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Abstract

This study aimed to explore advances in biomarkers related to anti-angiogenic therapy in patients with non-small cell lung cancer (NSCLC), thereby enhancing treatment selection, advancing personalized and precision medicine to improve treatment outcomes and patient survival rates. This article reviews key discoveries in predictive biomarkers for anti-angiogenic therapy in NSCLC in recent years, such as (1) liquid biopsy predictive biomarkers: studies have identified activated circulating endothelial cells (aCECs) via liquid biopsy as potential predictive biomarkers for the efficacy of anti-angiogenic therapy; (2) imaging biomarkers: advanced imaging technologies, such as dynamic contrast-enhanced integrated magnetic resonance positron emission tomography (MR-PET), are used to assess tumor angiogenesis in patients with NSCLC and evaluate the clinical efficacy of anti-angiogenic drugs; (3) genetic predictive biomarkers: research has explored polymorphisms of Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) and vascular endothelial growth factor-A (VEGF-A), as well as how plasma levels of VEGF-A can predict the outcomes and prognosis of patients with non-squamous NSCLC undergoing chemotherapy combined with bevacizumab. Despite progress in identifying biomarkers related to anti-angiogenic therapy, several challenges remain, including limitations in clinical trials, heterogeneity in NSCLC, and technical hurdles. Future research will require extensive clinical validation and in-depth mechanistic studies to fully exploit the potential of these biomarkers for personalized treatment.

Keywords

non-small cell lung cancer anti-angiogenic therapy bevacizumab predictive biomarkers

Introduction

With a global increase in the aging population, cancer incidence worldwide has notably escalated. Lung cancer poses persistent and severe threats to human health. Recent statistics from the International Agency for Research on Cancer indicate that lung cancer is the predominant cause of cancer-related mortality.¹ Annually, lung cancer diagnoses exceed two million cases, with non-small cell lung cancer (NSCLC) representing approximately 80%–85% of these cases.² The therapeutic landscape for NSCLC has broadened to include surgical interventions, radiotherapy, chemotherapy, immunotherapy, and targeted therapy. Surgical approaches are predominantly adopted for early-stage NSCLC, whereas advanced stages are managed through a multidisciplinary approach comprising chemotherapy, immunotherapy, and targeted therapies. Despite the continuous evolution of NSCLC management strategies, the 5-year survival rates remain disappointingly low. Angiogenesis is instrumental in the proliferation, growth, and metastasis of lung cancer,³ rendering the anti-angiogenic pathway a critical therapeutic target in NSCLC. Anti-angiogenic therapies that inhibit tumor vascularization to curtail tumor growth have been shown to enhance both progression-free survival (PFS) and overall survival (OS) in patients with NSCLC, albeit with a limited subset experiencing benefits from monotherapy. Hence, the integration of anti-angiogenic therapy with chemotherapy, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), and immune checkpoint inhibitors has emerged as a focal point in contemporary research. For instance, Zhou et al⁴ discovered that, in contrast to patients solely undergoing chemotherapy, those subjected to first-line therapy involving bevacizumab in conjunction with paclitaxel and carboplatin exhibited a median PFS extension of 2.7 months (9.2 months vs 6.5 months, HR = 0.40, 95% CI: 0.29∼0.54,P < 0.0001). Moreover, statistically significant disparities were evident in objective response rate (ORR) and median OS extension. The findings of the study suggest that patients receiving combined therapy with bevacizumab encounter a 60% decreased risk of disease progression compared to those undergoing chemotherapy alone. Furthermore, In a phase III randomized controlled trial conducted by Saito et al,⁵ results indicate a notable prolongation of median PFS in the bevacizumab plus erlotinib treatment cohort. Nonetheless, further longitudinal monitoring is warranted to amass data pertaining to overall survival. In addition, the ALTER-L004 study data presented by Zhong et al⁶ at the ESMO highlighted the efficacy of combining anlotinib with icotinib in patients positive for driver gene mutations, underscoring the potential of combining anti-angiogenic therapy with EGFR-TKIs. The synergistic application of anti-angiogenic agents and immunotherapies has been shown to enhance therapeutic efficacy. A clinical study involving atezolizumab combined with bevacizumab and chemotherapeutics confirmed significant improvements in OS and PFS irrespective of PD-L1 expression, EGFR mutation, or anaplastic lymphoma kinase gene alteration status, positioning this combination as a frontline therapy for non-squamous metastatic NSCLC.⁷ Additionally, preliminary clinical trials exploring the combination of ramucirumab with immunosuppressants, including pembrolizumab, have demonstrated promising safety profiles and antitumor activity.⁸ However, clinical observations have revealed variable patient responses to anti-angiogenic therapies, with some exhibiting no response or gradual resistance development, highlighting the importance of predictive biomarkers in identifying patients who are likely to benefit from such treatments.⁹ This article aims to succinctly review the progress in research on predictive biomarkers for anti-angiogenic therapy in NSCLC, offering insights for clinical application.

Anti-Angiogenic Therapy in NSCLC

Anti-angiogenic agents primarily function by inhibiting key signaling pathways known to promote tumor angiogenesis, downregulate the expression of vascular activity factors, and consequently suppress tumor neovascularization. Unlike traditional chemotherapeutic drugs, anti-angiogenic agents are categorized as targeted therapies that focus on angiogenesis-specific targets. By intervening in these targets, these drugs effectively prevent the formation of tumor vasculature. The journey of anti-angiogenic treatment in NSCLC and the evolution of various anti-angiogenic drugs with in this context are briefly outlined below (Figure 1).

Figure 1.

The development process of NSCLC Anti-Angiogenesis therapy in the main body (Refs. 6,7,10,11,70 –74).

In the 1970s, Folkman¹⁰ postulated the critical role of tumor angiogenesis in tumor growth and metastasis, laying the theoretical groundwork for subsequent anti-angiogenic therapies. Subsequent research identified a multitude of molecules and pathways that facilitate angiogenesis, with several factors and receptors, including the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), being implicated in this process. VEGF and its receptor (VEGFR) are key regulators of angiogenesis and are becoming primary targets for anti-angiogenic therapy. This was followed by the introduction of the first-generation anti-angiogenic drug, bevacizumab, a humanized monoclonal antibody against VEGF. Bevacizumab was the first anti-angiogenic inhibitor approved for the first-line treatment of lung adenocarcinoma, exhibiting antitumor activity across multiple tumor types. It inhibits endothelial cell proliferation and neovascularization by neutralizing VEGF activity, thereby reducing tumor microvasculature formation and hindering metastatic progression.¹¹ Beyond monoclonal antibodies targeting VEGF, small-molecule tyrosine kinase inhibitors (TKIs), particularly multi-targeted vascular TKIs, have been developed to selectively inhibit the activation mediated by downstream VEGFR pathways, effectively curtailing tumor vasculature formation.¹² Various small-molecule anti-angiogenic TKIs, including apatinib, anlotinib, fruquintinib, and nintedanib, have been assessed in numerous clinical studies in lung cancer research.

Potential Predictive Biomarkers for Large-Molecule Monoclonal Antibody Drug Efficacy in NSCLC

Liquid Biopsy Predictive Biomarkers

Serum inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR), have been established as prognostically relevant across various diseases, reflecting the systemic immune status. These serum inflammatory factors, closely associated with tumor angiogenesis, suggest that exploring the relationship between changes in these inflammatory factors and anti-angiogenic treatment in patients with NSCLC could be particularly meaningful.^13-16 A study on the prognostic value of inflammatory markers in patients with advanced NSCLC undergoing bevacizumab treatment highlighted that patients with high baseline NLR, PLR, SII, and low LMR had significantly lower median PFS and OS than those with low NLR, PLR, SII, and high LMR. A high baseline SII was independently associated with poorer progression-free and overall survival, whereas baseline LMR was an independent predictor of OS. Dynamic changes in systemic inflammatory markers have predictive value for the prognosis of patients with advanced NSCLC treated with bevacizumab.^17,18 Research indicates that anti-angiogenic therapy with bevacizumab may induce hypertension in patients by elevating serum nitric oxide levels, which is potentially linked to the mechanism of action of the drug. Muto et al¹⁹ investigated the relationship between changes in serum nitric oxide levels before and after bevacizumab administration and therapeutic outcomes in patients with advanced or recurrent non-squamous NSCLC undergoing chemotherapy combined with bevacizumab. This study found that changes in serum NO levels before and after two cycles could predict therapeutic efficacy. Patients with decreased serum nitric oxide levels after two cycles had a median progression-free survival of 11.0 months, compared to 7.6 months for those with increased levels. Additionally, serum nitric oxide levels after disease progression may serve as a useful biomarker for determining whether anti-VEGF treatment should be continued. Its level could be a biomarker for predicting the response of patients with NSCLC to the anti-angiogenic drug bevacizumab. The evidence provided by these studies underscores the potential of liquid biopsy-related markers in the personalized treatment of patients with NSCLC. By assessing patients’ inflammatory characteristics and serum NO levels, clinicians can better predict the efficacy of bevacizumab, tailor treatment plans for individual patients, and potentially improve outcomes. This also highlights the necessity of adopting a holistic approach to cancer treatment, considering not only tumor characteristics but also the patient’s systemic immune and inflammatory states.

Genetic Predictive Biomarkers

The chromatin remodeling factor, Bromodomain PHD Finger Transcription Factor (BPTF), plays a pivotal role in chromatin remodeling. Mutations and overexpression of BPTF have been identified in various tumors, signifying its critical importance in the formation and progression of malignant tumors. A study investigating the relationship between BPTF expression and the therapeutic efficacy of Bevacizumab in NSCLC found that BPTF was overexpressed in the bevacizumab-sensitive group and underexpressed in the bevacizumab-resistant group.²⁰ Among the 26 patients treated with bevacizumab, high BPTF expression was predictive of better therapeutic outcomes in NSCLC, whereas low BPTF expression suggested poorer efficacy. DNA methylation, an epigenetic modification, plays a crucial role in the transcription and expression of genes. It is also associated with the occurrence of lung cancer and resistance to treatment.^21,22 Previous studies have demonstrated that circulating DNA methylation can predict the efficacy of neoadjuvant chemotherapy in patients.²³ For the first time, Li et al²⁴ established the predictive role of DNA methylation characteristics in the prognosis of patients with NSCLC undergoing anti-angiogenic treatment with bevacizumab. This study highlights that DNA methylation patterns could serve as potential biomarkers for patients with cancer. Significant differences in DNA methylation patterns were observed between patients with better and worse prognoses following bevacizumab treatment, suggesting that a 10-gene methylation signature could serve as a novel biomarker for predicting therapeutic response to bevacizumab in patients with NSCLC. However, this study was retrospective and inevitably subject to a selection bias. Furthermore, the biological mechanisms underlying DNA methylation signals are not fully understood and require further investigation.

miRNA Biomarkers

Laura et al²⁵ identified the differential expression of miRNAs across various lung adenocarcinoma subtypes, which was inversely correlated with VEGF expression trends. This disparity holds promise for optimizing anti-angiogenic treatment strategies in patients. Recent studies have highlighted the role of miRNAs in targeting angiogenesis-related mRNA, thereby regulating angiogenesis. Therefore, this regulatory mechanism represents a novel therapeutic approach. Such findings mark the inception of identifying these biomarkers; however, substantial clinical research is required to corroborate these results. This will aid in identifying patients who may benefit from angiogenesis inhibitors and in observing the varying efficacies among patients stratified by different biomarkers.^26,27 miRNA-199a-5p, in particular, has been reported to play a significant role in various tumors. Its significant downregulation in NSCLC tissues suggests that it is a tumor suppressor.²⁸ Explorations into the specific mechanisms through which miR-199a-5p regulates NSCLC progression have revealed its capacity to inhibit hypoxia-inducible factor-1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3), thereby halting NSCLC progression and sensitizing NSCLC cells to Bevacizumab.²⁹ The ultimate aim of integrating miRNA profiles into clinical decision-making is to tailor treatment plans based on the molecular profiles of individual patients, thereby maximizing therapeutic efficacy and minimizing ineffective treatments. Research on miRNAs in lung adenocarcinoma, especially miRNA-199a-5p, represents a promising frontier in cancer therapy. Scientists and clinicians can develop more precise and effective treatment strategies by elucidating the mechanisms through which miRNAs regulate tumor angiogenesis and treatment response. Although these findings are promising, the translation of miRNA research into clinical practice requires extensive validation. Therefore, the heterogeneity of lung adenocarcinoma, compounded by the complex regulatory functions of miRNAs, requires large-scale studies to confirm their predictive value and therapeutic potential.

Additional Predictive Indicators

Given the intricate nature of anti-angiogenic therapy, comprehensive models that incorporate a multifactorial approach tend to outperform single-factor models in terms of predictive accuracy. In light of this, Li et al³⁰ utilized the DeepSurv and NMTLR algorithms to construct a novel multidimensional deep neural network (DNN) model. This model leveraged clinicopathological, inflammatory, and radiological features to predict the prognosis of patients with NSCLC undergoing bevacizumab treatment. The study revealed that patients categorized in the high-risk group exhibited statistically significant differences in progression-free survival (median PFS: 5.4 months vs 13.1 months, P < 0.0001) and overall survival (median OS: 16.4 months vs 21.3 months, P < 0.0001) compared to their low-risk counterparts. These findings underscore the superior predictive abilities of DNN models, particularly in analyzing high-dimensional features. The research results indicated that DNN have advantages in prognostic prediction, particularly in the analysis of high-dimensional features. Thus, DNN-based prognostic predictions are not only theoretically feasible but also can be extended to clinical practice to assist in decision-making.

Potential Predictive Biomarkers for the Efficacy of Small Molecule Multi-Target Tyrosine Kinase Inhibitor Drugs

Liquid Biopsy Predictive Biomarkers

Research conducted by Han et al³¹ used liquid biopsy to identify activated circulating vascular endothelial cells (aCECs) as potential biomarkers for predicting PFS during anlotinib treatment. Additionally, another study focusing on circulating DNA established that patients with lower germline and somatic mutation burdens (G+S MB), as well as non-synonymous and synonymous mutation burdens (N+S MB) exhibited higher sensitivity to anlotinib than those with higher mutation burdens.³² The likelihood of benefiting from anlotinib treatment increases as the tumor mutation index (TMI) decreases. However, the presence of an isocitrate dehydrogenase 1 (IDH1) exon 4 gene mutation may diminish the efficacy of anlotinib therapy.

Genetic Predictive Biomarkers

Long non-coding RNAs (lncRNAs) have been implicated in various biological processes, including epigenetic, transcriptional, and cellular regulation. Their involvement extends to the pathogenesis, progression, and prognosis of various diseases in humans. Research indicates that lncRNA NEAT1 overexpression is intricately linked to lung cancer cell growth and metastasis.³³ It has been found that the lncRNA NEAT1 plays a role in modulating NSCLC resistance to anti-angiogenic therapies by inhibiting mi-335, which in turn upregulates c-Met levels, thereby diminishing the sensitivity to sorafenib and intensifying drug resistance in NSCLC patients.³⁴

In recent years, the focus on exosome research has intensified, with their cargo being closely associated with the onset and progression of various diseases. Exosomes are implicated in the entire spectrum of tumor development, growth, and metastasis, secreting vast quantities into the surrounding cellular environment. These exosomes have emerged as potential biomarkers for tumor diagnosis, therapeutic intervention, and prognostic assessment. Previous studies have successfully isolated potential biomarkers from exosomes present in the plasma of patients with lung cancer.^35,36 A forward-looking study evaluated alterations in exosomal lnc-SNAPC 5-3:4 in patients with advanced NSCLC to assess its utility as a biomarker for gauging the effectiveness of anti-angiogenic treatments, such as anlotinib.³⁷ The authors of the study employed exosomal RNA extracted from the plasma of NSCLC patients for an exhaustive transcriptomic analysis. They conducted a comparative examination of the RNA profiles before, during, and after anlotinib treatment, distinguishing between periods of effective and ineffective treatment. The research findings indicate that the differential expression of lnc-SNAPC 5-3:4 during anlotinib therapy exhibited statistically significant variations. Specifically, lnc-SNAPC 5-3:4 demonstrated significant upregulation during effective anlotinib treatment, whereas it exhibited downregulation during ineffective treatment. Thus, lnc-SNAPC5-3:4 is a promising biomarker for predicting the success of anti-angiogenic therapy. Nonetheless, this study has limitations, including a lack of comprehensive basic research to further elucidate the regulatory mechanisms of these aberrantly expressed exosomes, necessitating future large-scale studies for biomarker validation. Additional findings indicated variations in the expression of other exosomal components, such as miR-34a-5p and miR-27b-5p, although without statistical significance, suggesting the need for further investigation. Moreover, Chang et al³⁸ discovered that exosomes derived from lung adenocarcinoma cells target TIMP2/3 in the metastasis of lung adenocarcinoma and are involved in the formation of tumor vasculature through miR-197-3p. Therefore, miR-197-3p may represent a promising therapeutic target and a potential predictive biomarker for the anti-angiogenic treatment of lung adenocarcinoma. Zhou F. et al³⁹ observed that the level of miR-30c in the serum increased with the extension of anti-angiogenic treatment cycles. Related research has indicated that miR-30c levels are associated with cardiotoxicity. Therefore, serum miR-30c levels could serve as an early predictive biomarker for cardiotoxicity in patients with NSCLC undergoing anti-angiogenic treatment. Furthermore, Ma et al⁴⁰ identified that miRNA-6077 enhances sensitivity to anlotinib in patient-derived lung adenocarcinoma cells by inhibiting the activation of the glucose transporter 1 pathway. These findings highlight the complexity of cancer biology and the potential of genes and molecular biomarkers in the personalized treatment of lung cancer. The identification of lncRNAs, exosomes, and miRNAs related to treatment response and resistance provides new therapeutic targets and offers novel strategies for monitoring treatment effectiveness and side effects. As research progresses, these biomarkers may lead to the development of new therapeutic drugs, enhance patient selection for specific treatments, and provide early warnings of adverse reactions, thereby significantly improving the care of patients with NSCLC.

Imaging Markers

The advent of anti-angiogenic therapy has transformed the treatment landscape for NSCLC, enabling the assessment of the clinical efficacy of these drugs using advanced imaging techniques. A recent study by Professor Huang et al⁴¹ focused on utilizing dynamic contrast-enhanced magnetic resonance positron emission tomography (MR-PET) to evaluate tumor angiogenesis in patients with NSCLC, thereby guiding the application of NSCLC angiogenesis inhibitors. Their study assessed the relationship between the MR-PET parameters and serum angiogenesis biomarkers. The results demonstrated a strong linear correlation between the MR-PET measurements and all tested serum angiogenesis-related biomarkers, indicating that quantitative MR-PET measurements reflect the concentrations of serum angiogenesis-related biomarkers. This study suggests that patients with higher initial MR-PET measurements may benefit from atalanib treatment, which significantly prolongs overall survival. MR-PET imaging and serological biomarkers can evaluate tumor angiogenesis and these imaging biomarkers can assist in selecting patients who are likely to benefit from angiogenesis inhibitor treatments and monitoring therapeutic outcomes, thereby playing a crucial role in the personalized treatment of NSCLC. Wang et al⁴² discovered that alterations in tumor blood volume (BV) detected through CT perfusion imaging during anti-angiogenic therapy typically manifest 1 to 2 months earlier than conventional CT observations, and combining this with activated circulating vascular endothelial cells (aCECs) could enhance the reliability and sensitivity of efficacy predictions. Additionally, various imaging biomarkers based on MRI, CT, and ultrasound technologies have been validated and found to be prognostically relevant in colorectal, renal, and liver cancers⁴³; however, similar roles in NSCLC have not been identified. The predictive utility of these imaging biomarkers for anti-angiogenic treatment is yet to be confirmed. Therefore, further research is necessary to determine whether these functional imaging biomarkers will play a significant role as predictive indicators in future clinical practice.

Additional Predictive Biomarkers

Studies evaluating the effects of body composition on lung cancer treatment outcomes have yielded mixed results. Research assessing the influence of obesity on OS, PFS, and the incidence of severe adverse events (SAE) in NSCLC patients undergoing bevacizumab therapy found no significant differences in OS or PFS between the obese and non-obese groups, indicating that obesity is not correlated with survival rates in patients with advanced NSCLC. Similarly, the incidence of severe adverse events was comparable between patients with and without obesity.⁴⁴ However, another study examining the role of obesity in patients with NSCLC treated with anlotinib reported contrary findings, in which obese patients exhibited poorer OS than non-obese patients when treated with anlotinib vs a placebo.⁴⁵ The interaction between Body Mass Index (BMI) stratification and treatment significantly affected OS, suggesting that obesity (BMI ≥28 kg/m^2) may serve as a predictive marker for suboptimal response to anlotinib treatment in NSCLC. The varied outcomes from studies on the impact of obesity on lung cancer treatment underscore the need for further investigation into how obesity might affect the efficacy of treatments across different cancers. This includes exploring the role of adipose tissue in drug distribution and metabolism, the impact of obesity-related inflammation and hormonal changes on tumor biology and treatment response, and the potential influence of obesity on the tumor microenvironment, thereby affecting the effectiveness of anti-angiogenic therapies. These findings highlight the importance of considering patient-specific factors, such as body composition, in treatment planning. Personalized medical approaches that tailor treatment based on individual patient characteristics, including genetic, phenotypic, and environmental factors, can enhance treatment efficacy while minimizing adverse reactions.

Predictive Biomarkers for Anti-Angiogenic Combination Therapy

Given the relatively limited efficacy of anti-angiogenic therapies when used in isolation, clinical research has increasingly favored combination therapy strategies to overcome these limitations. Combination therapies utilize distinct mechanisms of action and drug targets to enhance treatment outcomes. Consequently, considerable research has been conducted on predictive biomarkers for anti-angiogenic therapy in the context of combination therapy approaches.

Anti-Angiogenic Therapy Combined With Immunotherapy

The combination of anti-angiogenic agents and immunotherapy has shown significant efficacy in multiline treatments. However, the potential biomarkers for predicting and monitoring therapeutic responses to combination therapy remain unclear. In a study examining the combination of carrelizumab with apatinib in advanced NSCLC, circulating free DNA (cfDNA) concentration was identified as an independent predictor of PFS, with higher cfDNA concentrations associated with a poorer prognosis.⁴⁶ Additionally, patients with MIKI67 mutations or genetic variants associated with hyperprogressive disease (HPD) also correlated significantly with shorter PFS. Monitoring circulating tumor DNA (ctDNA) at various time points can effectively track disease remission or progression. Tumor-associated high endothelial venules (TA-HEVs), which originate from post-capillary venules and mediate lymphocyte entry into tumors, play a crucial role in lymphocyte recirculation and the formation of tertiary lymphoid structures (TLSs).^47,48 Anti-angiogenic therapy can downregulate sustained angiogenic signaling, leading to vascular normalization and consequently promoting TA-HEVs.⁴⁹ Ye et al⁵⁰ collected pre-reatment biopsy specimens from 14 patients with advanced NSCLC undergoing PD-1 inhibitor therapy combined with anti-angiogenic therapy. Based on PFS, patients were divided into effective (PFS >6 months, n = 8) and ineffective (PFS >6 months, n = 6) groups. Multiplex immunofluorescence staining of pre-treatment tumor biopsies revealed that peripheral node addressin (PNAd) positive high endothelial venules could predict better efficacy and survival rates for a combination of anti-angiogenic therapy and PD-1 inhibitors. Owing to the limited number of pathology specimens that met the study criteria, only 14 samples were eligible, and with a relatively short follow-up duration, OS analysis was not available. Given these limitations, the conclusions drawn may require further validation using a larger sample size.

Anti-Angiogenic Therapy Combined With Chemotherapy

The heterogeneity of non-small cell lung cancer (NSCLC) results in considerable variability in the clinical outcomes of NSCLC treatments. The use of the anti-angiogenic targeted drug bevacizumab in combination with chemotherapy has demonstrated superior PFS and improved OS in the first-line treatment of patients with advanced NSCLC. Despite this, significant individual variations have been observed, indicating the need for potential biomarkers to predict the clinical efficacy of bevacizumab in patients with advanced NSCLC. Thyroid Transcription Factor-1 (TTF-1), a transcription factor with a homologous domain, is expressed in approximately 75% of patients with NSCLC. Among those showing positive expression, the level and intensity of TTF-1 are often positively correlated with prognosis, making TTF-1 expression a favorable prognostic factor for survival in NSCLC.⁵¹ The VEGF promoter harbors TTF-1 response elements. TTF-1-positive cells, when contrasted with their TTF-1-negative counterparts, manifest elevated intracellular levels of VEGF mRNA and secrete VEGF protein. The expression status of tumor TTF-1 potentially governs VEGF levels, thereby influencing favorable clinical outcomes.⁵² Takeuchi et al⁵³ highlighted the divergence in cellular lineage origins between TTF-1-positive and negative lung adenocarcinomas, potentially impacting cell proliferation patterns and chemotherapy sensitivity, thus yielding disparate clinical outcomes. Consequently, they employed a retrospective research methodology to explore the correlation between TTF-1 expression and beneficial responses to bevacizumab combined with chemotherapy in non-squamous NSCLC patients. The investigation unveiled a tendency towards prolonged overall survival in TTF-1-positive patients receiving bevacizumab combined chemotherapy compared to their TTF-1-negative counterparts. This suggests that TTF-1 expression can serve as a predictive biomarker for identifying patients who will benefit from bevacizumab combined with platinum-based drug treatment. Lewintre et al⁵⁴ recently reported that polymorphisms in VEGFR-1 and VEGF-A, as well as in the plasma levels of VEGF-A, can predict the efficacy and prognosis of patients with non-squamous NSCLC treated with chemotherapy combined with bevacizumab. The results showed that VEGFR-1 rs9582036 and VEGF-A rs3025039 were independent prognostic markers of OS. Furthermore, a shorter PFS was associated with higher baseline plasma levels of VEGF-A and the presence of the CC allele at VEGFR-1 rs9582036; patients in the high VEGF-A group had significantly shorter PFS than those in the low VEGF-A group (5.9 months vs 8.4 months, P = 0.036). A similar trend was observed in OS (12.0 months vs 16.0 months, P = 0.095), but the difference was not statistically significant. Additionally, polymorphisms in VEGFR2, the most critical receptor for VEGF-A binding, can affect the effectiveness of bevacizumab. A study conducted by Fan et al⁵⁵ on the effect of VEGFR2 polymorphisms on the outcome and safety of bevacizumab combined with chemotherapy in the first-line treatment of patients with advanced NSCLC found that the VEGFR2 889C>T locus could reduce the efficacy of this treatment, with the 889C>T locus having an independent impact on progression-free survival after multivariable adjustment (OR = 1.96, P = 0.014). No correlation was found between the 889C>T locus and adverse reactions in the safety analysis. Although this study has some limitations, it provides clinically meaningful guidance for prognostic assessment of bevacizumab treatment in patients with advanced NSCLC. The Kinase Insert Domain Receptor (KDR) is another important receptor for VEGFA, and its polymorphism may have clinical relevance in the efficacy of anti-angiogenesis-targeted therapies. In a study exploring the impact of KDR gene variations on the efficacy and safety of first-line bevacizumab plus chemotherapy regimen in patients with advanced NSCLC, an analysis of the V297L genotype status and prognosis were analyzed.⁵⁶ These results suggest that the KDR V297L polymorphism could serve as a potential biomarker for predicting the outcomes of patients with advanced NSCLC receiving a first-line bevacizumab regimen. The KDR polymorphism V297L may influence the clinical prognosis of patients with advanced NSCLC receiving the first-line bevacizumab plus chemotherapy regimen by mediating the expression of KDR mRNA. Han et al⁵⁷ conducted polymorphism and GSTP1 mRNA expression analyses on available blood samples and peripheral blood mononuclear cells (PBMCs) of patients. Through this analysis of the correlation between rs1695 polymorphism status and prognosis, it was found that the median PFS for patients with AA and AG/GG genotypes was 9.5 months (95% CI: 7.99-11.01) and 5.6 months (95% CI: 3.35-7.85), respectively, with a statistically significant difference (χ2 = 7.237, P = 0.007). The median OS for patients with AA and AG/GG genotypes was 22.0 months (95% CI: 19.74-24.26) and 16.6 months (95% CI: 10.92-22.28), respectively, with a statistically significant difference (χ2 = 8.763, P = 0.003). After multivariate adjustment, the rs1695 polymorphism status was an independent factor affecting OS (Hazard Ratio [HR] = 0.76 [95% CI: 0.55-0.85], P = 0.008), indicating that GSTP1 polymorphism rs1695 could serve as a potential biomarker for assessing the prognosis of patients with advanced NSCLC receiving bevacizumab combined with chemotherapy. In summary, polymorphisms in genes involved in the anti-angiogenic pathway have potential predictive significance for the efficacy and prognosis of patients treated with bevacizumab. In addition to other markers, certain liquid biopsy indicators have also been proven to have predictive value. A randomized Phase II study of patients with advanced non-squamous NSCLC treated with cisplatin, pemetrexed, and bevacizumab showed that the pre-treatment monocyte (M)-derived suppressor cell (MDSC) count tended to be higher in the group with poorer PFS than in the group with better PFS.⁵⁸ The early response of pre-treatment M-MDSC counts may be associated with the survival benefit of adding Bevacizumab to the Cisplatin and Pemetrexed combination therapy. Chemokine (C-X-C motif) ligand 16 (CXCL16) and its receptor (CXCR6) affect tumor progression through various pathways, including leukocyte recruitment, cellular senescence, and tumor cell proliferation, survival, invasion, and metastasis.^59-62 Additionally, because of its relationship with hypoxia-inducible factors, CXCL16 is considered a marker of hypoxic stress in the tumor microenvironment, and hypoxia has been closely linked to angiogenesis. These results suggest that CXCL16 reflects the concentration of VEGF and the efficacy of anti-VEGF treatment. Yuji et al⁶³ evaluated the adequacy of CXCL16 as a biomarker for patients receiving chemotherapy regimens including bevacizumab. The study data indicated that bevacizumab combined with chemotherapy led to a reduction in post-treatment CXCL16 levels, which correlated with a better response rate. Furthermore, patients with a greater reduction in serum CXCL16 levels had a longer OS, establishing serum CXCL16 level as a potential biomarker for chemotherapy efficacy, especially for anti-VEGF treatment. The dynamic changes in systemic inflammation markers mentioned earlier (such as the lymphocyte-to-monocyte ratio) have predictive value for the prognosis of patients with advanced NSCLC treated with bevacizumab.^17,18 A study on selected laboratory markers and their potential association with prognosis in non-small cell lung cancer (NSCLC) patients receiving bevacizumab (BEV) combined with chemotherapy observed a similar phenomenon.⁶⁴ The team’s retrospective analysis suggested that lactate dehydrogenase (LDH) and sodium may serve as prognostic markers for NSCLC treatment with bevacizumab combined with chemotherapy. Parameters related to the inflammatory response (C-reactive protein, neutrophil-to-lymphocyte ratio, albumin, and possibly hemoglobin) appear to be promising predictive indicators of this combination treatment. Verifying their use in prospective studies (preferably in the form of proinflammatory indices) is appropriate. These studies emphasize the multifaceted nature of predictive markers for NSCLC treatment with anti-angiogenesis combined with chemotherapy. The identification of potential predictive factors for treatment response, including gene polymorphisms, protein expression levels, and systemic inflammatory markers, highlights the importance of personalized cancer treatment approaches. Future research should focus on validating these markers in prospective studies, exploring their mechanisms, and integrating them into clinical practice to optimize the treatment strategies for patients with NSCLC. The ultimate goals are to improve treatment outcomes, reduce adverse reactions, and enhance patient prognosis through tailored therapeutic interventions.

Anti-Angiogenic Therapy Combined With Targeted Therapy

The predictive role of plasma Vascular Endothelial Growth Factor A (pVEGFA) in bevacizumab treatment has been debated. A recent analysis of potential predictive biomarkers for favorable treatment outcomes with erlotinib combined with bevacizumab in patients with epidermal growth factor receptor (EGFR) positive NSCLC indicated that lower levels of pVEGFA are associated with better bevacizumab treatment outcomes.⁶⁵ This study also suggests that low baseline serum leptin levels might serve as potential biomarkers for bevacizumab treatment sensitivity, whereas high serum follistatin levels could be candidate biomarkers for bevacizumab treatment resistance and the production of various growth factors. Another interesting study found that adding an angiogenesis inhibitor (Bevacizumab or Ramucirumab) to EGFR TKI treatment in patients with advanced EGFR mutation-positive NSCLC and a history of smoking provided statistically significant benefits in PFS and OS.⁶⁶ In the subgroup of current and former smokers receiving combination therapy, the risk of PFS events and death decreased by 45% and 34%, respectively. Importantly, a significant interaction was identified, indicating that smoking status may be a potential predictive indicator of PFS and OS in this population. In summary, the predictive value of pVEGFA, serum leptin, and smoking status in determining the efficacy of combined anti-angiogenic and targeted therapies for NSCLC patients with NSCLC represents an important step towards more personalized and effective cancer treatment strategies. Further research is needed to validate these markers in larger and more diverse patient populations and to understand the potential mechanisms by which they influence the treatment response.

Summary and Outlook

Research on biomarkers related to anti-angiogenic therapy for NSCLC plays a crucial role in advancing personalized and precision medicine, as well as in improving treatment outcomes and survival rates for patients. Despite progress in the study of NSCLC anti-angiogenic therapy biomarkers, significant challenges remain, such as: 1. Clinical trials for most anti-angiogenic drugs are combination trials, making it unclear whether there is sufficient activity to use single-drug responses as outcomes for exploring predictive biomarkers. Additionally, there is a lack of consistency and standardization across different study results. 2. The inherent heterogeneity within NSCLC means that tumor characteristics and responses can vary greatly among patients, making it more difficult to identify effective biomarkers. 3. Current technologies struggle to accurately monitor the effects of anti-angiogenic therapies, such as the degree of tumor shrinkage and post-treatment tumor residuals. 4. The predominant focus of the discussed studies within the article lies on non-squamous NSCLC, possibly because squamous cell NSCLC tends to be centrally located, often involving major blood vessels. Anti-angiogenic drugs, such as bevacizumab, may increase the risk of severe bleeding (hemoptysis) in these patients, and the response of squamous cell NSCLC to anti-angiogenic therapy in terms of vascular pathways and tumor microenvironment may be less effective than that of adenocarcinoma et al. Hence, this restricts the investigation of relevant predictive biomarkers in non-squamous NSCLC. Addressing these challenges requires extensive clinical validation and further mechanistic studies to fully leverage the potential of these biomarkers, making them powerful tools for guiding NSCLC anti-angiogenic therapy. To date, predictive biomarkers for NSCLC anti-angiogenic therapy have not been prospectively validated or widely accepted as reliable criteria for selecting appropriate patients. Future directions and trends include the following:

1. Microbiome and Treatment Response Association: Studies have suggested a close relationship between the gut microbiome and both tumor development and treatment response. Associating microbiome information with anti-angiogenic therapy outcomes may reveal microbiome-based biomarkers related to treatment responses, thereby offering new strategies for predicting and modulating treatment effects.⁶⁷

2. Application of Artificial Intelligence and Machine Learning: By integrating big data analytics and artificial intelligence algorithms with various data sources, such as clinical data, genomics, and transcriptomics, more accurate and reliable prediction models can be established to assist in clinical decision-making and biomarker screening.^68,69

3. Discovery of New Biomarkers: Advances in technology may lead to the discovery of novel biomarkers, such as circulating tumor DNA, tumor-associated protein markers, and non-coding RNAs. These markers could be more specific and sensitive, aiding in predicting treatment responses, monitoring disease progression, and facilitating personalized treatment.

4. Development of Personalized Treatment Strategies: By integrating multiple biomarkers and clinical indicators, further development of personalized treatment strategies is possible. Selective treatment strategies based on specific biomarkers or their combinations may become a future trend, enabling patients to receive more precise and effective anti-angiogenic therapy.

5. Optimization of Combination Therapy Strategies: The combination of anti-angiogenic therapy with other treatment methods (e.g., immunotherapy and targeted therapy) may become a focus of future research. Optimizing treatment protocols and sequences can further improve treatment outcomes and survival prognosis.

The development of these areas will offer more possibilities for research and application of biomarkers in NSCLC anti-angiogenic therapy, providing patients with more accurate and personalized treatment options, thereby improving treatment efficacy and survival outcomes.

Conclusion

This passage delineates the crucial functions of specific biological markers, including liquid biopsy markers, imaging biomarkers, and genetic predictive factors et al, within the context of anti-angiogenic therapy for non-small cell lung NSCLC. In the contemporary landscape characterized by personalized and precision medicine, the advancement of research and the utilization of predictive biomarkers in anti-angiogenic therapy for NSCLC hold the potential to yield treatments characterized by heightened precision and efficacy. Consequently, this endeavor stands to enhance patient prognoses and augment survival rates.

Footnotes

Acknowledgments

The authors thank Jun Jiang (Oncology Department, Affiliated Hospital of Qinghai University, Xining, China) Prof for his insightful comments that ultimately gave the idea for this review.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the Science and Technology Agency of Qinghai Province (2022-ZJ-719).

Ethical statement

ORCID iD

Weixing Zhao

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Advances in Predictive Biomarkers for Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer

Abstract

Keywords

Introduction

Anti-Angiogenic Therapy in NSCLC

Potential Predictive Biomarkers for Large-Molecule Monoclonal Antibody Drug Efficacy in NSCLC

Liquid Biopsy Predictive Biomarkers

Genetic Predictive Biomarkers

miRNA Biomarkers

Additional Predictive Indicators

Potential Predictive Biomarkers for the Efficacy of Small Molecule Multi-Target Tyrosine Kinase Inhibitor Drugs

Liquid Biopsy Predictive Biomarkers

Genetic Predictive Biomarkers

Imaging Markers

Additional Predictive Biomarkers

Predictive Biomarkers for Anti-Angiogenic Combination Therapy

Anti-Angiogenic Therapy Combined With Immunotherapy

Anti-Angiogenic Therapy Combined With Chemotherapy

Anti-Angiogenic Therapy Combined With Targeted Therapy

Summary and Outlook

Conclusion

Footnotes

Acknowledgments

Declaration of Conflicting Interests

Funding

Ethical statement

ORCID iD

References