Pub Date : 2025-02-01DOI: 10.1016/j.ctrv.2025.102880
Stavroula L. Kastora , Eirini Pantiora , Yong Hwa Hong , Meenakshi Veeramani , Hatem A Azim Jr , Rima Chakrabarti , Jürgen Geisler , Ann Knoop , Matteo Lambertini , Barbro Linderholm , Icro Meattini , Ann H Partridge , Ines Vaz-Luis , Denise Vorburger , Gabriella Yongue , Andreas Karakatsanis , Antonios Valachis
<div><h3>Importance</h3><div>Endocrine treatments, such as Tamoxifen (TAM) and/or Aromatase inhibitors (AI), are the adjuvant therapy of choice for hormone-receptor positive breast cancer. These agents are associated with menopausal symptoms, adversely affecting drug compliance. Topical estrogen (TE) has been proposed for symptom management, given its’ local application and presumed reduced bioavailability, however its oncological safety remains uncertain.</div></div><div><h3>Objective</h3><div>The present systematic review, <em>meta</em>-analysis and expert panel review aimed to evaluate the strength of the available evidence on the risk of recurrence and mortality when TE is utilised in congruence with TAM or AI treatment, among BC survivors.</div></div><div><h3>Data Sources</h3><div>Six databases and two prospective registers, were interrogated from inception to January 3rd, 2024. Search terms were Breast cancer AND Hormone replacement therapy AND topical/vaginal oestrogen AND recurrence/mortality.</div></div><div><h3>Study selection</h3><div>All study designs reporting the use vs. non-use of TE in breast cancer survivors receiving adjuvant endocrine treatment were included. Six observational studies were deemed eligible for inclusion.</div></div><div><h3>Data extraction and synthesis</h3><div>Sources of heterogeneity were explored using subgroup analysis by risk of bias, median follow-up period, node positivity and menopausal status. Trial sequential analysis was performed to quantify outcome reliability. A global expert panel was called to deliberate on the data, pinpoint areas of limited understanding, and determine the most important areas for future research.</div></div><div><h3>Main outcomes and measures</h3><div>Risk ratio effect sizes (RR) and corresponding 95 % Confidence Intervals (CI) of breast cancer recurrence and mortality in survivors on endocrine treatment (TAM and/or AI) exposed to TE were reported. Expert panel appraisal of <em>meta</em>-analysis evidence with definition of current knowledge gaps and future research aims.</div></div><div><h3>Results</h3><div>In 38 050 female patients receiving adjuvant endocrine treatment, of whom 1805 had been exposed to TE, TE exposure of those on AI, did not increase all-cause mortality (RR 0.99 [95 %CI 0.58, 1.69], I<sup>2</sup> = 81 %, P = 0.96; moderate GRADE certainty). However, such exposure may convey an increased risk of recurrence (RR 2.51 [95 % CI 1.10, 5.72], I<sup>2</sup> = 9 %, P = 0.03; low-GRADE certainty). Exposure to TE during TAM did not increase either recurrence risk or all-cause mortality. Clinical factors such as lymph node positivity at the time of diagnosis and menopausal status and follow-up time appeared to be significant confounders.</div></div><div><h3>Conclusions and relevance</h3><div>The use of TE does not appear to increase either recurrence or mortality risk among BC survivors treated with TAM. An increased recurrence risk, without an increase in mortality,
{"title":"Safety of topical estrogen therapy during adjuvant endocrine treatment among patients with breast cancer: A meta-analysis based expert panel discussion","authors":"Stavroula L. Kastora , Eirini Pantiora , Yong Hwa Hong , Meenakshi Veeramani , Hatem A Azim Jr , Rima Chakrabarti , Jürgen Geisler , Ann Knoop , Matteo Lambertini , Barbro Linderholm , Icro Meattini , Ann H Partridge , Ines Vaz-Luis , Denise Vorburger , Gabriella Yongue , Andreas Karakatsanis , Antonios Valachis","doi":"10.1016/j.ctrv.2025.102880","DOIUrl":"10.1016/j.ctrv.2025.102880","url":null,"abstract":"<div><h3>Importance</h3><div>Endocrine treatments, such as Tamoxifen (TAM) and/or Aromatase inhibitors (AI), are the adjuvant therapy of choice for hormone-receptor positive breast cancer. These agents are associated with menopausal symptoms, adversely affecting drug compliance. Topical estrogen (TE) has been proposed for symptom management, given its’ local application and presumed reduced bioavailability, however its oncological safety remains uncertain.</div></div><div><h3>Objective</h3><div>The present systematic review, <em>meta</em>-analysis and expert panel review aimed to evaluate the strength of the available evidence on the risk of recurrence and mortality when TE is utilised in congruence with TAM or AI treatment, among BC survivors.</div></div><div><h3>Data Sources</h3><div>Six databases and two prospective registers, were interrogated from inception to January 3rd, 2024. Search terms were Breast cancer AND Hormone replacement therapy AND topical/vaginal oestrogen AND recurrence/mortality.</div></div><div><h3>Study selection</h3><div>All study designs reporting the use vs. non-use of TE in breast cancer survivors receiving adjuvant endocrine treatment were included. Six observational studies were deemed eligible for inclusion.</div></div><div><h3>Data extraction and synthesis</h3><div>Sources of heterogeneity were explored using subgroup analysis by risk of bias, median follow-up period, node positivity and menopausal status. Trial sequential analysis was performed to quantify outcome reliability. A global expert panel was called to deliberate on the data, pinpoint areas of limited understanding, and determine the most important areas for future research.</div></div><div><h3>Main outcomes and measures</h3><div>Risk ratio effect sizes (RR) and corresponding 95 % Confidence Intervals (CI) of breast cancer recurrence and mortality in survivors on endocrine treatment (TAM and/or AI) exposed to TE were reported. Expert panel appraisal of <em>meta</em>-analysis evidence with definition of current knowledge gaps and future research aims.</div></div><div><h3>Results</h3><div>In 38 050 female patients receiving adjuvant endocrine treatment, of whom 1805 had been exposed to TE, TE exposure of those on AI, did not increase all-cause mortality (RR 0.99 [95 %CI 0.58, 1.69], I<sup>2</sup> = 81 %, P = 0.96; moderate GRADE certainty). However, such exposure may convey an increased risk of recurrence (RR 2.51 [95 % CI 1.10, 5.72], I<sup>2</sup> = 9 %, P = 0.03; low-GRADE certainty). Exposure to TE during TAM did not increase either recurrence risk or all-cause mortality. Clinical factors such as lymph node positivity at the time of diagnosis and menopausal status and follow-up time appeared to be significant confounders.</div></div><div><h3>Conclusions and relevance</h3><div>The use of TE does not appear to increase either recurrence or mortality risk among BC survivors treated with TAM. An increased recurrence risk, without an increase in mortality, ","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"133 ","pages":"Article 102880"},"PeriodicalIF":9.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ctrv.2025.102886
Juan Martin-Liberal , Iván Márquez-Rodas , Pablo Cerezuela-Fuentes , Ainara Soria , Fernando Garicano , Javier Medina , Regina García Galindo , Juana Oramas , José Luis Manzano , Mayte Delgado , Javier Valdivia , Pedro Sanchez
The global incidence of metastatic melanoma with BRAF mutations, characterized by aggressive behavior and poor prognosis, is rising. Recent treatment advances, including immune checkpoint inhibitors (ICI) and targeted therapies (TT) such as BRAF and MEK inhibitors, have significantly enhanced patient outcomes. Although guidelines recommend sequencing strategies, real-world implementation can be influenced by clinical scenarios. This article highlights the importance of tailored treatment strategies, emphasizing that the decision to initiate immunotherapy (IT) or TT hinges on multiple factors, including tumor burden, LDH levels, presence of brain metastases, and patient symptomatic status. Managing brain metastases also poses a challenge, as these patients are typically excluded from pivotal clinical trials. While insights from phase II studies provide some guidance, there is a critical need for more quality data to inform comprehensive recommendations. Furthermore, although triple therapy combining IT and TT was initially thought to be promising, it has failed to clearly demonstrate benefit over current treatments. For all these reasons, there is an imperative need for further research on biomarkers and predictive factors, as well as real-world studies, that will help tailor treatment strategies across diverse patient subsets, thereby refining therapeutic approaches for BRAF-mutated metastatic melanoma.
{"title":"Challenges and perspectives in the management of BRAF-mutated metastatic melanoma: Systemic treatment sequencing and brain metastases","authors":"Juan Martin-Liberal , Iván Márquez-Rodas , Pablo Cerezuela-Fuentes , Ainara Soria , Fernando Garicano , Javier Medina , Regina García Galindo , Juana Oramas , José Luis Manzano , Mayte Delgado , Javier Valdivia , Pedro Sanchez","doi":"10.1016/j.ctrv.2025.102886","DOIUrl":"10.1016/j.ctrv.2025.102886","url":null,"abstract":"<div><div>The global incidence of metastatic melanoma with BRAF mutations, characterized by aggressive behavior and poor prognosis, is rising. Recent treatment advances, including immune checkpoint inhibitors (ICI) and targeted therapies (TT) such as BRAF and MEK inhibitors, have significantly enhanced patient outcomes. Although guidelines recommend sequencing strategies, real-world implementation can be influenced by clinical scenarios. This article highlights the importance of tailored treatment strategies, emphasizing that the decision to initiate immunotherapy (IT) or TT hinges on multiple factors, including tumor burden, LDH levels, presence of brain metastases, and patient symptomatic status. Managing brain metastases also poses a challenge, as these patients are typically excluded from pivotal clinical trials. While insights from phase II studies provide some guidance, there is a critical need for more quality data to inform comprehensive recommendations. Furthermore, although triple therapy combining IT and TT was initially thought to be promising, it has failed to clearly demonstrate benefit over current treatments. For all these reasons, there is an imperative need for further research on biomarkers and predictive factors, as well as real-world studies, that will help tailor treatment strategies across diverse patient subsets, thereby refining therapeutic approaches for BRAF-mutated metastatic melanoma.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"133 ","pages":"Article 102886"},"PeriodicalIF":9.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ctrv.2025.102882
Isabella Michelon , Caio E.R. Castro , Thiago Madeira , Maria Inez Dacoregio , Carlos Stecca , Leonardo R. Soares , Anwaar Saeed , Maysa Vilbert , Ludimila Cavalcante
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.
{"title":"Trastuzumab deruxtecan in human epidermal growth factor receptor 2-positive breast cancer brain metastases: A systematic review and updated meta-analysis","authors":"Isabella Michelon , Caio E.R. Castro , Thiago Madeira , Maria Inez Dacoregio , Carlos Stecca , Leonardo R. Soares , Anwaar Saeed , Maysa Vilbert , Ludimila Cavalcante","doi":"10.1016/j.ctrv.2025.102882","DOIUrl":"10.1016/j.ctrv.2025.102882","url":null,"abstract":"<div><h3>Background</h3><div>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 <em>meta</em>-analysis, we explore the effectiveness of T-DXd in a large subset of patients with HER2-positive BC and CNS disease.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>This updated <em>meta</em>-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.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"133 ","pages":"Article 102882"},"PeriodicalIF":9.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ctrv.2025.102884
Ana Isabel Sebastião , Gonçalo Simões , Filomena Oliveira , Daniela Mateus , Amílcar Falcão , Mylène A. Carrascal , Célia Gomes , Bruno Neves , Maria Teresa Cruz
Breast cancer is the second most commonly diagnosed cancer in women and the fifth leading cause of cancer-related deaths worldwide. It is a highly heterogeneous disease, consisting of multiple subtypes that vary significantly in clinical characteristics and survival outcomes. Triple-negative breast cancer (TNBC) is a particularly aggressive and challenging subtype of breast cancer. Several immunotherapeutic approaches have been tested in patients with TNBC to improve disease outcomes, including the administration of dendritic cell (DC)-based vaccines. DCs are a heterogeneous cell population that play a crucial role in bridging the innate and adaptive immune systems. Therefore, DCs have been increasingly used in cancer vaccines due to their ability to prime and boost antigen specific T-cell immune responses. This review aims to provide a comprehensive overview of TNBC, including potential targets and pharmacological strategies, as well as an overview of DCs and their relevance in TNBC. In addition, we review ongoing clinical trials and shed light on the evolving landscape of DC-based immunotherapy for TNBC.
{"title":"Dendritic cells in triple-negative breast cancer: From pathophysiology to therapeutic applications","authors":"Ana Isabel Sebastião , Gonçalo Simões , Filomena Oliveira , Daniela Mateus , Amílcar Falcão , Mylène A. Carrascal , Célia Gomes , Bruno Neves , Maria Teresa Cruz","doi":"10.1016/j.ctrv.2025.102884","DOIUrl":"10.1016/j.ctrv.2025.102884","url":null,"abstract":"<div><div>Breast cancer is the second most commonly diagnosed cancer in women and the fifth leading cause of cancer-related deaths worldwide. It is a highly heterogeneous disease, consisting of multiple subtypes that vary significantly in clinical characteristics and survival outcomes. Triple-negative breast cancer (TNBC) is a particularly aggressive and challenging subtype of breast cancer. Several immunotherapeutic approaches have been tested in patients with TNBC to improve disease outcomes, including the administration of dendritic cell (DC)-based vaccines. DCs are a heterogeneous cell population that play a crucial role in bridging the innate and adaptive immune systems. Therefore, DCs have been increasingly used in cancer vaccines due to their ability to prime and boost antigen specific T-cell immune responses. This review aims to provide a comprehensive overview of TNBC, including potential targets and pharmacological strategies, as well as an overview of DCs and their relevance in TNBC. In addition, we review ongoing clinical trials and shed light on the evolving landscape of DC-based immunotherapy for TNBC.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"133 ","pages":"Article 102884"},"PeriodicalIF":9.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ctrv.2024.102878
Philipp Melhorn, Markus Raderer, Barbara Kiesewetter
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.
{"title":"Selecting systemic treatment for metastatic neuroendocrine tumors of the lung—current evidence and clinical implications","authors":"Philipp Melhorn, Markus Raderer, Barbara Kiesewetter","doi":"10.1016/j.ctrv.2024.102878","DOIUrl":"10.1016/j.ctrv.2024.102878","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"133 ","pages":"Article 102878"},"PeriodicalIF":9.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Dynamics of resistance to immunotherapy and TKI in patients with advanced renal cell carcinoma","authors":"Matteo Santoni , Veronica Mollica , Alessandro Rizzo , Francesco Massari","doi":"10.1016/j.ctrv.2025.102881","DOIUrl":"10.1016/j.ctrv.2025.102881","url":null,"abstract":"<div><div>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.</div><div>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.</div><div>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.</div><div>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.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"133 ","pages":"Article 102881"},"PeriodicalIF":9.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-26DOI: 10.1016/j.ctrv.2025.102891
Gabrielle Knafler , Alan L. Ho , Kathleen N. Moore , Seth M. Pollack , Jean-Marc Navenot , Joseph P. Sanderson
T-cell receptor (TCR) T-cell therapies are adoptive cell therapies in which patient cells are engineered to express TCRs targeting specific cancer antigens and infused back into the patient. Since TCR recognition depends on antigen presentation by the human leukocyte antigen system, TCRs can respond to intracellular antigens. Cancer/testis antigens (CTAs) are a large family of proteins, many of which are only expressed in cancerous tissue and immune-privileged germline sites. Melanoma-associated antigen A4 (MAGE-A4) is an intracellular CTA expressed in healthy testis and placenta, and in a range of cancers, including esophageal, head and neck, gastric, ovarian, colorectal, lung, endometrial, cervical, bladder, breast and prostate cancers; soft tissue sarcomas; urothelial and hepatocellular carcinomas; osteosarcoma; and melanoma. This expression pattern, along with the immunogenicity and potential role in tumorigenesis of MAGE-A4 make it a prime target for TCR T-cell therapy. We outline the preclinical and clinical development of TCR T-cell therapies targeting CTAs for treatment of solid tumors, highlighting the need for extensive preclinical characterization of putative off-target, and potential on-target but off-tumor, effects. We identified ten clinical trials assessing TCR T-cell therapies targeting MAGE-A4. Overall, manageable safety profiles and signals of efficacy have been observed, especially in patients with advanced synovial sarcoma, myxoid/round cell liposarcoma, ovarian, head and neck, and urothelial cancers, with one TCR T-cell therapy approved by the US Food and Drug Administration in August 2024. We also review the limitations, and strategies to enhance efficacy and improve safety, of these therapies, and summarize related immunotherapies targeting MAGE-A4.
{"title":"Melanoma-associated antigen A4: A cancer/testis antigen as a target for adoptive T-cell receptor T-cell therapy","authors":"Gabrielle Knafler , Alan L. Ho , Kathleen N. Moore , Seth M. Pollack , Jean-Marc Navenot , Joseph P. Sanderson","doi":"10.1016/j.ctrv.2025.102891","DOIUrl":"10.1016/j.ctrv.2025.102891","url":null,"abstract":"<div><div>T-cell receptor (TCR) T-cell therapies are adoptive cell therapies in which patient cells are engineered to express TCRs targeting specific cancer antigens and infused back into the patient. Since TCR recognition depends on antigen presentation by the human leukocyte antigen system, TCRs can respond to intracellular antigens. Cancer/testis antigens (CTAs) are a large family of proteins, many of which are only expressed in cancerous tissue and immune-privileged germline sites. Melanoma-associated antigen A4 (MAGE-A4) is an intracellular CTA expressed in healthy testis and placenta, and in a range of cancers, including esophageal, head and neck, gastric, ovarian, colorectal, lung, endometrial, cervical, bladder, breast and prostate cancers; soft tissue sarcomas; urothelial and hepatocellular carcinomas; osteosarcoma; and melanoma. This expression pattern, along with the immunogenicity and potential role in tumorigenesis of MAGE-A4 make it a prime target for TCR T-cell therapy. We outline the preclinical and clinical development of TCR T-cell therapies targeting CTAs for treatment of solid tumors, highlighting the need for extensive preclinical characterization of putative off-target, and potential on-target but off-tumor, effects. We identified ten clinical trials assessing TCR T-cell therapies targeting MAGE-A4. Overall, manageable safety profiles and signals of efficacy have been observed, especially in patients with advanced synovial sarcoma, myxoid/round cell liposarcoma, ovarian, head and neck, and urothelial cancers, with one TCR T-cell therapy approved by the US Food and Drug Administration in August 2024. We also review the limitations, and strategies to enhance efficacy and improve safety, of these therapies, and summarize related immunotherapies targeting MAGE-A4.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"134 ","pages":"Article 102891"},"PeriodicalIF":9.6,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1016/j.ctrv.2025.102889
Monica K Wattana , Jonathan Rowland , Aiham Qdaisat , Hannah Levavi , Theodora Anagnostou , Larysa Sanchez , Philip Friedlander , Nicholas Rohs , Demis N. Lipe , Joshua Richter
Background
T-cell-engaging bispecific antibodies (BsAbs) are a newer type of immunotherapy designed to boost T-cell cytotoxicity. They are increasingly used in cancer treatment, with drugs currently being tested and authorized for treating both liquid and solid tumors. It’s becoming more likely that emergency physicians and other acute care practitioners will treat patients experiencing adverse events related to bispecific antibodies, as these drugs are regularly given in the outpatient setting. Currently, BsAb-associated side effects are not routinely taught to Emergency Medicine residents, and a paucity of literature exists to guide currently practicing Emergency Medicine physicians and other acute care practitioners about these medications.
Objective of the review
This review was written by emergency medicine physicians in collaboration with oncologists who routinely administer BsAbs to provide guidelines and an overview on diagnosis, treatment, and management strategies for adverse events related to bispecific antibodies.
Discussion
Side effects related to BsAbs require a multidisciplinary treatment approach ideally with oncologists notified early when an adverse event is suspected. Symptom presentation is subtle with BsAb toxicity and the main adverse events to consider working up are cytokine release syndrome, immune effector cell neurotoxicity, and infection. The article also discusses unique side effects specific to FDA-approved drugs to treat leukemia, multiple myeloma, lymphoma, lung cancer, and melanoma given that this drug class has heterogeneous receptor-specific side effects.
{"title":"Diagnosis and management of bispecific T cell–engaging antibody toxicity: A primer for emergency physicians","authors":"Monica K Wattana , Jonathan Rowland , Aiham Qdaisat , Hannah Levavi , Theodora Anagnostou , Larysa Sanchez , Philip Friedlander , Nicholas Rohs , Demis N. Lipe , Joshua Richter","doi":"10.1016/j.ctrv.2025.102889","DOIUrl":"10.1016/j.ctrv.2025.102889","url":null,"abstract":"<div><h3>Background</h3><div>T-cell-engaging bispecific antibodies (BsAbs) are a newer type of immunotherapy designed to boost T-cell cytotoxicity. They are increasingly used in cancer treatment, with drugs currently being tested and authorized for treating both liquid and solid tumors. It’s becoming more likely that emergency physicians and other acute care practitioners will treat patients experiencing adverse events related to bispecific antibodies, as these drugs are regularly given in the outpatient setting. Currently, BsAb-associated side effects are not routinely taught to Emergency Medicine residents, and a paucity of literature exists to guide currently practicing Emergency Medicine physicians and other acute care practitioners about these medications.</div></div><div><h3>Objective of the review</h3><div>This review was written by emergency medicine physicians in collaboration with oncologists who routinely administer BsAbs to provide guidelines and an overview on diagnosis, treatment, and management strategies for adverse events related to bispecific antibodies.</div></div><div><h3>Discussion</h3><div>Side effects related to BsAbs require a multidisciplinary treatment approach ideally with oncologists notified early when an adverse event is suspected. Symptom presentation is subtle with BsAb toxicity and the main adverse events to consider working up are cytokine release syndrome, immune effector cell neurotoxicity, and infection. The article also discusses unique side effects specific to FDA-approved drugs to treat leukemia, multiple myeloma, lymphoma, lung cancer, and melanoma given that this drug class has heterogeneous receptor-specific side effects.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"134 ","pages":"Article 102889"},"PeriodicalIF":9.6,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143223576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.ctrv.2025.102887
Pier Paolo M. Berton Giachetti , Ambra Carnevale Schianca , Dario Trapani , Antonio Marra , Angela Toss , Caterina Marchiò , Maria Vittoria Dieci , Oreste Davide Gentilini , Carmen Criscitiello , Kevin Kalinsky , Joseph A. Sparano , Giuseppe Curigliano
Multigene prognostic genomic assays have become essential tools in the management of early breast cancer (BC), providing information that help in risk-stratification, to provide risk-adapted decision-making of adjuvant treatments. Clinical practice guidelines recommend refining the prognostic information provided by clinical and pathology features with the use of genomic tests, such as Oncotype DX®, to classify cancers into risk groups and inform adjuvant treatment strategies. However, the clinical value (i.e., prognostic and/or predictive) and applicability of these assays vary due to differences in the clinical setting, especially in those populations that were underrepresented in pivotal clinical trials. Oncotype DX® is a broadly utilized genomic test for breast cancer, having the highest level of supporting evidence to inform clinical practice. Our manuscript provides a comprehensive overview on this recurrence score assay, evaluates supporting evidence across patient populations, and discusses their impact on treatment decisions in those groups of patients underrepresented in pivotal clinical trials, where evidence is limited with the use of Oncotype DX.
{"title":"Current controversies in the use of Oncotype DX in early breast cancer","authors":"Pier Paolo M. Berton Giachetti , Ambra Carnevale Schianca , Dario Trapani , Antonio Marra , Angela Toss , Caterina Marchiò , Maria Vittoria Dieci , Oreste Davide Gentilini , Carmen Criscitiello , Kevin Kalinsky , Joseph A. Sparano , Giuseppe Curigliano","doi":"10.1016/j.ctrv.2025.102887","DOIUrl":"10.1016/j.ctrv.2025.102887","url":null,"abstract":"<div><div>Multigene prognostic genomic assays have become essential tools in the management of early breast cancer (BC), providing information that help in risk-stratification, to provide risk-adapted decision-making of adjuvant treatments. Clinical practice guidelines recommend refining the prognostic information provided by clinical and pathology features with the use of genomic tests, such as Oncotype DX®, to classify cancers into risk groups and inform adjuvant treatment strategies. However, the clinical value (i.e., prognostic and/or predictive) and applicability of these assays vary due to differences in the clinical setting, especially in those populations that were underrepresented in pivotal clinical trials. Oncotype DX® is a broadly utilized genomic test for breast cancer, having the highest level of supporting evidence to inform clinical practice. Our manuscript provides a comprehensive overview on this recurrence score assay, evaluates supporting evidence across patient populations, and discusses their impact on treatment decisions in those groups of patients underrepresented in pivotal clinical trials, where evidence is limited with the use of Oncotype DX.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"135 ","pages":"Article 102887"},"PeriodicalIF":9.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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