Prognostic significance of integrating total metabolic tumor volume and EGFR mutation status in patients with lung adenocarcinoma

Introduction

Lung cancer continues to be a prominent contributor to global cancer-related deaths, showing minimal progress in prognosis despite advancements made in the field of diagnosis and treatment approaches (Siegel et al., 2023; Xia et al., 2022). Lung adenocarcinoma (LUAD) represents a predominant subtype of non-small cell lung cancer (NSCLC), accounting for approximately 40% of all cases among pulmonary malignancies (Kleczko et al., 2019; Zhang et al., 2022). Advances in molecular research have resulted in the emergence of promising treatments for advanced NSCLC, such as gefitinib, a targeted agent that effectively inhibits epidermal growth factor receptor (EGFR) tyrosine kinase (Yi et al., 2023). Patients with NSCLC harboring EGFR mutations and treated with tyrosine kinase inhibitors (TKIs) achieved significantly prolonged progression-free survival (PFS) and/or overall survival (OS) compared to those receiving conventional chemotherapy (Zhong et al., 2021; Liu et al., 2021; Greenhalgh et al., 2021; Sperduto et al., 2017; Cadranel et al., 2012). The presence of EGFR mutations has been proposed as a crucial determinant of prognosis in individuals with NSCLC (Wu et al., 2010; Choi et al., 2012; Deng et al., 2021), but the predictive significance of EGFR mutations in NSCLC patients remains controversial (Zhang et al., 2014; Lin et al., 2017). Due to a paucity of studies specifically investigating the prognostic impact stratified by clinical TNM stages, histologic subtypes, or metabolic phenotypes on ¹⁸F-2-fluoro-2-deoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT), it becomes challenging to adequately control for confounding variables.

At present, the utilization of ¹⁸F-FDG PET/CT is extensive in the management of lung cancer and has been recognized for providing prognostic insights through metabolic parameters (e.g., maximum standardized uptake value of primary tumors (pSUV_max), total metabolic tumor volume (TMTV), and whole-body total lesion glycolysis (TLG_WB)) derived from PET images (Pellegrino et al., 2019; Mahmoud et al., 2022; Monaco et al., 2021; Chen et al., 2012). Essentially, patients diagnosed with lung cancer who exhibit elevated pSUV_max, TMTV and TLG_WB values are indicative of a poor prognosis. The occurrence of EGFR mutations in individuals diagnosed with lung cancer generally results in a positive reaction to targeted treatment, which contributes to prolonged survival. However, several studies have reported inconsistent findings regarding the correlation between EGFR mutation and decreased ¹⁸F-FDG uptake in lung cancer, with some indicating a negative association and others suggesting otherwise (Shi et al., 2022; Hong et al., 2020; Ko et al., 2014). Additionally, certain studies have failed to identify any significant correlations between these factors (Chung et al., 2014; Lee et al., 2015). The inconsistent findings could be attributed to the limited sample size and potential confounding variables, such as the TNM stage and histological subtype of the tumor.

NSCLC can be categorized into two primary subtypes, LUAD and squamous cell carcinoma (SCC), each exhibiting distinct features. Wang et al. (2020) demonstrated that it is crucial to analyze LUAD and lung SCC separately to obtain precise prognostic information due to significant outcome differences between these two distinct cancer types. In this study, we specifically chose LUAD as the subject and hypothesized that the presence of EGFR mutations could serve as a prognostic indicator for patients with LUAD; however, further stratification by metabolic parameters on ¹⁸F-FDG PET/CT is necessary to refine these results.

Therefore, we conducted a retrospective analysis to investigate the prognostic significance of the TMTV derived from baseline ¹⁸F-FDG PET/CT scans in conjunction with EGFR mutation status among patients diagnosed with LUAD.

Materials and Methods

Patient selection

We retrospectively analyzed a cohort of 1,104 patients diagnosed with lung cancer who underwent ¹⁸F-FDG PET/CT at Ningbo No. 2 Hospital in China between October 2019 and March 2022. To be eligible for the study, patients were required to meet specific criteria, which included: (i) no prior pretreatment before undergoing ¹⁸F-FDG PET/CT, (ii) a confirmed diagnosis of LUAD through histopathological examination, (iii) determination of EGFR mutation status, and (iv) at least 1 month of follow-up. The study included a cohort of 141 individuals who were diagnosed with LUAD, selected according to the established criteria (Fig. 1). Individuals who had smoked less than 100 cigarettes in their lifetime were categorized as never smokers, while the rest of the participants were considered smokers (Kawaguchi et al., 2010). The research plan obtained approval from the Institutional Review Board of Ningbo No. 2 Hospital, and informed consent was not required (protocol No. YJ-NBEY-KY202108401).

Results

Patient characteristics

Table 1 presents a comprehensive overview of the clinical and metabolic profiles of patients with wild-type and mutant EGFR, encompassing factors such as age, sex, smoking status, clinical TNM stage, pSUV_max, TMTV and TLG_WB data. In the cohort of 141 participants, comprising 74 males and 67 females, the average age was 66.6 ± 9.8 years (mean ± standard deviation, with a median age of 67 years), ranging from 34 to 86 years. PFS was followed up for a median duration of 16 months (ranging from 1 to 36 months), with IQRs of 9–26 months. Regarding OS, the follow-up period lasted for a median of 21 months (ranging from 3 to 38 months), with IQRs of 11–27 months. During the entire follow-up period, a total of 26 deaths were recorded. The study population as a whole demonstrated a 2-year PFS rate of 66.3% and an OS rate of 78.2%, as shown in Fig. 2.

Table 1:

Comparison of clinical features and metabolic parameters between EGFR wild-type and mutant-type patients with adenocarcinoma.

Characteristics	Total	EGFR		P value
		Wild-type	Mutant-type
Age, years				0.439
Median	67	68	67
Range	34–86	34–86	36–85
Gender (n, %)				0.006
Male	74 (52.5)	41 (29.1)	33 (23.4)
Female	67 (47.5)	21 (14.9)	46 (32.6)
Smoking history (n, %)				0.001
Never-smoker	96 (68.1)	33 (23.4)	63 (44.7)
Ever-smoker	45 (31.9)	29 (20.6)	16 (11.3)
Clinical TNM stage (n, %)				0.570
I	52 (36.9)	20 (14.2)	32 (22.7)
II	21 (14.9)	8 (5.7)	13 (9.2)
III	19 (13.5)	10 (7.1)	9 (6.4)
IV	49 (34.7)	24 (17.0)	25 (17.7)
pSUVmax				0.044
Median	8.96	10.53	8.56
IQR	6.31–12.91	7.23–14.64	5.91–12.00
pMTV				0.057
Median	6.87	9.95	4.39
IQR	2.59–229.39	3.25–38.0	2.52–19.95
pTLG				0.032
Median	36.93	62.98	20.65
IQR	9.77–188.5	12.08–249.3	9.05–116.1
TMTV				0.048
Median	14.83	28.43	9.47
IQR	3.72–54.86	4.87–74.39	3.52–45.42
TLG				0.025
Median	88.17	147.4	30.73
IQR	12.67–322.9	25.52–508.1	10.43–249.9

DOI: 10.7717/peerj.16807/table-1

Outcomes according to EGFR mutation status

The presence of EGFR mutations was observed in 79 (56.0%) patients, as indicated in Table 1, while the remaining patients (n = 62, 44.0%) were classified as EGFR wild-type. Based on our findings, patients with EGFR mutations demonstrated significantly higher rates of 2-year PFS (Fig. 3A) and OS (Fig. 4A) than those with wild-type EGFR, with rates of 74.2% vs 69.2% (P = 0.029) and 86.1% vs 67.7% (P = 0.009), respectively.

Discussion

In the present study, we have demonstrated that both the EGFR mutation status and the TMTV, determined on baseline ¹⁸F-FDG PET/CT, are independent prognostic factors for OS in patients with LUAD. Furthermore, we found that TMTV is also an independent prognostic factor for PFS in LUAD patients. When evaluating the prognostic significance of EGFR mutation status, it is crucial to consider the level of TMTV. The combination of pretreatment TMTV and EGFR mutation status has the potential to enhance accuracy in predicting prognosis and aid in decision-making regarding intensive therapy.

The prognostic role of EGFR mutation status in patients with lung cancer was investigated as early as 2004 to 2005 (Taron et al., 2005; Lynch et al., 2004). Patients with EGFR mutations tend to have a high response to TKIs, leading to prolonged survival (Han et al., 2005). Nonetheless, there has been considerable fluctuation in the outcomes over the past 20 years. Mitsudomi et al. (2005) demonstrated that the presence of genetic alterations in the EGFR gene is associated with improved survival outcomes following gefitinib therapy among NSCLC patients who experience recurrence after surgery. However, Deng et al. (2021) discovered a contradictory result indicating that EGFR was a significant negative prognostic indicator in patients with radiologic solid and different forms of LUAD. In comparison to the wild-type group, patients with EGFR mutations exhibited notably higher occurrences of brain and bone metastases (Deng et al., 2021). Interestingly, Liu et al. (2014) and Li et al. (2019) found that primary resected LUAD does not exhibit substantial prognostic significance in relation to EGFR mutations.

Overall, several factors may have contributed to these disparate findings. First, the patient cohorts exhibited heterogeneity in terms of TNM staging, with some only at stage I and having undergone radical surgery while others were at stages I–IV with varying treatment modalities (Deng et al., 2021; Liu et al., 2014; Li et al., 2019). Second, the sample size enrolled in these studies varied greatly from 59 to 1,512 patients (Deng et al., 2021; Mitsudomi et al., 2005). Third, there was also histological diversity among the cohorts, with some being enrolled as NSCLC and others solely as LUAD (Zhang et al., 2014; Li et al., 2019). To a certain extent, the prognostic significance of EGFR mutation status in lung cancer has captured the attention of researchers. Our study demonstrates that EGFR mutation is an independent and favorable prognostic factor for patients with LUAD.

The incidence of EGFR mutations is reportedly higher in patients diagnosed with LUAD, particularly among female individuals, never-smokers, and East Asian populations (Shi et al., 2015; Shi et al., 2014). Our study consistently observed these findings. ¹⁸F-FDG PET/CT has become a widely utilized tool in the management of lung cancer, encompassing diagnosis, treatment response assessment and prognostication (Lim et al., 2022; Peng et al., 2022). In terms of prognosis, high metabolic activity as measured by ¹⁸F-FDG PET/CT is typically indicative of poor survival outcomes in patients with LUAD. Relevant investigations have been conducted to explore the associations between EGFR mutation status and metabolic parameters on FDG PET/CT (Jiang et al., 2022; Jiang et al., 2023; Guo et al., 2021). We previously observed that male patients with NSCLC harboring EGFR mutations frequently exhibit low pSUV_max (Jiang et al., 2023; Zhang et al., 2023). Similar findings were also reported by Wang et al. (2022). The role of EGFR signaling is pivotal in facilitating aerobic glycolysis in LAD cells harboring EGFR mutations (Makinoshima et al., 2014). Decreased expression of glucose transporter 3 (GLUT3), responsible for glucose transport, was observed in TKI-responsive LAD cells (Makinoshima et al., 2014), which may contribute to the lower metabolic activity associated with the EGFR mutant type. In this study, a lower level of metabolic parameters, including pSUV_max, pTLG, TMTV and TLG_WB, was associated with a higher incidence of EGFR mutations. However, a number of factors may influence the correlations between EGFR mutation status and SUV_max in LUAD, particularly with regard to smoking status (Gao et al., 2023). Furthermore, a greater intratumor heterogeneity factor was observed in EGFR-mutant LUAD patients than in those with wild-type EGFR (Ni et al., 2023). Therefore, the integration of EGFR mutation status and ¹⁸F-FDG metabolic activity is imperative and holds paramount significance for a comprehensive evaluation of prognostic outcomes in patients with LUAD.

Accordingly, we investigated the prognostic value of various metabolic parameters, including pSUV_max, pMTV, pTLG, TMTV and TLG_WB. Upon comparison of these parameters, TMTV exhibited the highest prognostic efficacy for patients diagnosed with LUAD. A meta-analysis comprising thirty-six studies and 5,807 patients demonstrated that elevated pSUV_max, MTV, and TLG_WB were associated with a poor prognosis in surgical NSCLC patients (Liu et al., 2016). Salavati et al. (2017) found that volumetric parameters derived from both primary tumors and whole-body lesions exhibit comparable prognostic value for survival in stage IIB/III NSCLC patients. As stated, both the EGFR mutation status and metabolic parameters can serve as crucial factors for assessing treatment response sensitivity and prognosis, exhibiting a significant correlation between them. However, there have been limited studies integrating EGFR mutation status and metabolic parameters to evaluate the prognosis of patients with LUAD. In our findings, not only in EGFR wild-type patients but also in those with EGFR mutations, the parameter of TMTV could effectively stratify them into distinct prognostic groups. It is crucial to take into account the volumetric parameter of TMTV when prognosticating based on EGFR mutation status.

However, it is important to acknowledge its limitations. First, the delineation of lesions relied on a single threshold technique, and although CT images were incorporated for improved accuracy, the choice of threshold value can still impact the quantification of tumor volume, average SUV, and TMTV. Future research should explore alternative thresholds to optimize these measurements since there is currently no standardized approach for determining the optimal cutoff value for SUV_max. Second, the duration of follow-up was relatively short, and the sample size was limited. Third, this study was conducted retrospectively at a single center. Therefore, it is necessary to validate these findings through larger-scale prospective randomized studies involving multiple institutions.

Conclusions

In conclusion, both the EGFR mutation status and the TMTV measured on baseline ¹⁸F-FDG PET/CT can independently serve as prognostic factors for OS in patients with LUAD. Furthermore, the TMTV is also an independent predictor for PFS in LUAD patients. Integrating them may enhance the predictive accuracy for patient outcomes, which could be valuable for clinicians when making decisions regarding treatment modalities and follow-up.

Supplemental Information