Pub Date : 2025-07-03DOI: 10.1016/j.ctrv.2025.102991
Zoulikha M. Zaïr , Gemma Butterworth , Mariam Shalaby , Eduard Oštarijaš , Fiona Thisthlethwaite
Engineered to activate a patient’s own immune response, T Cell Engagers (TCEs) are positioned to mediate T cell directed cytotoxicity through targeted engagement of a tumour antigen. Despite their attractive properties TCE therapies have yet to be widely used in the treatment of solid tumours with several obstacles that include adverse toxicity profiles.
This systematic review and meta-analysis assessed the toxicity associated with T-cell engagers (TCEs) in the treatment of solid tumours. Papers were sourced from MEDLINE, Cochrane Library, CINHL, EMBASE, Web of Knowledge, Scopus. Prevalence data from the identified primary studies was pooled using an inverse variance method with a restricted maximum likelihood estimator. Freeman-Tukey double arcsine transformation to determine toxicity prevalence and confidence intervals.
A total of 1147 publications were identified of which 30 were included for systematic review. Toxicity profiles from 17 TCEs, comprising 9 different ligands that utilised the CD3, CD40, CD28 or CD64 signalling pathways were characterised in this study. Of these studies, 21 publications were included for meta-analysis, focussing on four TCEs: catumaxomab, ertumaxomab, tebentafusb, and MDX-H210. Meta-analysis found that the most prevalent toxicities were gastrointestinal and inflammatory. Subgroup analysis revealed that Gastrointestinal toxicity (GI) toxicity was independent of tumour type or ligand. Cytokine Release Syndrome (CRS) is potentially being under-reported due to challenges of differentiation of CRS from other inflammatory mediated constituent symptoms, although Fc-independent TCEs were linked to lower inflammatory toxicity. The review highlights TCE-dependent toxicity profiles and highlights key features that may ameliorate TCE tolerance.
T细胞接合物（tce）被设计为激活患者自身的免疫反应，通过靶向接合肿瘤抗原介导T细胞定向的细胞毒性。尽管具有吸引人的特性，但TCE疗法尚未广泛应用于实体肿瘤的治疗，存在一些障碍，包括不良毒性特征。本系统综述和荟萃分析评估了与t细胞接合剂（TCEs）治疗实体肿瘤相关的毒性。论文来源于MEDLINE， Cochrane Library， CINHL， EMBASE, Web of Knowledge, Scopus。来自确定的主要研究的患病率数据使用限制最大似然估计的反方差方法进行汇总。Freeman-Tukey双反正弦变换确定毒性流行率和置信区间。共确定了1147份出版物，其中30份纳入系统评价。本研究表征了17种tce的毒性特征，包括9种不同的配体，利用CD3、CD40、CD28或CD64信号通路。在这些研究中，21篇出版物被纳入荟萃分析，重点是四种TCEs: catumaxomab、ertumaxomab、tebentafusb和MDX-H210。荟萃分析发现，最常见的毒性是胃肠道和炎症。亚组分析显示胃肠道毒性（GI）毒性与肿瘤类型或配体无关。细胞因子释放综合征（CRS）可能被低估，因为CRS与其他炎症介导的成分症状难以区分，尽管不依赖fc的tce与较低的炎症毒性有关。该综述强调了TCE依赖性毒性特征，并强调了可能改善TCE耐受性的关键特征。
{"title":"T-cell engager toxicity in clinical phase trials; A systematic review and meta-analysis","authors":"Zoulikha M. Zaïr , Gemma Butterworth , Mariam Shalaby , Eduard Oštarijaš , Fiona Thisthlethwaite","doi":"10.1016/j.ctrv.2025.102991","DOIUrl":"10.1016/j.ctrv.2025.102991","url":null,"abstract":"<div><div>Engineered to activate a patient’s own immune response, T Cell Engagers (TCEs) are positioned to mediate T cell directed cytotoxicity through targeted engagement of a tumour antigen. Despite their attractive properties TCE therapies have yet to be widely used in the treatment of solid tumours with several obstacles that include adverse toxicity profiles.</div><div>This systematic review and <em>meta</em>-analysis assessed the toxicity associated with T-cell engagers (TCEs) in the treatment of solid tumours. Papers were sourced from MEDLINE, Cochrane Library, CINHL, EMBASE, Web of Knowledge, Scopus. Prevalence data from the identified primary studies was pooled using an inverse variance method with a restricted maximum likelihood estimator. Freeman-Tukey double arcsine transformation to determine toxicity prevalence and confidence intervals.</div><div>A total of 1147 publications were identified of which 30 were included for systematic review. Toxicity profiles from 17 TCEs, comprising 9 different ligands that utilised the CD3, CD40, CD28 or CD64 signalling pathways were characterised in this study. Of these studies, 21 publications were included for <em>meta</em>-analysis, focussing on four TCEs: catumaxomab, ertumaxomab, tebentafusb, and MDX-H210. Meta-analysis found that the most prevalent toxicities were gastrointestinal and inflammatory. Subgroup analysis revealed that Gastrointestinal toxicity (GI) toxicity was independent of tumour type or ligand. Cytokine Release Syndrome (CRS) is potentially being under-reported due to challenges of differentiation of CRS from other inflammatory mediated constituent symptoms, although Fc-independent TCEs were linked to lower inflammatory toxicity. The review highlights TCE-dependent toxicity profiles and highlights key features that may ameliorate TCE tolerance.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"139 ","pages":"Article 102991"},"PeriodicalIF":9.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588857","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 : 2025-07-01DOI: 10.1016/j.ctrv.2025.102990
Paul K. Paik , Wade T. Iams , Hatim Husain , Richard M. O’Hara Jr , Emmanuel Adewusi , Xiuning Le
The management of non-small cell lung cancer (NSCLC) has been transformed by the identification of specific therapies which target oncogenic drivers, including MET exon 14 (METex14) skipping, which occurs in 3–4% of patients. The development of selective MET inhibitors, such as tepotinib, has provided much-needed oral, targeted treatment options for these patients who otherwise have poor outcomes. In the largest trial involving patients with METex14 skipping NSCLC, the Phase II VISION study, tepotinib demonstrated robust and durable efficacy, which was especially notable when used in the first-line setting. Subgroup analyses demonstrated consistent efficacy in older and younger patients, Asian patients, and patients with brain metastases. The trial supported initial approval of tepotinib in Japan in 2020 and later in the US (accelerated approval: 2021; full approval: 2024) and many other countries worldwide. Here we delve into published literature on tepotinib, overview the mechanism of action and pharmacology, and provide a deep-dive into data from the pivotal VISION study, examining long-term outcomes, insights relevant for treatment sequencing, and biomarker analyses. We also discuss real-world data for tepotinib, indirect comparisons versus immuno- and/or chemotherapy, and provide experience from clinical practice, including guidance on managing adverse events, to provide a valuable aid for clinical practitioners.
{"title":"Tepotinib in patients with MET exon 14 skipping non-small cell lung cancer","authors":"Paul K. Paik , Wade T. Iams , Hatim Husain , Richard M. O’Hara Jr , Emmanuel Adewusi , Xiuning Le","doi":"10.1016/j.ctrv.2025.102990","DOIUrl":"10.1016/j.ctrv.2025.102990","url":null,"abstract":"<div><div>The management of non-small cell lung cancer (NSCLC) has been transformed by the identification of specific therapies which target oncogenic drivers, including <em>MET</em> exon 14 (<em>MET</em>ex14) skipping, which occurs in 3–4% of patients. The development of selective MET inhibitors, such as tepotinib, has provided much-needed oral, targeted treatment options for these patients who otherwise have poor outcomes. In the largest trial involving patients with <em>MET</em>ex14 skipping NSCLC, the Phase II VISION study, tepotinib demonstrated robust and durable efficacy, which was especially notable when used in the first-line setting. Subgroup analyses demonstrated consistent efficacy in older and younger patients, Asian patients, and patients with brain metastases. The trial supported initial approval of tepotinib in Japan in 2020 and later in the US (accelerated approval: 2021; full approval: 2024) and many other countries worldwide. Here we delve into published literature on tepotinib, overview the mechanism of action and pharmacology, and provide a deep-dive into data from the pivotal VISION study, examining long-term outcomes, insights relevant for treatment sequencing, and biomarker analyses. We also discuss real-world data for tepotinib, indirect comparisons versus immuno- and/or chemotherapy, and provide experience from clinical practice, including guidance on managing adverse events, to provide a valuable aid for clinical practitioners.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"139 ","pages":"Article 102990"},"PeriodicalIF":10.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722878","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}
Ovarian cancer (OC) is the leading cause of death among gynecological malignancies, with limited treatment options for advanced and platinum-resistant disease. This systematic review analyzes phase I trials to assess recent therapeutic advancements.
Methods
We performed a systematic review of phase I trials in OC, published between 2012 and 2023, retrieving data on trial characteristics and outcomes. Studies were classified according to the tested treatment strategies into chemotherapy-only (CO), chemotherapy + non-chemotherapy agents (CNC) and chemotherapy-free (CF).
Results
78 trials were included, with more than 50 % of them published in the last four years. Overall, chemotherapy and immunotherapy were the most investigated agents. Fourteen trials (17.9 %) evaluated a CO strategy, 42 (53.8 %) a CNC combination and 22 (28.2 %) a CF therapy. Dose-limiting toxicities and toxic deaths were observed in 71 % and 100 % of CO studies, in 45.2 % and 21 % of CNC trials and in 37.4 % and 13.6 % of CF trials, respectively. CNC regimens outperformed the other treatment types in terms of efficacy outcomes, including overall response rate (11.5 % CO; 32.2 % CNC; 25.5 % CF), clinical benefit rate (40 % CO; 62 % CNC; 52 % CF) and median progression free survival (mPFS 5.9 months CO; 6.45 months CNC; 4.85 months CF). Trials enrolling platinum resistant or agnostic patients displayed worse clinical outcomes.
Conclusions
In the last years, there has been an increasing number of phase 1 trials assessing new agents and new combinations in patients with OC. Chemotherapy-free strategies display a more favorable safety profile, while regimens combining CNC agents seem to be more effective compared to CO approaches.
{"title":"A systematic review of phase I trials in patients with ovarian cancer","authors":"Giuliana Pavone , Federica Martorana , Vincenza Ricco , Esteban Andres Ciliberti , Marta Nerone , Cristiana Sessa , Ilaria Colombo","doi":"10.1016/j.ctrv.2025.102982","DOIUrl":"10.1016/j.ctrv.2025.102982","url":null,"abstract":"<div><h3>Background</h3><div>Ovarian cancer (OC) is the leading cause of death among gynecological malignancies, with limited treatment options for advanced and platinum-resistant disease. This systematic review analyzes phase I trials to assess recent therapeutic advancements.</div></div><div><h3>Methods</h3><div>We performed a systematic review of phase I trials in OC, published between 2012 and 2023, retrieving data on trial characteristics and outcomes. Studies were classified according to the tested treatment strategies into chemotherapy-only (CO), chemotherapy + non-chemotherapy agents (CNC) and chemotherapy-free (CF).</div></div><div><h3>Results</h3><div>78 trials were included, with more than 50 % of them published in the last four years. Overall, chemotherapy and immunotherapy were the most investigated agents. Fourteen trials (17.9 %) evaluated a CO strategy, 42 (53.8 %) a CNC combination and 22 (28.2 %) a CF therapy. Dose-limiting toxicities and toxic deaths were observed in 71 % and 100 % of CO studies, in 45.2 % and 21 % of CNC trials and in 37.4 % and 13.6 % of CF trials, respectively. CNC regimens outperformed the other treatment types in terms of efficacy outcomes, including overall response rate (11.5 % CO; 32.2 % CNC; 25.5 % CF), clinical benefit rate (40 % CO; 62 % CNC; 52 % CF) and median progression free survival (mPFS 5.9 months CO; 6.45 months CNC; 4.85 months CF). Trials enrolling platinum resistant or agnostic patients displayed worse clinical outcomes.</div></div><div><h3>Conclusions</h3><div>In the last years, there has been an increasing number of phase 1 trials assessing new agents and new combinations in patients with OC. Chemotherapy-free strategies display a more favorable safety profile, while regimens combining CNC agents seem to be more effective compared to CO approaches.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"139 ","pages":"Article 102982"},"PeriodicalIF":9.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502652","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 : 2025-06-16DOI: 10.1016/j.ctrv.2025.102981
Vittorio Stumpo , Alessandro Carretta , Jacopo Bellomo , Luis Padevit , Victor Staartjes , Nicolai Maldaner , Penelope Coker , Jorn Fierstra , Michael Weller , Emilie Le Rhun , Marcus Czabanka , Oliver Bozinov , Luca Regli , Marian Christoph Neidert , Carlo Serra , Stefanos Voglis
Background
Microsurgical resection of brain metastases (BM) has traditionally been a mainstay of local control for large or symptomatic lesions. Maximal tumor burden reduction remains controversial in the multidisciplinary management of BM patients and needs to be re-evaluated in view of new systemic treatment options. We conducted a systematic review and meta-analysis to evaluate the role of extent of resection (EOR)/residual volume (RV) for progression-free (PFS) and overall survival (OS) in patients with BM.
Methods
A systematic review was performed according to PRISMA guidelines and included studies’ quality was assessed with the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. Study characteristics were tabulated and critically reviewed. Results from Cox-regression models and log-rank tests for the association of gross total resection (GTR) versus subtotal resection (STR) with PFS and OS were extracted to perform separate random-effects meta-analyses.
Results
Thirty-nine articles were included, all of them being retrospective and all but 3 monocentric. Most studies included BM from heterogenous primary tumors, with 9 focusing on BM from a single primary. Systemic therapies were variably reported and only 2 studies reported on the use of steroids. Twenty-one studies showed a significant association of EOR/RV with improved OS. Meta-analysis of studies reporting multivariable Cox-regression models (n = 11) showed a significant association of GTR with longer OS (HR 0.67, 95 %CI 0.56–0.81, p < 0.001).
Conclusion
Although in several studies higher EOR/lower RV was associated with improved OS, evidence consists of heterogeneous cohorts and rarely includes primary tumor-specific systemic therapies or relevant confounding covariates. New studies are needed to elucidate the role of microsurgical tumor burden reduction in BM patients in the era of targeted or immune modulatory therapies.
背景：显微外科手术切除脑转移瘤（BM）传统上是局部控制大型或症状性病变的主要方法。最大限度地减轻肿瘤负担在BM患者的多学科管理中仍然存在争议，需要根据新的全身治疗方案重新评估。我们进行了一项系统回顾和荟萃分析，以评估切除范围(EOR)/残余体积（RV）对BM患者无进展（PFS）和总生存期（OS）的作用。方法按照PRISMA指南进行系统评价，采用推荐、评估、发展和评价分级（GRADE）工具对纳入研究的质量进行评价。将研究特征制成表格并进行严格审查。从cox回归模型和log-rank检验中提取总全切除（GTR）与次全切除（STR）与PFS和OS相关性的结果，进行单独的随机效应荟萃分析。结果共纳入39篇文献，均为回顾性文献，除3篇为单中心文献外，其余均为回顾性文献。大多数研究包括来自异质原发肿瘤的脑转移，其中9项研究关注来自单一原发肿瘤的脑转移。系统性治疗的报道各不相同，只有2项研究报道了类固醇的使用。21项研究显示EOR/RV与OS改善有显著关联。对报告多变量cox回归模型的研究（n = 11）进行荟萃分析显示，GTR与较长的生存期显著相关(HR 0.67, 95% CI 0.56-0.81, p <；0.001)。虽然在一些研究中，较高的EOR/较低的RV与改善的OS相关，但证据是由异质性队列组成的，很少包括原发性肿瘤特异性全身治疗或相关的混杂协变量。在靶向或免疫调节治疗时代，需要新的研究来阐明显微外科手术减轻BM患者肿瘤负担的作用。
{"title":"Surgical tumor volume reduction in patients with brain metastases: A systematic review and meta-analysis","authors":"Vittorio Stumpo , Alessandro Carretta , Jacopo Bellomo , Luis Padevit , Victor Staartjes , Nicolai Maldaner , Penelope Coker , Jorn Fierstra , Michael Weller , Emilie Le Rhun , Marcus Czabanka , Oliver Bozinov , Luca Regli , Marian Christoph Neidert , Carlo Serra , Stefanos Voglis","doi":"10.1016/j.ctrv.2025.102981","DOIUrl":"10.1016/j.ctrv.2025.102981","url":null,"abstract":"<div><h3>Background</h3><div>Microsurgical resection of brain metastases (BM) has traditionally been a mainstay of local control for large or symptomatic lesions. Maximal tumor burden reduction remains controversial in the multidisciplinary management of BM patients and needs to be re-evaluated in view of new systemic treatment options. We conducted a systematic review and <em>meta</em>-analysis to evaluate the role of extent of resection (EOR)/residual volume (RV) for progression-free (PFS) and overall survival (OS) in patients with BM.</div></div><div><h3>Methods</h3><div>A systematic review was performed according to PRISMA guidelines and included studies’ quality was assessed with the Grading <em>of Recommendations,</em> Assessment<em>, Development, and</em> Evaluations (GRADE) tool. Study characteristics were tabulated and critically reviewed. Results from Cox-regression models and log-rank tests for the association of gross total resection (GTR) versus subtotal resection (STR) with PFS and OS were extracted to perform separate random-effects <em>meta</em>-analyses.</div></div><div><h3>Results</h3><div>Thirty-nine articles were included, all of them being retrospective and all but 3 monocentric. Most studies included BM from heterogenous primary tumors, with 9 focusing on BM from a single primary. Systemic therapies were variably reported and only 2 studies reported on the use of steroids. Twenty-one studies showed a significant association of EOR/RV with improved OS. Meta-analysis of studies reporting multivariable Cox-regression models (n = 11) showed a significant association of GTR with longer OS (HR 0.67, 95 %CI 0.56–0.81, p < 0.001).</div></div><div><h3>Conclusion</h3><div>Although in several studies higher EOR/lower RV was associated with improved OS, evidence consists of heterogeneous cohorts and rarely includes primary tumor-specific systemic therapies or relevant confounding covariates. New studies are needed to elucidate the role of microsurgical tumor burden reduction in BM patients in the era of targeted or immune modulatory therapies.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"139 ","pages":"Article 102981"},"PeriodicalIF":9.6,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338812","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 : 2025-06-15DOI: 10.1016/j.ctrv.2025.102976
L. Cortesi , F. Miglietta , L. Arecco , D. Bernardi , L. Biganzoli , L. Del Mastro , MV. Dieci , J. Foglietta , L. Fortunato , P. Franco , E.Lucci Cordisco , P. Mantellini , C. Marchio’ , B. Meduri , G. Micallo , A. Musolino , A. Salvetti , D. Turchetti , A. Zambelli , C. Angiolini , S. Gori
The introduction of Poly (ADP-ribose) Polymerase (PARP) inhibitors in both metastatic and early-stage breast cancer (BC) treatment has led to the emergence of Mainstreaming Cancer Genetics (MCG) as a new approach to genetic counselling, predictive of therapy outcomes. Therefore, the BRCA testing criteria for therapeutic purposes require further implementation. This position paper outlines the Italian indications for predictive genetic testing, approved by a multidisciplinary Expert Panel representing major scientific societies involved in BC treatment in Italy.
We utilized the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, and framed clinical questions as population, intervention, comparison and outcome (PICO). The final recommendations were determined through a voting process, covering key topics such as eligibility criteria for onco-genetic counselling, the role of contralateral prophylactic mastectomy (CPM) in patients harboring BRCA1/2 germline pathogenic variants (gPV), and the positioning of predictive BRCA1/2 test.
As results, the Expert Panel defined three distinct patient groups eligible for onco-genetic counselling, based on the a priori likelihood of carrying a gPV and the purpose of testing (predictive vs preventive). A conditional recommendation in favor of CPM in patients with a history of surgically treated BC and a BRCA gPV was suggested. Finally, a multidisciplinary pathway for BRCA testing was proposed, for patients with triple negative and hormone receptor-positive (HR+)/HER2-negative (HER2−) BC.
In conclusion, the predictive BRCA testing inside the onco-genetic framework marks an important step-forward in BC management. However, the integration of somatic testing, digital pathology, and artificial intelligence-driven models could refine patient selection for tailored treatments.
{"title":"PREDICTIVE BRCA GENETIC TESTING IN ITALIAN PATIENTS WITH BREAST CANCER: A POSITION PAPER OF ITALIAN SCIENTIFIC SOCIETIES [Italian Association of Medical Oncology(AIOM); Italian Association of Radiotherapy and Clinical Oncology (AIRO); Italian National Association of Breast Surgeons (ANISC); Italian Society of Pathological Anatomy and Diagnostic Cytology (SIAPeC-IAP); Italian Society of Surgical Oncology (SICO); Italian Society of Human Genetic (SIGU); Italian Society of General Practice (SIMG); Italian Society of Medical and Interventional Radiology (SIRM)]","authors":"L. Cortesi , F. Miglietta , L. Arecco , D. Bernardi , L. Biganzoli , L. Del Mastro , MV. Dieci , J. Foglietta , L. Fortunato , P. Franco , E.Lucci Cordisco , P. Mantellini , C. Marchio’ , B. Meduri , G. Micallo , A. Musolino , A. Salvetti , D. Turchetti , A. Zambelli , C. Angiolini , S. Gori","doi":"10.1016/j.ctrv.2025.102976","DOIUrl":"10.1016/j.ctrv.2025.102976","url":null,"abstract":"<div><div>The introduction of Poly (ADP-ribose) Polymerase (PARP) inhibitors in both metastatic and early-stage breast cancer (BC) treatment has led to the emergence of Mainstreaming Cancer Genetics (MCG) as a new approach to genetic counselling, predictive of therapy outcomes. Therefore, the <em>BRCA</em> testing criteria for therapeutic purposes require further implementation. This position paper outlines the Italian indications for predictive genetic testing, approved by a multidisciplinary Expert Panel representing major scientific societies involved in BC treatment in Italy.</div><div>We utilized the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, and framed clinical questions as population, intervention, comparison and outcome (PICO). The final recommendations were determined through a voting process, covering key topics such as eligibility criteria for onco-genetic counselling, the role of contralateral prophylactic mastectomy (CPM) in patients harboring <em>BRCA1/2</em> germline pathogenic variants (gPV), and the positioning of predictive <em>BRCA1/2</em> test.</div><div>As results, the Expert Panel defined three distinct patient groups eligible for onco-genetic counselling, based on the <em>a priori</em> likelihood of carrying a gPV and the purpose of testing (predictive vs preventive). A conditional recommendation in favor of CPM in patients with a history of surgically treated BC and a <em>BRCA</em> gPV was suggested. Finally, a multidisciplinary pathway for <em>BRCA</em> testing was proposed, for patients with triple negative and hormone receptor-positive (HR+)/HER2-negative (HER2−) BC.</div><div>In conclusion, the predictive <em>BRCA</em> testing inside the onco-genetic framework marks an important step-forward in BC management. However, the integration of somatic testing, digital pathology, and artificial intelligence-driven models could refine patient selection for tailored treatments.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"139 ","pages":"Article 102976"},"PeriodicalIF":9.6,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330689","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 : 2025-06-14DOI: 10.1016/j.ctrv.2025.102980
Federica Giugliano , Carmine De Angelis , Barbara Pistilli , Giulia Viale , Giampaolo Bianchini , Mario Giuliano , Luca Malorni , Beatrice Taurelli Salimbeni , Angela Esposito , Antonio Giordano , Timothy A. Yap , Giuseppe Curigliano , Carmen Criscitiello
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) improve outcomes patients affected by metastatic and early-stage hormone receptor-positive, HER2-negative breast cancer. However, approximately 20% of these tumors exhibit intrinsic resistance to such therapies, and most develop acquired resistance mechanisms that drive progression. Biomarker analyses of biological samples from patients treated with CDK4/6i plus ET have identified potential targets for therapeutic combinations. In this review, we discuss the mechanisms of action and resistance to CDK4/6i, providing a comprehensive overview of emerging efficacy and safety data, biomarker-driven strategies, and ongoing clinical trials. Finally, we delineate key research priorities aimed at guiding the development of innovative therapeutic combinations.
{"title":"Overcoming Resistance to CDK4/6 inhibitors in Hormone Receptor positive, HER2 negative breast cancer: Innovative Combinations and Emerging Strategies","authors":"Federica Giugliano , Carmine De Angelis , Barbara Pistilli , Giulia Viale , Giampaolo Bianchini , Mario Giuliano , Luca Malorni , Beatrice Taurelli Salimbeni , Angela Esposito , Antonio Giordano , Timothy A. Yap , Giuseppe Curigliano , Carmen Criscitiello","doi":"10.1016/j.ctrv.2025.102980","DOIUrl":"10.1016/j.ctrv.2025.102980","url":null,"abstract":"<div><div>Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) improve outcomes patients affected by metastatic and early-stage hormone receptor-positive, HER2-negative breast cancer. However, approximately 20% of these tumors exhibit intrinsic resistance to such therapies, and most develop acquired resistance mechanisms that drive progression. Biomarker analyses of biological samples from patients treated with CDK4/6i plus ET have identified potential targets for therapeutic combinations. In this review, we discuss the mechanisms of action and resistance to CDK4/6i, providing a comprehensive overview of emerging efficacy and safety data, biomarker-driven strategies, and ongoing clinical trials. Finally, we delineate key research priorities aimed at guiding the development of innovative therapeutic combinations.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"139 ","pages":"Article 102980"},"PeriodicalIF":9.6,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330688","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 : 2025-06-14DOI: 10.1016/j.ctrv.2025.102974
Saby George , Maria T. Bourlon , Michael J. Overman , Matt Dixon , Karishma Shelley , Kristen J. Markus , Rachel M. Kewley , Sophie I. Pope , Laurence Albigès
Subcutaneous (SC) formulations of oncology therapies offer a potentially less time-consuming and more convenient alternative to intravenous (IV) administration. However, exploring the potential benefits of SC over IV administration from a broader perspective is necessary to understand the larger-scale impact. In this systematic literature review (SLR), we evaluated the efficacy, pharmacokinetics/pharmacodynamics (PK/PD), safety, and patient and healthcare provider (HCP) preference for SC/IV oncology therapies, along with differences in patient outcomes, costs, and time requirements. The SLR was conducted in January 2019 and updated in May 2023, and included 169 publications. Studies providing comparative results between IV and SC formulations regarding clinical, economic, and patient outcomes were included. The focus was anticancer therapies for which both IV and SC formulations are being developed in phase 3 clinical trials, or are regulatory approved. SC administration was associated with savings in HCP time and patient chair time. Direct and indirect cost-savings were also observed. Increased treatment satisfaction and patient/HCP preference was reported with SC administration, as was improved caregiver productivity. The relative tolerability of SC and IV formulations for oncology drugs was similar; however, a higher incidence of injection-site reactions was reported with SC administration. Overall survival, PK/PD, and overall response rate results were comparable between IV and SC administration. This SLR demonstrates that SC and IV administration had comparable efficacy, PK/PD, and tolerability profiles, with SC administration associated with cost and time savings, and generally preferred by patients and HCPs. Therefore, SC administration of oncology therapies may offer advantages over IV administration.
{"title":"Systematic literature review of intravenous versus subcutaneous administration of oncology therapies: A clinical, economic and patient perspective","authors":"Saby George , Maria T. Bourlon , Michael J. Overman , Matt Dixon , Karishma Shelley , Kristen J. Markus , Rachel M. Kewley , Sophie I. Pope , Laurence Albigès","doi":"10.1016/j.ctrv.2025.102974","DOIUrl":"10.1016/j.ctrv.2025.102974","url":null,"abstract":"<div><div>Subcutaneous (SC) formulations of oncology therapies offer a potentially less time-consuming and more convenient alternative to intravenous (IV) administration. However, exploring the potential benefits of SC over IV administration from a broader perspective is necessary to understand the larger-scale impact. In this systematic literature review (SLR), we evaluated the efficacy, pharmacokinetics/pharmacodynamics (PK/PD), safety, and patient and healthcare provider (HCP) preference for SC/IV oncology therapies, along with differences in patient outcomes, costs, and time requirements. The SLR was conducted in January 2019 and updated in May 2023, and included 169 publications. Studies providing comparative results between IV and SC formulations regarding clinical, economic, and patient outcomes were included. The focus was anticancer therapies for which both IV and SC formulations are being developed in phase 3 clinical trials, or are regulatory approved. SC administration was associated with savings in HCP time and patient chair time. Direct and indirect cost-savings were also observed. Increased treatment satisfaction and patient/HCP preference was reported with SC administration, as was improved caregiver productivity. The relative tolerability of SC and IV formulations for oncology drugs was similar; however, a higher incidence of injection-site reactions was reported with SC administration. Overall survival, PK/PD, and overall response rate results were comparable between IV and SC administration. This SLR demonstrates that SC and IV administration had comparable efficacy, PK/PD, and tolerability profiles, with SC administration associated with cost and time savings, and generally preferred by patients and HCPs. Therefore, SC administration of oncology therapies may offer advantages over IV administration.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"139 ","pages":"Article 102974"},"PeriodicalIF":9.6,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513968","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 : 2025-06-14DOI: 10.1016/j.ctrv.2025.102979
Peng Qiu , Xiaopeng Yu , Fushuang Zheng , Xi Gu , QianQiu Huang , Ke Qin , Yueting Hu , Bowen Liu , Tianming Xu , Tao Zhang , Guanglei Chen , Yang Liu
Breast cancer is characterized by significant molecular heterogeneity; therefore, there are distinct clinical features, treatment modalities, and prognostic outcomes across its various molecular subtypes. In the era of precision medicine, liquid biopsy has emerged as a convenient and minimally invasive technique capable of dynamically representing the comprehensive tumor gene spectrum. This review systematically elaborates the clinical value of liquid biopsy as a breakthrough tool for precision diagnosis and treatment in breast cancer through dynamic detection of key biomarkers, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and non-coding RNA (ncRNA). Specific genetic mutations and methylation signatures in ctDNA can be applied to early breast cancer screening, minimal residual disease monitoring, and tracking drug resistance mechanisms. CTCs enumeration (≥1/7.5 mL in early-stage cancer or ≥ 5/7.5 mL in metastatic cancer) and PD-L1 expression levels demonstrate direct correlations with prognostic stratification and the efficacy of immunotherapy. As the specificity and sensitivity of liquid biopsy continue to improve, personalized treatment strategies, informed by biomarker analysis and targeted precision therapies, have unveiled new avenues of hope for patients with breast cancer. However, several challenges persist in the practical application of liquid biopsy. Despite persistent challenges, such as insufficient standardization and difficulties in resolving low-abundance variants, future advancements should focus on multi-omics integration and AI-driven technological breakthroughs to overcome bottlenecks in clinical translation. This review summarizes cutting-edge liquid biopsy technologies for identifying clinically significant molecular biomarkers, focusing on discussing critical challenges in the strategies to advance precision oncology applications for optimized treatment guidance and disease surveillance in breast cancer.
{"title":"Advancements in liquid biopsy for breast Cancer: Molecular biomarkers and clinical applications","authors":"Peng Qiu , Xiaopeng Yu , Fushuang Zheng , Xi Gu , QianQiu Huang , Ke Qin , Yueting Hu , Bowen Liu , Tianming Xu , Tao Zhang , Guanglei Chen , Yang Liu","doi":"10.1016/j.ctrv.2025.102979","DOIUrl":"10.1016/j.ctrv.2025.102979","url":null,"abstract":"<div><div>Breast cancer is characterized by significant molecular heterogeneity; therefore, there are distinct clinical features, treatment modalities, and prognostic outcomes across its various molecular subtypes. In the era of precision medicine, liquid biopsy has emerged as a convenient and minimally invasive technique capable of dynamically representing the comprehensive tumor gene spectrum. This review systematically elaborates the clinical value of liquid biopsy as a breakthrough tool for precision diagnosis and treatment in breast cancer through dynamic detection of key biomarkers, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and non-coding RNA (ncRNA). Specific genetic mutations and methylation signatures in ctDNA can be applied to early breast cancer screening, minimal residual disease monitoring, and tracking drug resistance mechanisms. CTCs enumeration (≥1/7.5 mL in early-stage cancer or ≥ 5/7.5 mL in metastatic cancer) and PD-L1 expression levels demonstrate direct correlations with prognostic stratification and the efficacy of immunotherapy. As the specificity and sensitivity of liquid biopsy continue to improve, personalized treatment strategies, informed by biomarker analysis and targeted precision therapies, have unveiled new avenues of hope for patients with breast cancer. However, several challenges persist in the practical application of liquid biopsy. Despite persistent challenges, such as insufficient standardization and difficulties in resolving low-abundance variants, future advancements should focus on multi-omics integration and AI-driven technological breakthroughs to overcome bottlenecks in clinical translation. This review summarizes cutting-edge liquid biopsy technologies for identifying clinically significant molecular biomarkers, focusing on discussing critical challenges in the strategies to advance precision oncology applications for optimized treatment guidance and disease surveillance in breast cancer.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"139 ","pages":"Article 102979"},"PeriodicalIF":9.6,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321570","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 : 2025-06-13DOI: 10.1016/j.ctrv.2025.102978
Stefano Agliardi , Chiara Veronese , Ferdinando Panzeri , Simonetta Palazzini , Greta Guarnieri , Stefano Loiacono , Vanessa Martinelli , Anna Maria Potenza , Emanuele Sbraga , Eleonora Rissotto , Elvira Inglese , Federica Tosi , Federica Villa , Giorgio Patelli , Letizia Monti , Arianna Pani , Romano Danesi , Diego Fornasari , Salvatore Siena , Andrea Sartore-Bianchi
Introduction
Immunocytokines are an emerging class of antibody-cytokine fusion proteins combining the specificity of monoclonal antibodies with the potent immunostimulatory effects of cytokines, potentially enhancing the anti-tumor immune response while reducing systemic toxicity.
Methods
We conducted a systematic review following the PRISMA guidelines. We performed a comprehensive literature search using PubMed and ClinicalTrials.gov databases. The search strategy included the terms “immunocytokine”, “cytokine”, “tumor”, and “cancer”. Filters were applied to retrieve only peer-reviewed articles and clinical trials.
Results
25 publications were retrieved: 15 were Phase I studies; 2 Phase I/II, and 8 Phase II. Regarding ongoing clinical trials, 62 studies were included: 30 were Phase I studies, 2 Phase III, and the remaining 30 were either Phase II (n = 13) or Phase I/II (n = 17). In 50/62 trials, the primary and co-primary outcomes included safety measures, such as adverse effects, dose-limiting toxicities, and maximum tolerated dose. In both studies from literature and ongoing clinical trials, the most common target was extra-domain B (EDB) of fibronectin, and the most investigated type of cancer was melanoma. While all published studies focused on solid tumors, several ongoing trials include hematologic malignancies.
Conclusions
Research interest in immunocytokines as a potential cancer treatment is increasing, although only limited data are currently available. Several trials, mainly in the early phase, are ongoing, paving the way for a possible broader clinical application of this class of immunotherapeutics.
免疫细胞因子是一类新兴的抗体-细胞因子融合蛋白，结合了单克隆抗体的特异性和细胞因子的强免疫刺激作用，潜在地增强抗肿瘤免疫反应，同时降低全身毒性。方法我们按照PRISMA指南进行了系统评价。我们使用PubMed和ClinicalTrials.gov数据库进行了全面的文献检索。搜索策略包括“免疫细胞因子”、“细胞因子”、“肿瘤”和“癌症”。筛选只用于检索同行评议的文章和临床试验。结果：共检索到25篇文献：15篇为I期研究；第I/II期工程2项及第II期工程8项关于正在进行的临床试验，纳入了62项研究：30项为I期研究，2项为III期研究，其余30项为II期（n = 13）或I/II期（n = 17）。在50/62项试验中，主要和共同主要结局包括安全性措施，如不良反应、剂量限制性毒性和最大耐受剂量。在文献研究和正在进行的临床试验中，最常见的靶点是纤维连接蛋白的extra-domain B (EDB)，研究最多的癌症类型是黑色素瘤。虽然所有发表的研究都集中在实体肿瘤上，但一些正在进行的试验包括血液恶性肿瘤。结论免疫细胞因子作为一种潜在的癌症治疗方法的研究兴趣正在增加，尽管目前可用的数据有限。几项主要处于早期阶段的试验正在进行中，为这类免疫疗法可能更广泛的临床应用铺平了道路。
{"title":"Immunocytokines in cancer treatment: A systematic review","authors":"Stefano Agliardi , Chiara Veronese , Ferdinando Panzeri , Simonetta Palazzini , Greta Guarnieri , Stefano Loiacono , Vanessa Martinelli , Anna Maria Potenza , Emanuele Sbraga , Eleonora Rissotto , Elvira Inglese , Federica Tosi , Federica Villa , Giorgio Patelli , Letizia Monti , Arianna Pani , Romano Danesi , Diego Fornasari , Salvatore Siena , Andrea Sartore-Bianchi","doi":"10.1016/j.ctrv.2025.102978","DOIUrl":"10.1016/j.ctrv.2025.102978","url":null,"abstract":"<div><h3>Introduction</h3><div>Immunocytokines are an emerging class of antibody-cytokine fusion proteins combining the specificity of monoclonal antibodies with the potent immunostimulatory effects of cytokines, potentially enhancing the anti-tumor immune response while reducing systemic toxicity.</div></div><div><h3>Methods</h3><div>We conducted a systematic review following the PRISMA guidelines<strong>.</strong> We performed a comprehensive literature search using PubMed and <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> databases. The search strategy included the terms “immunocytokine”, “cytokine”, “tumor”, and “cancer”. Filters were applied to retrieve only peer-reviewed articles and clinical trials.</div></div><div><h3>Results</h3><div>25 publications were retrieved: 15 were Phase I studies; 2 Phase I/II, and 8 Phase II. Regarding ongoing clinical trials, 62 studies were included: 30 were Phase I studies, 2 Phase III, and the remaining 30 were either Phase II (n = 13) or Phase I/II (n = 17). In 50/62 trials, the primary and co-primary outcomes included safety measures, such as adverse effects, dose-limiting toxicities, and maximum tolerated dose. In both studies from literature and ongoing clinical trials, the most common target was extra-domain B (EDB) of fibronectin, and the most investigated type of cancer was melanoma. While all published studies focused on solid tumors, several ongoing trials include hematologic malignancies.</div></div><div><h3>Conclusions</h3><div>Research interest in immunocytokines as a potential cancer treatment is increasing, although only limited data are currently available. Several trials, mainly in the early phase, are ongoing, paving the way for a possible broader clinical application of this class of immunotherapeutics.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"139 ","pages":"Article 102978"},"PeriodicalIF":9.6,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338813","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 : 2025-06-13DOI: 10.1016/j.ctrv.2025.102977
Felix Blanc-Durand , Natalie Ngoi , Diana Lim , Isabelle Ray-Coquard , David SP Tan
This review aims to consolidate the current understanding of Clear Cell Ovarian Carcinoma (CCOC), a rare yet distinct subtype of epithelial ovarian cancer. CCOC exhibits unique epidemiological, clinical and molecular features, being one of the most frequent subtypes in East Asia, often diagnosed at an early stage and frequently affecting younger women.
Its hallmark characteristics include high resistance to conventional chemotherapy, poor prognosis in advanced stage and a molecular profile distinct from high-grade serous histotype. Specifically, CCOC is characterized by a low prevalence of TP53 mutations, BRCA1/2 mutations and homologous-recombination deficiency, but a high frequency of ARID1A, along with other SWI/SNF alterations, and PIK3CA mutations, both of which represent promising therapeutic targets.
Despite the absence of validated therapies for CCOC so far, significant advancements in preclinical research and emerging clinical strategies including immunotherapy combinations offer hope for improved outcomes. Given the rarity of this cancer type, collaborative research and global partnerships have enabled robust studies and the implementation of trials with innovative personalized therapeutic approaches.
The objective of this report is to explore the epidemiology, clinical and molecular characteristics, current standard of care and evolving therapeutic strategies for CCOC patients. It will not only highlight the progress made so far, but most importantly identifies critical research priorities to optimizing patient outcomes.
{"title":"Clearer Horizons: The latest advances in clear cell ovarian cancer treatment","authors":"Felix Blanc-Durand , Natalie Ngoi , Diana Lim , Isabelle Ray-Coquard , David SP Tan","doi":"10.1016/j.ctrv.2025.102977","DOIUrl":"10.1016/j.ctrv.2025.102977","url":null,"abstract":"<div><div>This review aims to consolidate the current understanding of Clear Cell Ovarian Carcinoma (CCOC), a rare yet distinct subtype of epithelial ovarian cancer. CCOC exhibits unique epidemiological, clinical and molecular features, being one of the most frequent subtypes in East Asia, often diagnosed at an early stage and frequently affecting younger women.</div><div>Its hallmark characteristics include high resistance to conventional chemotherapy, poor prognosis in advanced stage and a molecular profile distinct from high-grade serous histotype. Specifically, CCOC is characterized by a low prevalence of <em>TP53</em> mutations, <em>BRCA1/2</em> mutations and homologous-recombination deficiency, but a high frequency of <em>ARID1A</em>, along with other SWI/SNF alterations, and <em>PIK3CA</em> mutations, both of which represent promising therapeutic targets.</div><div>Despite the absence of validated therapies for CCOC so far, significant advancements in preclinical research and emerging clinical strategies including immunotherapy combinations offer hope for improved outcomes. Given the rarity of this cancer type, collaborative research and global partnerships have enabled robust studies and the implementation of trials with innovative personalized therapeutic approaches.</div><div>The objective of this report is to explore the epidemiology, clinical and molecular characteristics, current standard of care and evolving therapeutic strategies for CCOC patients. It will not only highlight the progress made so far, but most importantly identifies critical research priorities to optimizing patient outcomes.</div></div>","PeriodicalId":9537,"journal":{"name":"Cancer treatment reviews","volume":"138 ","pages":"Article 102977"},"PeriodicalIF":9.6,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144280374","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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