Rare among male cancers, male breast cancer (MBC) accounts for less than one percent of all male tumors. The prevalence of this illness and female breast cancer (FBC) have both been on the rise in recent years. While reports have implicated hormonal, environmental, and genetic variables in the development of MBC, nothing is known about its aetiology. Radiation exposure, hormonal imbalances caused by other medical conditions, and, most significantly, a positive family history of breast cancer-which indicates a hereditary predisposition-are major risk factors. While low-penetrance gene mutations (such as CHEK-2) are more prevalent, they do not enhance the risk of breast cancer development to the same extent as rare mutations in high-penetrance genes (such as BRCA1 and BRCA2). Speculated risk factors, including BRCA2 and lifestyle changes in the last few decades, are considered in light of the reasons for the rising occurrence. Topics covered include aromatase inhibitors, fulvestrant, and the prolactin and androgen receptor targeting pathways, as well as the therapeutic therapy of male breast cancer. Invasive ductal carcinomas, which account for about 90% of breast cancers in men, express many hormone receptors and show clear signs of treatment benefit. No single therapy method has been supported by published evidence from prospective randomized trials in MBC to yet. The treatment decision should be guided by the primary prognostic markers, which include tumor size and the number of axillary nodes involved. Detailed descriptions of the clinicopathologic characteristics of MBC are included in the present review. Our focus is on molecular profiling of MBC as a means to discover potential biomarkers and potential pharmacologic intervention targets. Endocrine treatment, which includes tamoxifen, aromatase inhibitors, and GnRH analogues, as well as cytotoxic chemotherapy, are characterized in light of the existing research. We also outline the possible function of targeted medications such as HER2-directed treatments, PARP inhibitors, and angiogenesis inhibitors.

This study aims to assess the therapeutic efficacy and safety of nivolumab combined with chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, specifically comparing the outcomes of oxaliplatin-based versus albumin-bound paclitaxel (nab-paclitaxel)-based therapies.

We retrospectively analyzed 93 patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma treated at the First Medical Center of Chinese PLA General Hospital from September 2017 to November 2022. Patients were categorized into the nivolumab + oxaliplatin (N-OX group) or nivolumab + nab-paclitaxel (N-AP group) based on the chemotherapy regimen. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated as endpoints.

At the end of the follow-up period on September 31, 2023, we reported an ORR of 65.6% and DCR of 95.7% across all patients. The median PFS was 8.4 months, with no significant difference between the N-OX and N-AP groups (median, 7.8 vs 9.5 months; P = 0.450). Notably, patients with diffuse gastric cancer in N-AP group showed a 44.7% reduction in tumor progression risk compared with the N-OX group (P = 0.046). The overall safety profile was acceptable in two groups.

Our study suggested that nivolumab combined with chemotherapy was effective and safe as a first-line intervention for advanced gastric cancer. While both oxaliplatin and nab-paclitaxel regimens showed similar efficacy, the nab-paclitaxel may offer additional benefits for patients with diffuse gastric cancer. Further research is encouraged to confirm these findings and refine treatment strategies.

Optimal first-line therapy for metastatic triple-negative breast cancer (mTNBC) varied in different situations. This phase II trial explores the efficacy and safety of combination regimens with bevacizumab, tislelizumab and nab-paclitaxel (BETINA) in first-line setting for mTNBC.

Patients with previously untreated advanced TNBC received tislelizumab 200 mg and bevacizumab on day 1 and nab-paclitaxel 125 mg/m2 on day 1, day 8 in 3-week cycles. Patients were randomized to bevacizumab 7.5 mg/kg or 15 mg/kg. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The trial was registered at the Chinese Clinical Trial Registry (No. ChiCTR2200058567).

30 female patients were enrolled from March 11, 2021 to February 5, 2024. Nine patients receiving bevacizumab 15 mg/kg experienced significantly higher hypertension rates versus 7.5 mg/kg (55.5% vs 0%), prompting subsequent enrollment of 12 additional patients at 7.5 mg/kg. By November 30, 2024, the ORR was 73.3% and the disease control rate was 90.0%, while the median PFS was 6.0 months and the median OS was 19.8 months. No new safety signal was reported. Common treatment-related adverse events (AEs) included peripheral sensory neuropathy (83.3%), dyspepsia (70.0%), anemia (70.0%), leukocytopenia (66.7%), and pruritus (53.3%). Hypothyroidism (30.0%) was the most frequent immune-related AE. Biomarker analysis indicated that lower baseline interleukin (IL)-1α was associated with poor survival, while IL-2, vascular endothelial growth factor-A and insulin-like growth factor binding protein-7 levels significantly decreased at progression. RNA sequencing highlighted the enrichment of the fatty acid metabolism pathway in poor responders.

BETINA study demonstrated promising efficacy and favorable tolerance in treating patients with mTNBC with bevacizumab with tislelizumab and nab-paclitaxel.

Breast cancer (BC) is one of the leading causes of cancer-related deaths among women worldwide. Paclitaxel (PTX), a chemotherapeutic agent derived from the taxane family, is commonly used in treating BC due to its ability to disrupt microtubule dynamics and induce cell death. However, resistance to PTX presents a significant challenge, as it diminishes the drug's effectiveness and can lead to treatment failure. This review explores the mechanisms by which PTX exerts its effects and the various factors contributing to resistance. These factors include genetic mutations that affect tubulin dynamics, the role of non-coding RNAs, molecular pathways involved in chemoresistance, epigenetic changes, post-transcriptional modifications, increased activity of ABC transporters that promote drug efflux, immunosuppressive interactions within the tumor microenvironment, and resistance mediated by autophagy. This review also explores strategies to overcome PTX resistance, including molecular and genetic innovations, combination therapies, and nanotechnology-based approaches. These strategies may improve PTX efficacy and enhance treatment outcomes for BC patients.

The "angiogenesis switch"-defined as the active process by which solid tumors develop their own circulation-plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the "angiogenic switch" acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents.

Breast cancer (BC) is the most common malignant tumor in women and the leading cause of cancer-related deaths in women. As one of the most common subtypes of breast cancer, patients with hormone receptor-positive (HR+) breast cancer usually experience disease progression over an extended period of time, triggering the search for therapeutic strategies other than endocrine therapy. In recent years, continuous research on various targets has led to dramatic changes in the treatment of hormone receptor-positive breast cancer patients, resulting in prolonged clinical survival. With the redefinition of human epidermal growth factor-2 (HER2) expression, more precise and individualized treatment is possible. This review comprehensively reviews targeted therapies and critical clinical trials for HR+ breast cancer and tracks the latest advances. It also provides valuable insights into the future direction of targeted therapies.

Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.

In clinical use, bevacizumab has improved the overall survival (OS) and progression-free survival (PFS) of malignant solid tumors, and the safe use of bevacizumab has gradually become the mainstream direction of clinical, nursing and pharmaceutical research. Bevacizumab is a humanized anti-VEGF drug. By binding to VEGF, it loses the opportunity to activate VEGFR and then plays an anti-angiogenic role. In addition, more and more studies have emphasized the efficacy and safety of bevacizumab in the treatment of brain metastases from solid tumors. Bevacizumab has its advantages in terms of crossing the blood-brain barrier, increasing radiosensitivity, and reducing radiation-induced brain edema. However, VEGF can maintain the normal function of vascular endothelial cells. Blocking the VEGF pathway can lead to endothelial dysfunction, and the anti-VEGF mechanism of bevacizumab will inevitably lead to a series of thrombotic events and bleeding events. This study reported six cases of cerebrovascular accidents, including ischemic stroke and cerebral hemorrhage, after bevacizumab use. At the same time, this study reviewed the related studies of cardiovascular and cerebrovascular accidents caused by bevacizumab, and analyzed the management of such bevacizumab-related adverse events. We put forward our own views on the early identification and long-term management of adverse events, as well as the subsequent reuse of bevacizumab, hoping to provide more basis for the management of clinical bevacizumab application.

Syringaresinol, a phytochemical constituent belonging to lignan, is formed from two sinapyl alcohol units linked via a β-β linkage, which can be found in a wide variety of cereals and medicinal plants. Medical researches revealed that Syringaresinol possesses a broad spectrum of biological activities, including anti-inflammatory, anti-oxidation, anticancer, antibacterial, antiviral, neuroprotection, and vasodilation effects. These pharmacological properties lay the foundation for its use in treating various diseases such as inflammatory diseases, neurodegenerative disorders, diabetes and its complication, skin disorders, cancer, cardiovascular, and cerebrovascular diseases. As the demand for natural therapeutics increases, Syringaresinol has garnered significant attention for its pharmacological properties. Despite the extensive literature that highlights the various biological activities of this molecule, the underlying mechanisms and the interrelationships between these activities are rarely addressed from a comprehensive perspective. Moreover, no thorough comprehensive summary and evaluation of Syringaresinol has been conducted to offer recommendations for potential future clinical trials and therapeutic applications of this bioactive compound. Thus, a comprehensive review on Syringaresinol is essential to advance scientific understanding, assess its therapeutic applications, ensure safety, and guide future research efforts. This will ultimately contribute to its potential integration into clinical practice and public health. This study aims to provide a comprehensive overview of Syringaresinol on its sources and biological activities to provide insights into its therapeutic potential, and to provide a basis for high-quality studies to determine the clinical efficacy of this compound. Additionally, we explored the pharmacokinetics, toxicology, and drug development aspects of Syringaresinol to guide future research efforts. The review also discussed the limitations of current research on Syringaresinol and put forward some new perspectives and challenges, which laid a solid foundation for further study on clinical application and new drug development of Syringaresinol in the future.

Gastric-type endocervical adenocarcinoma (GEA) is a rare malignant tumor that is not associated with high-risk HPV infection, known for its high invasiveness and resistance to current treatments. This study assessed the effectiveness of anti-angiogenic regimens in real-world GEA patients.

Patients with GEA were enrolled between February 2012 and March 2023, and their clinicopathological characteristics were collected from their medical records. The patients were categorized into groups based on whether they received anti-angiogenic treatments or not. Survival analysis was conducted using the Kaplan-Meier method.

A total of 43 GEA patients were enrolled in this study, with 23 cases who received anti-angiogenic drugs (nine received them as the primary treatment, 12 as first-line therapy after recurrence/metastasis, and two as second-line therapy) as the observation group. The other 20 patients who received similar treatments without the anti-angiogenic regimens serve as the control group. Compared to the control group, the addition of anti-angiogenic drugs as the primary treatment mildly extended progression-free survival (PFS) while not being statistically significant (16 months vs 11 months, p = 0.744). The negative results were also observed in 12 patients who started anti-angiogenic therapy as first-line therapy after recurrence/metastasis (8.5 months vs 9 months, p = 0.518). As for the overall survival (OS), no benefits were detected in either patients who started the anti-angiogenic therapy as primary or subsequent treatments (p = 0.499 and 0.450, respectively).

We firstly evaluated the efficacy of anti-angiogenic drugs in treating patients with GEA. Although with a small sample size, our preliminary results clearly proposed that the anti-angiogenic therapy failed in suppressing tumors and should not be a preferred choice for GEA. As a much rarer tumor without standard treatments, we herein warned of a pitfall for gynecologic oncologists when facing this malignancy.

Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.

Nanomedicines offer high promise for the treatment of various diseases, and numerous novel approaches using nanomaterials have been developed over the years. In this report, we introduce a new strategy utilizing ZnO nanoparticles (nZnO) to trigger the rapid release of lipid-encapsulated therapeutics upon photo-irradiation with UV light (365 nm). In vitro studies demonstrate that encapsulation of nZnO effectively eliminates the cytotoxicity of nZnO, but this can be re-established upon release from the lipid coating. Using 5(6)-carboxyfluorescein as a model for hydrophilic drug loading, we show the ability to co-load drugs with nZnO into liposomes. Kinetic studies reveal the ability to release the majority of the dye within 60 minutes post-photo-irradiation and provide insights into factors that impact release kinetics. To further explore this, Jurkat T cell leukemia and T47D breast cancer cells were treated with co-encapsulated nZnO and the hydrophobic cancer drug paclitaxel. These studies revealed enhanced toxicity of the triggered release groups with an extreme difference noted in the viability profiles of the T47D breast cancer cell model. Taken together, these studies indicate that this system of co-encapsulating nZnO and chemotherapeutic drugs has the potential to minimize systemic toxicity, by controlling therapeutic release, while allowing for the localized selective destruction of cancer.

The complex signaling network within the breast tumor microenvironment is crucial for its growth, metastasis, angiogenesis, therapy escape, stem cell maintenance, and immunomodulation. An array of secretory factors and their receptors activate downstream signaling cascades regulating breast cancer progression and metastasis. Among various signaling pathways, the EGFR, ER, Notch, and Hedgehog signaling pathways have recently been identified as crucial in terms of breast cancer proliferation, survival, differentiation, maintenance of CSCs, and therapy failure. These receptors mediate various downstream signaling pathways such as MAPK, including MEK/ERK signaling pathways that promote common pro-oncogenic signaling, whereas dysregulation of PI3K/Akt, Wnt/β-catenin, and JAK/STAT activates key oncogenic events such as drug resistance, CSC enrichment, and metabolic reprogramming. Additionally, these cascades orchestrate an intricate interplay between stromal cells, immune cells, and tumor cells. Metabolic reprogramming and adaptations contribute to aggressive breast cancer and are unresponsive to therapy. Herein, recent insights into the novel signaling pathways operating within the breast TME that aid in their advancement are emphasized and current developments in practices targeting the breast TME to enhance treatment efficacy are reviewed.

Paclitaxel is a widely used anticancer drug for ovarian, lung, breast, and stomach cancers; however, its clinical use is often limited by the side effects of peripheral neuropathy. This study evaluated the effects of Cyperus rotundus (C. rotundus) extract and its active metabolite, α-cyperone, on paclitaxel-induced neuropathic pain.

The oral administration of C. rotundus extract at doses of 500 mg/kg and intraperitoneal administration of α-cyperone at doses of 480 and 800 μg/kg prevented both the development of cold and mechanical pain.

The gene and protein expressions of tyrosine hydroxylase and noradrenergic receptors (α1- and α2-adrenergic), which were upregulated by paclitaxel, were significantly downregulated in the C. rotundus extract-treated group. In the locus coeruleus region of the mouse brain, C. rotundus extract administration also reduced the elevated expression of tyrosine hydroxylase induced by paclitaxel. The concentration of α-cyperone in C. rotundus extract was quantified using high-performance liquid chromatography (HPLC). In the group treated with α-cyperone, at levels corresponding to its content in C. rotundus, both cold and mechanical allodynia were effectively prevented.

This study suggests that α-cyperone shows potential as a preventive agent for paclitaxel-induced neuropathic pain.

Breast cancer is the most frequently diagnosed neoplasm all over the world and the second leading cause of cancer death in women. Breast cancer prognosis has significantly improved in the last years due to the advent of novel therapeutic options, both in the early and in advanced stages. However, the spread of the disease to the brain, accounting for 15-30% of the metastatic diagnoses, is challenging, and its poor prognosis represents an unmet medical need, leading to deterioration of quality of life and causing morbidity and mortality. Generally, triple-negative and HER2-positive breast cancer subtypes more frequently spread to the brain or in the leptomeningeal space. Consequently, according to international guidelines, several systemic treatments can be offered as a first option in some subsets of patients. However, a multidisciplinary approach is recommended to offer the most appropriate strategy to patients. Antibody-drug conjugates such as trastuzumab deruxtecan or sacituzumab govitecan along with small molecules have led to important achievements in the treatment of brain metastases from HER2-positive and triple-negative breast cancer. In this narrative review, we will focus on the molecular features leading to the development of brain metastases and explore the risk and the prognostic factors involved in the development of brain metastases. Finally, we will review the major achievements in the treatment landscape of brain metastases from breast cancer and novel medical approaches.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with high aggressiveness and poor prognosis. For patients who have undergone multiple treatments, systemic drug therapy often presents challenges with limited efficacy and significant side effects. Radiotherapy, a pivotal local treatment, has shown substantial local control benefits in patients with inoperable locally advanced or metastatic disease. Clinical evidence suggests that integrating systemic therapy with locoregional radiotherapy can confer survival advantages in advanced malignancies. Within multidisciplinary treatment, the synergy between radiotherapy and systemic therapies shows promise for enhancing outcomes and extending survival. This review synthesizes recent advances in combining radiotherapy and systemic therapy in managing advanced TNBC, focusing on preclinical and clinical evidence regarding efficacy and safety. By reviewing these advancements, we aim to identify novel therapeutic strategies and integrate clinical evidence to inform best practices in TNBC management, ultimately improving patient outcomes.

Breast cancer is a challenging global health problem among women. This study investigates the intricate breast tumour microenvironment (TME) dynamics utilizing data from mammary-specific polyomavirus middle T antigen overexpression mouse models (MMTV-PyMT). It incorporates endothelial cells (ECs), oxygen and vascular endothelial growth factors (VEGF) to examine the interplay of angiogenesis, hypoxia, VEGF and immune cells in cancer progression. We introduce an approach to impute immune cell fractions within the TME using single-cell RNA-sequencing (scRNA-seq) data from MMTV-PyMT mice. We quantify our analysis by estimating cell counts using cell size data and laboratory findings from existing literature. We perform parameter estimation via a Hybrid Genetic Algorithm (HGA). Our simulations reveal various TME behaviours, emphasizing the critical role of adipocytes, angiogenesis, hypoxia and oxygen transport in driving immune responses and cancer progression. Global sensitivity analyses highlight potential therapeutic intervention points, such as VEGFs' role in EC growth and oxygen transportation and severe hypoxia's effect on cancer and the total number of cells. The VEGF-mediated production rate of ECs shows an essential time-dependent impact, highlighting the importance of early intervention in slowing cancer progression. These findings align with clinical observations demonstrating the VEGF inhibitors' efficacy and suggest a timely intervention for better outcomes.

Tumor immunotherapy has revolutionized cancer treatment, but limitations remain, including low response rates and immune complications. Extracellular vesicles (EVs) are emerging as a new class of therapeutic agents for various diseases. Recent research shows that changes in the amount and composition of EVs can reshape the tumor microenvironment (TME), potentially improving the effectiveness of immunotherapy. This exciting discovery has sparked clinical interest in using EVs to enhance the immune system's response to cancer. In this Review, we delve into the world of EVs, exploring their origins, how they're generated, and their complex interactions within the TME. We also discuss the crucial role EVs play in reshaping the TME during tumor development. Specifically, we examine how their cargo, including molecules like PD-1 and non-coding RNA, influences the behavior of key immune cells within the TME. Additionally, we explore the current applications of EVs in various cancer therapies, the latest advancements in engineering EVs for improved immunotherapy, and the challenges faced in translating this research into clinical practice. By gaining a deeper understanding of how EVs impact the TME, we can potentially uncover new therapeutic vulnerabilities and significantly enhance the effectiveness of existing cancer immunotherapies.

At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm3 in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.

Anlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC.

Locally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1.

A total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common.

Anlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted.

As angiogenesis was recognized as a core hallmark of cancer growth and survival, several strategies have been implemented to target the tumour vasculature. Yet to date, attempts have rarely been so diverse, ranging from vessel growth inhibition and destruction to vessel normalization, reprogramming and vessel growth promotion. Some of these strategies, combined with standard of care, have translated into improved cancer therapies, but their successes are constrained to certain cancer types. This Review provides an overview of these vascular targeting approaches and puts them into context based on our subsequent improved understanding of the tumour vasculature as an integral part of the tumour microenvironment with which it is functionally interlinked. This new knowledge has already led to dual targeting of the vascular and immune cell compartments and sets the scene for future investigations of possible alternative approaches that consider the vascular link with other tumour microenvironment components for improved cancer therapy.

Metastatic breast cancer is responsible for 90% of mortalities among women suffering from various types of breast cancers. Traditional cancer treatments such as chemotherapy and radiation therapy can cause significant side effects and may not be effective in many cases. However, recent advances in nanomedicine have shown great promise in the treatment of metastatic breast cancer. For example, nanomedicine demonstrated robust capacity in detection of metastatic cancers at early stages (i.e., before the metastatic cells leave the initial tumor site), which gives clinicians a timely option to change their treatment process (for example, instead of endocrine therapy they may use chemotherapy). Here recent advances in nanomedicine technology in the identification and treatment of metastatic breast cancers are reviewed.

Breast-cancer metastasis has seen an increased incidence in recent years, owing to advancements in surveillance, diagnostic imaging, histopathological assessment, and treatment modalities. Metastasis to various sites, including the bone, lung, liver, and brain, is common in cancer patients. Orbital metastasis (OM) from breast cancer can lead to a range of symptoms, such as pain, palpebral ptosis, diplopia, ocular pain, vision loss, and a recessed eyeball. To explore the topic of systemic malignancies metastasizing to the orbit, a search was conducted on the PubMed service using keywords such as "orbit," "orbital," "cancer," "malignancy," and "metastasis." This review article aims to summarize the findings from the identified literature. Overall, 103 patients with breast cancer from 77 articles were investigated. The patients' mean age ± standard deviation was 58.73 ± 11.86 years. Types of breast pathology observed in the evaluated patients included lobular (32.1%), ductal pathology (35.9%), and unspecified (32%). The most common symptom was vision change 37.9% and diplopia 26.2%. Despite the rarity of OM in breast cancer, it is crucial to consider this condition due to its potential to exacerbate the functional status of the neoplastic disease. The primary treatment approach for orbital metastasis involves radiation therapy, often combined with systemic chemotherapy, hormone therapy or targeted therapy. These interventions aim to minimize symptoms and control disease progression. It is encouraging that advancements in medication, along with timely diagnosis and treatment, have the potential to improve outcomes for patients with orbital metastasis. However, further research is necessary to comprehensively evaluate all aspects of breast cancer metastasis to rare organs. A deeper understanding of the underlying mechanisms and identification of potential therapeutic targets could enhance treatment strategies and ultimately improve patient prognosis.

The likelihood of survival for cancer patients has greatly improved due to chemotherapy medicines. However, these antitumor agents might also have unfavorable effects on the cardiovascular system, which could result in sudden or gradual cardiac failure. The production of free radicals that result in oxidative stress appears to be the key mechanism by which chemotherapy-induced cardiotoxicity (CIC) happens. Reports suggest that the Sirtuin-1 (Sirt1)/Nuclear factor E2-associated factor 2 (Nrf2) signaling pathway has been considered an alternative path for counteracting cardiotoxicity by suppressing oxidative stress, inflammation, and apoptosis. This review concludes recent knowledge about CIC with a special focus on the anti-oxidative regulation properties of the Sirt1/Nrf2 pathway.

For treating recurrent glioblastoma, for which there is no established treatment, the antiangiogenic antibody, bevacizumab, is used alone or with irinotecan. This study was aimed at comparing the survival of patients with recurrent glioblastoma receiving bevacizumab monotherapy and those receiving bevacizumab plus irinotecan combination therapy (B+I) by using a nationwide population-based dataset.

Patients matching the International Classification of Diseases code C71.x were screened from the Health Insurance Review and Assessment Service database. From January 2008 to November 2021, patients who underwent surgery or biopsy and subsequent standard concurrent chemoradiation with temozolomide were included. Among them, those who received bevacizumab monotherapy or B+I were selected. Demographic characteristics, inpatient stay, prescription frequency, survival outcomes, and steroid prescription duration were compared between these two groups.

Eight hundred and forty-six patients who underwent surgery or biopsy and received concurrent chemoradiotherapy with temozolomide were included. Of these, 450 and 396 received bevacizumab monotherapy and B+I, respectively. The corresponding median overall survival from the initial surgery was 22.60 months (95% confidence interval [CI], 20.50-24.21) and 20.44 months (95% CI, 18.55-22.60; P = 0.508, log-rank test). The B+I group had significantly more bevacizumab prescriptions (median 5 times; BEV group: median 3 times). Cox analysis, based on the postsurgery period, revealed that male sex (hazard ratio [HR], 1.28; P = 0.002), older age (HR, 1.01; P = 0.042), and undergoing biopsy instead of surgery (HR, 1.79; P < 0.0001) were significantly associated with decreased survival. Fewer radiotherapy cycles correlated with improved survival outcomes (HR, 0.63; P = 0.001). Cox analysis, conducted from the start of chemotherapy including bevacizumab, showed that male sex was the only variable significantly associated with decreased survival (HR, 1.18; P = 0.044).

We found no significant difference in overall survival between the bevacizumab monotherapy and B+I groups. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy could be a suitable treatment option for treating recurrent glioblastoma.

We developed an aptamer-based fluorescence resonance energy transfer (FRET) assay capable of recognizing therapeutic monoclonal antibody bevacizumab and rapidly quantifying its concentration with just one mixing step. In this assay, two fluorescent dyes (fluorescein and tetramethylrhodamine) labeled aptamers bind to two Fab regions on bevacizumab, and FRET fluorescence is observed when both dyes come into close proximity. We optimized this assay in three different formats, catering to a wide range of analytical needs. When applied to hybridoma culture samples in practical settings, this assay exhibited a signal response that was concentration-dependent, falling within the range of 50-2000 μg/mL. The coefficients of determination (r2) ranged from 0.998 to 0.999, and bias and precision results were within ±24.0 % and 20.3 %, respectively. Additionally, during thermal and UV stress testing, this assay demonstrated the ability to detect denatured samples in a manner comparable to conventional Size Exclusion Chromatography. Notably, it offers the added advantage of detecting decreases in binding activity without changes in molecular weight. In contrast to many existing process analytical technology tools, this assay not only identifies bevacizumab but also directly measures the quality attributes related to mAb efficacy, such as the binding activity. As a result, this assay holds great potential as a valuable platform for providing highly reliable quality attribute information in real-time. We consider this will make a significant contribution to the worldwide distribution of high-quality therapeutic mAbs in various aspects of antibody manufacturing, including production monitoring, quality control, commercial lot release, and stability testing.

Robust molecular subtyping of triple-negative breast cancer (TNBC) is a prerequisite for the success of precision medicine. Today, there is a clear consensus on three TNBC molecular subtypes: luminal androgen receptor (LAR), basal-like immune-activated (BLIA), and basal-like immune-suppressed (BLIS). However, the debate about the robustness of other subtypes is still open.

An unprecedented number (n = 1942) of TNBC patient data was collected. Microarray- and RNAseq-based cohorts were independently investigated. Unsupervised analyses were conducted using k-means consensus clustering. Clusters of patients were then functionally annotated using different approaches. Prediction of response to chemotherapy and targeted therapies, immune checkpoint blockade, and radiotherapy were also screened for each TNBC subtype.

Four TNBC subtypes were identified in the cohort: LAR (19.36%); mesenchymal stem-like (MSL/MES) (17.35%); BLIA (31.06%); and BLIS (32.23%). Regarding the MSL/MES subtype, we suggest renaming it to mesenchymal-like immune-altered (MLIA) to emphasize its specific histological background and nature of immune response. Treatment response prediction results show, among other things, that despite immune activation, immune checkpoint blockade is probably less or completely ineffective in MLIA, possibly caused by mesenchymal background and/or an enrichment in dysfunctional cytotoxic T lymphocytes. TNBC subtyping results were included in the bc-GenExMiner v5.0 webtool ( http://bcgenex.ico.unicancer.fr ).

The mesenchymal TNBC subtype is characterized by an exhausted and altered immune response, and resistance to immune checkpoint inhibitors. Consensus for molecular classification of TNBC subtyping and prediction of cancer treatment responses helps usher in the era of precision medicine for TNBC patients.

Therapeutics targeting tumor endothelial cells (TECs) have been explored for decades, with only suboptimal efficacy achieved, partly due to an insufficient understanding of the TEC heterogeneity across cancer patients. We integrated single-cell RNA-seq data of 575 cancer patients from 19 solid tumor types, comprehensively charting the TEC phenotypic diversities. Our analyses uncovered underappreciated compositional and functional heterogeneity in TECs from a pan-cancer perspective. Two subsets, CXCR4 + tip cells and SELE + veins, represented the prominent angiogenic and proinflammatory phenotypes of TECs, respectively. They exhibited distinct spatial organization patterns, and compared to adjacent non-tumor tissues, tumor tissue showed an increased prevalence of CXCR4 + tip cells, yet with SELE + veins depleted. Such functional and spatial characteristics underlie their differential associations with the response of anti-angiogenic therapies and immunotherapies. Our integrative resources and findings open new avenues to understand and clinically intervene in the tumor vasculature.

Claudin-low breast cancers (BCs) exhibit more aggressive behaviour compared to claudin-high types. Claudin-low BCs are often characterized by features such as a higher grade, enrichment of stemness characteristics, and a propensity for metastasis. Tumour microenvironment (TME) defined as the intricate network of surrounding cells, blood vessels, and extracellular matrix components influences the behaviour of cancer cells within the breast tissue. Understanding the TME is crucial for comprehending the aggressive characteristics of claudin-low BCs.

In this study, we have studied the morphology of immune and non-immune TME using Haematoxylin and eosin (H&E)-stained slides of 15 claudin-low and 12 claudin-high tissue samples of BC.

TME of claudin-low BCs was observed to have a significantly higher frequency of retraction clefts (66.6 %; n = 10/15), immature desmoplastic response (40 %; n = 6/15), higher stromal cellularity (60 %; n = 9/15); and fibroblastic proliferation (53.3 %; n = 8/15) with a low prevalence of elastosis (66.6 %; n = 10/15). The immune microenvironment revealed a higher frequency of total (80 %; n = 12/15) as well as stromal (86.67 %; n = 13/15) and intra-tumoural TILs (60 %; n = 9/15) in them.

The above morphology-based study revealed that claudin-low tumours have unique immune and non-immune TME as compared to claudin-high tumours. Future studies exploring the molecular correlates of each of the above morphological features can help in identifying novel therapeutic targets for the treatment of claudin-low BCs.

Drug resistance of malignant tumor leads to disease progression be the bottleneck in clinical treatment. Antiangiogenic therapy, which aims to "starve" the tumor by inhibiting angiogenesis, is one of the key strategies in clinical oncology treatments. Recently, dozens of investigational antibody drugs and biosimilars targeting angiogenesis have obtained regulatory approval for the treatment of various malignancies. Moreover, a new generation of bispecific antibodies based on the principle of antiangiogenesis are being advanced for clinical trial to overcome antiangiogenic resistance in tumor treatment or enhance the efficacy of monotherapy. Tumors often develop resistance to antiangiogenesis therapy, presenting as refractory and sometimes even resistant to new therapies, for which there are currently no effective management strategies. Thus, a detailed understanding of the mechanisms mediating resistance to antiangiogenesis antibodies is crucial for improving drug effectiveness and achieving a durable response to antiangiogenic therapy. In this review, we provide a novel perspective on the tumor microenvironment, including antibody structure, tumor stroma, and changes within tumor cells, to analyze the multifactorial reasons underlying resistance to antiangiogenesis antibodies. The review also enumerates biomarkers that indicate resistance and potential strategies for monitoring resistance. Furthermore, based on recent clinical and preclinical studies, we summarize potential strategies and translational clinical trials aimed at overcoming resistance to antiangiogenesis antibodies. This review provides a valuable reference for researchers and clinical practitioners involved in the development of new drugs or therapeutic strategies to overcome antiangiogenesis antibodies resistance.

In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC.

96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab.

In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

NCT00520975.

The US FDA's Project Optimus initiative that emphasizes dose optimization prior to marketing approval represents a pivotal shift in oncology drug development. It has a ripple effect for rethinking what changes may be made to conventional pivotal trial designs to incorporate a dose optimization component. Aligned with this initiative, we propose a novel seamless phase II/III design with dose optimization (SDDO framework). The proposed design starts with dose optimization in a randomized setting, leading to an interim analysis focused on optimal dose selection, trial continuation decisions, and sample size re-estimation (SSR). Based on the decision at interim analysis, patient enrollment continues for both the selected dose arm and control arm, and the significance of treatment effects will be determined at final analysis. The SDDO framework offers increased flexibility and cost-efficiency through sample size adjustment, while stringently controlling the Type I error. This proposed design also facilitates both accelerated approval (AA) and regular approval in a "one-trial" approach. Extensive simulation studies confirm that our design reliably identifies the optimal dosage and makes preferable decisions with a reduced sample size while retaining statistical power.

Treatment with the anti-angiogenic drug bevacizumab in addition to chemotherapy has shown efficacy for breast cancer in some clinical trials, but better biomarkers are needed to optimally select patients for treatment. Here, we present an omics approach where DNA methylation profiles are integrated with gene expression and results from proteomic data in breast cancer patients to predict response to therapy and pinpoint response-related epigenetic events. Fresh-frozen tumor biopsies taken before, during, and after treatment from human epidermal growth factor receptor 2 negative non-metastatic patients receiving neoadjuvant chemotherapy with or without bevacizumab were subjected to molecular profiling. Here, we report that DNA methylation at enhancer CpGs related to cell cycle regulation can predict response to chemotherapy and bevacizumab for the estrogen receptor positive subset of patients (AUC = 0.874), and we validated this observation in an independent patient cohort with a similar treatment regimen (AUC = 0.762). Combining the DNA methylation scores with the scores from a previously published protein signature resulted in a slight increase in the prediction performance (AUC = 0.784). We also show that tumors receiving the combination treatment underwent more extensive epigenetic alterations. Finally, we performed an integrative expression-methylation quantitative trait loci analysis on alterations in DNA methylation and gene expression levels, showing that the epigenetic alterations that occur during treatment are different between responders and non-responders and that these differences may be explained by the proliferation-epithelial-to-mesenchymal transition axis through the activity of grainyhead like transcription factor 2. Using tumor purity computed from copy number data, we developed a method for estimating cancer cell-specific methylation to confirm that the association to response reflects DNA methylation in cancer cells. Taken together, these results support the potential for clinical benefit of the addition of bevacizumab to chemotherapy when administered to the correct patients.

Overall, it is estimated that more than 3,500,000 patients have received Bevacizumab as part of systemic oncologic treatment. Bevacizumab and its biosimilars are currently marketed in over 130 countries. Given the wide usage of Bevacizumab in current oncological practice, it is very important to compare the "real-world" results to those obtained in controlled clinical trials. This study aims to describe the clinical experience of using Bevacizumab in a large cohort of cancer patients in "non-controlled real-world" conditions with regard to effectiveness, safety, and cost of therapy.

For this purpose, we conducted an open, observational, retrospective study involving all patients treated for solid malignant tumors in the Bucharest Institute of Oncology with "Prof. Dr. Al. Trestioreanu" with Bevacizumab-based systemic therapy, between 2017 and 2021.

The study consisted of 657 treatment episodes in 625 patients (F/B = 1.62/1, with a median age of 57.6 years) which were treated for malignant tumors (majority colorectal, non-small cell lung, ovarian, and breast cancer). First-line treatment was administered in 229 patients, and the rest received Bevacizumab as second or subsequent lines of treatment. The overall response rate to Bevacizumab-based therapies was around 60-65% across all indication except for subsequent treatment lines in colorectal and ovarian cancers, where lower values were recorded (27.1%, and 31.5% respectively). Median PFS for the entire cohort was 8.2 months (95% CI 6.8-9.6), and the median OS was 13.2 months (95% CI 11.5-14.9). Usual bevacizumab-related toxicities were observed, including bleeding, hypertension, wound-healing complications, gastrointestinal perforation, other types of fistulas, septic complications, and thromboembolic events. Although the clinical benefits are undeniable, the addition of Bevacizumab to standard chemotherapy increased the overall treatment cost by 213%.

Bevacizumab remains a high-cost therapy, but it can add to clinical benefits (like overall survival, progression-free survival, and response rate) when used in conjunction with standard chemotherapy. Similar results as those presented in various controlled trials are observable even on unselected cohorts of patients in the uncontrolled conditions of "real-world" oncological practice. Off-label usage is encountered in clinical practice, and this aspect should be monitored given the potential adverse effects of the therapy.

Recurrent glioblastoma (rGBM) is a brain tumor that is resistant to standard treatments. Although stereotactic radiosurgery (SRS) is a non-invasive radiation technique, it cannot fully prevent tumor recurrence and progression. Bevacizumab blocks tumor blood supply and has been approved for rGBM. However, the best way to combine SRS and bevacizumab is still unclear. We did a systematic review and meta-analysis of studies comparing SRS alone and SRS plus bevacizumab for rGBM. We searched three databases for articles published until June 2023. All statistical analysis was performed by STATA v.17. Our meta-analysis included 20 studies with 926 patients. We found that the combination therapy had a significantly lower rate of overall survival (OS) than SRS alone at 6-month 0.77[95%CI:0.74-0.85] for SRS alone and (100%) for SRS plus bevacizumab. At 1-year OS, 0.39 [95%CI: 0.32-0.47] for SRS alone and 0.61 [95%CI:0.44-0.77] for SRS plus bevacizumab (P-value:0.02). However, this advantage was not seen in the long term (18 months and two years). Additionally, the combination therapy had lower chances of progression-free survival (PFS) than SRS alone at the 6-month and 1-year time points, but the differences were insignificant. Our study indicates that incorporating bevacizumab with SRS may lead to a short-term increase in OS for rGBM patients but not long-term. Additionally, the PFS rate did not show significant improvement in the group receiving combination therapy. Further clinical trials are necessary to validate the enhanced overall survival with combination therapy for rGBM.

Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.