer Res Clin Oncol
Journal of Cancer Research and Clinical Oncology
0171-5216
1432-1335
Springer Berlin Heidelberg Berlin/Heidelberg

39230677
5931
10.1007/s00432-024-05931-y
Research
The role of local ablative therapy in patients with advanced invasive mucinous adenocarcinoma of the lung
Kim Soo Han 123
Seong Hayoung 12
Lee Jonggeun 4
Ahn Hyo Yeong 4
Cho Jeong Su 4
I Hoseok 4
Kim Yeong Dae 4
Lee Min Ki 12
Eom Jung Seop 12
Kim Mi-Hyun mihyunkim@pusan.ac.kr

123
1 https://ror.org/01an57a31 grid.262229.f 0000 0001 0719 8572 Department of Internal Medicine, Pusan National University School of Medicine, 179 Gudeok-ro, Seo-gu, Busan, 49241 Republic of Korea
2 https://ror.org/027zf7h57 grid.412588.2 0000 0000 8611 7824 Department of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea
3 https://ror.org/027zf7h57 grid.412588.2 0000 0000 8611 7824 Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
4 grid.262229.f 0000 0001 0719 8572 Department of Thoracic and Cardiovascular Surgery, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
4 9 2024
4 9 2024
2024
150 9 40915 7 2024
22 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Purpose

Invasive mucinous adenocarcinoma (IMA) of the lungs is a rare subtype of lung adenocarcinoma with a limited understanding of its prognosis, particularly in advanced stages. This study aimed to assess the prognosis of patients with advanced IMA by focusing on treatment modalities.

Methods

This single-center retrospective study evaluated 33 patients with IMAs diagnosed with advanced-stage disease or disease progression after curative treatment between 2011 and 2021. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). OS and PFS were calculated from the date of the diagnosis of advanced IMA.

Results

The study cohort included 13 patients at the initial advanced stage and 20 patients who progressed after curative treatment. Treatment modalities included conventional chemotherapy in 24 patients (72.7%), targeted therapy in seven (21.2%), immunotherapy in 13 (39.4%), and local ablative therapy (LAT) in 13 (39.4%). The median OS was 32 months (95% confidence interval [CI], 2.9–61.0), with LAT significantly associated with improved OS compared to non-LAT treatment (not reached vs. 11.3 months, p = 0.001). However, there was no significant difference in OS based on conventional chemotherapy (p = 0.396), targeted therapy (p = 0.655), or immunotherapy (p = 0.992). In multivariate analysis, LAT remained an independent prognostic factor for OS (hazard ratio, 0.125; 95% CI, 0.026–0.608; p = 0.01). PFS was 8.6 months (95% CI, 3.6–13.7), with no significant differences observed among the treatment modalities.

Conclusion

Our findings suggest that LAT may provide favorable survival outcomes in patients with advanced IMA.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00432-024-05931-y.

Keywords

Adenocarcinoma
Mucinous
Local ablative therapy
Lung neoplasms
Prognosis
issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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pmcIntroduction

Primary pulmonary invasive mucinous adenocarcinoma (IMA) is a variant of adenocarcinoma (ADC) that comprises approximately 5–10% of lung ADCs (Guo et al. 2017; Travis et al. 2011). Formerly known as bronchioloalveolar carcinoma, IMAs are characterized by histological goblet and/or columnar cells with basal nuclei and abundant intracytoplasmic mucin within lung tumors (Travis et al. 2011). In 2011, the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society proposed renaming mucinous bronchioloalveolar carcinoma as IMA (Travis et al. 2011). In 2015, the World Health Organization (WHO) officially classified IMA as an invasive ADC variant (Travis et al. 2015).

Immunohistochemically, IMAs exhibit a profile distinct from that of invasive non-mucinous ADCs (INMAs). Specifically, IMAs are characterized by positive expression of cytokeratin 20, caudal type homeobox 2, and hepatic nuclear factor 1 alpha and negative expression of thyroid transcription factor 1 (Cha and Shim 2017; Travis et al. 2011). Recent research highlights that the Kirsten rat sarcoma virus (KRAS) mutation is the most common oncogenic driver mutation in IMAs, occurring in 35–75% of cases (Hata et al. 2010; Ichinokawa et al. 2013). Other significant factors include neuregulin-1 fusions, which occur in 7–27% of cases (Cha and Shim 2017; Shim et al. 2015). Compared with that in INMAs, IMAs exhibit a lower rate of epidermal growth factor receptor (EGFR) mutations (0–5%), but a higher rate of anaplastic lymphoma kinase (ALK) rearrangements (1.9%) and erb-b2 receptor tyrosine kinase 2 mutations (1.2%) (Cha and Shim 2017). Radiologically, IMAs may present as either a solitary mass or pneumonic infiltrates, with pneumonic infiltrates being associated with a poor prognosis (Wang et al. 2021).

Patients with IMAs generally present at earlier tumor stages than those with other types of lung ADC (Boland et al. 2018). Some studies suggest that patients with surgically resected IMAs have similar overall survival (OS) outcomes as those with INMAs (Lee et al. 2016). However, in advanced stages, one study concluded that patients with IMAs exhibit a worse prognosis than those with INMAs in stage IV (Cha et al. 2016), whereas other studies found no significant difference in prognosis between these two groups (Gow et al. 2021). Therapeutic options for IMAs are limited owing to the scarcity of targetable mutations, with conventional chemotherapy and targeted therapies providing limited survival benefits (Cha et al. 2016). Recently, immune checkpoint inhibitors have been introduced for the treatment of non-small cell lung cancer (NSCLC) (Garassino et al. 2023). However, programmed cell death-ligand 1 (PD-L1) expression in patients with IMAs is reported to be relatively low, suggesting that the efficacy of immune checkpoint inhibitors in this subgroup requires further exploration due to limited existing data (Xu et al. 2021).

Given the low incidence of IMA, the prognosis based on treatment modalities for advanced IMA remains unclear. Thus, this study aimed to evaluate the prognosis of IMA and related factors, with a focus on treatment modalities at an advanced stage.

Materials and methods

Study design

This retrospective study evaluated patients with IMA between 2011 and 2021 at Pusan National University Hospital, a tertiary referral center in Busan, Republic of Korea. The diagnosis of IMA was based on the histopathological report of biopsy specimens and in accordance with the WHO classification of lung tumors, including cases classified as mucinous ADC prior to the 2015 WHO classification update (Travis et al. 2015). The inclusion criteria for the patients were as follows: (1) a pathological diagnosis of advanced IMA (stages IIIB to IV) at the initial diagnosis, (2) a pathological diagnosis of early IMA (stages I to IIIA) that progressed or locally recurred after curative treatment, and (3) receipt of treatment at an advanced stage. In total, 101 patients with IMAs were identified. Among them, 68 patients were excluded for the following reasons: (1) 58 patients underwent curative surgery and showed no recurrence, and (2) 10 patients received supportive care only after the diagnosis of IMA at an advanced stage.

Clinicopathological features

Data on clinical characteristics, radiologic findings, treatment options, and follow-up records were obtained from electronic medical records. The collected variables included age, sex, smoking history (never smoked and regular smoker), body mass index (BMI), Eastern Cooperative Oncology Group performance status, initial clinical stage by TNM 8th edition (Goldstraw et al. 2016), initial chest computed tomography (CT) morphology (nodule, consolidation), recurred or metastatic sites, central nervous system metastasis, mutational status (EGFR mutation, ALK rearrangement, c-ros oncogene 1 [ROS1] rearrangement, or KRAS mutation), PD-L1 expression, and treatment options at advanced stage (surgery, radiotherapy, concurrent chemoradiation, or chemotherapy).

Regarding CT morphology, a nodular pattern is defined as a rounded opacity with a clear margin, whereas a consolidative pattern is defined as increased parenchymal attenuation that lacks a definable shape or distribution (Wang et al. 2021). For mutation status, EGFR and KRAS mutations were evaluated using polymerase chain reaction, ALK and ROS1 rearrangements were evaluated using immunohistochemistry (IHC) or fluorescent in situ hybridization, and PD-L1 expression was evaluated using IHC. Local ablative therapy (LAT) for primary and/or metastatic sites at an advanced stage includes options, such as surgery, radiotherapy, concurrent chemoradiation, or thermal ablation (Na and Kim 2023; Ni et al. 2020). Chemotherapy can be categorized into conventional cytotoxic chemotherapy, targeted therapy, and immunotherapy.

Outcomes

The primary outcome of the study was OS, defined as the time from the date of advanced IMA diagnosis to death from any cause or the last follow-up. The secondary outcome was PFS, defined as the interval from the diagnosis of advanced IMA to disease progression, death, or the last follow-up.

Statistical analysis

Categorical variables were analyzed using the χ2 test, Fisher’s exact test, or the linear association test, as appropriate. Continuous variables were analyzed using the independent two-sample t-test, Mann–Whitney U test, or Wilcoxon signed-rank test. Kaplan–Meier survival curve analysis was used to evaluate median OS and PFS. Univariate and multivariate Cox proportional hazards regression models were used to identify risk factors associated with OS and PFS, with variables achieving p-values < 0.05 in univariate analysis considered for multivariate analysis. All tests were two-sided, and statistical significance was set at p < 0.05. Statistical analyses were performed using SPSS ver. 26.0 (IBM Corporation, Armonk, NY, USA) and GraphPad Prism 10.0 (GraphPad Software, Inc., San Diego, CA, USA).

Results

Patient characteristics

A total of 33 patients with IMA were identified in this study, consisting of 13 patients at the initial advanced stage and 20 patients who progressed after curative treatment. Baseline characteristics of the IMA cohort are shown in Table 1. The median age was 67.0 years (interquartile range, 56.0–71.5). Moreover, 57.6% (n = 19) of the patients were men and 66.7% (n = 22) were regular smokers. The distribution of stages at initial diagnosis was as follows: 9.1% (n = 3), stage I; 18.2% (n = 6), stage II; 39.4% (n = 13), stage III; and 33.3% (n = 11), stage IV. The CT morphology predominantly showed a nodular type (66.7%, n = 22). Regarding the mutation profile, EGFR mutations were present in 3.1% (n = 1/32), ALK rearrangements in 3.3% (n = 1/30), ROS1 rearrangements in 8.3% (n = 1/12), and KRAS mutations in 60% (n = 3/5) of patients. PD-L1 expression was observed in 50% of patients (n = 12/24).

Table 1 Clinical and molecular characteristics of patients with advanced invasive mucinous adenocarcinoma

	All (n = 33)	
Age	67.0 [56.0–71.5]	
Regular smoker	22 (66.7)	
Men	19 (57.6)	
BMI	24.8 [22.8–27.2]	
ECOG		
 0	29 (87.9)	
 1 or 2	4 (12.1)	
Stage at diagnosis (TNM 8th edition)		
 I	3 (9.1)	
 II	6 (18.2)	
 III	13 (39.4)	
 IV	11 (33.3)	
Number of metastases at advanced stage or a recurrence		
 0	1 (3)	
 1	21 (63.6)	
 2	10 (30.3)	
 3	1 (3)	
CNS metastasis at advanced stage or a recurrence	5 (15.2)	
CT findings		
 Nodular type	22 (66.7)	
 Consolidative type	11 (33.3)	
Mutational status		
 EGFR (n = 32)	1 (3.1)	
 ALK (n = 30)	1 (3.3)	
 ROS1 (n = 12)	1(8.3)	
 KRAS (n = 5)	3 (60.0)	
PD-L1 (n = 24)		
 PD-L1 = 0	12 (50.0)	
 PD-L1 ≥ 1 and PD-L1 < 50	11 (41.7)	
 PD-L1 ≥ 50	1 (8.3)	
The results were reported as numbers (%) or medians (interquartile ranges). BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; CNS, central nervous system; CT, computed tomography; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ROS1, c-ROS oncogene 1; KRAS, Kirsten rat sarcoma virus; PD-L1, programmed cell death ligand 1

Treatment modalities

In our study cohort, conventional chemotherapy was administered to 24 (72.7%) patients. The predominant chemotherapy regimen was platinum with pemetrexed (n = 19, 57.6%), followed by platinum with gemcitabine (n = 11, 33.3%). Targeted therapy was administered to seven patients (21.2%); of these, six patients (18.2%) received EGFR TKIs and one patient (3.0%) received ALK TKI. Immunotherapy was administered to 13 patients (39.4%), with atezolizumab as the predominant agent (n = 10, 30.3%). One patient (3.0%) was treated with a combination of immunotherapy and conventional chemotherapy (pembrolizumab, pemetrexed, and carboplatin) as first-line treatment. LAT was administered to 13 patients (39.4%), with surgery being the most common (n = 12, 36.3%). Treatment modalities for patients with advanced IMA are shown in Table 2. Baseline characteristics of the IMA cohort based on LAT status are shown in Table S1.

Table 2 Treatment modalities in patients with advanced invasive mucinous adenocarcinoma

	All (n = 33)	
Initial treatment at an advanced stage or a recurrence		
 Surgery	5 (15.2)	
 Surgery + radiotherapy	1 (3.0)	
 Surgery + chemotherapy	6 (18.2)	
 Concurrent chemoradiotherapy	1 (3.0)	
 Chemotherapy	20 (60.6)	
Local ablative therapy	13 (39.4)	
Chemotherapy line		
 1st line, palliative	11 (33.3)	
 2nd line, palliative	7 (21.2)	
 3rd line, palliative	6 (18.2)	
 4th line, palliative	2 (6.1)	
 5th line, palliative	2 (6.1)	
Conventional chemotherapy regimen		
 Platinum and pemetrexed	19 (57.6)	
 Platinum and gemcitabine	11 (33.3)	
 Platinum and taxane	1 (3.0)	
 Taxane	3 (9.1)	
 Pemetrexed	2 (6.1)	
 Gemcitabine	2 (6.1)	
 Irinotecan	2 (6.1)	
 Navelbine	1 (3.0)	
Target therapy		
 EGFR TKI	6 (18.2)	
 ALK TKI	1 (3.0)	
Immunotherapy		
 Pembrolizumab + pemetrexed + platinum	1 (3.0)	
 Atezolizumab	10 (30.3)	
 Nivolumab	1 (3.0)	
 Pembrolizumab	1 (3.0)	
The results are reported as numbers (%). EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor

OS and PFS

The median OS was 32.0 months (95% confidence interval [CI], 2.9–61.0) (Fig. 1). When stratified by treatment modality, there was no significant difference in OS between conventional chemotherapy and non-conventional chemotherapy (32.0 months versus non-evaluable; p = 0.396) (Fig. 2A). Similarly, no significant difference was observed in OS between targeted therapy versus non-targeted therapy (32.0 months versus 34.6 months; p = 0.655) (Fig. 2B), or between immunotherapy versus non-immunotherapy (34.6 months versus 32.0 months; p = 0.992) (Fig. 2C). However, the LAT group demonstrated significantly improved OS compared with that of the non-LAT group (not reached vs. 11.3 months, p = 0.001) (Fig. 3). The median PFS was 8.6 months (95% CI, 3.6–13.7) (Fig. S1). PFS analysis revealed no significant differences; conventional chemotherapy (8.6 months vs. 9.7 months; p = 0.444) (Fig. S2A), targeted therapy (12.7 months vs. 8.0 months; p = 0.785) (Fig. S2B), immunotherapy (7.1 months vs. 18.5 months; p = 0.260) (Figure S2-c), and LAT (18.5 vs. 6.2 months, p = 0.113) (Fig. S3).

Fig. 1 Overall survival (OS) curve of all patients with advanced invasive mucinous adenocarcinoma

Fig. 2 Kaplan–Meier curves of overall survival (OS) in patients with advanced invasive mucinous adenocarcinoma based on (A) conventional chemotherapy (CTx), (B) target therapy, and (C) immunotherapy

Fig. 3 Kaplan–Meier curves of overall survival (OS) in patients with advanced invasive mucinous adenocarcinoma based on local ablative therapy (LAT)

Prognostic factors for OS and PFS

On univariate analysis, age (hazard ratio [HR], 1.07; 95% CI, 1.01–1.12; p = 0.016), regular smoker (HR, 3.07; 95% CI, 0.96–9.81; p = 0.059), number of metastases (HR, 3.51; 95% CI, 1.41–8.78; p = 0.007), and LAT (HR, 0.119; 95% CI, 0.03–0.51; p = 0.004) were identified as significant variables for OS. On multivariate Cox proportional hazards analysis, LAT was shown to be the only significant independent prognostic factor for death (HR, 0.124; 95% CI, 0.03–0.60; p = 0.01) (Table 3). Regarding PFS, age (HR, 1.04; 95% CI, 1.00–1.08; p = 0.04), BMI (HR, 0.90; 95% CI, 0.80–1.00; p = 0.51), and number of metastases (HR, 3.53; 95% CI, 1.50–8.34; p = 0.004) were identified as significant variables for PFS. Multivariate analysis identified BMI as a significant independent prognostic factor for disease progression (HR, 0.89; 95% CI, 0.79–1.00; p = 0.043) (Table S2).

Table 3 Cox proportional hazards model analysis of death in patients with advanced invasive mucinous adenocarcinoma

Variable	Univariate	Multivariate	
HR	95% CI	p-value	HR	95% CI	p-value	
Age	1.065	1.012–1.122	0.016	1.05	0.996–1.107	0.067	
Regular smoker (vs. non-smoker)	3.068	0.959–9.813	0.059	3.318	0.894–12.322	0.073	
Men (vs. women)	2.089	0.762–5.725	0.152				
BMI	0.904	0.794–1.029	0.128				
ECOG 1 or 2 (vs. ECOG 0)	1.765	0.559–5.574	0.333				
Stage at diagnosis (TNM 8th edition) (vs. I)			0.626				
 II	0.900	0.08–10.185	0.932				
 III	2.119	0.265–16.936	0.479				
 IV	2.194	0.266–18.071	0.465				
2 or 3 metastases at advanced stage or recur (vs. 0 or 1)	3.514	1.406–8.781	0.007	0.789	0.258–2.410	0.678	
CNS metastasis at advanced stage or recur	1.878	0.614–5.746	0.269				
Consolidative type (vs. nodular type)	0.951	0.351–2.574	0.921				
Local ablative therapy	0.119	0.027–0.517	0.004	0.124	0.025–0.605	0.01	
Conventional chemotherapy	1.705	0.490–5.937	0.402				
Target therapy	1.255	0.462–3.410	0.656				
Immunotherapy	1.005	0.394–2.561	0.992				
HR, hazard ratio; CI, confidence interval; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; CNS, central nervous system

Discussion

In this study, we evaluated the prognoses and factors influencing the outcomes of patients with advanced IMA in relation to different treatment modalities. The results indicated that patients with advanced IMA had a comparatively favorable OS, with a median OS of 32.0 months. Importantly, LAT was identified as a significant predictor of improved survival outcomes in multivariate analysis. However, conventional chemotherapy, targeted therapy, and immunotherapy showed no significant effect on survival.

The efficacy of LAT has been predominantly assessed in patients with NSCLC presenting with oligo-metastasis (OM). OM has been reported in 21% of resected NSCLC cases, ranging from pathological stage IA–IIIB (Hishida et al. 2016) to 25% of patients with stage IV NSCLC (Parikh et al. 2014). The introduction of LAT aimed to enhance the prognosis in these scenarios, defined as the application of radical therapy (such as surgery and radiotherapy) to all technically feasible tumor sites capable of influencing disease progression while maintaining acceptable toxicity levels (Na and Kim 2023). A meta-analysis examining the role of LAT in NSCLC with OM, encompassing 1,750 patients from 20 studies, revealed pooled odds ratios for OS and PFS of 3.492 (95% CI, 2.612–4.699; p < 0.001) and 3.743 (95% CI, 2.586–5.419, p < 0.001), respectively, favoring LAT (Rim et al. 2023). Similarly, our study demonstrated a significant survival benefit associated with LAT in patients with advanced IMA, with an HR of 0.119. Moreover, in our study cohort, 39.4% (n = 13/33) of the patients received LAT for OM, a proportion higher than that observed in the general NSCLC population. This discrepancy could be attributed to the distinctive characteristics of IMA, which are characterized by aerogenous spread with intrapulmonary metastasis and fewer occurrences of lymph node and distant metastases, thus rendering LAT more feasible (Lee et al. 2016; Shim et al. 2015). Therefore, LAT is a promising treatment modality, particularly for IMA.

In our study, surgery was the preferred modality in 92.3% (n = 12/13) of cases among various LAT modalities. A previous meta-analysis of 54 studies on the treatment of NSCLC with OM found no significant difference in OS between surgery and radiotherapy (p = 0.65) (Schanne et al. 2019). However, another meta-analysis focusing on LAT for NSCLC with OM, including 499 patients from eight studies, revealed a lower HR of 0.33 (95% CI, 0.22–0.48) for PFS in LAT cases incorporating surgery, compared to 0.55 (95% CI, 0.36–0.83) for those without surgical intervention (Zhang et al. 2021). Critical pathological parameters, such as tumor cell spread size, invasive size, and mucin spread size, which are known to correlate with poor prognosis (Saito et al. 2020), are not easily identifiable through the radiological means. Given the lower incidence of lymph node metastasis and the challenge of encompassing pathological parameters within radiation fields during radiotherapy for IMA, surgery may represent a viable modality to improve prognosis and provide feasibility for patients with IMAs and OMs. Nonetheless, further studies are imperative to validate these findings and elucidate the full extent of its efficacy.

Unfortunately, our study showed that conventional chemotherapy had no significant effect on patient survival. This aligns with the findings of Cha et al., indicating limited survival improvements with chemotherapy (p = 0.667) (Cha et al. 2016), possibly because of the protective role of extracellular mucus expressing MUC1 and MUC5AC in fostering chemoresistance (Lakshmanan et al. 2015; Saito et al. 2020). Thus, novel approaches targeting the mucinous nature of the IMA have shown promise. In a rat patient-derived xenograft model, pretreatment with a mucolytic therapy comprising bromelain and N-acetylcysteine significantly augmented drug delivery, improved chemosensitivity, and mitigated mucinous tumor growth (Dilly et al. 2021). Hence, the integration of mucolytics into chemotherapeutic regimens has the potential to become an effective strategy. Combining cisplatin/pemetrexed with bevacizumab has also shown prolonged survival, ranging from 12.6 to 30 months, which is likely attributed to increased drug delivery (Sun et al. 2018). Furthermore, our study showed no significant benefit of targeted therapy on survival. Although targetable mutations, such as EGFR mutations, are rare in IMA. KRAS mutations could offer opportunities for targeted therapy, with G12D and G12V mutations accounting for 42.0% and 31.0%, respectively (Xu et al. 2023). Clinical trials investigating the efficacy of the KRAS G12D inhibitor MRTX1133 are underway (Zeissig et al. 2023). Moreover, neuregulin-1 fusion, the second most frequent genetic alteration in IMA, has identified afatinib, an irreversible erb-b2 receptor tyrosine kinase family inhibitor, as a promising therapeutic option (Rosas et al. 2021).

Previous studies have reported low expression of PD-L1 (≥ 1%) in patients with IMA compared with that of those with NIMA (48.1% vs. 9.7%; p = 0.001), along with diminished CD8 + infiltration (≥ 10%) (81.5% vs. 35.5%; p < 0.001) (Xu et al. 2021). These findings suggest a poor response rate to immune checkpoint inhibitors in patients with IMA. However, in advanced IMA, we observed a relatively high proportion of PD-L1 expression (50%), which did not significantly affect survival. Interestingly, Jang et al. reported similar PD-L1 expression levels (42.4%) in advanced IMA but observed better survival rates with immunotherapy compared with those of non-immunotherapy treatments (undefined vs. 17.0 months; p < 0.001) (Jang et al. 2021). This discrepancy might be attributed to differences in co-mutations, such as KRAS, which were more prevalent in the study by Jang et al. (91.7%) than in ours (60%) (Jang et al. 2021). Peng et al. demonstrated that KRAS mutations are positively associated with the immunotherapy response, which might be linked to high PD-L1 expression, an inflammatory tumor microenvironment, and enhanced tumor immunogenicity (Peng et al. 2022). Additionally, differences in the immunotherapy regimen, especially in the combination of conventional chemotherapy and immunotherapy, were noted (3.0% in our study vs. 5.1% in Jang et al.’s study) (Jang et al. 2021). IMA also exhibit unique inhibitory immune checkpoints, such as VTCN1, suggesting potential targets for overcoming immune resistance (Guo et al. 2017). Further research is needed to validate our results and improve treatment strategies by focusing on optimized combination therapies with immunotherapy and targeting the tumor microenvironment.

Our study had some limitations. First, the number of patients was relatively small, owing to the rarity of IMA. This limited sample size reduces the generalizability of our findings and may impact the statistical power, particularly in subgroup analyses. Second, its retrospective design from a single institution may have introduced selection bias. LAT might have been more frequently administered to patients with favorable prognostic factors, such as lower tumor burden. However, we addressed this potential limitation by performing a multivariate analysis that adjusted for these factors, thereby strengthening the validity of our findings. Third, not all patients in our cohort underwent mutational profiling or PD-L1 IHC assays, which could have limited the efficacy of therapies based on these profiles. Despite these limitations, this study is the first to offer significant insights into the use of LAT in the treatment and prognosis of patients with IMAs. Further largescale prospective studies are required to address these limitations.

Conclusions

In conclusion, this study suggests that LAT may provide favorable survival outcomes for patients with advanced IMA. However, conventional chemotherapy, targeted therapy, and immunotherapy showed no significant association with survival in these patients. Further research is warranted to evaluate the efficacy of existing treatments, including exploring the optimal combination of current treatments, developing new gene-targeted therapies, and investigating immunotherapies targeting novel biomarkers.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

This work was supported by a clinical research grant from the National Research Foundation of Korea, funded by the Korean government (Ministry of Science and ICT) (NRF-2022R1F1A1074117) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0026).We would like to thank Editage (www.editage.com) for English language editing.

Author contributions

S.H.K.: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft. H.S.: Data curation, Investigation, Writing – review & editing. J.L.: Formal analysis, Visualization, Writing – review & editing. H.Y.A.: Methodology, Software, Writing – review & editing. J.S.C.: Formal analysis, Resource, Writing – review & editing. H.I.: Methodology, Resource, Writing – review & editing. Y.D.K.: Formal analysis, Resource, Writing – review & editing. M.K.L.: Project administration, Supervision, Validation. J.S.E.: Supervision, Validation, Writing – review & editing. M.K.: Conceptualization, Formal analysis, Funding acquisition, Investigation, Project administration, Validation, Writing – original draft.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval

This study was approved by the Institutional Review Board of Pusan National University Hospital (IRB No. 2404-020-138). Written informed consent was not required for this study in accordance with national legislation and institutional requirements.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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