Effect of antihypertensive drugs on survival in patients with non-small cell lung cancer on epidermal growth factor receptor inhibitors

Abstract

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show efficacy against non-small cell lung cancer (NSCLC) in patients with EGFR mutations. However, the impact of antihypertensive medications, particularly beta-blockers (BBs) and renin-angiotensin system blockers (RASBs), on survival outcomes in this population remains controversial. We evaluated the effects of BBs and RASBs on progression-free survival (PFS) and overall survival (OS) in patients with NSCLC receiving EGFR-TKIs. This retrospective study included patients diagnosed with NSCLC who received EGFR-TKIs at a regional teaching hospital in Taiwan between 2009 and 2023. Overall, 308 patients were categorized into groups: EGFR-TKIs only (n=175), BBs(+)/EGFR-TKIs(+) (n=70), and RASBs(+)/EGFR-TKIs(+) (n=63). Primary and secondary outcomes were PFS and OS, respectively. Multivariate Cox proportional-hazards models were used for analysis. Median PFS was 7.79, 11.74, and 10.42 months in the EGFR-TKIs only, BBs(+)/EGFR-TKIs(+), and RASBs(+)/EGFR-TKIs(+) groups, respectively (P=0.056). However, OS was higher in BBs(+)/EGFR-TKIs(+) (17.79 months) and RASBs(+)/EGFR-TKIs(+) (16.64 months) groups than in the EGFR-TKIs only group (12.59 months) (P=0.009). Multivariate analysis identified concomitant BBs or RASBs with EGFR-TKIs as independent prognostic factors for improved OS, particularly in patients without skin toxicity and with favorable Eastern Cooperative Oncology Group performance status. BBs and RASBs have a potential adjunctive role in NSCLC therapy.

Introduction

In 2022, lung cancer was the most frequently diagnosed cancer, with an estimated 2.5 million new cases documented, accounting for 12.4% of all cancer cases worldwide. Furthermore, lung cancer was responsible for approximately 1.8 million fatalities, representing 18.7% of global cancer-related mortality [1]. Approximately 85% of lung cancer cases are classified as non-small cell lung cancer (NSCLC), with adenocarcinoma being the most prevalent histological subtype. At diagnosis, patients frequently present with advanced or metastatic disease [2]. Mutations in the epidermal growth factor receptor (EGFR) gene are frequently observed in NSCLC, especially in adenocarcinoma. In the Asia-Pacific region, the overall EGFR mutation frequency is reported at 47%, with Taiwan having the highest prevalence at 55% [3,4]. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have demonstrated efficacy as first-line therapeutic options for advanced NSCLC with activating mutations in the EGFR gene.

Preclinical research has indicated that chronic stress leads to an increase in catecholamine levels in the bloodstream, which activate adrenergic receptors in target tissues, including cancer cells, thereby promoting carcinogenesis [5,6]. The stimulation of the beta-adrenergic receptor pathway in cancer has been linked to the facilitation of angiogenesis, the upregulation of genes associated with metastasis and inflammation, an increase in the proliferation of cancer cells, and modifications in the tumor immune microenvironment. These elements are essential constituents of the pathophysiological mechanisms that contribute to tumorigenesis, angiogenesis, and the metastasis of tumors [7,8]. Consequently, it has been postulated that the administration of beta-blockers (BBs) may provide anticancer benefits through the specific inhibition of the beta-adrenergic receptor pathway, thereby affecting tumor development and progression. Prior research has established a correlation between BB use and a decreased incidence of liver cancer [9], as well as improved survival rates in patients with prostate cancer [10]. Nevertheless, studies investigating the association between BB utilization and survival outcomes in lung cancer have produced variable results [11-17]. An initial investigation indicated that the administration of BBs during chemotherapy may correlate with enhanced survival outcomes for patients with metastatic NSCLC [12]. Nonetheless, numerous studies have failed to demonstrate a substantial survival benefit of BB use in patients with lung cancer [14-17]. Consequently, ascertaining whether patients with lung cancer benefit from BB therapy is crucial. This knowledge could be instrumental in determining the efficacy of BBs in cancer care.

The renin-angiotensin system (RAS) is integral to the regulation of arterial blood pressure. The intracellular effects of the RAS are primarily facilitated by derivatives of angiotensinogen, including angiotensin II (Ang II) and various other peptides. This process predominantly occurs through the activation of several receptors, including angiotensin II receptor type 1 (AT1R), angiotensin II receptor type 2 (AT2R), angiotensin II receptor type 4, MAS receptor, and insulin-regulated aminopeptidase. Signaling through AT1R facilitates cell proliferation in malignant environments through two primary mechanisms: it exerts a direct effect on tumor cells and regulates the proliferation of vascular cells during angiogenesis [18]. A growing body of research suggests that Ang II, the principal effector of the RAS, is significantly involved in the different phases of cancer metastasis. Specifically, it promotes cancer cell adhesion to endothelial cells, enhances their transendothelial migration, and facilitates tumor cell traversal through the extracellular matrix [19].

Renin-angiotensin system blockers (RASBs), which include angiotensin-receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), are commonly utilized pharmacological agents known for their efficacy in lowering blood pressure and protecting end-organ function. ARBs specifically target AT1Rs, whereas ACEIs affect the RAS by inhibiting the production of Ang II. This inhibition subsequently prevents the physiological responses that are mediated by AT1Rs [20]. Preclinical studies have demonstrated that RAS signaling is a crucial factor in the promotion of tumorigenesis in multiple cancer types, including NSCLC [21]. AT1R signaling can transactivate certain tyrosine kinases, such as the EGFR, thereby activating pro-oncogenic pathways [22]. Moreover, this effect could be reversed by RASBs [23-26], indicating that these agents hold potential as therapeutic options for NSCLC. RAS inhibitors positively impact overall survival (OS) across multiple cancer types, including NSCLC [27-29]. Most preclinical studies exploring the impact of RAS signaling on the development and advancement of NSCLC are based on experimental methods [30-32]. A retrospective analysis has suggested that the combination of ACEIs or ARBs with chemotherapy enhances clinical outcomes and provides a long-term survival advantage for patients with mNSCLC [27].

Currently, insufficient clinical data are available to assess the effects of RAS inhibitors on the survival outcomes of patients with NSCLC. Therefore, the aim of this study was to evaluate the impact of BBs and RASBs on the efficacy of EGFR-TKI therapy in individuals with NSCLC.

Materials and methods

Ethics approval

The research was carried out in compliance with the ethical guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Taichung Tzu Chi Hospital (REC112-12). The requirement for informed consent was waived owing to the retrospective nature of the study.

Study design and patient population

This retrospective cohort study was conducted at a regional teaching hospital in Taiwan, covering the period between January 2009 and December 2023. The inclusion criteria were as follows: (1) age ≥20 years; (2) diagnosis of NSCLC with an International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code ranging from C34.0 to C34.9; (3) cytological or histological confirmation of NSCLC at stages IIIA, IIIB, or IV, along with documented EGFR mutations, in accordance with the eighth edition of the Tumor Node Metastasis Staging classification established by the Study of Lung Cancer; and (4) treatment with an EGFR-TKI, specifically gefitinib or erlotinib, for a minimum duration of 2 weeks prior to participation in the study. Patients with incomplete electronic medical records were excluded from the study. The index date was defined as the date on which EGFR-TKI therapy commenced.

Drug use assessment

Exposure to BBs or RASBs was assessed prior to the index date. Patients were categorized into three groups:

(1) EGFR-TKIs(+) group: patients who received only EGFR-TKIs+ therapy (control group).

(2) BBs(+)/EGFR-TKIs(+) group: patients who were administered BBs (specifically propranolol, carvedilol, labetalol, atenolol, or bisoprolol) for at least 90 defined daily doses (DDDs) within the 180 days preceding the commencement of EGFR-TKI therapy.

(3) RASBs(+)/EGFR-TKIs(+) group: patients who were administered ACEIs or ARBs (specifically captopril, ramipril, valsartan, irbesartan, or candesartan) for at least 90 DDDs within the 180 days preceding the commencement of EGFR-TKI therapy.

Statistical analysis

The principal objective of this study was to assess progression-free survival (PFS), defined as the duration from the commencement of EGFR-TKI therapy to disease progression. The secondary outcome assessed was OS, defined as the interval from EGFR-TKI therapy initiation to death. The date on which EGFR-TKI treatment commenced was designated as the index date. Patient follow-up continued until the achievement of the clinical endpoint or until June 30, 2024.

The dataset comprised various variables, such as BB and RASB use, and demographic characteristics, including age and sex. Furthermore, it encompassed smoking history, family history of cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS), number of metastases, presence of brain metastases, instances of skin toxicity, and documented medical records of hypertension and cardiovascular diseases (CVDs), including arrhythmia, coronary artery disease, heart failure, and stroke.

The chi-squared test or Fisher’s exact test was used to analyze categorical variables, whereas the Kruskal-Wallis H-test was utilized to assess continuous variables among the three groups. A post hoc Bonferroni test was used for pairwise comparisons between the groups. Kaplan-Meier curves were generated to illustrate PFS and OS among the three groups. Differences among groups over the follow-up period were assessed using the log-rank test. In addition, a Cox proportional-hazards regression model was used to determine hazard ratios (HRs) and their associated 95% confidence intervals (CIs). All statistical analyses were conducted using SPSS, version 28 (IBM Corp., Armonk, NY, USA). Statistical significance was set at P<0.05. OS data from the Cox regression model yielded an HR of 0.57 for BBs(+)/EGFR-TKIs(+) vs. EGFR-TKIs(+). This analysis demonstrated a statistical power exceeding 96% at a significance threshold of 0.05.

Results

Selection process and baseline characteristics of the study participants

Between January 2009 and December 2023, 372 patients diagnosed with NSCLC were identified using ICD-10-CM codes C34.0-C34.9. Ultimately, 308 patients (116 males and 192 females) who met the eligibility criteria were enrolled in the study (Figure 1). The average participant age was 65.7 years (standard deviation, 11.5 years).

Figure 1.

Flow diagram illustrating patient enrollment in the study. EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitors (erlotinib, gefitinib); BBs, beta-blockers (propranolol, carvedilol, labetalol, atenolol, bisoprolol); RASBs, renin-angiotensin system blockers; ACEIs, angiotensin-converting enzyme inhibitors (captopril, ramipril); ARBs, angiotensin-receptor blockers (valsartan, irbesartan, candesartan); DDDs, defined daily doses.

The EGFR-TKIs(+), BBs(+)/EGFR-TKIs(+), and RASBs(+)/EGFR-TKIs(+) groups included 175 (56.8%), 70 (22.7%), and 63 individuals (20.5%), respectively. Most patients (n=280, 90.9%) presented with stage IV cancer at baseline, whereas the rest were classified as having stage IIIA or IIIB NSCLC. Of the study population, 189 individuals (61.4%) did not have brain metastases, whereas 240 (77.9%) had an ECOG PS score of 0-1 at the initiation of EGFR-TKI treatment. Adenocarcinoma was the predominant histopathological subtype of NSCLC, comprising 296 cases (96.1%), whereas squamous cell carcinoma accounted for 12 cases (3.9%). Exon 19 deletions were identified in 131 patients (42.5% of the cohort), whereas mutations in exon 21 (L858R) were identified in 177 patients (57.5%). Skin toxicity was classified into four distinct grades (0, 1, 2, and 3-4), reflecting increasing severity of the adverse effects. The distribution of cases was as follows: Grade 0 skin toxicity was observed in 105 instances (34.1%), Grade 1 in 94 instances (30.5%), Grade 2 in 63 instances (20.5%), and Grade 3-4 in 46 instances (14.9%). At the commencement of EGFR-TKI therapy, comorbidities included CVD in 30 patients (9.7%) and hypertension in 90 patients (29.2%). Age, skin toxicity, hypertension, and CVD were the only factors that exhibited significant differences across the patient cohorts (Table 1).

Table 1.

Characteristics of the study population

Variable	Group
	EGFR-TKIs (+)		BBs (+)/EGFR-TKIs (+)		RASBs (+)/EGFR-TKIs (+)		p-value
	n=175		n=70		n=63
	n	%	n	%	n	%
Age (mean ± SD)	63.2±12.5a		66.2±14.5a,b		68.2±9.4b		0.009
Sex (male)	72	41.1	22	31.4	22	34.9	0.323
Smoke	52	29.7	19	27.1	10	15.9	0.100
Family history of cancer	18	10.3	7	10.0	5	7.9	0.862
ECOG performance status							0.144
0	39	22.3	13	18.6	11	17.5
1	96	54.9	47	67.1	34	54.0
2	35	20.0	8	11.4	12	19.0
3	5	2.9	2	2.9	6	9.5
cStage							0.553†
IIIA	1	0.6	1	1.4	2	3.2
IIIB	15	8.6	5	7.1	4	6.3
IV	159	90.9	64	91.4	57	90.5
Histology							1.000†
Adenocarcinoma	168	96.0	67	95.7	61	96.8
Squamous cell carcinoma	7	4.0	3	4.3	2	3.2
Number of metastases							0.804
0	16	9.1	6	8.6	7	11.1
1	73	41.7	32	45.7	29	46.0
2	54	30.9	20	28.6	21	33.3
≥3	32	18.3	12	17.1	6	9.5
Brain metastasis	66	37.7	29	41.4	24	38.1	0.860
EGFR gene							0.097
Exon 19 deletion	67	38.3	30	42.9	34	54.0
Exon 21 L858R	108	61.7	40	57.1	29	46.0
Skin toxicity							0.002
Grade 0	49	28.0	29	41.4	27	42.9
Grade 1	45	25.7	25	35.7	24	38.1
Grade 2	46	26.3a	10	14.3a,b	7	11.1b
Grade 3-4	35	20.0	6	8.6	5	7.9
Hypertension	23	13.1	34	48.6	33	52.4	<0.001
Cardiovascular disease	9	5.1	11	15.7	10	15.9	0.008

Abbreviations: SD, standard deviation; BBs, beta-blockers; RASBs, renin-angiotensin system blockers; EGFR-TKIs, epidermal growth factor receptor tyrosine kinase inhibitors; ECOG, Eastern Cooperative Oncology Group. Categorical variables: chi-square test and ^†fisher’s exact test; continuous variables: Kruskal-Wallis H-test. Notes: Different letters (a, b) indicate statistically significant results at the 0.05 level of significance in sequential Bonferroni multiple comparison adjustment.

Primary endpoints

At the conclusion of the study, 286 of 308 patients (92.9%) had either experienced disease progression or died. The projected median PFS for the overall study population was 9.30 (95% CI: 8.57-10.04) months. Furthermore, the estimated median PFS for patients categorized into the EGFR-TKIs(+) group was 7.79 months (95% CI: 6.24-9.35), whereas those in the BBs(+)/EGFR-TKIs(+) group had a median PFS of 11.74 months (95% CI: 8.84-14.64). Additionally, patients in the RASBs(+)/EGFR-TKIs(+) group had a median PFS of 10.42 months (95% CI: 9.54-11.31). The Kaplan-Meier cumulative PFS rates showed no significant differences among the three groups (log-rank P=0.056; Figure 2). Univariate Cox proportional-hazards analysis identified a significant correlation between PFS and several factors, including BBs(+)/EGFR-TKIs(+), an ECOG PS score of 1, an ECOG PS score of ≥2, the presence of brain metastases, the Exon 21 L858R mutation, and Grade 1 skin toxicity. The respective results were as follows: 0.73 (95% CI: 0.55-0.98; P=0.038), 1.71 (95% CI: 1.26-2.33; P<0.001), 2.82 (95% CI: 1.96-4.05; P<0.001), 1.73 (95% CI: 1.34-2.23; P<0.001), 1.36 (95% CI: 1.07-1.72; P=0.012), and 0.69 (95% CI: 0.51-0.92; P=0.011) (Table 2). After adjusting for ECOG PS, brain metastases, EGFR gene alterations, and skin toxicity, the associations between the drug group (BBs(+)/EGFR-TKIs(+)) and Grade 1 skin toxicity with PFS were attenuated and no longer significant (adjusted HR=0.76, 95% CI: 0.55-1.03, P=0.077 for BBs(+)/EGFR-TKIs(+); adjusted HR=0.77, 95% CI: 0.57-1.05, P=0.095 for Grade 1 skin toxicity). The ECOG PS was a significant predictor of PFS. Patients with an ECOG PS of 1 had a significantly higher risk of progression (HR=1.59, 95% CI: 1.15-2.18, P=0.005), and those with an ECOG PS of ≥2 had an even higher risk (HR=2.59, 95% CI: 1.78-3.77, P<0.001), than those with an ECOG PS of 0. Brain metastases were significantly associated with a higher risk of progression, with an adjusted HR of 1.48 (95% CI: 1.14-1.93, P=0.004). For EGFR gene mutations, patients with the Exon 21 L858R mutation had a significantly higher progression risk than those with Exon 19 deletions. The adjusted HR was 1.36 (95% CI: 1.07-1.73, P=0.013).

Figure 2.

Kaplan-Meier curves of PFS for the EGFR-TKIs(+), BBs(+)/EGFR-TKIs(+), and RASBs(+)/EGFR-TKIs(+) groups. EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitors; BBs, beta-blockers; RASBs, renin-angiotensin system blockers; PFS, progression-free survival.

Table 2.

Cox proportional hazards model for evaluating the effect of the clinical variables on progression-free survival

Variable	Crude			Adjusted†
	HR	(95% CI)	p-value	HR	(95% CI)	p-value
Age (every one year)	1.01	0.99-1.02	0.209
Sex (male vs. female)	1.27	0.99-1.62	0.051
Drug group
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.73	0.55-0.98	0.038*	0.76	0.55-1.03	0.077
RASBs(+)/EGFR-TKIs(+)	0.77	0.57-1.04	0.092	0.79	0.57-1.08	0.136
Smoke	1.27	0.98-1.65	0.074
Family history of cancer	1.21	0.82-1.81	0.340
ECOG performance status
0	Ref.			Ref.
1	1.71	1.26-2.33	<0.001*	1.59	1.15-2.18	0.005*
≥2	2.82	1.96-4.05	<0.001*	2.59	1.78-3.77	<0.001*
Brain metastases	1.73	1.34-2.23	<0.001*	1.48	1.14-1.93	0.004*
EGFR gene
Exon 19 deletion	Ref.			Ref.
Exon 21 L858R	1.36	1.07-1.72	0.012*	1.36	1.07-1.73	0.013*
Skin toxicity
Grade 0	Ref.			Ref.
Grade 1	0.69	0.51-0.92	0.011*	0.77	0.57-1.05	0.095
Grade 2	0.77	0.56-1.07	0.121	0.88	0.62-1.25	0.468
Grade 3-4	0.82	0.57-1.17	0.278	0.86	0.59-1.26	0.451
Hypertension	0.83	0.64-1.08	0.171
Cardiovascular disease	1.07	0.73-1.57	0.741

^†Adjusted for ECOG, brain metastases, EGFR gene and skin toxicity.

Abbreviations: BBs, beta-blockers; RASBs, renin-angiotensin system blockers; EGFR-TKIs, epidermal growth factor receptor tyrosine kinase inhibitors; ECOG, Eastern Cooperative Oncology Group.

^*P<0.05.

A subgroup analysis using the Cox proportional-hazards model was conducted to assess the effects of various drug combinations on PFS in patients with varying levels of skin toxicity (Table 3). For patients with Grade 0 skin toxicity, those receiving BBs(+)/EGFR-TKIs(+) had a significantly lower risk of progression than those receiving EGFR-TKIs(+) alone. The adjusted HR was 0.60 (95% CI: 0.36-0.99, P=0.044). In summary, BBs(+)/EGFR-TKIs(+) demonstrated a significant correlation with a reduced risk of disease progression in patients with Grade 0 skin toxicity. Conversely, for other toxicity grades, the drug combinations did not significantly affect the risk of progression.

Table 3.

Hazard ratio and 95% confidence interval of subgroup of progression-free survival

Variable	Crude			Adjusted†
	HR	(95% CI)	p-value	HR	(95% CI)	p-value
Grade 0
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.56	0.35-0.91	0.019*	0.60	0.36-0.99	0.044*
RASBs(+)/EGFR-TKIs(+)	0.63	0.38-1.04	0.071	0.59	0.34-1.02	0.058
Grade 1
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.77	0.46-1.30	0.326	0.76	0.45-1.28	0.301
RASBs(+)/EGFR-TKIs(+)	1.11	0.65-1.89	0.701	0.97	0.57-1.67	0.920
Grade 2
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.98	0.47-2.03	0.950	1.97	0.87-4.47	0.104
RASBs(+)/EGFR-TKIs(+)	0.23	0.08-0.66	0.006*	0.59	0.17-1.97	0.389
Grade 3-4
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.71	0.27-1.83	0.475	0.76	0.26-2.24	0.618
RASBs(+)/EGFR-TKIs(+)	1.12	0.43-2.89	0.823	1.20	0.44-3.27	0.729

^†Adjusted for ECOG, brain metastases and EGFR gene.

Abbreviations: BBs, beta-blockers; RASBs, renin-angiotensin system blockers; EGFR-TKIs, epidermal growth factor receptor tyrosine kinase inhibitors.

^*P<0.05.

Secondary endpoints

Ultimately, 266 of the 308 participants (86.4%) died. The estimated median OS for the entire study cohort was 15.09 (95% CI: 13.26-16.92) months. Furthermore, the estimated median OS for patients in the EGFR-TKIs(+) group was 12.59 months (95% CI: 10.05-15.14), whereas those in the BBs(+)/EGFR-TKIs(+) group had a median OS of 17.79 months (95% CI: 13.59-21.98). Additionally, patients in the RASBs(+)/EGFR-TKIs(+) group had a median OS of 16.64 months (95% CI: 13.61-19.66). The Kaplan-Meier cumulative OS rates differed significantly among the three groups (log-rank P=0.009; Figure 3). Univariate Cox proportional-hazards analysis identified a significant correlation between PFS and several factors, including age, BBs(+)/EGFR-TKIs(+), RASBs(+)/EGFR-TKIs(+), an ECOG PS score of 1, an ECOG PS score of ≥2, brain metastases, Exon 21 L858R mutation, and Grade 2 skin toxicity. The respective results were as follows: 1.01 (95% CI: 1.00-1.02; P=0.026), 0.68 (95% CI: 0.50-0.93; P=0.014), 0.68 (95% CI: 0.49-0.94; P=0.02), 2.25 (95% CI: 1.61-3.14; P<0.001), 4.57 (95% CI: 3.09-6.76; P<0.001), 2.17 (95% CI: 1.66-2.82; P<0.001), 1.32 (95% CI: 1.03-1.69; P=0.026), AND 0.62 (95% CI: 0.43-0.87; P=0.006) (Table 4). After adjusting for age, ECOG PS, brain metastases, EGFR gene alterations, and skin toxicity, the HR for the BBs(+)/EGFR-TKIs(+) group was 0.61 (95% CI: 0.44-0.84, P=0.002), whereas the HR for the RASBs(+)/EGFR-TKIs(+) group was 0.62 (95% CI: 0.44-0.86, P=0.005). These results suggest that combination therapy confers a survival benefit. The patients’ ECOG PS was also strongly associated with OS. Patients with an ECOG PS of 1 had a higher risk of mortality than those with an ECOG PS of 0 (HR=1.96, 95% CI: 1.38-2.78, P<0.001). Furthermore, patients with an ECOG PS of ≥2 had an even higher risk (HR=3.87, 95% CI: 2.55-5.87, P<0.001). These results emphasize the significance of ECOG PS in forecasting survival rates. The presence of brain metastases was linked to a significantly elevated risk of mortality, with an adjusted HR of 2.05 (95% CI: 1.56-2.71, P<0.001), indicating that patients with brain metastases had more than double the risk of mortality than those without. Regarding skin toxicity, patients with Grade 2 skin toxicity had a significantly lower risk of mortality than those without any skin toxicity (adjusted HR=0.65, 95% CI: 0.45-0.93, P=0.020). However, no significant difference in survival was observed for patients with Grade 3-4 skin toxicity (P=0.244). Smoking status, familial cancer history, hypertension, and CVD had no significant effect on OS.

Figure 3.

Kaplan-Meier curves of OS for the EGFR-TKIs(+), BBs(+)/EGFR-TKIs(+), and RASBs(+)/EGFR-TKIs(+) groups. EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitors; BBs, beta-blockers; RASBs, renin-angiotensin system blockers; OS, overall survival.

Table 4.

Cox proportional hazards model for evaluating the effect of the clinical variables on overall survival

Variable	Crude			Adjusted†
	HR	(95% CI)	p-value	HR	(95% CI)	p-value
Age (every one year)	1.01	1.00-1.02	0.026*	1.01	0.99-1.02	0.149
Sex (male vs. female)	1.20	0.94-1.54	0.145
Drug group
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.68	0.50-0.93	0.014*	0.61	0.44-0.84	0.002*
RASBs(+)/EGFR-TKIs(+)	0.68	0.49-0.94	0.020*	0.62	0.44-0.86	0.005*
Smoke	1.11	0.85-1.45	0.456
Family history of cancer	1.20	0.80-1.80	0.373
ECOG performance status
0	Ref.			Ref.
1	2.25	1.61-3.14	<0.001*	1.96	1.38-2.78	<0.001*
≥2	4.57	3.09-6.76	<0.001*	3.87	2.55-5.87	<0.001*
Brain metastases	2.17	1.66-2.82	<0.001*	2.05	1.56-2.71	<0.001*
EGFR gene
Exon 19 deletion	Ref.			Ref.
Exon 21 L858R	1.32	1.03-1.69	0.026*	1.27	0.99-1.63	0.065
Skin toxicity
Grade 0	Ref.			Ref.
Grade 1	0.76	0.56-1.03	0.074	0.81	0.59-1.11	0.185
Grade 2	0.62	0.43-0.87	0.006*	0.65	0.45-0.93	0.020*
Grade 3-4	0.79	0.55-1.15	0.218	0.79	0.54-1.17	0.244
Hypertension	0.90	0.69-1.18	0.438
Cardiovascular disease	0.83	0.55-1.25	0.373

^†Adjusted for age, ECOG, brain metastases, EGFR gene and skin toxicity.

Abbreviations: BBs, beta-blockers; RASBs, renin-angiotensin system blockers; EGFR-TKIs, epidermal growth factor receptor tyrosine kinase inhibitors; ECOG, Eastern Cooperative Oncology Group.

^*P<0.05.

A subgroup analysis utilizing the Cox proportional-hazards model was conducted to evaluate the impact of various drug combinations on OS among patients with varying degrees of skin toxicity (Table 5). For patients with Grade 0 skin toxicity, those who received BBs(+)/EGFR-TKIs(+) had a significantly lower risk of death than those who received EGFR-TKIs alone. The unadjusted HR was 0.53 (95% CI: 0.32-0.88, P=0.015). Following adjustment, the HR was further reduced to 0.44 (95% CI: 0.26-0.75, P=0.003). Similarly, patients treated with RASBs(+)/EGFR-TKIs(+) had a significantly lower risk of mortality, as indicated by an unadjusted HR of 0.51 (95% CI: 0.30-0.88, P=0.015) and an adjusted HR of 0.37 (95% CI: 0.21-0.68, P=0.001). Overall, for patients with Grade 0 skin toxicity, combining BBs or RASBs with EGFR-TKIs significantly reduced the risk of death. For other skin toxicity grades, these drug combinations did not significantly affect OS.

Table 5.

Hazard ratio and 95% confidence interval of subgroup of overall survival

Variable	Crude			Adjusted†
	HR	(95% CI)	p value	HR	(95% CI)	p value
Grade 0
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.53	0.32-0.88	0.015*	0.44	0.26-0.75	0.003*
RASBs(+)/EGFR-TKIs(+)	0.51	0.30-0.88	0.015*	0.37	0.21-0.68	0.001*
Grade 1
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.80	0.47-1.35	0.401	0.78	0.46-1.31	0.344
RASBs(+)/EGFR-TKIs(+)	0.95	0.55-1.62	0.843	0.83	0.48-1.43	0.493
Grade 2
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.74	0.34-1.60	0.441	0.86	0.37-1.96	0.711
RASBs(+)/EGFR-TKIs(+)	0.32	0.12-0.84	0.020*	0.66	0.21-2.10	0.484
Grade 3-4
EGFR-TKIs(+)	Ref.			Ref.
BBs(+)/EGFR-TKIs(+)	0.45	0.16-1.29	0.138	0.56	0.17-1.81	0.332
RASBs(+)/EGFR-TKIs(+)	0.90	0.31-2.56	0.837	1.11	0.36-3.41	0.855

^†Adjusted for age, ECOG, brain metastasis and EGFR gene.

Abbreviations: BBs, beta-blockers; RASBs, renin-angiotensin system blockers; EGFR-TKIs, epidermal growth factor receptor tyrosine kinase inhibitors.

^*P<0.05.

Discussion

The findings of this study indicate that the concomitant use of BBs or RASBs alongside EGFR-TKIs is associated with improved OS, especially among patients with Grade 0 skin toxicity.

Numerous epidemiological and clinical investigations indicate that BBs, widely recognized for their effectiveness in treating various cardiovascular conditions, may also have antitumor properties. These properties include the potential to reduce metastasis, tumor recurrence, and cancer-specific mortality across various malignancies, including breast [8,33] and colon [8,34] cancers. Nonetheless, systematic reviews of clinical studies conducted in recent years assessing the potential effects of BBs on the survival outcomes of patients with cancer have produced inconsistent results. In 2025, a systematic review and meta-analysis identified a correlation between beta-blocker usage and enhanced survival outcomes, especially among patients with early-stage tumors who underwent surgical intervention, encompassing breast cancer, ovarian cancer, and melanoma [35]. Conversely, research carried out in 2018 demonstrated that the administration of BBs does not exert a substantial effect on cancer recurrence, disease-free survival, or OS across a range of tumor types, including breast, colorectal, endometrial, head and neck, lung, melanoma, esophageal, ovarian, pancreatic, prostate, renal, and gastric cancers [36]. Nevertheless, an examination of the effects of BBs within various cancer subgroups reveals that these effects are inconsistent and specific to the type of tumor. Notably, BBs appear to confer a protective benefit in melanoma, whereas it is associated with a reduction in OS in cases of endometrial, head and neck, and prostate cancers [36]. Nonetheless, recent observational studies in NSCLC have yielded findings that remain contentious. A retrospective cohort study conducted in 2020 demonstrated that prior treatment with BBs was associated with improved survival outcomes in patients with lung adenocarcinoma possessing sensitive mutations in the EGFR who were undergoing first-line therapy with EGFR-TKIs [37]. A meta-analysis performed in 2021 found no significant relationship between BB use and improved OS in patients with lung cancer [38]. The present study showed that PFS in the BBs(+)/EGFR-TKIs(+) cohort compared with the EGFR-TKIs(+) cohort. Although an improvement in PFS was observed, the difference was not significant. In contrast, for OS in the BBs(+)/EGFR-TKIs(+) group compared with the EGFR-TKIs(+) group, demonstrating a significant improvement in OS. These findings highlight the need for further prospective research to enhance our understanding of the function of BBs in cancer therapy.

Research conducted using both in vitro and in vivo approaches has demonstrated that ACEIs and ARBs have the potential to inhibit cellular proliferation and the advancement of metastatic tumors across several cancer types, including breast, lung, and prostate cancers. Angiogenesis is recognized as a pivotal process by which the RAS facilitates tumor development. ACEIs and ARBs significantly reduce the expression of vascular endothelial growth factor (VEGF) and various other angiogenic factors, as demonstrated in cellular models [25,39] and animal studies [40]. Furthermore, distinct components of the RAS pathway are expressed in diverse cancer sites and may play a significant role in essential processes related to cancer progression, including cell proliferation and apoptosis [41].

The activation of AT1R initiates the mitogen-activated protein kinase/signal transducer and activator of transcription (MAPK/STAT) signaling pathway. This signaling pathway is integral to the mediation of cellular responses to various growth factors that regulate fundamental biological processes, such as cell proliferation, differentiation, and apoptosis [42]. EGFR can undergo transactivation through both AT1R and AT2R. Epidermal growth factor mediates its biological effects, in part, through the activation of the MAPK/STAT signaling pathway. This mechanism has led to the formulation of anti-EGFR therapeutics, which represent a crucial strategy in the treatment of cancer [22]. Furthermore, the activation of analogous downstream effectors may lead to the direct transactivation of the EGFR subsequent to the stimulation of AT1R [22]. ACEI/ARB in combination with standard chemotherapy or TKIs has a positive effect on PFS and OS, regardless of whether the lung cancer is in an early or advanced stage [43]. A 2010 retrospective cohort study on pancreatic cancer and advanced NSCLC identified a significant relationship between the utilization of ACEIs and ARBs and improved survival outcomes when these agents were used in conjunction with standard first-line chemotherapy [29]. Furthermore, a 2015 retrospective cohort study indicated that the administration of ARBs alongside erlotinib therapy may improve OS in patients with metastatic NSCLC [44]. Additionally, a 2016 study suggested that the inhibition of the RAS in patients with NSCLC could improve PFS, although it appeared to have a minimal impact on OS [43].

The present study showed that PFS in the RASBs(+)/EGFR-TKIs(+) group compared with the EGFR-TKIs(+) group. Although improvement in PFS was noted, the observed difference was not significant. In contrast, the OS in the RASBs(+)/EGFR-TKIs(+) group, compared with the EGFR-TKIs(+) group, demonstrated a significant improvement in OS. This study indicates that the inhibition of the RAS pathway in human NSCLC may improve OS, although its impact on PFS is minimal. These results highlight the need for prospective studies with larger sample sizes to confirm our hypothesis.

This study has some limitations. First, in our study, hypertension was identified based solely on clinical records without further classification into primary or tumor-associated hypertension. We recognize that this distinction is clinically significant and represents a potential limitation of the current analysis. Additionally, our subgroup analysis showed that in patients without hypertension, the use of antihypertensive drugs was still associated with a reduced risk of overall mortality, suggesting that these medications have beneficial effects beyond blood pressure control, possibly through the modulation of tumor biology. However, the routine use of antihypertensive drugs in normotensive patients for potential anti-tumor effects is not currently recommended, pending further evidence from prospective clinical trials. Second, the retrospective design of the study may lead to selection bias, given that patients were not randomly allocated to treatment groups. Additionally, confounding variables, including treatment adherence and unmeasured lifestyle factors, could not be comprehensively controlled for. Third, the limited sample size, especially within the subgroups of patients administered BBs or RASBs, may restrict the applicability of the results to larger populations. Fourth, this study did not assess other potential factors, such as the impact of different EGFR-TKI treatment durations, comorbidities, or the use of additional therapies, which may have affected survival outcomes. Fifth, although this study focused on OS and PFS, quality of life and long-term side effects were not evaluated. These factors could provide important insights into the clinical applicability of combining BBs or RASBs with EGFR-TKIs. Finally, BB and RASB exposure in our study was defined as receiving at least 90 DDDs within 180 days prior to EGFR-TKI initiation to ensure consistent use before cancer treatment began. However, owing to the retrospective nature of this study, we were unable to verify whether these medications were continuously taken after the initiation of EGFR-TKI therapy. Some patients may have discontinued BBs or RASBs during follow-up, potentially diminishing the observed survival benefit. Future prospective studies with real-time medication monitoring are needed to confirm the sustained effect of these agents when combined with EGFR-TKI therapy.

In conclusion, this retrospective cohort study indicates that combining BBs or RASBs with EGFR-TKIs may offer notable survival benefits for patients with advanced NSCLC, particularly those without skin toxicity. Although PFS did not differ significantly among the treatment groups, OS improved substantially with combined therapies, particularly in patients with a favorable PS and no brain metastases. These findings highlight the potential of BBs and RASBs as adjunctive treatments in EGFR-TKI therapy for NSCLC. Nonetheless, further prospective studies with larger cohorts are warranted to confirm these findings.

Disclosure of conflict of interest

None.