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Molecular characterization of early-stage lung adenocarcinoma presenting as subsolid nodules in a real-life European cohort

BMC Cancer volume 25, Article number: 647 (2025) Cite this article

Abstract

Objectives

Subsolid nodules emerged as frequent radiological variants of lung adenocarcinoma. Radiological features including solid-component prevalence and larger tumour dimensions prompt tumoral invasiveness guiding prognosis and management. Thus, we aimed to clarify the molecular grounds that dictate these radiological appearances and clinical behaviour in a real-life European-cohort. Additionally, following the growing interest toward targeted-therapies in early-stage diseases, we aimed to present real-life epidemiological data of actionable mutations in these patients.

Methods

In this retrospective single-centre study, targeted next-generation sequencing was performed continuatively in all the resected subsolid lung adenocarcinomas in the period between May 2016 and December 2023. Clinico-radiological data were collected. The genetic landscape of our real-life European subsolid adenocarcinoma population is defined. Common and actionable mutations (frequency > 5%) relation to key clinico-radiological features are evaluated.

Results

Overall, 156 subsolid adenocarcinomas were analysed. KRAS-mutations, mostly KRAS p.G12C, were the most prevalent followed by EGFR, including 25% uncommon EGFR-mutations, TP53 and MET mutations. Amongst the clinico-radiological variables, KRAS-mutations and KRAS p.G12C-mutation were associated to smoking history (≥ 20 pack/years), aggressive histologic subtype and higher consolidation-to-tumor ratio (CTR). Moreover, KRAS-mutated nodules had faster tumour-doubling-time. Conversely, EGFR-mutations were associated to female sex and lower CTR. The latter not being confirmed in common EGFR-mutations. Additionally, in common EGFR-mutated nodules, aggressive histological components were rarer.

Conclusion

Our study presents the molecular profile of subsolid lung adenocarcinoma in a real-life European-cohort. KRAS-mutations were the most prevalent, and were related to smoking history, higher CTR and faster growth. Conversely, common EGFR-mutations were rarer than expected and unrelated to smoking history and radiological features.

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Introduction

Low-dose computed tomography (CT) lung cancer screening has completely reshaped early-stage lung adenocarcinoma landscape [1]. Besides solid nodules, several subsolid lesions with heterogeneous densities, morphologies, and dimensions have emerged as alternative radiological patterns of lung adenocarcinomas [2, 3]. Subsolid nodules includes pure ground-glass opacities (GGOs), presenting as areas of increased lung opacity with preservation of bronchial and vascular margins, and part-solid nodules presenting as solid nodules surrounded by a GGO [4, 5].

Overall, lung adenocarcinomas presenting as subsolid nodules have an indolent clinical behaviour showing less invasive histological patterns compared to those presenting as solid nodules [6]. However, solid component dimension diversifies subsolid nodules clinical behaviour prompting tumoral invasiveness and jeopardizing clinical outcomes [7, 8].

Due to the prognostic impact of the solid component in these tumours, a morphological classification, based on consolidation-to-tumour ratio (CTR) and nodules’ dimension, has been adopted in the clinical setting and trials as a reference to stratify patients’ risk and allocate treatment opportunity [9,10,11].

Accordingly, most of the decision making about early-stage lung cancer management is guided by radiological features. However, besides radiological innovations, molecular biology has emerged as a prognostic tool in advanced lung cancer directly targeting the molecular grounds of cancer development [12]. Particularly, genetic landscape characterization in advanced-stage lung adenocarcinoma has completely changed the treatment paradigm and has improved our ability to predict metastatic pathways and the overall clinical behaviour of the tumours [13]. The results achieved in the advanced-stages have triggered the interest to extend molecular characterization in early-stage lung adenocarcinomas [14, 15]. However, to date, molecular profile in these patients and particularly in subsolid nodules remains poorly investigated and limited to a few non-European reports [16,17,18].

In this single centre retrospective study, we present the molecular features retrieved by targeted next generation sequencing (NGS) of our subsolid early-stage lung adenocarcinomas cohort identifying the most frequent and clinically relevant molecular alterations. Moreover, we analyse the molecular differences amongst subsolid nodules according to clinical and radiological characteristics.

Materials and methods

The study was designed as a retrospective analysis of the molecular characteristics of subsolid nodules (CTR < 1). Inclusion and exclusion criteria are detailed in Table 1. The study was performed in accordance with the Declaration of Helsinki and was approved by the ethics committee of our institution (Approval number:1465/21;23/02/2021). Before each procedure, the patients were extensively informed and written informed consent was obtained. This manuscript was written according to the STrengthening the Reporting of OBservational studies in Epidemiology (supplementary Fig. 1).

Table 1 Inclusion and exclusion criteria
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According to the study aim, preoperative radiological data, clinical charts, pathological reports as well as molecular biology reports of patients undergoing either lobectomy or segmentectomy in the period between May 2016 and September 2023 were retrieved and collected in a database with previously chosen entries.

For the study purposes, CT scans were assessed and reviewed by three investigators including two thoracic surgeons (RT and FTG) and an experienced radiologist (MC) under the lung window setting (window level, 1500 HU; width, -700 HU). Pure GGOs were defined according to guidelines as focal nodular areas of increased lung attenuation, including both well and poorly defined lesions through which normal parenchymal structures, including airways and vessels, can be visualized. Conversely part-solid GGO include a combination of ground-glass and solid components, the latter obscuring the underlying lung architecture [4, 5]. Preoperative chest CT scans were performed within 4 weeks prior of surgery. For each nodule, tumour average diameter was measured as the average of long and short-axis diameter. Similarly, the average diameter of the solid-component was measured as the average of long and short-axis diameter of the solid-component. All the measures were approximated to the nearest millimetre. CTR was also estimated as the solid component maximal diameter to the overall maximal tumour diameter ratio.

In those patients undergoing more than one preoperative CT-scan (interval between scans more than one month), tumour doubling time (TDT) was estimated consistently with existing guidelines [19]. Diameter was used to estimate TDT. A 400-days cut-off was chosen to identify fast growing from slow growing nodules [20, 21].

Before surgery all the patients underwent the same preoperative evaluation including total body contrast-enhanced CT scan and F18-fluorodeoxyglucose positron emission tomography/CT. Further radiological or minimally invasive staging examinations were conducted according to current guidelines [22].

After surgery, all formalin-fixed paraffin-embedded tissue sections were reviewed by pathologists for histopathological confirmation and tumour content assessment. Pathological stage was evaluated according to the 8th Edition of the tumour node metastases (TNM) staging system for lung cancer [23]. Predominant invasive lung adenocarcinoma histologic subtypes were classified according to current classification as lepidic or not-lepidic [24]. Moreover, the worst histological subtype component was retrieved.

Targeted-NGS analysis was performed using the Oncomine Precision Assay (Thermo Fisher Scientific, Inc.) for mutation, copy number variation, and fusion variant types across 50 key genes amongst the most common and potentially relevant cancer drivers in lung adenocarcinoma. Particularly the assay analyses 78 variants, including mutations, copy number variations, and fusion variants across 50 genes including oncogenic mutations, likely oncogenic mutations, actionable mutations, and resistance mutations. Complete list of the evaluated genes is presented in supplementary materials Table 1. Due to the clinical relevancy of Epidermal growth factor receptor (EGFR) mutations were also stratified as common, including L858R mutation and exon 19 deletion, and uncommon mutations, including all the other EGFR mutations. Kirsten Rat Sarcoma Virus (KRAS) mutations were stratified according to the oncogene substitution. Complete list of the evaluated genomic alterations is presented as supplementary Table 1. ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) was retrieved from molecular biology report for each patient as I, II and III [25]. In those patients presenting co-occurring mutations, the lowest ESCAT value was reported.

Statistical analysis was performed by an experienced biostatistician using SPSS 20 (IBM SPSS Statistics, IBM Corporation, Chicago, IL). Descriptive statistics were calculated and expressed as median and interquartile ranges and categorical variables as overall number and percentage. We dichotomized all continuous and ordinal data to values between 0 and 1. Intergroup analysis was performed according to age, sex, smoking habit (≥ 20 pack-years), predominant lepidic histological subtypes, occurrence of solid or micropapillary as worst histological pattern and pathological stage and according to radiological characteristics such as tumour average diameter > 20 mm, solid part average diameter > 5 mm, CTR (CTR > 0; CTR > 25 and CTR > 50), and growing pattern (TDT ≤ 400days). Comparison between categorical variables was made using Fisher Exact test. Significance was assessed for p-value below 0.05.

Results

Eligibility and patients’ selection process are presented in supplementary Fig. 1. Of the 457 evaluated patients, 156 had subsolid nodules and underwent targeted-NGS. Overall, 50 (32.1%) patients had pGGOs and 106 (67.9%) patients had part-solid nodule. Clinical and radiological characteristics of the enrolled patients are summarized in Table 2. In 127 patients TDT could be estimated and 52 of these patients (40.9%) had fast growing nodules (TDT ≤ 400 days).

Table 2 Clinical and radiological characteristics of the enrolled population
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The clinical and mutational landscape of the 156 subsolid nodules according to CTR are presented in Fig. 1a. Amongst the analysed genetic variations, KRAS mutations were the most common mutations (29.5%) followed by EGFR (25.6%), TP53 (6.4%) and MET mutations (6.4%). Moreover, RET rearrangements and PIK3CA alterations happened in 2.6% of the population. ALK and CD74-NRG1 rearrangements as well as BRAF, ERBB2 and FGFR3 mutations were found in 1.3% of the patients. Finally, 6.4% of the population had rarer mutations such as STK11, NRAS, CTNNB1, IDH1, PDGFRA and ARAF variations. Co-mutations were found in 11.5% of the patients. Among these 17 patients, rarer genetic variations co-occurred to EGFR mutations in 9 patients and to KRAS mutations in 6 patients, respectively. In two patients more than three genetic alterations co-occurred. Comprehensively 27.6% of the patients had no variations in the evaluated genes. The distribution of the ESCAT ranking according to CTR is presented in Fig. 1a.

Fig. 1
figure 1

Mutational landscape of subsolid nodules (CTR < 1) in a real-life European cohort (A) In the upper panel, measured consolidation-to-tumour ratio (CTR) of each nodule is presented in ascending order. In the middle panel clinical and radiological characteristics are presented. In the heatmap below the somatic mutations of each subsolid nodule are presented ordered by mutation frequency. (B) Mutational landscape of KRAS oncogene substitutions and EGFR variants in our subsolid cohort according to their frequency. (C) Activated cancer-related pathway by somatic mutations expressed by subsolid adenocarcinomas. The vertical axis represents the number of mutated genes participating to each cancer-related pathway. CTR: consolidation-to-tumour ratio, TNM: tumour, node, metastases staging system, TDT: tumour doubling time

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As KRAS and EGFR mutations were the more frequent molecular alterations expressed in our subsolid adenocarcinoma cohort, we also investigated the genetic landscape of KRAS substitutions and EGFR variants (Fig. 1b).

Amongst the 46 KRAS-mutated subsolid adenocarcinomas, KRAS p.G12C was enriched in 41.3% patients, p.G12V in 15.2%, p. G12D in 15.2% while, in 28.3% of the patients, rarer oncogene substitutions were found. Amongst the 40 EGFR mutated subsolid adenocarcinomas, L858R mutation and exon 19 deletion were found in 40% and 35% of the population, respectively. Uncommon EGFR mutations were found in the 25% of the population. In supplementary Table 2, EGFR and KRAS variants and their frequency is presented.

Activated cancer-related pathway according to the Cancer Genome Atlas Oncogenic pathways are shown in Fig. 1C and demonstrated the prevalence of RTK-pathway and RAS-pathway in subsolid adenocarcinomas.

Genetic profile of the subsolid nodules according to clinical characteristics

The distribution of the most common genetic variations (frequency > 5%) was analysed according to clinical, and pathological characteristics (Fig. 2 and supplTable 3). Namely KRAS, EGFR and TP53-mutations as well as MET-amplifications were evaluated. No differences could be found among the different genetic patterns according to age even if EGFR-mutated subsolid adenocarcinomas were more frequently observed in younger patients, but the difference was not statistically significant. Conversely, EGFR was more frequently mutated in females compared to males (32.2% vs. 17.4%; p = 0.04). Similarly common EGFR-mutations were more frequent in female (male 11.6% vs. female 25.3%; p = 0.04). Patients with a ≥ 20 pack/year smoking history had higher rate of KRAS-mutations compared to non- or light-smokers (45.8% vs. 19.6%; p = 0.001). Correspondingly, KRAS p. G12C mutation was mostly enriched in moderate-to-heavy smokers (heavy smokers 22% vs. non or light smokers 6.2%; p = 0.005). As it concerns the pathologic results, EGFR-mutations were more frequently enriched in patients with predominant lepidic lung adenocarcinomas compared to the other histological subtypes (40% vs. 20.7%; p = 0.02). Differently, KRAS p. G12C was prevalent in those without predominant lepidic histologic subtypes (predominant lepidic 2.5% non-predominant lepidic 15.5%; p = 0.04). Moreover, EGFR-common-mutations and overall EGFR-mutations were less frequently enriched in those patients with occurrence of solid or micropapillary histologic patterns (solid/micropapillary vs. other histologic patterns: 4.2% vs. 22.0%; p = 0.02 and 7.4% vs. 29.5%; p = 0.04, respectively).

No differences could be found in the molecular pattern of the patients with pathological stage IA compared to those with higher pathological stage.

Fig. 2
figure 2

Analysis of the most common (frequency > 5%) somatic mutations prevalence and of KRAS G12C as well as EGFR common mutations according to clinical variables. The vertical axis indicates the percentual frequency of the somatic mutation. Significance was ascertained by Fisher exact test, *:p < 0.05

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Genetic profile of the subsolid nodules according to radiological characteristics

According to the study aim, we compared the distribution of the analysed driver mutations according to the radiological characteristics of the included nodules as it is shown in Fig. 3. In the overall population 50 (32.1%) patients had pure-GGO nodules, while 106 (67.9%) patients had part-solid nodules. Differently, both KRAS p.G12C (CTR ≤ 0.50 vs. CTR > 0.50: 7.4 vs. 19.7%; p = 0.02) and the whole family of KRAS-mutations (CTR ≤ 0.50 vs. CTR > 0.50: 23.3 vs. 39.3p = 0.04) were more frequent in patients with CTR > 0.50 while EGFR-mutations were more frequent in those with CTR ≤ 0.50 (CTR ≤ 0.50 vs. CTR > 0.50: 31.6 vs. 16.4 p = 0.04). Conversely, no difference could be found when either between nodules with CTR > 0.25 vs. CTR ≤ 0.25 or between pGGO and part-solid nodules. Similarly, no differences were retrieved in the distribution of the main molecular patterns according to tumour diameter or to solid component diameter. Finally, amongst the 127 patients who underwent preoperative radiological follow up to assess nodule growth, KRAS-mutations were more frequently enriched in the nodules with fast growth as estimated by a TDT ≤ 400 days compared to those with a slower growing pattern (TDT > 400 days). The difference was statistically significant (50% vs. 17.3; p < 0.001).

Fig. 3
figure 3

Analysis of the most common (frequency > 5%) somatic mutations prevalence and of KRAS G12C as well as EGFR common mutations according to radiological variables. The vertical axis indicates the percentual frequency of the somatic mutation. CTR: consolidation to tumour ratio; TDT: tumour doubling time. Significance was ascertained by Fisher exact test, *:p < 0.05

Full size image

Discussion

Due to the widespread of low-dose CT screening programs and to the refinement of the diagnostic tools, subsolid pulmonary nodules are frequently encountered in the clinical practice. Subsolid nodules are generally considered indolent tumours and observation following surgery is the standard treatment. Thus, molecular profiling is generally waived until recurrence leading to a paucity of real-world data about genetic alterations prevalence especially in the European population [26]. However, the results achieved by targeted-therapies in lung cancer has triggered the interest toward perioperative treatment even in these very early-stage lung adenocarcinomas [27].

Our study provides a comprehensive landscape of the molecular characteristics of early-stage lung adenocarcinoma presenting as subsolid nodules in a real-world European-cohort. According to our findings, KRAS, EGFR, TP53 and MET molecular alterations were the most frequently encountered in subsolid adenocarcinomas. Interestingly, KRAS-mutations were the most frequent as they were found in 29.5% of the patients being KRAS p. G12C the most prevalent. The unexpected frequency of KRAS-mutations in our population considerably differs to those presented in previous analyses in which KRAS-mutations frequence ranged from 5 to 9% of the patients [17, 18]. Under a clinical perspective, KRAS-mutations, and particularly KRAS p. G12C, present a more aggressive clinical behaviour with higher recurrence risk even in stage I disease and subsolid nodules and underline the necessity of preoperative molecular and pathological examination to define tailored therapeutic strategy [28, 29].

In our population, EGFR-mutations were found in 25.6% of the patients. Even if EGFR is still one of the most frequently mutated gene in our subsolid adenocarcinomas cohort, its prevalence is meaningfully lower to similar cohorts presented in previous non-European analyses [17, 18, 30]. Interestingly, a difference can be also found in the distribution of uncommon EGFR-mutations, 25% of our EGFR-mutated nodules, compared to 19.3% [17]. The lower-than-expected prevalence of EGFR-mutations as well as the relatively higher frequency of uncommon EGFR-mutations may be particularly relevant within the introduction of adjuvant EGFR-targeted treatments in the very early-stages that is limited to common EGFR-mutations [31]. Indeed, uncommon EGFR-mutations, such as EGFR exon 20 insertion, found in 7.5% of our EGFR-mutated adenocarcinomas, may exert worse respond or resistance to EGFR-targeted-therapies [32]. Amongst the less prevalent mutated genes, both TP53-mutations and MET-mutations occurred in 6.4% of the patients in accordance with previous reports analysing subsolid nodules and early-stage lung adenocarcinoma [17, 33]. Particularly the lower incidence of TP53-mutations compared to advanced-stage lung adenocarcinomas, confirming the role on this molecular pathway in lung adenocarcinoma progression [12]. Taken together, our results match with European and North American studies and confirm the difference in EGFR- and KRAS-mutations prevalence between European and non-European subsolid adenocarcinomas cohorts [34, 35]. Moreover, despite the differences in KRAS and EGFR prevalence, both these mutations participate to RTK/RAS-pathway activation remarking the pathogenetic proliferative tendency of subsolid nodules.

The outlined epidemiological and potentially pathogenetic differences in subsolid adenocarcinomas molecular pattern may also resides in clinical and demographical characteristics. According to previous reports [12], our analysis confirms the higher EGFR-mutations prevalence in female patients. However, no differences could be found in EGFR-mutations prevalence according to smoking habit questioning the role of smoking history as a selection factor for EGFR testing in the European population [35]. Differently, smoking habit was strongly related to KRAS-mutations and particularly with KRAS p. G12C. Moreover, EGFR-mutations were more frequently encountered in predominant lepidic adenocarcinomas and, in only 3.3% of the adenocarcinomas with common EGFR-mutations, solid or micropapillary histological features were noticed. Conversely, KRAS p. G12C mutation was more prevalent in predominant non-lepidic adenocarcinomas.

According to the evaluated radiological features, EFGR mutations were harvested more frequently in subsolid nodules with CTR ≤ 0.50 however EGFR common mutations were homogeneously distributed according CTR questioning the possibility to predict EGFR-mutation on morphological bases. Differently KRAS mutations and KRAS p. G12C were significantly prevalent in subsolid nodules with CTR > 0.50. This finding compares well with previous reports demonstrating a worse clinical behaviour of KRAS mutated lung adenocarcinoma even in the early stages [17, 36]. Furthermore, we showed a higher rate of KRAS mutations in subsolid nodules with a TDT ≤ 400 days. Again, this result confirms, even in subsolid nodules, the higher tendency of KRAS-mutated adenocarcinoma to invasiveness and growth.

This study has several limitations, first whole genome analysis was not available for this cohort of patients and only NGS for targeted genes has been performed. This may have resulted in a lack of sensitivity toward non-frequently mutated genes in lung adenocarcinoma. Moreover, despite a larger number of patients screened, only a relatively limited sample size was eligible. This may have hindered comparison between groups especially for rarer mutations, as TP53- or MET-mutations or intergroup comparison. Additionally, due to the retrospective nature of the study, other clinically relevant biomarkers such as programmed death ligand 1 expression could not be retrieved for all the patients. Finally, most of the patients were older than 65 years old. Even if this may have altered the prevalence of the retrieved genetic profiles, still it may reflect real-life European epidemiology of subsolid nodules.

Conclusions

Our study presents a comprehensive analysis of the molecular profile of early-stage lung adenocarcinoma presenting as subsolid nodules in a European-cohort. KRAS-mutations were the most prevalent, and were related to smoking history, higher CTR and faster growth. Conversely, common EGFR-mutations were rarer than expected and probably unrelated to smoking history and radiological features. Further, multicentric studies are compulsory.

Data availability

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

Abbreviations

ALK:

Anaplastic lymphoma kinase

CT:

Computed tomography

CTR:

Consolidation-to-tumour ratio

DFS:

Disease-free survival

EGFR:

Epidermal growth factor receptor

GGO:

Ground-glass opacity

HR:

Hazard ratio

NGS:

Next generation sequencing

KRAS:

Kirsten rat sarcoma virus

NSCLC:

Non-small cell lung cancer

TDT:

Tumour doubling time

TKI:

Tyrosine kinase inhibitor

TNM:

Tumour node metastases

WT:

Wild type

18FDG-PET:

18-fluorodeoxyglucose positron emission tomography

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Acknowledgements

We would like to extend our deepest gratitude to those who have contributed to our project over the last few years. The authors want to thank the Scientific Direction of the IRCCS “Regina Elena” National Cancer Institute for the support of our study.

Funding

This work was financially supported through funding from the institutional “Ricerca Corrente” granted by the Italian Ministry of Health.

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Authors and Affiliations

  1. Doctoral School of Microbiology, Immunology, Infectious Diseases and Transplants, MIMIT, University of Rome “Tor Vergata”, Rome, Italy

    Riccardo Tajè & Alexandro Patirelis

  2. Thoracic Surgery Unit, IRCCS “Regina Elena” National Cancer Institute, Via Elio Chianesi 53, Rome, 00144, Italy

    Riccardo Tajè, Filippo Tommaso Gallina, Daniele Forcella, Gabriele Alessandrini & Enrico Melis

  3. Tumor Immunology and Immunotherapy Unit, IRCCS “Regina Elena” National Cancer Institute, Rome, Italy

    Filippo Tommaso Gallina

  4. Department of Radiology, IRCCS “Regina Elena” National Cancer Institute, Rome, Italy

    Mauro Caterino, Federico Cappelli & Antonello Vidiri

  5. Department of Thoracic Surgery, Tor Vergata University, Rome, Italy

    Alexandro Patirelis & Vincenzo Ambrogi

  6. Department of Pathology, IRCCS “Regina Elena” National Cancer Institute, Rome, Italy

    Simonetta Buglioni & Paolo Visca

  7. Medical Oncology 2, IRCCS “Regina Elena” National Cancer Institute, Rome, Italy

    Fabiana Letizia Cecere, Francesca Fusco & Federico Cappuzzo

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  1. Riccardo Tajè
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Contributions

RT Conceptualization, Data curation, Validation, Writing– original draft; FTG Conceptualization, Data curation, Formal analysis, Writing– original draft; MC Visualization, Formal analysis, Writing– original draft; DF Conceptualization, Supervision, Formal analysis, Validation; AP Supervision, Data curation, Validation, Visualization; GA Validation, Visualization; SB Supervision, Resources, Validation; FLC Conceptualization, Supervision, Validation; FF Investigation, Supervision, Validation, Visualization; FC Supervision, Validation, Visualization; EM Supervision, Validation; PV Supervision, Validation, Visualization; FC Conceptualization, Supervision, Validation, Visualization; VA Investigation, Supervision, Validation, Visualization; AV Investigation, Supervision, Validation, Visualization; All authors reviewed the manuscript.

Corresponding author

Correspondence to Filippo Tommaso Gallina.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the Ethics committee of the IRCCS Regina Elena National Cancer Institute– Fondazione G.B. Bietti. (Approval number:1465/21;23/02/2021).

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Not applicable.

Competing interests

The authors declare no competing interests.

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Tajè, R., Gallina, F.T., Caterino, M. et al. Molecular characterization of early-stage lung adenocarcinoma presenting as subsolid nodules in a real-life European cohort. BMC Cancer 25, 647 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-13998-0

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BMC Cancer

ISSN: 1471-2407

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