Cancer Treat. Rev. [JOURNAL]
Sun
200 papers
Trastuzumab deruxtecan in human epidermal growth factor receptor 2-positive breast cancer brain metastases: A systematic review and updated meta-analysis.
Michelon I, Castro CER, Madeira T … +6 more , Dacoregio MI, Stecca C, Soares LR, Saeed A, Vilbert M, Cavalcante L
Cancer Treat Rev · 2025 Feb · PMID 39805165 · Publisher ↗
BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown promising activity in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) and central nervous system (CNS) involvement. In this u...
BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown promising activity in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) and central nervous system (CNS) involvement. In this updated meta-analysis, we explore the effectiveness of T-DXd in a large subset of patients with HER2-positive BC and CNS disease. METHODS: A systematic search was made on September 16th, 2024, for studies investigating T-DXd in the scenario of HER2-positive BC and brain metastases (BMs) and/or leptomeningeal disease (LMD). We used random effects models for all statistical analyses. RESULTS: We included 18 studies with 786 HER2-positive BC patients with CNS involvement (16 studies with 750 BMs patients and three studies with 36 LMD patients). We observed high overall antitumor responses (objective response rate [ORR], 60.4 %; disease control rate [DCR], 94.4 %; and clinical benefit rate [CBR], 79.3 %) and a 12-month PFS of 64.7 % and OS of 82.7 %. Intracranial ORR, DCR, and CBR were seen in 62.2 %, 88.6 %, and 68.6 % of patients, respectively, and 67.4 % achieved intracranial PFS at 12 months. Both stable and active BMs subgroups derived similar benefit from T-DXd. Better intracranial responses were seen for 33 patients with untreated BMs compared to 56 patients with previously treated or progressing lesions (odds ratio 3.82, 95 % confidence interval 1.3-10.8, p = 0.01). For the LMD group, T-DXd elicited intracranial ORR and CBR in 59.4 % and 94.1 % of patients, respectively. CONCLUSIONS: This updated meta-analysis continues to support the overall and intracranial activity of T-DXd in patients with HER2-positive BC and CNS involvement, including those with LMD.
Dynamics of resistance to immunotherapy and TKI in patients with advanced renal cell carcinoma.
Santoni M, Mollica V, Rizzo A … +1 more , Massari F
Cancer Treat Rev · 2025 Feb · PMID 39799795 · Publisher ↗
Immune-based combinations are the cornerstone of the first-line treatment of metastatic renal cell carcinoma patients, leading to outstanding outcomes. Nevertheless, primary resistance and disease progression is a critic...
Immune-based combinations are the cornerstone of the first-line treatment of metastatic renal cell carcinoma patients, leading to outstanding outcomes. Nevertheless, primary resistance and disease progression is a critical clinical challenge. To properly address this issue, it is pivotal to understand the mechanisms of resistance to immunotherapy and tyrosine kinase inhibitors, that tumor eventually develop under treatment. In this review of the literature, we aim at exploring resistance mechanisms arising in patients treated with first-line immune-based combinations in order to understand the biological pattern that should be investigated to overcome them. In more detail, mechanisms of resistance to nivolumab and pembrolizumab are divided into intrinsic to cancer cells and extrinsic (stromal or immune cells). Regarding axitinib, the increased expression of Nuclear protein 1 (NUPR1) or decreased levels of insulin receptor (INSR) characterize resistant cells. The secretion of non-VEGF pro-angiogenic factors, such as PDGF-BB, IL-1β, MMP-9, Gro-α, IL-8, IL-6, and CCL-2, can lead to resistance to cabozantinib. The reactivation of pathways previously targeted by lenvatinib or the activation of alternative pathways, such as EGFR-PAK2-ERK pathway, underlie the development of resistance to lenvatinib. Exploring resistance mechanism that arise during first-line therapy can lead to the development of treatment strategy able to overcome them in order to improve duration of response and patients outcomes.
Managing strategies of chemotherapy and radiotherapy-induced oral mucositis.
Wu Y, Shi W, Li C … +5 more , Liu X, Jiang Y, Qiu Y, Chen Q, Luo X
Cancer Treat Rev · 2025 Feb · PMID 39799794 · Publisher ↗
Radiotherapy and chemotherapy are widely employed as primary non-surgical cancer treatments; however, their non-selective cytotoxicity often leads to adverse events such as oral mucositis (OM), particularly in head and n...
Radiotherapy and chemotherapy are widely employed as primary non-surgical cancer treatments; however, their non-selective cytotoxicity often leads to adverse events such as oral mucositis (OM), particularly in head and neck cancer therapies. International guidelines provide recommendations for managing chemoradiotherapy-induced OM in various clinical contexts. Subsequently, emerging researches have introduced evidence supporting novel approaches or existing regimens for OM prevention and treatment. The repurposing of established drugs has garnered significant interest due to its shorter development timeline, improved safety profiles, and lower costs compared to new drug development. For example, clinical trials assessing established drugs such as melatonin, clonidine, and pentoxifylline indicate promising potential for managing OM. Additionally, several emerging pharmacological interventions have demonstrated considerable efficacy; SAMITAL and rhIL-11 are supported by phase II clinical trials and prospective studies, while probiotics like Streptococcus salivarius K12 and curcumin have shown effectiveness in randomized clinical trials. Furthermore, recent high-level studies have reinforced the efficacy of non-pharmacological interventions, such as photobiomodulation (PBM) and cryotherapy, over the past two years. In all, given the evidence supporting different strategies, PBM and oral cryotherapy are highly recommended for managing OM when feasible. Topical clonidine, melatonin, oral pentoxifylline, topical SAMITAL or rhIL-11, oral SsK12, and curcumin may also be utilized but would benefit from validation in larger trials. Besides, Verbascoside, Palifermin, Amifostine, and Avasopasem manganese can be suggested for OM management, while the side effects should be monitored. The accessibility and cost/effectiveness of specific managing strategies of OM should be considered when selecting appropriate options.
CAR-T cell therapy for breast cancer: Current status and future perspective.
Buono G, Capozzi M, Caputo R … +12 more , Lauro VD, Cianniello D, Piezzo M, Cocco S, Martinelli C, Verrazzo A, Tafuro M, Calderaio C, Calabrese A, Nuzzo F, Pagliuca M, Laurentiis M
Cancer Treat Rev · 2025 Feb · PMID 39798230 · Publisher ↗
Within the expanding therapeutic landscape for breast cancer (BC), metastatic breast cancer (MBC) remains virtually incurable and tend to develop resistance to conventional treatments ultimately leading to metastatic pro...
Within the expanding therapeutic landscape for breast cancer (BC), metastatic breast cancer (MBC) remains virtually incurable and tend to develop resistance to conventional treatments ultimately leading to metastatic progression and death. Cellular immunotherapy (CI), particularly chimeric antigen receptor-engineered T (CAR-T) cells, has emerged as a promising approach for addressing this challenge. In the wake of their striking efficacy against hematological cancers, CAR-T cells have also been used where the clinical need is greatest - in patients with aggressive BCs. Unfortunately, current outcomes fall considerably short of replicating that success, primarily owing to the scarcity of tumor-specific antigens and the immunosuppressive microenvironment within BC. Herein, we provide an up-to-date overview of both preclinical and clinical data concerning the application of CAR-T cell therapy in BC. By surveying the existing literature, we discuss the prevailing constrains of this therapeutic approach and overview possible strategies to advance it in the context of breast malignancies. Possible approaches include employing synthetic biology to refine antigen targeting and mitigate off-target toxicity, utilizing logic-gated CAR constructs to enhance specificity, and leveraging armored CARs to remodel the tumor micro-environment. Temporal and spatial regulation of CAR-T cells using inducible gene switches and external triggers further improves safety and functionality. In addition, promoting T cell homing through chemokine receptor engineering and enhancing manufacturing processes with universal CAR platforms expand therapeutic applicability. These innovations not only address antigen escape and T cell exhaustion but also optimize the efficacy and safety profile of CAR-T cell therapy. We, therefore, outline a trajectory wherein CAR-T cells may evolve from a promising experimental approach to a standard modality in BC therapy.
Incomplete ovarian function suppression in premenopausal breast cancer patients treated with gonadotropin-releasing hormone agonists.
Lin J, Zheng S, Liu Q
Cancer Treat Rev · 2025 Feb · PMID 39793457 · Publisher ↗
BACKGROUND: Ovarian function suppression (OFS) has emerged as a crucial adjuvant therapy for premenopausal breast cancer patients. Some patients fail to achieve complete OFS with commonly used OFS drugs. The definition o...
BACKGROUND: Ovarian function suppression (OFS) has emerged as a crucial adjuvant therapy for premenopausal breast cancer patients. Some patients fail to achieve complete OFS with commonly used OFS drugs. The definition of incomplete OFS remains unclear, and large-scale data on its incidence are lacking. This review provides a comprehensive overview of the definition, occurrence, impact on therapeutic efficacy and corresponding treatment measures for incomplete OFS. METHODS: We searched PubMed, Embase and Cochrane Library databases in recent twenty years with keywords as "ovarian function escape", "incomplete OFS" and "estrogen breakthrough", and carried out a snowballing of references to important literature. Clinical literature of premenopausal breast cancer patients treated with OFS was screened. The patient characteristics, definition and incidence of incomplete OFS, prognosis, interventions and other information were extracted. RESULTS: A total of 17 studies were included in the analysis, including RCTs, retrospective or prospective cohort studies and case reports. Literature indicates that the incidence of incomplete OFS is around 5-50 % when the estradiol (E2) threshold is set as 2.72 pg/mL, 10 pg/mL, 20 pg/mL, or 30 pg/mL. Young age, high body mass index (BMI), and no prior chemotherapy were the risk factors for incomplete OFS. The treatment of incomplete OFS included dose adjustments, alternative OFS drugs, or the adoption of other OFS measures. CONCLUSIONS: The incomplete OFS rate decreased with the extension of treatment time. It is reasonable to monitor E2 levels to ensure successful OFS in the patients with high risk factors for incomplete OFS or with concurrent use of aromatase inhibitor (AI). Transient incomplete OFS seems to have no impact on prognosis, but sustained incomplete OFS needs personalized adjustment of treatment strategy to ensure complete OFS.
Selecting systemic treatment for metastatic neuroendocrine tumors of the lung-current evidence and clinical implications.
Melhorn P, Raderer M, Kiesewetter B
Cancer Treat Rev · 2025 Feb · PMID 39787793 · Publisher ↗
Neuroendocrine tumors (NET) of the lung are a slowly growing subtype of lung cancer that has a different treatment paradigm than aggressive and more common forms of lung neuroendocrine neoplasms (NEN) like small cell lun...
Neuroendocrine tumors (NET) of the lung are a slowly growing subtype of lung cancer that has a different treatment paradigm than aggressive and more common forms of lung neuroendocrine neoplasms (NEN) like small cell lung cancer (SCLC). Current guidelines for metastatic lung NET advocate a handful of treatment options, including somatostatin analogs (SSA), everolimus, temozolomide- or platin-based chemotherapy, and peptide receptor radionuclide therapy (PRRT). However, there is no clear treatment sequence, and the therapy of choice may depend on several factors such as tumor grade / growth rate, tumor burden / symptoms, disease progression status, and somatostatin receptor (SSTR) expression. In order to tailor treatment to each individual patient, the latest scientific findings and patient-specific clinical features must be considered together. This review critically evaluates the available evidence with regards to relevant patient characteristics, inclusion and exclusion criteria, and outcome metrics of clinical trials given the presumed natural disease course. Specific patient subgroups with an unmet therapeutic need are identified and discussed in the context of ongoing clinical trials.
Maintenance therapy after first-line platinum-based chemotherapy in gastroenteropancreatic neuroendocrine carcinomas: A literature review.
Tissera NS, Balconi F, García-Álvarez A … +4 more , Cubero JH, O'Connor JM, Chacón M, Capdevila J
Cancer Treat Rev · 2025 Jan · PMID 39721305 · Publisher ↗
Neuroendocrine carcinomas are rare and aggressive malignancies, often diagnosed at advanced stages, leading to poor prognosis. Platinum-based chemotherapy is the standard first-line treatment for advanced neuroendocrine...
Neuroendocrine carcinomas are rare and aggressive malignancies, often diagnosed at advanced stages, leading to poor prognosis. Platinum-based chemotherapy is the standard first-line treatment for advanced neuroendocrine carcinomas; however after achieving response no consensus exists on maintenance therapies and the results are inconsistent. This review examines the role of maintenance therapy following response to first-line chemotherapy in gastroenteropancreatic neuroendocrine carcinomas. We identified limited supporting evidence, primarily from phase II trials and case reports, that suggested maintenance therapy could be considered for prolonging progression-free survival, balancing toxicity, and maintaining quality of life. Nevertheless, prospective studies are needed to validate its clinical efficacy.
Efficacy and safety of antibody-drug conjugates in pretreated HER2-low metastatic breast cancer: A systematic review and network meta-analysis.
Schettini F, Nucera S, Pascual T … +18 more , Martínez-Sáez O, Sánchez-Bayona R, Conte B, Buono G, Lambertini M, Punie K, Cejalvo JM, Arpino G, Vigneri P, Generali D, Ciruelos E, Cortés J, Gennari A, Muñoz M, Vidal Losada MJ, Tolaney SM, Prat A, Villacampa G
Cancer Treat Rev · 2025 Jan · PMID 39709655 · Publisher ↗
INTRODUCTION: Antibody-drug conjugates (ADCs) trastuzumab-deruxtecan (T-DXd) and sacituzumab-govitecan (SG) provided significant progression-free survival (PFS) and overall survival (OS) improvements over chemotherapy (C...
INTRODUCTION: Antibody-drug conjugates (ADCs) trastuzumab-deruxtecan (T-DXd) and sacituzumab-govitecan (SG) provided significant progression-free survival (PFS) and overall survival (OS) improvements over chemotherapy (CT) in pretreated hormone receptor-positive (HR+) and triple-negative (TN)/HER2-low metastatic breast cancer (MBC). However, no direct comparison between the two exists, nor with the more recent datopotamab-deruxtecan (Dato-DXd). METHODS: We conducted a network meta-analysis (NMA) to compare efficacy and safety of T-DXd and SG in CT-pretreated HR+ and TN/HER2-low MBC and assess their benefit over standard CT, exploring also a comparison with Dato-DXd. Hazard ratios (HRs) with 95 % confidence intervals (CI) were calculated for PFS/OS. P-score was used for treatment ranking. RESULTS: Three RCTs (956 patients) were included in the primary analysis and 5 (1,445) in the exploratory NMA with Dato-DXd. In HR+/HER2-low, T-DXd showed no significant difference in PFS and OS when compared to SG. Similarly, in TN/HER2-low, PFS and OS did not differ significantly between the two ADCs. The P-score analysis favored T-DXd over SG in HR+/HER2-low in PFS (0.90 vs. 0.60) and OS (0.89 vs. 0.60). SG was favored over T-DXd in OS in TN/HER2-low (0.80 vs. 0.69). Similar results were obtained for HR+ MBC when including Dato-Dxd, which showed the worst performance, while T-DXd was the only ADC significantly outperforming CT in OS. The ADCs showed significantly better PFS and OS than CT in HR+/HER2-low and TN/HER2-low (all p < 0.001). SG had higher rates of neutropenia, diarrhea and alopecia vs. T-DXd, which showed more thrombocytopenia, fatigue and nausea. Pneumonitis and cardiotoxicity were typically T-DXd-related, and T-DXd showed more toxicity-related discontinuations. CONCLUSIONS: Similar efficacy with T-DXd and SG in HER2-low MBC was observed, regardless of HR status. Safety profile, local drug-approval criteria and guidelines, patients' preferences and overall quality of evidence should ultimately guide therapeutic decision-making. Dato-DXd role remains uncertain.
Corrigendum to "PARP inhibitors in gliomas: Mechanisms of action, current trends and future perspectives" [Cancer Treat. Rev. 131 (2024) 102850].
Cella E, Bosio A, Persico P … +13 more , Caccese M, Padovan M, Losurdo A, Maccari M, Cerretti G, Ius T, Minniti G, Idbaih A, Sanai N, Weller M, Preusser M, Simonelli M, Lombardi G
Cancer Treat Rev · 2025 Jan · PMID 39709267 · Publisher ↗
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Current status and future prospects of combined immunotherapy and epidermal growth factor receptor inhibitors in head and neck squamous cell carcinoma.
Tian X, Zhang H, Han Y … +2 more , Gu B, Zhang Z
Cancer Treat Rev · 2025 Jan · PMID 39672091 · Publisher ↗
Head and neck squamous cell carcinoma (HNSCC) is a malignancy with a poor prognosis, and the majority of patients with HNSCC are diagnosed at later stages owing to its hidden anatomical location and atypical clinical sym...
Head and neck squamous cell carcinoma (HNSCC) is a malignancy with a poor prognosis, and the majority of patients with HNSCC are diagnosed at later stages owing to its hidden anatomical location and atypical clinical symptoms. It is notably prone to recurrence and metastasis. The traditional treatments include surgery, radiotherapy, chemotherapy, and targeted therapy. Although multiple treatment strategies have been established, the prognosis remains poor because most patients develop resistance to traditional treatments. In recent years, epidermal growth factor receptor (EGFR) inhibitors and immune checkpoint inhibitors (ICIs) have been shown to provide clinical benefits to these patients. Based on the promising results of both anti-EGFR therapy and immunotherapy, as well as the biological rationale for combining immunotherapy with anti-EGFR drugs, numerous preclinical and ongoing or completed clinical trials have explored the use of their synergistic effects. This review summarizes the feasibility of combining immunotherapy with EGFR inhibitors for HNSCC treatment and analyses the relevant biomarkers. It also summarizes the strategies for clinical applications. We found that immunotherapy and EGFR inhibitor combination therapy showed promise in treating patients with HNSCC and exhibited safety with acceptable adverse events. This review may provide valuable insights for the future development of treatments and formulation of therapeutic strategies for HNSCC, as well as useful information for the future design of clinical trials.
PI3K/AKT/mTOR inhibitors for hormone receptor-positive advanced breast cancer.
Hao C, Wei Y, Meng W … +2 more , Zhang J, Yang X
Cancer Treat Rev · 2025 Jan · PMID 39662202 · Publisher ↗
Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays a pivotal role in the development and progression of various cancers. In hormone receptor-po...
Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays a pivotal role in the development and progression of various cancers. In hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, aberrations in this pathway are increasingly recognized as key drivers of resistance to endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, the first-line treatments for this disease subtype. Recognizing the urgent need for alternative therapeutic strategies, significant advancements have been made in developing PI3K/AKT/mTOR inhibitors for HR+ advanced/metastatic breast cancer. Among these inhibitors, capivasertib and alpelisib have received approval as targeted therapies for this indication. This review provides a comprehensive summary of the latest developments in PI3K/AKT/mTOR inhibitors for HR+ breast cancer. It also delves into different aspects, including sampling, testing method and timing, of PI3K/AKT/mTOR diagnostic testing. Additionally, the review discusses key considerations for integrating these inhibitors into clinical practice, such as timing and choice of PI3K/AKT/mTOR inhibitors, and management of treatment toxicities. By examining these different aspects, this review aims to provide valuable insights into optimizing the clinical utility of PI3K/AKT/mTOR inhibitors in HR+ advanced breast cancer.
Expert consensus on the prevention of brain metastases in patients with HER2-positive breast cancer.
Müller V, Bachelot T, Curigliano G … +10 more , de Azambuja E, Furtner J, Gempt J, Jereczek-Fossa BA, Jerzak KJ, Rhun EL, Palmieri C, Pravettoni G, Saura C, Bartsch R
Cancer Treat Rev · 2025 Jan · PMID 39612906 · Publisher ↗
BACKGROUND: Patients with HER2-positive breast cancer have a significant risk of developing brain metastases (BrM), which have detrimental effects on survival outcomes and quality of life. Although there are several syst...
BACKGROUND: Patients with HER2-positive breast cancer have a significant risk of developing brain metastases (BrM), which have detrimental effects on survival outcomes and quality of life. Although there are several systemic treatment options available that may delay the appearance of BrM and secondary progression of previously treated BrM, there are still substantial unmet needs for this patient population and primary prevention remains elusive. METHODS: A group of experts created consensus statements, through a modified Delphi process, to bridge the gap between current unmet needs, available evidence, and international guidelines. RESULTS: The steering committee reviewed all relevant literature and formed research questions to be answered by the subsequent consensus statements. In total, 61 contributors provided feedback on the consensus statements, with 34 statements reaching agreement out of the 55 statements that were voted on altogether. Statements with consensus aimed to define BrM primary and secondary prevention, screening procedures, assessment of symptoms, treatment efficacy, and preventing the occurrence and progression of BrM, while acknowledging the possibilities and limitations in daily clinical practice. Some statements did not reach agreement for a variety of reasons, mostly due to lack of evidence. CONCLUSIONS: The consensus statements outlined in this publication provide a point of reference for daily clinical practice and can act as recommendations for clinical trial procedures and future guidelines.
Expert recommendations on treatment sequencing and challenging clinical scenarios in human epidermal growth factor receptor 2-positive (HER2-positive) metastatic breast cancer.
Bartsch R, Cameron D, Ciruelos E … +10 more , Criscitiello C, Curigliano G, Duhoux FP, Foukakis T, Gligorov J, Harbeck N, LeVasseur N, Okines A, Penault-Llorca F, Müller V
Cancer Treat Rev · 2025 Jan · PMID 39580869 · Publisher ↗
Human epidermal growth factor receptor 2 (HER2) overexpression and/or ERBB2 gene amplification occurs in approximately 15-20% of breast cancers and is associated with poor prognosis. While the introduction of HER2-target...
Human epidermal growth factor receptor 2 (HER2) overexpression and/or ERBB2 gene amplification occurs in approximately 15-20% of breast cancers and is associated with poor prognosis. While the introduction of HER2-targeted therapies has significantly improved survival in patients with HER2-positive metastatic breast cancer, the incidence of brain metastases has increased due to patients living longer. Current recommendations sequence treatments by line of therapy, as well as by the status of brain metastases in patients with HER2-positive breast cancer. However, in the third-line treatment setting and beyond, there is a lack of clarity of the preferred choice of therapy. In clinical practice, clinicians may also encounter challenging scenarios where the optimal therapeutic approach has not been defined by clinical studies, so there is a need for clarity in such situations. Two consensus meetings of expert oncologists (12 from Europe and one from Canada) were convened to discuss these scenarios. We subsequently developed this article to present an overview of current treatment recommendations for HER2-positive metastatic breast cancer and give practical guidance on addressing challenging scenarios in a real-world setting. Based on our clinical experience, we provide a unanimous consensus concerning the treatment of elderly patients as well as those with brain-only metastases, leptomeningeal disease, oligometastatic disease, central nervous system oligo-progressive disease or ERBB2-mutant disease. We also discuss how to combine HER2-targeted therapy with endocrine therapy in patients with HER2-positive/hormone-receptor-positive disease, considerations for potential discontinuation of HER2-targeted therapy in patients with long-term remission and how to treat patients whose metastatic biopsy no longer confirms their HER2-positive status.
Estrogen Signaling in Early-Stage Breast Cancer: Impact on Neoadjuvant Chemotherapy and Immunotherapy.
Corti C, Binboğa Kurt B, Koca B … +11 more , Rahman T, Conforti F, Pala L, Bianchini G, Criscitiello C, Curigliano G, Garrido-Castro AC, Kabraji SK, Waks AG, Mittendorf EA, Tolaney SM
Cancer Treat Rev · 2025 Jan · PMID 39571402 · Publisher ↗
Neoadjuvant chemoimmunotherapy (NACIT) has been shown to improve pathologic complete response (pCR) rates and survival outcomes in stage II-III triple-negative breast cancer (TNBC). Promising pCR rate improvements have a...
Neoadjuvant chemoimmunotherapy (NACIT) has been shown to improve pathologic complete response (pCR) rates and survival outcomes in stage II-III triple-negative breast cancer (TNBC). Promising pCR rate improvements have also been documented for selected patients with estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). However, one size does not fit all and predicting which patients will benefit from NACIT remains challenging. Accurate predictions would be useful to minimize immune-related toxicity, which can be severe, irreversible, and potentially impact fertility and quality of life, and to identify patients in need of alternative treatments. This review aims to capitalize on the existing translational and clinical evidence on predictors of treatment response in patients with early-stage BC treated with neoadjuvant chemotherapy (NACT) and NACIT. It summarizes evidence suggesting that NACT/NACIT effectiveness may correlate with pre-treatment tumor characteristics, including mutational profiles, ER expression and signaling, immune cell presence and spatial organization, specific gene signatures, and the levels of proliferating versus quiescent cancer cells. However, the predominantly qualitative and descriptive nature of many studies highlights the challenges in integrating various potential response determinants into a validated, comprehensive, and multimodal predictive model. The potential of novel multi-modal approaches, such as those based on artificial intelligence, to overcome current challenges remains unclear, as these tools are not free from bias and shortcut learning. Despite these limitations, the rapid evolution of these technologies, coupled with further efforts in basic and translational research, holds promise for improving treatment outcome predictions in early HER2- BC.
PARP inhibitors in gliomas: Mechanisms of action, current trends and future perspectives.
Cella E, Bosio A, Persico P … +13 more , Caccese M, Padovan M, Losurdo A, Maccari M, Cerretti G, Ius T, Minniti G, Idbaih A, Sanai N, Weller M, Preusser M, Simonelli M, Lombardi G
Cancer Treat Rev · 2024 Dec · PMID 39531943 · Publisher ↗
Gliomas are the most common primary malignant brain tumours in adults. Despite decades of research into novel therapeutic approaches, the prognosis remains poor. PARP1-2 are critical for DNA repair, cell survival and gen...
Gliomas are the most common primary malignant brain tumours in adults. Despite decades of research into novel therapeutic approaches, the prognosis remains poor. PARP1-2 are critical for DNA repair, cell survival and genomic stability and PARP inhibition (PARPi) may be a promising therapeutic approach for gliomas. Inhibition of PARP activity leads to homologous recombination deficiency (HRD), which, in combination with DNA damage, results in cell death. This review summarises the current knowledge and future perspectives of PARPi in glioma. The available literature was reviewed using PubMed, recent major international oncology congresses were consulted, and ongoing clinical trials were searched using ClinicalTrials.gov. In translational research, PARPi have demonstrated a strong scientific rationale for their use in the treatment of glioma. They have been evaluated both alone and in combination with radiotherapy, temozolomide, anti-angiogenic agents, immunotherapy and other new drugs in newly diagnosed or recurrent glioma. Most studies were open-label, non-randomised, dose-escalation phase I-II trials. Early results show promising anti-tumour activity, and key challenges include identifying predictive biomarkers, elucidating synergistic effects in combination therapies, addressing the development of resistance, and managing hematological toxicity. In conclusion, early phase studies have shown promising anti-tumour activity of PARPi that should be confirmed in larger prospective and randomised trials. In addition, the development of novel PARPi with improved blood brain barrier (BBB) penetration and PARP inhibitor activity with new synergistic treatment combinations seems promising and needs to be further explored.
False Positive Rate from Prospective Studies of PET-CT in Cutaneous Malignant Melanoma: A Systematic Review and Meta-Analysis.
Smith B, Church-Martin J, Abed H … +2 more , Lloyd E, Hardwicke JT
Cancer Treat Rev · 2024 Dec · PMID 39522329 · Publisher ↗
BACKGROUND: Cutaneous malignant melanoma (CMM) is increasing in prevalence and possesses the highest mortality rate of any skin cancer. Positron Emission Tomography and Computed Tomography (PET-CT) may be utilised in eit...
BACKGROUND: Cutaneous malignant melanoma (CMM) is increasing in prevalence and possesses the highest mortality rate of any skin cancer. Positron Emission Tomography and Computed Tomography (PET-CT) may be utilised in either radiological staging or surveillance, primarily in stage III-IV disease. False positive (FP) results lead to patient distress, increased costs, and unnecessary follow-up. The FP rate in CMM literature varies widely, altering calculations of positive predictive value and has not undergone pooled meta-analytic. MATERIALS AND METHODS: A systematic review and meta-analysis of FP results in prospective studies of PET-CT in CMM was performed in accordance with PRISMA guidelines. RESULTS: The systematic review produced 14 trials for inclusion. Patient-based reporting had the lowest pooled proportion of FP results with 5.8 % (95 % CI = 3.3 % to 8.8 %), lesion-based was highest with 9.1 % (95 % CI = 3.4 % to 17.2 %) and combined was 6.1 % (95 % CI = 4.3 % to 8.1 %). Bias was low to unclear other than for FP reporting. Heterogeneity (I2) was variable across all analyses. FP findings were mainly lymphatic, dermatological, respiratory, or skeletal. Diagnostic information was not provided. CONCLUSIONS: This study was the first attempt to quantify the pooled proportion of FP results from PET-CT in CMM. A small number of studies (n = 14) were available due to the predominance of retrospective methodology. Due to inconsistent reporting the true proportion of FP results is unclear. Systemic distribution was expected but limited diagnostic information was provided. Repeat meta-analysis using retrospective work should be performed. Future work should be prospective with clearly documented FP proportion, distribution, diagnosis, and follow-up.
Optimizing outcomes and personalizing care with targeted agents in advanced cholangiocarcinoma.
Mahmood U, Abbass A, Khan K
Cancer Treat Rev · 2024 Dec · PMID 39515274 · Publisher ↗
Traditional chemotherapy and immunotherapy-based systemic treatments for locally advanced or metastatic cholangiocarcinoma have been associated with poor clinical outcomes driven partly by molecular heterogeneity promoti...
Traditional chemotherapy and immunotherapy-based systemic treatments for locally advanced or metastatic cholangiocarcinoma have been associated with poor clinical outcomes driven partly by molecular heterogeneity promoting early treatment resistance and a higher toxicity profile associated with these regimens. Few patients are eligible for upfront surgical resection and clinical studies have been traditionally difficult to conduct due to the orphan nature of this disease. However, increasing use of genomic profiling in clinical practice have led to active investigations of aberrant albeit promising mechanistic therapeutic targets such as IDH-1, FGFRs, BRAF, HER-2 and NTRK. This review article aims to highlight the complex genomic landscape of this difficult-to-treat disease, followed by a discussion of evidence-based biological mechanisms that can be actioned using targeted agents. We explore the clinical rationale behind a targeted therapeutic strategy, the role of liquid biopsies in guiding clinical decisions and future treatment pathways for cholangiocarcinoma management. We also discuss the challenges and opportunities originating from recent clinical trials evaluating targeted treatments and our own institutional experience at UCLH that have aimed to address some of these biological complexities and have translated into improved patient outcomes via effective molecularly driven patient selection strategies. We also provide perspectives on emerging novel, next generation targeted inhibitors overcoming treatment resistance to previous targeted agents with demonstrated clinical value in a challenging patient population.
Malignant ascites: Current therapy options and treatment prospects.
Berger JM, Preusser M, Berghoff AS … +1 more , Bergen ES
Cancer Treat Rev · 2023 Oct · PMID 39492370 · Publisher ↗
Ascites formation is a common complication of cancer with a significant symptomatic burden for patients. Malignant ascites (MA) is defined by the presence of tumor cells within the ascitic fluid. It does not only cause s...
Ascites formation is a common complication of cancer with a significant symptomatic burden for patients. Malignant ascites (MA) is defined by the presence of tumor cells within the ascitic fluid. It does not only cause substantial morbidity, but is also associated with impaired survival. Considering the frequent occurrence of MA, it still represents a clinical challenge for physicians with limited therapy options, mainly comprising of the treatment of the primary tumor and effusion drainage. Particularly the lack of pathophysiological insight limits the development of effective, causative therapies. Causes of MA development such as lymphatic vessel obstruction and the effects of tumor secreted vascular endothelial growth factor (VEGF) have been known for decades. Novel research suggests that the intraperitoneal immune system may also induce and maintain MA accumulation. In this review, we assess current knowledge on the pathophysiology of MA and summarize available evidence of treatment approaches. Also, factors contributing to ascites formation without proof of tumor cells in the peritoneal cavity, defined as paramalignant ascites, with potential treatment strategies are discussed. We further focus on novel findings in the pathophysiology of MA that might lead to treatment improvement in the near future and discussed relevant knowledge gaps in this field.
Local administration of immunotherapy for patients with skin cancer: A systematic review.
Janssen JC, van Dijk B, Hoeijmakers LL … +6 more , Grünhagen DJ, Bramer WM, Verhoef C, de Gruijl TD, Blank CU, van der Veldt AAM
Cancer Treat Rev · 2024 Dec · PMID 39486396 · Publisher ↗
Since the introduction of immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors, survival has improved significantly for patients with irresectable and metastatic skin cancer, including cutaneous squamo...
Since the introduction of immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors, survival has improved significantly for patients with irresectable and metastatic skin cancer, including cutaneous squamous cell cancer and melanoma. However, systemic administration of these drugs is associated with immune related adverse events (irAEs), which can be severe, irreversible and even fatal. To reduce the risk of irAEs associated with systemic exposure to immunotherapeutic drugs, local administration of low doses could be considered. This systematic review provides an overview of early phase clinical trials with drugs that are currently under investigation for intratumoral administration in patients with melanoma and non-melanoma skin cancer.
Safety and efficacy of antibody-drug conjugates plus immunotherapy in solid tumours: A systematic review and meta-analysis.
Villacampa G, Cresta Morgado P, Carità L … +3 more , Navarro V, Pascual T, Dienstmann R
Cancer Treat Rev · 2024 Dec · PMID 39454548 · Publisher ↗
BACKGROUND: Combining antibody-drug conjugate (ADCs) with immune checkpoint inhibitors (ICIs) is emerging as a promising treatment option to increase efficacy outcomes. However, concerns arise regarding the safety of the...
BACKGROUND: Combining antibody-drug conjugate (ADCs) with immune checkpoint inhibitors (ICIs) is emerging as a promising treatment option to increase efficacy outcomes. However, concerns arise regarding the safety of these combinations, as some toxicities may overlap. Currently, there is still limited information about the safety profiles of this strategy. METHODS: A systematic review and meta-analysis was conducted to identify clinical trials investigating FDA-approved ADCs in combination with ICI drugs in the metastatic setting across all solid tumors. The primary endpoint of this study was the percentage of adverse events (AEs) of any grade and grade ≥ 3. Secondary endpoints include the percentage of patients with AEs leading to death, treatment discontinuation, proportion of complete responses (CR) and overall response rate (ORR). A parallel search was conducted to quantify the safety profile of ADCs and ICIs in monotherapy. Random effects models were used to estimate pooled outcomes. RESULTS: Sixteen trials involving 1,133 patients treated with ADC plus ICI met the inclusion criteria with six different ADCs evaluated. Overall, 55.3 % of patients developed grade ≥ 3 AEs, 30.0 % of patients had treatment discontinuation, and 3.0 % experienced AEs leading to death. When compared to trials evaluating ADC or ICI as monotherapy, the combination results in similar rates of the most common AEs. However, it increases the risk of specific toxicities, such as ILD/pneumonitis (15.0 % with T-DXd plus ICI vs. 11.5 % with T-DXd alone). The pooled ORR was 48.8 % (95 %CI 39.4 % - 58.4 %) and the CR rate was 9.0 % (95 %CI 5.5 - 14.5). PD-L1-positive tumors showed numerically better efficacy outcomes. CONCLUSIONS: This meta-analysis shows that the safety profile of the ADC plus ICI is comparable to that of ADC monotherapy. However, it increases the risk of certain toxicities of special interest, such as ILD/pneumonitis, highlighting the need for careful monitoring.
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