The efficacy of angiogenesis inhibitors combined with chemotherapy in advanced breast cancer: a systematic review and meta-analysis

Abstract

Clinical trial registration:

Globally, breast cancer is the most common malignancy in women. Despite treatment advances, 20–30% of early-stage patients progress to advanced disease, which remains largely incurable with a 5-year survival rate of only ~20%. Chemotherapy, the current mainstay, has reached a therapeutic plateau, with limited efficacy and potential pro-metastatic effects. Anti-angiogenic agents targeting VEGF/VEGFR2 (e.g., bevacizumab, TKIs) are used clinically, but their benefit in advanced breast cancer is controversial: progression-free survival (PFS) gains are inconsistent, overall survival (OS) benefits are unclear, and resistance with class-specific toxicities (e.g., hypertension) is common. Furthermore, comparative efficacy across drug classes and optimal patient selection remain undefined. These unresolved issues highlight the urgent need for a comprehensive synthesis to guide clinical decisions and future research.

Methods:

Systematic search of PubMed/Web of Science (up to July 16, 2025) identified 29 phase II/III RCTs (N = 8,480) comparing angiogenesis inhibitors + chemotherapy vs. chemotherapy alone (± placebo) in advanced breast cancer. Outcomes included PFS, OS, objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and safety. Two independent reviewers performed screening, extraction, and quality assessment. Pooled HRs (95% CI) for PFS/OS; ORs for binary outcomes. Random-effects model used if I² ≥ 50%; prespecified subgroup/sensitivity analyses explored heterogeneity.

Results:

This meta-analysis (29 RCTs, N = 11,068) showed that adding angiogenesis inhibitors in advanced breast cancer significantly improved PFS (HR 0.75), ORR, CBR, and DCR (all P<0.001), but not OS (HR 0.95, P = 0.171). PFS benefit varied by subtype: mAbs (e.g., bevacizumab) outperformed TKIs in TNBC (HR 0.59 vs. 0.75); TKIs trended better in HR+ disease (HR 0.67). Benefit was consistent across metastasis patterns but greater in patients without bone metastasis. Safety risks increased significantly, including hypertension (OR 4.59), thrombocytopenia (OR 4.54), proteinuria (OR 2.38), hand-foot syndrome (OR 2.14), and diarrhea (OR 1.97).

Conclusions:

This meta-analysis (29 RCTs) finds that adding angiogenesis inhibitors to chemotherapy significantly improves PFS and response in advanced breast cancer—especially in TNBC with mAbs and HR+ disease with TKIs—but not OS. Benefit is independent of visceral metastasis but reduced in bone metastases. Increased toxicities (hypertension, proteinuria, hand-foot syndrome, diarrhea) warrant proactive management.

Introduction

Breast cancer represents the most prevalent malignant tumor among women globally, with an annual incidence exceeding 2 million cases, and stands as one of the primary causes of cancer-related mortality in the female population (1). Approximately 20% to 30% of patients diagnosed with early-stage breast cancer will ultimately progress to advanced (recurrent or metastatic) disease (2).The prognosis for advanced breast cancer remains poor, with a five-year survival rate of only about 20%, a stark contrast to the rate exceeding 90% observed in early-stage cases. Critically, advanced breast cancer is currently considered incurable. Consequently, the therapeutic paradigm has shifted from seeking a cure to focusing on prolonging survival, controlling disease progression, and improving quality of life. This reality underscores the urgent and unmet need for more effective treatment strategies. In the management of advanced breast cancer, chemotherapy-based regimens remain a cornerstone of standard care. However, this approach has reached a significant “therapeutic plateau,” characterized by two major limitations: 1) Limited response rates, wherein current chemotherapeutic agents offer minimal curative potential, particularly in the metastatic setting (3); and 2) Short duration of response, as the benefits of chemotherapy are often transient. Emerging evidence suggests that chemotherapy-induced tissue damage may trigger pro-tumorigenic inflammatory responses, potentially undermining its efficacy and even promoting metastasis and recurrence (4).

Despite advances in existing therapies, the management of advanced breast cancer continues to face formidable challenges. Drug resistance remains a central obstacle, as cancer cells rapidly adapt and develop resistance to treatments (5). For instance, the survival benefit of anti-angiogenic therapies targeting vascular endothelial growth factor receptor 2 (VEGFR2) is limited, in part due to the swift emergence of resistant tumor clones (6). Treatment-related toxicity presents another major constraint. Targeted agents, including anti-angiogenic drugs, are frequently associated with class-specific adverse effects, such as an elevated risk of hypertension and proteinuria (7). These toxicities can impair patients’ quality of life, necessitate dose reductions or interruptions, and ultimately limit the intensity and duration of therapy. In summary, while current therapeutic modalities have achieved some progress, they exhibit pronounced shortcomings in substantially extending OS for patients with advanced breast cancer. The critical barriers of intrinsic and acquired drug resistance, coupled with dose-limiting toxicities, highlight the pressing need to overcome these therapeutic bottlenecks and develop novel, more effective interventions.

Angiogenesis is an established hallmark of tumor development (8). In breast cancer, sustained angiogenesis is critical for tumor growth and metastasis. The abnormal vasculature it generates creates a tumor microenvironment characterized by hypoxia, elevated interstitial fluid pressure, and immune suppression. This aberrant vascular network not only facilitates tumor progression and distant spread but also contributes significantly to therapy resistance (9). Specifically, it can impede the delivery and efficacy of chemotherapeutic agents and targeted drugs while promoting the development of treatment-resistant tumor cell populations through hypoxia-driven selection and immune-editing mechanisms (6). Clinically, the degree of abnormal angiogenesis is strongly correlated with poor prognosis and serves as a key driver of metastatic disease. Inhibitors of angiogenesis primarily function by targeting the VEGF/VEGFR2 signaling axis, a central pathway in tumor vessel growth. Clinically available agents fall into two main categories: mAb (e.g., bevacizumab, which targets VEGFA) and small-molecule TKIs(e.g., sunitinib, sorafenib) (10). While mAb may face challenges related to limited tumor penetration, TKIs can exhibit off-target effects due to their broader kinase inhibition profiles. These agents work by blocking new blood vessel formation, thereby starving the tumor of oxygen and nutrients (11). A significant clinical limitation, however, is the rapid development of resistance to single-agent anti-VEGFR2 therapy, often through the upregulation of alternative pro-angiogenic pathways. The vascular normalization theory offers a refined strategy for combining anti-angiogenic drugs with chemotherapy (12). This paradigm posits that at optimal doses, certain anti-angiogenic agents can “prune” the most immature and dysfunctional tumor vessels, thereby improving the structure and function of the remaining vasculature. In breast cancer, this transient normalization window can enhance blood perfusion, reduce hypoxia, and improve the delivery and efficacy of concurrently administered chemotherapeutic agents. Mechanistic studies suggest that vascular normalization may reversechronic stress-induced vascular dysfunction and potentiate chemotherapy by modulating pathways such as cAMP/PKA/CREB1-mediated glycolysis (13). Furthermore, by alleviating hypoxia and remodeling the tumor microenvironment, vascular normalization can also enhance the efficacy of immunotherapy. Despite its promise, clinical translation faces two major bottlenecks: 1) determining the precise, optimal drug dose and schedule to achieve and maintain the normalization window without inducing excessive vessel pruning, and 2) the lack of reliable, non-invasive biomarkers or imaging techniques to monitor this dynamic window in real-time to guide treatment timing (14).

Current clinical evidence regarding the efficacy of angiogenesis inhibitors in advanced breast cancer is characterized by significant heterogeneity and apparent contradictions. Multiple studies indicate that while anti-angiogenic agents can improve PFS, the benefit in OS is often limited and inconsistent (15). For instance, bevacizumab, the first approved anti-angiogenic drug for breast cancer, has been shown to improve ORR. However, emerging preclinical evidence suggests it may paradoxically activate pro-metastatic pathways such as Wnt/β-catenin signaling, potentially increasing tumor invasiveness and metastasis risk (16). This raises questions about the overall risk-benefit balance, where survival gains may be offset by toxicity risks. Furthermore, comparative efficacy between different drug classes (e.g., mAb vs. TKIs) remains unclear, and conclusions from subgroup analyses—such as potential differential benefits in patients with HER2-positive disease or visceral metastases—are often conflicting (17). The first phase III trial of an anti-angiogenic agent plus a PARP inhibitor in breast cancer showed that the fluzoparib and apatinib group had a median PFS of 11.0 months (HR 0.27 vs chemotherapy). The combination worked better than the single drug (HR 0.60) (18). At the 2025 ASCO annual meeting, a quick oral report said that Hengrui’s rezetuximab (disitamab vedotin) alone or with bevacizumab gave high intracranial response rates (84.4% and 72.7%). This gives a possible new treatment for HER2-positive breast cancer patients with brain metastases. In the context of contemporary, more effective subsequent-line therapies, another critical question arises: does the PFS advantage conferred by angiogenesis inhibitors still translate into a meaningful clinical net benefit for patients? Concurrently, the management and clinical impact of their class-specific toxicities (e.g., hypertension, proteinuria) require systematic evaluation.

This study aims to comprehensively and quantitatively evaluate the efficacy (OS, PFS, ORR) and safety of angiogenesis inhibitors combined with chemotherapy versus chemotherapy alone in advanced breast cancer through a meta-analysis, while exploring potential beneficiary subgroups and influencing factors via pre-specified subgroup analyses. Ultimately, this research is committed to providing high-level evidence-based medical evidence to address current controversies in clinical practice, offering direct and reliable references for clinicians in formulating individualized treatment plans, for researchers in designing subsequent clinical trials, and for health policymakers in optimizing resource allocation.

Materials and methods

The paper of this systematic review and meta-analysis adhered to the PRISMA guidelines, while its methodological rigor was ensured by following the AMSTAR guidelines.

The methodological quality of this systematic review and meta-analysis was assessed using the AMSTAR checklist. AMSTAR is a validated tool consisting of 16 items that evaluate key aspects of systematic review conduct, including study design, search strategy, data extraction, risk of bias assessment, statistical methods, heterogeneity assessment, and publication bias. This study adhered to the AMSTAR guidelines to ensure methodological rigor and reporting transparency.

Data sources and search strategy

We systematically searched PubMed and Web of Science using the keywords “Angiogenesis Inhibitor”, “breast cancer”, “Bevacizumab”, “Sunitinib”, “Sorafenib”, and “Anlotinib” for records published up to July 16, 2025, with no language restrictions. This meta-analysis ultimately included 8,480 patients from 29 RCTs. To ensure the inclusion of all currently available RCTs, we also manually screened the reference lists of relevant reviews and meta-analyses. The literature search and selection process were conducted independently by two investigators, with any disagreements resolved through consultation with a third researcher until a consensus was reached.

Inclusion and exclusion criteria

Studies were eligible if they met the following inclusion criteria: (1)Phase II or III RCTs involving patients with recurrent or metastatic breast cancer confirmed by immunohistochemistry. (2)The experimental group received angiogenesis inhibitors combined with chemotherapy, while the control group received chemotherapy with or without placebo. (3)The primary endpoint was PFS or ORR, and secondary endpoints included CBR, DCR, OS, or safety outcomes.

Only Phase II or III randomized controlled trials were eligible for inclusion. Phase I trials, single-arm studies, observational studies, case reports, and reviews were excluded. This criterion was adopted because Phase II and III RCTs provide higher-quality evidence with adequate sample sizes, randomization, and predefined endpoints, thereby minimizing bias and enabling reliable efficacy and safety comparisons.

The exclusion criteria were as follows: (1) Non-randomized or single-arm clinical trials.(2) Control groups that did not receive chemotherapy combined with placebo.(3) Incomplete or ongoing trials with unpublished results.(4) Unavailable data or inability to extract relevant outcomes.(5) Non-original research, including reviews, systematic reviews, basic research, case reports, meta-analyses, letters, editorials, or expert opinions.

Data extraction

The data extraction process was conducted in two phases. First, general study characteristics were collected from the included RCTs, including clinical trial registration number, study title, trial phase, year of publication, number of patients in experimental and control groups, tumor stage, treatment regimens in the study and control arms, as well as the dosage and duration of angiogenesis inhibitor therapy. Second, outcome measures were extracted, including PFS, ORR, CBR, DCR, OS, along with corresponding HRs and 95% CIs. Two investigators independently performed the data extraction, with any discrepancies resolved through consultation with a third researcher.

Literature quality evaluation

All statistical analyses were performed using RevMan (version 5.4, Cochrane Collaboration, Oxford, UK) and Stata (version 17.0, StataCorp, College Station, TX, USA). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled for time-to-event outcomes (PFS and OS) using the generic inverse-variance method. Risk ratios (RRs) with 95% CIs were calculated for dichotomous outcomes (ORR, CBR, DCR). Heterogeneity across studies was assessed using the I² statistic and the Cochran Q test. I² values of <25%, 25–50%, and >50% were considered low, moderate, and high heterogeneity, respectively. A random-effects model was applied when I² > 50% or the Q test p-value < 0.10; otherwise, a fixed-effects model was used. Subgroup analyses were performed based on breast cancer subtype (TNBC vs. HR+/HER2–) and drug class (monoclonal antibodies vs. small-molecule TKIs). Publication bias was evaluated using funnel plots and Egger’s regression test when at least 10 studies were available. All p-values were two-sided, and p < 0.05 was considered statistically significant.

Results

Literature search results

The initial database search identified 2,637 non-duplicate records. After title and abstract screening, 2,542 articles were excluded, including reviews, case reports, case series, meta-analyses, retrospective studies, non-RCTs, phase I studies, and trials involving non-breast cancer populations. This resulted in 95 potentially eligible records for full-text review. Following detailed full-text assessment, 66 studies were further excluded due to the following reasons: not evaluating angiogenesis inhibitors, testing monotherapy regimens, or being single-arm clinical trials. After this comprehensive evaluation process, 29 RCTs were ultimately included in the analysis (Figure 1).

Figure 1

Study characteristics and quality assessment

The baseline characteristics of the 29 studies included in this research are detailed in Table 1. A total of 11,068 patients with advanced breast cancer were enrolled, all studies being RCTs. Among them, 19 studies employed bevacizumab in the experimental arm, 5 used sorafenib, 2 used sunitinib, 2 utilized anlotinib, and 1 employed ramucirumab.

Efficacy outcomes

CBR

Among the eight studies that reported CBR, a total of 1993 patients were included to evaluate the efficacy of angiogenesis inhibitors compared to the control group in improving the CBR. The random-effects meta-analysis showed that the CBR in the experimental group was significantly higher than that in the control group (OR = 1.92, 95% CI: 1.58 - 2.32, P < 0.001). Low heterogeneity was observed among the studies (I² = 0%, P = 0.61) (Figure 2).

Figure 2

DCR

To evaluate the DCR of angiogenesis inhibitors compared to the control group, we conducted a meta-analysis of 13 studies that reported this outcome, involving a total of 2317 patients. The random-effects model analysis showed that the DCR in the experimental group was significantly higher than that in the control group (OR = 1.58, 95% CI: 1.31 - 1.91, P < 0.001) (Figure 3). High heterogeneity was observed among the studies (I² = 72%, P < 0.001). In addition, funnel plot analysis indicated no evidence of publication bias (Supplementary Figure 1).

Figure 3

ORR

This meta-analysis of 27 included RCTs evaluated the efficacy of angiogenesis inhibitors compared to control in improving the ORR. The analysis included a total of 8422 patients. Random-effects model results showed that the ORR in the experimental group was significantly higher than that in the control group (OR = 1.76, 95% CI: 1.60 - 1.93, P < 0.001) (Figure 4). However, moderate heterogeneity was observed among the studies (I² = 44%, P = 0.009). In addition, funnel plot analysis indicated no evidence of publication bias (Supplementary Figure 2).

Figure 4

PFS

This meta-analysis of 27 RCTs evaluated the efficacy of angiogenesis inhibitors compared to control in prolonging PFS. The random-effects model showed that angiogenesis inhibitors significantly reduced the risk of disease progression or death compared to the control group (HR = 0.75, 95% CI: 0.69-0.81, P < 0.001). Low heterogeneity was observed among the studies (I² = 53.5%, P = 0.001) (Figure 5).

Figure 5

OS

We identified 22 studies that evaluated OS in patients with advanced/recurrent breast cancer. The analytical conclusions indicate that, compared to chemotherapy alone, angiogenesis inhibitors did not significantly improve OS (HR 0.95; 95% CI 0.89-1.02; P = 0.171) (Figure 6).

Figure 6

Subtype

This study investigated two breast cancer subtypes. The analysis showed that the addition of angiogenesis inhibitors significantly prolonged PFS in both TNBC and HR(+) breast cancer patients (TNBC: HR = 0.63, (Figure 7). HR(+) breast cancer: HR = 0.75) (Figure 8).

Figure 7

Figure 8

This study analyzed two types of angiogenesis inhibitors. The results showed that for TKIs, the CBR OR = 1.82 (Figure 9A). for mAb, the CBR OR = 2.03 (Figure 9B).

Figure 9

This study analyzed two types of angiogenesis inhibitors. The results showed that for TKIs, the DCR OR = 1.25. (Figure 10A) for mAb, the DCR OR = 2.17 (Figure 10B).

Figure 10

This study analyzed two types of angiogenesis inhibitors. The results showed that for TKIs, the ORR OR = 1.49 (Figure 11A) for mAb, the ORR OR = 1.88 (Figure 11B).

Figure 11

This study analyzed two types of angiogenesis inhibitors. The results showed that for TKIs, the PFS HR = 0.81 (Figure 12A) for mAbs, the PFS HR = 0.72 (Figure 12B).

Figure 12

The results showed that for TKIs, the OS HR = 1.05. (Figure 13A). for mAbs, the OS HR = 0.91 (Figure 13B).

Figure 13

The results showed that in TNBC, the PFS HR for TKIs was 0.75 (Figure 14A) and the PFS HR for mAbs was 0.59 (Figure 14B).

Figure 14

The results showed that in HR(+) breast cancer, the PFS HR for TKIs was 0.67 (Figure 15A) and the PFS HR for mAbs was 0.76 (Figure 15B).

Figure 15

Subgroup analysis

Bone metastasis status

Three studies were included in the subgroup of patients without bone metastasis, and four studies were included in the subgroup with bone metastasis. The results demonstrated that angiogenesis inhibitors significantly improved PFS regardless of bone metastasis status (bone metastasis group: HR 0.64. (Figure 16A). Bnon-bone metastasis group: HR 0.56. (Figure 16B), with potentially greater benefit observed in patients without bone metastasis.

Figure 16

Visceral metastasis status

Eight studies were included in the subgroup of patients with visceral metastasis, and eight studies were included in the subgroup without visceral metastasis. Subgroup analysis revealed that angiogenesis inhibitors significantly improved PFS in both patients without visceral metastasis (HR 0.69) (Figure 17A) and those with visceral metastasis (HR 0.70), (Figure 17B) with highly consistent risk reduction magnitudes (approximately 30%). This indicates that visceral metastasis status does not affect the intrinsic antitumor activity of this treatment regimen.

Figure 17

No. of metastasis sites

Seven studies were included in the subgroup of patients with ≤3 metastatic sites, and seven studies were included in the subgroup with >3 metastatic sites. Subgroup analysis demonstrated that angiogenesis inhibitors significantly improved PFS regardless of the number of metastatic sites (≤3 vs >3: HR 0.68 vs 0.65), (Figure 18). with highly consistent risk reduction (approximately 35%). These findings indicate that this treatment regimen remains equally effective in patients with high tumor burden, demonstrating universal efficacy independent of metastatic site number.

Figure 18

Safety outcome

We analyzed the safety of angiogenesis inhibitors combined with chemotherapy versus chemotherapy alone in patients with advanced or recurrent breast cancer. Overall, the incidence of adverse events (AEs) in the angiogenesis inhibitor combination group was 1.47 times higher than in the chemotherapy-alone group (OR = 1.47). (Supplementary Figure 3). The incidence rates of most other selected AEs showed no significant differences between the two groups. However, we found that the following AEs occurred at significantly higher rates in the angiogenesis inhibitor combination group: anorexia (OR = 1.82), (Supplementary Figure 4). diarrhea (OR = 1.97), (Supplementary Figure 5) hand-foot syndrome (OR = 2.14), (Supplementary Figure 6) headache (OR = 2.11), (Supplementary Figure 7) hypertension (OR = 4.59), (Supplementary Figure 8). neutropenia (OR = 1.64), (Supplementary Figure 9). proteinuria (OR = 2.38), (Supplementary Figure 10) and thrombocytopenia (OR = 4.54) (Supplementary Figure 11).

Discussion

This study synthesizes the latest evidence from 29 RCTs to systematically evaluate the efficacy and safety of combining angiogenesis inhibitors with chemotherapy in advanced breast cancer. Our analysis not only confirms the definitive value of this combination strategy in enhancing tumor control metrics but also, through in-depth subgroup analyses, reveals underlying patterns of efficacy variation. Furthermore, it provides a critical foundation for informing personalized clinical treatment decisions.

The most pivotal finding of this meta-analysis is that angiogenesis inhibitors, when combined with chemotherapy, can improve disease control in patients with advanced breast cancer across multiple dimensions—significantly enhancing the CBR, DCR, ORR, and prolonging PFS. This outcome robustly supports the clinical translational value of the “vascular normalization” theory: appropriate vascular-targeted therapy can modify the tumor microenvironment and enhance the delivery efficiency of chemotherapeutic agents (48), thereby generating synergistic anti-tumor effects (12). Notably, in the most aggressive TNBC subtype, we observed the most pronounced PFS benefit. This is closely associated with the typically hyperactive angiogenic phenotype of this subtype (49, 50). Although OS did not demonstrate a significant extension, in the current era of multi-line sequential therapy, the significant prolongation of PFS itself holds substantial clinical significance—it provides patients with the opportunity to receive subsequent novel treatments and maintains a better quality of life during this period.

Our subgroup analyses revealed efficacy differences among patients with varying metastatic characteristics, a finding of profound biological implication and clinical guidance value. Subgroup analyses were conducted for two breast cancer subtypes: TNBC and HR(+)/HER2(-) breast cancer. These subtypes were selected because they represent the majority of HER2(-) breast cancer cases, have distinct biological features, and had sufficient patient numbers across the included trials for meaningful subgroup comparisons. HER2(+) breast cancer was excluded due to the confounding effect of concurrent anti-HER2 therapy. First, the phenomenon that patients without bone metastases derived more significant benefit likely reflects two distinct tumor microenvironment types: the unique osteoblast-osteoclast interactions within bone metastasis niches may create a distinctive immunosuppressive and pro-angiogenic ecological niche through the secretion of cytokines such as IL-6 and TGF-β, thereby attenuating the effect of exogenous vascular-targeted agents (51) (52).Second, the finding that visceral metastasis status and the number of metastatic sites had minimal impact on anti-tumor activity is particularly crucial. It suggests that the mechanism of action of angiogenesis inhibitors is broad-spectrum, with its efficacy not constrained by tumor burden size. This provides clinicians with significant confidence—even patients with extensive metastases may still derive substantial benefit from combination therapy, provided their biological characteristics align (e.g., absence of bone metastases). Finally, we identified significant efficacy heterogeneity across different drug classes and breast cancer subtypes. In the overall population, mAb (e.g., bevacizumab) demonstrated more robust benefits in both PFS and OS compared to small-molecule TKIs (PFS HR 0.72 vs. 0.81; OS HR 0.91 vs. 1.05). This difference was particularly pronounced in advanced TNBC, where the efficacy advantage of mAb was evident (HR 0.59 vs. 0.75). Conversely, in HR(+) breast cancer, TKIs showed a superior point estimate of efficacy (HR 0.67 vs. 0.76), suggesting they may more effectively inhibit bypass signaling pathways associated with endocrine resistance in this subtype. The results above strongly indicate that angiogenesis inhibitors are not a homogeneous therapeutic option. Clinical decision-making should be differentiated based on molecular subtype and drug class: mAb should be prioritized in TNBC, while TKIs may represent a potential optimized choice for specific subgroups within HR(+) breast cancer.

Potential pro-metastatic effects of angiogenesis inhibitors have been described in preclinical and clinical studies. Mechanistically, anti-angiogenic therapy-induced hypoxia can stabilize HIF-1α and HIF-2α (53), leading to upregulation of EMT-related genes (e.g., Snail, Twist, MMPs) and enhanced tumor cell invasion and intravasation. Additionally, chronic VEGF blockade may select more aggressive tumor clones that utilize alternative pro angiogenic pathways associated with aggressive phenotypes (54). Clinically, while some trials have reported improved PFS with angiogenesis inhibitors, the absence of OS benefit and potential early increases in distant metastases in certain subgroups warrant cautious interpretation. These findings highlight the need for careful patient selection, optimized dosing schedules, and combination strategies to mitigate potential pro-metastatic risks.

This study systematically delineated the specific toxicity profile of angiogenesis inhibitors. AEs associated with VEGF pathway inhibition, such as hypertension and proteinuria, along with chemotherapy-overlapping toxicities like myelosuppression and gastrointestinal reactions, necessitate the establishment of a comprehensive clinical framework for proactive monitoring and graded management. Based on our analysis, we propose the following structured recommendations for clinical practice: 1) Pre-Treatment Baseline Assessment: A thorough evaluation prior to initiation of therapy is mandatory. This assessment must include a detailed evaluation of cardiovascular risk factors, baseline renal function, and screening for pre-existing proteinuria. 2) Intensified Monitoring During Initial Treatment: Vigilant monitoring is crucial, particularly during the first two treatment cycles. Blood pressure should be monitored closely, and prophylactic or early intervention with antihypertensive agents should be implemented based on established guidelines to prevent severe hypertension. 3) Dynamic Monitoring Protocol for Proteinuria: A protocol for the dynamic monitoring of urine protein levels should be established. Timely intervention, which may include dose modification or temporary suspension of the angiogenesis inhibitor, is required for persistent or Grade 2 (or higher) proteinuria according to Common Terminology Criteria for AEs (CTCAE) grading (55). Furthermore, special attention must be paid to toxicities that profoundly impact quality of life and treatment adherence, such as hand-foot syndrome (palmar-plantar erythrodysesthesia) and diarrhea. Proactive patient education regarding these potential AEs and the pre-emptive formulation of supportive care plans for symptom management are essential components of patient care. In conclusion, the meticulous optimization of these toxicity management strategies is not merely supportive but a critical determinant of therapeutic success. It ensures that patients can tolerate and sustainably receive the full intended course of effective combination therapy, thereby creating the necessary conditions to ultimately translate treatment efficacy into maximized clinical benefit.

This study has several limitations. First, although we attempted to conduct subgroup analyses on key factors such as chemotherapy regimens and lines of therapy, no statistically significant subgroup analysis results were ultimately obtained due to excessive heterogeneity among studies and the presence of other confounding factors. Second, the majority of included studies lacked detailed biomarker information, which limited our ability to identify the specific patient subgroups most likely to derive maximum benefit from the treatment. Third, a limited number of studies (8/29) reported CBR data. This is largely because CBR is not a mandatory endpoint in most angiogenesis inhibitor trials, and definitions of CBR varied across studies, particularly regarding the minimum duration of stable disease. Additionally, many trials prioritized ORR and PFS as primary or secondary endpoints without systematically collecting or reporting the data necessary for CBR calculation. Based on these findings, future research should focus on the following directions: 1) Develop Predictive Biomarkers: Efforts should be concentrated on biomarker research based on circulating tumor DNA (ctDNA), dynamic angiogenic factor profiles, or radiomic features, aiming to construct precise patient selection models for treatment individualization. 2) Design randomized trials comparing different categories of angiogenesis inhibitors (such as mAb and TKIs) to clarify their optimal respective application scenarios. 3) Explore Novel Combination Therapeutic Strategies: It is worthwhile to investigate triple-combination regimens involving angiogenesis inhibitors, immune checkpoint inhibitors, and chemotherapy. This strategy aims to achieve a breakthrough in synergistic antitumor effects by simultaneously modulating both the vascular and immune tumor microenvironments.

Conclusion

This meta-analysis based on 29 RCTs demonstrated that the combination of angiogenesis inhibitors and chemotherapy could improve the CBR, DCR, ORR, and PFS in patients with advanced breast cancer. Particularly in advanced TNBC, the PFS benefit was more pronounced, although OS was not prolonged. Further analysis revealed that compared to chemotherapy alone, patients without bone metastases derived significantly greater benefit from angiogenesis inhibitor combination therapy. Visceral metastasis status and the number of metastatic sites had minimal impact on antitumor activity. Monoclonal antibodies should be prioritized for use in TNBC, whereas TKIs may represent a potential optimized choice for specific subgroups with HR(+) breast cancer. Additionally, closer monitoring of adverse reactions in patients receiving angiogenesis inhibitors is warranted, including anorexia, diarrhea, hand-foot syndrome, headache, hypertension, neutropenia, proteinuria, and thrombocytopenia.

References

• 1

  KimJHarperAMcCormackVSungHHoussamiNMorganE. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med. (2025) 31:1154–62. doi: 10.1038/s41591-025-03502-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 2

  RiveraEGomezH. Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone. Breast Cancer Res. (2010) 12 Suppl 2:S2. doi: 10.1186/bcr2573

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 3

  HuangSXuZ. Indole hybrids: emerging therapeutic candidates for breast cancer (2023-2025). Eur J Med Chem. (2026) 303:118449. doi: 10.1016/j.ejmech.2025.118449

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 4

  MonteranLErshaidNDoronHZaitYScharffYBen-YosefS. Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer. Nat Commun. (2022) 13:5797. doi: 10.1038/s41467-022-33598-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 5

  WangDHLiuXZHongWMXiaoTZXuYDFangX. Muscone abrogates breast cancer progression through tumor angiogenic suppression via VEGF/PI3K/Akt/MAPK signaling pathways. Cancer Cell Int. (2024) 24:214. doi: 10.1186/s12935-024-03401-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 6

  ZhangZGYangCHLiLZhuYSuKZhaiLY. γδT Cell-IL17A-Neutrophil" axis drives immunosuppression and confers breast cancer resistance to high-dose anti-VEGFR2 therapy. Front Immunol. (2021) 12:699478. doi: 10.2139/ssrn.3829636

  • CrossRef
  • Google Scholar
  • View reference in article

• 7

  TaoYXCuiWLSongWYXuHTZengJLiHX. Major adverse cardiovascular events in angiogenesis inhibitor-based cancer therapy: a systematic review and meta-analysis. J Am Heart Assoc. (2025) 14:e042896. doi: 10.1161/jaha.125.042896

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 8

  MouJCLiCHZhengQHMengXMTangHC. Research progress in tumor angiogenesis and drug resistance in breast cancer. Cancer Biol Med. (2024) 21:571–85. doi: 10.20892/j.issn.2095-3941.2023.0515

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 9

  YangFLeeGFanY. Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism. Angiogenesis. (2024) 27:333–49. doi: 10.1007/s10456-024-09913-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 10

  ShamshiripourPRahnamaMNikoobakhtMFarzam RadVMoradiARAhmadvandD. Extracellular vesicles derived from dendritic cells loaded with VEGF-A siRNA and doxorubicin reduce glioma angiogenesis in vitro. J Control Release. (2024) 369:128–45. doi: 10.1016/j.jconrel.2024.03.042

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 11

  ShashniBNishikawaYNagasakiY. Management of tumor growth and angiogenesis in triple-negative breast cancer by using redox nanoparticles. Biomaterials. (2021) 269:120645. doi: 10.1016/j.biomaterials.2020.120645

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 12

  QiZWYangQFWangYJSongYZDengYH. Vicious-cycle-breaking antiangiogenic nano-delivery systems potentiate and simplify the tumor vascular normalization strategy. Int J Pharm. (2025) 681:125788. doi: 10.1016/j.ijpharm.2025.125788

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 13

  LiZBWangZJYangWLLiYYLiYCXuEP. Chaihu Longgu Muli Decoction attenuates chronic stress-induced endothelial dysfunction and potentiates chemotherapy in breast cancer by inhibiting cAMP/PKA/CREB1 mediated glycolysis. J Ethnopharmacol. (2026) 355:120670. doi: 10.1016/j.jep.2025.120670

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 14

  LiuZJZhaoQZhengZZLiuSYMengLBDongLH. Vascular normalization in immunotherapy: a promising mechanisms combined with radiotherapy. BioMed Pharmacother. (2021) 139:111607. doi: 10.1016/j.biopha.2021.111607

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 15

  RubinLTalmonARibakYLavieDNechushtanHCaplanN. Therapeutic potential of HDAC inhibitors in a xenograft model of cancers: a special focus on breast cancer. Biochem Pharmacol. (2025) 240:117101. doi: 10.1016/j.bcp.2025.117101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 16

  RubinLTalmonARibakYLavieDNechushtanHCaplanN. Targeted inhibition of the IL5 axis for immune checkpoint inhibitors eosinophilic-induced adverse events. J Immunother Cancer. (2024) 12(10):e009658. doi: 10.1136/jitc-2024-009658

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 17

  PeixFCasanovasO. Promalignant effects of antiangiogenics in the tumor microenvironment. Semin Cancer Biol. (2022) 86:199–206. doi: 10.1016/j.semcancer.2022.03.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 18

  LiHPLiuJQOuyangQCWangSSLiuYXTengYE. Fuzuloparib with or without apatinib in patients with HER2-negative metastatic breast cancer with germline BRCA1/2 mutations (FABULOUS): interim analysis of a multicentre, three-arm, open-label, randomised, phase 3 trial. Lancet Oncol. (2025) 26:1563–74. doi: 10.1016/s1470-2045(25)00523-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 19

  MillerKWangMGralowJDicklerMCobleighMPerezEA. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. (2007) 357:2666–76. doi: 10.1056/nejmoa072113

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 20

  MayerELTayobNRenSSavoieJJSpigelDRBurrisHA. A randomized phase II study of metronomic cyclophosphamide and methotrexate (CM) with or without bevacizumab in patients with advanced breast cancer. Breast Cancer Res Treat. (2024) 204:123–32. doi: 10.1007/s10549-023-07167-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 21

  VaklavasCRobertsBSVarleyKELinNULiuMCRugoHS. TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer. Breast Cancer Res. (2020) 22:22. doi: 10.1186/s13058-020-01258-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 22

  MartinMRocheHPinterTCrownJKennedyMJProvencherL. Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol. (2011) 12:369–76. doi: 10.1016/s1470-2045(11)70037-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 23

  GianniLRomieuGHLichinitserMSerranoVSMansuttiMPivotX. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. (2013) 31:1719–25. doi: 10.1200/jco.2012.44.7912

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 24

  MillerKDO'NeillAGradisharWJHobdayTJGoldsteinLJMayerIA. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. (2018) 36:2621–9. doi: 10.1200/jco.2018.79.2028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 25

  CrownJPDiérasVStaroslawskaEYardleyDABachelotTDavidsonN. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol. (2013) 31:2870–8. doi: 10.1200/jco.2012.43.3391

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 26

  GradisharWJKaklamaniVSahooTPLokanathaDRainaVBondardeS. A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer. (2013) 49:312–22. doi: 10.1016/j.ejca.2012.08.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 27

  DiérasVWildiersHJassemJDirixLYGuastallaJPBonoP. Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: a phase 2 randomized study. Breast. (2015) 24:182–90. doi: 10.1016/j.breast.2014.11.003

  • CrossRef
  • Google Scholar
  • View reference in article

• 28

  Mezzanotte-SharpeJONeillAMayerIAArteagaCLYangXJWagnerLI. A randomized phase III double-blind placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105). Breast Cancer Res Treat. (2024) 207:275–82. doi: 10.1007/s10549-024-07417-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 29

  MartínMLoiblSvon MinckwitzGMoralesSMartinezNGuerreroA. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study. J Clin Oncol. (2015) 33:1045–52. doi: 10.1200/JCO.2014.57.2388

  • CrossRef
  • Google Scholar
  • View reference in article

• 30

  DicklerMNBarryWTCirrincioneCTEllisMJMoynahanMEInnocentiF. Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance). J Clin Oncol. (2016) 34:2602–9. doi: 10.1200/jco.2015.66.1595

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 31

  RugoHSBarryWTMoreno-AspitiaALyssAPCirrincioneCLeungE. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. (2015) 33:2361–9. doi: 10.1200/jco.2014.59.5298

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 32

  DiérasVCamponeMYardleyDARomieuGValeroVIsakoffSJ. Randomized, phase II, placebo-controlled trial of onartuzumab and/or bevacizumab in combination with weekly paclitaxel in patients with metastatic triple-negative breast cancer. Ann Oncol. (2015) 26:1904–10. doi: 10.1093/annonc/mdv263

  • CrossRef
  • Google Scholar
  • View reference in article

• 33

  BaselgaJZamagniCGómezPBermejoBNagaiSEMelicharB. RESILIENCE: phase III randomized, double-blind trial comparing sorafenib with capecitabine versus placebo with capecitabine in locally advanced or metastatic HER2-negative breast cancer. Clin Breast Cancer. (2017) 17:585–594.e4. doi: 10.1016/j.clbc.2017.05.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 34

  von MinckwitzGPuglisiFCortesJVrdoljakEMarschnerNZielinskiC. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. (2014) 15:1269–78. doi: 10.1016/s1470-2045(14)70439-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 35

  DeckerTOverkampFRöselSNuschAGöhlerTIndorfM. A randomized phase II study of paclitaxel alone versus paclitaxel plus sorafenib in second- and third-line treatment of patients with HER2-negative metastatic breast cancer (PASO). BMC Cancer. (2017) 17:499. doi: 10.1186/s12885-017-3492-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 36

  YardleyDAReevesJDeesECOsborneCPaulDAdemuyiwaF. Ramucirumab with eribulin versus eribulin in locally recurrent or metastatic breast cancer previously treated with anthracycline and taxane therapy: a multicenter, randomized, phase II study. Clin Breast Cancer. (2016) 16:471–479.e1. doi: 10.1016/j.clbc.2016.07.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 37

  MilesDCameronDBondarenkoIManzyukLAlcedoJCLopezRI. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): a double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. (2017) 70:146–55. doi: 10.1016/j.ejca.2016.09.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 38

  van RossumAGJMandjesIAMvan WerkhovenEvan TinterenHvan Leeuwen-StokAENederlofP. Carboplatin-cyclophosphamide or paclitaxel without or with bevacizumab as first-line treatment for metastatic triple-negative breast cancer (BOOG 2013-01). Breast Care (Basel). (2021) 16:598–606. doi: 10.1159/000512200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 39

  LiDDTaoZHWangBYWangLPCaoJHuXC. Apatinib plus vinorelbine versus vinorelbine for metastatic triple-negative breast cancer who failed first/second-line treatment: the NAN trial. NPJ Breast Cancer. (2022) 8:110. doi: 10.1038/s41523-022-00462-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 40

  FanLWangZHMaLXWuSYWuJYuKD. Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial. Lancet Oncol. (2024) 25:184–97. doi: 10.1016/s1470-2045(23)00579-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 41

  LiuBLiuLRanJXieNLiJXiaoH. A randomized trial of eribulin monotherapy versus eribulin plus anlotinib in patients with locally recurrent or metastatic breast cancer. ESMO Open. (2023) 8:101563. doi: 10.1016/j.esmoop.2023.101563

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 42

  MillerKDChapLIHolmesFACobleighMAMarcomPKFehrenbacherL. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. (2005) 23:792–9. doi: 10.1200/jco.2005.05.098

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 43

  MilesDWChanADirixLYCortesJPivotXTomczakP. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. (2010) 28:3239–47. doi: 10.1200/jco.2008.21.6457

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 44

  RobertNJDiérasVGlaspyJBrufskyAMBondarenkoILipatovON. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. (2011) 29:1252–60. doi: 10.1200/jco.2010.28.0982

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 45

  BerghJBondarenkoIMLichinitserMRLiljegrenAGreilRVoytkoNV. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol. (2012) 30:921–9. doi: 10.1200/jco.2011.35.7376

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 46

  BaselgaJMartins SegallaJGRochéHDel GiglioAPinczowskiHCiruelosEM. Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol. (2012) 30:1484–91. doi: 10.1200/jco.2011.36.7771

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 47

  MavratzasABaekSGerberBSchmidtMMoebusVFoersterF. Sorafenib in combination with docetaxel as first-line therapy for HER2-negative metastatic breast cancer: final results of the randomized, double-blind, placebo-controlled phase II MADONNA study. Breast. (2019) 45:22–8. doi: 10.1016/j.breast.2019.02.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 48

  BinnewiesMRobertsEWKerstenKChanVFearonDFMeradM. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. (2018) 24:541–50. doi: 10.1038/s41591-018-0014-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 49

  ZhangLLYangLGeYZhuZWChenBYangCQ. Neoadjuvant anlotinib/sintilimab plus chemotherapy in triple-negative breast cancer (NeoSACT): phase 2 trial. Cell Rep Med. (2025) 6:102193. doi: 10.1016/j.xcrm.2025.102193

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 50

  WuSQTangQFangWFSunZZhangMLiuEG. Targeting stem-property and vasculogenic mimicry for sensitizing paclitaxel therapy of triple-negative breast cancer by biomimetic codelivery. Acta Pharm Sin B. (2025) 15:3226–42. doi: 10.1016/j.apsb.2025.04.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  VasiyaniHManeMRanaKShindeARoyMSinghJ. DNA damage induces STING mediated IL-6-STAT3 survival pathway in triple-negative breast cancer cells and decreased survival of breast cancer patients. Apoptosis. (2022) 27:961–78. doi: 10.1007/s10495-022-01763-8

  • CrossRef
  • Google Scholar

• 52

  WeilbaecherKNGuiseTAMcCauleyLK. Cancer to bone: a fatal attraction. Nat Rev Cancer. (2011) 11:411–25. doi: 10.1038/nrc3055

  • CrossRef
  • Google Scholar

• 53

  WicksEESemenzaGL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest. (2022) 132(11):e159839. doi: 10.1172/JCI159839

  • CrossRef
  • Google Scholar

• 54

  WeiPLiJQChengXYLuYXXiaQWangZY. Brake" and "accelerator": revisiting tumor cell direct responses and the paradox of aggression in anti-VEGF therapy. Front Immunol. (2025) 16:1718894. doi: 10.3389/fimmu.2025.1718894

  • CrossRef
  • Google Scholar

• 55

  PandeySKashfiSHongSKalariaAKimAS. Onco-hypertension in patients with kidney disease. Am J Nephrol. (2024) 57(2):235–248. doi: 10.1159/000538375

  • CrossRef
  • Google Scholar