Cancer Treat. Rev. [JOURNAL]
Sun
200 papers
Antiangiogenic therapies in gastric cancer: future directions for 2026 and beyond: an UNICANCER gastrointestinal group (UCGI) perspective.
Raimbourg J, Abdelghani MB, Boige V … +17 more , Botsen D, Carnot A, Coutzac C, Delaye M, De Sousa Carvalho N, Dos Santos M, Edeline J, Ghiringhelli F, Lambert A, Le Sourd S, Palmieri LJ, Pernot S, Samalin E, Smolenschi C, Vivier-Chicoteau J, Marion S, de la Fouchardière C
Cancer Treat Rev · 2026 Jun · PMID 42385352 · Publisher ↗
Antiangiogenic therapies have been extensively investigated in advanced/metastatic gastric cancers, but also in neoadjuvant settings. The anti-Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) monoclonal antibody ra...
Antiangiogenic therapies have been extensively investigated in advanced/metastatic gastric cancers, but also in neoadjuvant settings. The anti-Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) monoclonal antibody ramucirumab was the first antiangiogenic agent approved for HER2-negative metastatic gastric adenocarcinomas and remains a standard second-line treatment either alone or in combination with paclitaxel. Other VEGFR-targeting agents, such as the tyrosine kinase inhibitors (TKI) regorafenib and apatinib, have failed to demonstrate any survival benefit in the first-line settings, while providing modest improvements in pretreated patients, even when combined with Immune Checkpoint Inhibitors (ICI). Despite showing no significant benefit in Caucasian patients, apatinib has been approved in China for pretreated patients with advanced/metastatic gastric cancer. Dose-limiting toxicities, and the lack of robust predictive biomarkers for patients' stratification may both contribute to the limited efficacy of these multi-target tyrosine kinase inhibitors in gastric cancers. Several ongoing clinical trials mostly conducted in China suggest that new generation of antiangiogenic agents, particularly bispecific antibodies targeting both VEGF and Programmed Cell Death 1 (PD-1) or its ligand PD-L1, may offer greater efficacy with reduced toxicity. However, these promising preliminary data await mature overall survival results as well as clinical validation in the global population. Developing more effective drugs is closely linked to identifying reliable predictive biomarkers, which are crucial for guiding patients' selection, monitoring treatment response and optimizing therapeutic combinations and sequencing. Although several biomarker candidates have been explored, reliable predictors are still awaited. This review summarizes current evidence and explores the future of antiangiogenic agents in gastric cancers.
Treatment of breast cancer brain metastases in the era of novel drugs.
Etessami JD, Dalla Via G, Ferraro E … +3 more , Trapani D, Curigliano G, Marra A
Cancer Treat Rev · 2026 Jun · PMID 42372577 · Publisher ↗
Brain metastases from breast cancer (BCBMs) are a major cause of morbidity and mortality and remain a critical unmet clinical need across molecular subtypes. Their incidence is rising as improved systemic therapies prolo...
Brain metastases from breast cancer (BCBMs) are a major cause of morbidity and mortality and remain a critical unmet clinical need across molecular subtypes. Their incidence is rising as improved systemic therapies prolong survival in metastatic breast cancer and advances in neuroimaging allow earlier detection of central nervous system (CNS) disease. Historically, management relied mainly on local approaches such as surgery and radiotherapy because many systemic agents have limited ability to cross the blood-brain barrier. However, the therapeutic landscape is rapidly evolving with the development of systemic treatments showing clinically meaningful intracranial activity. In hormone receptor-positive/HER2-negative disease, treatment options are expanding with targeted and novel endocrine-based therapies that may achieve therapeutically relevant CNS concentrations. In addition, targeting the PI3K/AKT/mTOR pathway and the increasing use of antibody-drug conjugates (ADCs), including trastuzumab deruxtecan in HER2-low and-ultralow disease, may further broaden systemic strategies. In HER2-positive breast cancer, brain-penetrant tyrosine kinase inhibitors and highly active ADCs have significantly improved outcomes. Tucatinib-based combinations and trastuzumab deruxtecan have demonstrated substantial intracranial activity in prospective trials, shifting the treatment paradigm by supporting systemic therapy even in the presence of active brain metastases. Lastly, in triple-negative breast cancer, outcomes remain poor, but ADCs, immunotherapy-based strategies, and PARP inhibitors for germline BRCA-mutated disease are under investigation. A major limitation remains the underrepresentation of patients with brain metastases in clinical trials. This review summarizes current evidence on systemic therapies for BCBM across subtypes and highlights the need for CNS-inclusive trials and the development of effective CNS-active treatments.
Standardization of objectives and response criteria for neoadjuvant immunotherapy in resectable squamous cell carcinoma of the head and neck.
Resteghini C, Argiris A, Blanchard P … +25 more , Braña I, Camarda AM, Chan ATC, Ferris R, Gregoire V, Harrington KJ, Tinhofer-Keilholz I, Koljenović S, Lee NY, Leemans CR, Machiels JP, Mehanna H, Metclaff R, O'Sullivan B, Oosting S, Orlandi E, Paleri V, Psyrri A, Saba NF, Schmitz S, Simon C, Tahara M, Poorten VV, Vošmik M, Bossi P
Cancer Treat Rev · 2026 Jun · PMID 42365828 · Publisher ↗
The management of locally-advanced, resectable head and neck squamous cell carcinoma (HNSCC) is undergoing a major shift driven by the integration of neoadjuvant immunotherapy (nIO). The rationale for nIO lies in its adm...
The management of locally-advanced, resectable head and neck squamous cell carcinoma (HNSCC) is undergoing a major shift driven by the integration of neoadjuvant immunotherapy (nIO). The rationale for nIO lies in its administration within an immunologically active, treatment-naïve microenvironment that enhances immune priming and anti-tumor response. Despite encouraging clinical data, including the pivotal KEYNOTE-689 trial and multiple phase II studies, methodological heterogeneity in trial design, endpoint definitions, and response criteria currently hampers data comparability and the establishment of new standards of care. This expert narrative review proposes a structured framework for standardizing clinical, pathologic, imaging, and translational endpoints in HNSCC nIO trials, highlighting harmonized definitions of pathologic response, practical reporting templates, and methods to evaluate immune priming. Standardization of response evaluation, biomarker integration, and trial methodology is essential to accelerate the translation of neoadjuvant immunotherapy into routine clinical practice for HNSCC.
Precision targeting of CLDN18.2: A new therapeutic paradigm for gastric cancer.
Zhou W, Mei W, Zeng C
Cancer Treat Rev · 2026 Jun · PMID 42364314 · Publisher ↗
Claudin 18.2 (CLDN18.2) is an attractive therapeutic target in gastric cancer (GC). Zolbetuximab, a CLDN18.2-targeted monoclonal antibody, has been approved in combination with chemotherapy as a first-line treatment opti...
Claudin 18.2 (CLDN18.2) is an attractive therapeutic target in gastric cancer (GC). Zolbetuximab, a CLDN18.2-targeted monoclonal antibody, has been approved in combination with chemotherapy as a first-line treatment option for patients with HER2-negative and CLDN18.2-positive gastric adenocarcinoma. This review summarizes current advances in CLDN18.2-targeted therapies for GC, with a focus on the clinical development of monoclonal antibodies (mAbs), particularly zolbetuximab and emerging next-generation antibodies, as well as mAb-based combination strategies. This review also summarizes CLDN18.2-targeted antibody-drug conjugates (ADCs), bispecific antibodies (BsAbs), and chimeric antigen receptor (CAR)-T cell therapy, highlighting emerging therapeutic strategies. Furthermore, major challenges and considerations in clinical and translational research are outlined. In conclusion, precision targeting of CLDN18.2 represents a promising approach in GC therapy, shifting from conventional chemotherapy to biomarker-guided strategies. Continued development of next-generation agents and rational combination therapies may enhance outcomes and expand benefit.
Beyond body surface area: CT-derived body composition as a predictor of chemotherapy toxicity and survival in pancreatic ductal adenocarcinoma: a systematic review.
Chacón-Ovejero B, Pacheco-Barcia V, Palka-Kotlowska M … +6 more , Custodio-Cabello S, Guerra-Hernandez R, Jimenez-Fonseca P, Muñoz-Martin A, Gómez-Cerezo JF, Cabezón-Gutiérrez L
Cancer Treat Rev · 2026 Jun · PMID 42361440 · Publisher ↗
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterised by a high prevalence of severe muscle wasting (sarcopenia) and fatty muscle infiltration (myosteatosis), yet chemotherapy dosing still relies on body s...
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterised by a high prevalence of severe muscle wasting (sarcopenia) and fatty muscle infiltration (myosteatosis), yet chemotherapy dosing still relies on body surface area (BSA), a metric that does not reflect individual patients' lean body mass (LBM) or muscle quality. A growing body of evidence from oncology meta-analyses demonstrates that low skeletal muscle mass (sarcopenia) independently predicts chemotherapy toxicity across multiple cancer types, and that myosteatosis is associated with significantly increased mortality risk. We performed a systematic review to determine whether CT-based body composition metrics better predict chemotherapy toxicity and survival outcomes in PDAC than conventional BSA-based dosing. METHODS: We searched PubMed and EMBASE (up to 10 April 2026) according to PRISMA 2020 guidelines. Of 340 identified records, a total of 16 were included after screening and eligibility assessment: 14 primary studies/abstracts (10 retrospective cohorts, 1 prospective study, 3 conference abstracts); 2 prior systematic reviews were appraised qualitatively for contextual background. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies and AMSTAR-2 for systematic reviews. Conference abstracts were assessed qualitatively; their inclusion and associated limitations are transparently acknowledged. Data were extracted on severe (grade ≥ 3) toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), dose-limiting toxicities (DLT), treatment modifications, and overall survival. Body composition measures assessed included skeletal muscle index (SMI) and skeletal muscle density (SMD) (surrogates for muscle quantity and quality, respectively), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and longitudinal changes in these parameters. RESULTS: Muscle quality (low SMD/myosteatosis) was as predictive of severe toxicity as muscle mass (SMI) in multiple studies, and when low SMI and SMD co-occurred, patients had significantly higher odds of grade ≥ 3 toxicity (odds ratio ∼ 1.7 in the largest cohort of 636 patients). Patients receiving high chemotherapy doses relative to LBM (e.g. >5.8 mg of nab-paclitaxel per kg LBM) were significantly more likely to experience DLT (p = 0.028), whereas standard BSA-normalised dosing did not discriminate risk. Early skeletal muscle loss (≥7.9% SMI decline within 2 months of FOLFIRINOX) was linked to a fourfold higher risk of mortality (HR 4.02; 95% CI 1.54-10.5). Overall, CT-derived body composition measures consistently outperformed BSA for toxicity and outcome prediction, although evidence remains largely retrospective and heterogeneous. Automated CT body composition analysis was demonstrated to be feasible, supporting integration into routine PDAC care. CONCLUSIONS: CT-derived body composition metrics, particularly LBM-normalised dosing parameters and serial skeletal muscle measurements, appear to provide a more patient-tailored, physiologically relevant approach to chemotherapy dosing in PDAC than exclusive reliance on BSA. Given the predominantly retrospective evidence base and limited prospective validation to date, these findings should be interpreted as hypothesis-generating rather than practice-changing. Prospective trials of LBM-adapted dosing protocols are needed to validate their impact on toxicity and survival.
Early onset pancreatic Cancer: epidemiology, molecular features, and clinical outcomes.
Petrelli F, Dottorini L, Celotti A … +7 more , Meriggi F, Cherri S, Oneda E, Tomasello G, Ghidini M, Baiocchi G, Zaniboni A
Cancer Treat Rev · 2026 Jun · PMID 42341370 · Publisher ↗
Background Early onset pancreatic cancer (EOPC), defined for the primary analysis as pancreatic ductal adenocarcinoma (PDAC) diagnosed before the age of 50 years, is an increasingly recognised clinical and epidemiologica...
Background Early onset pancreatic cancer (EOPC), defined for the primary analysis as pancreatic ductal adenocarcinoma (PDAC) diagnosed before the age of 50 years, is an increasingly recognised clinical and epidemiological entity. Because published studies use heterogeneous age thresholds, the present review prespecified <50 years as the main definition and interpreted studies using other cutoffs in sensitivity or narrative analyses. Methods We systematically searched PubMed, EMBASE, and the Cochrane Library for studies published between January 1990 and December 2024 that reported outcomes specific to EOPC. Search terms were reformatted with standard quotation marks and included "pancreatic cancer", "pancreatic adenocarcinoma", "pancreatic ductal adenocarcinoma", "early onset", "young onset", "young adult", "age < 50", "age less than 50", and "premature". Meta-analytic procedures and epidemiological interpretation were re-reviewed with statistical/epidemiological input. Results 40 studies encompassing more than 285,000 patients were included. Global incident EOPC cases increased from 24,480 (1990) to 42,254 (2021), representing a 72·6% rise. Age-standardised prevalence rate increased by 17·0% (1·65 per 100,000 in 2021). EOPC patients have a 3·08% per year increase in the youngest age group (20-29 years) over 2010-2021. Germline pathogenic variants were identified in 17·3% of EOPC patients (vs 6·4% in older cohorts; OR 2·41, 95% CI 1·87-3·11). EOPC patients were more likely to receive treatment (OR 2·95, 95% CI 2·54-3·43; I = 13%) and showed modestly improved overall survival (pooled HR 0·89, 95% CI 0·80-0·99; I = 16%) compared with average or late onset disease. Conclusions EOPC is an increasingly recognised and clinically challenging subset of PDAC. The substantial hereditary and potentially actionable molecular burden supports universal germline testing and comprehensive tumour genomic profiling, particularly in younger patients and in KRAS wild-type disease. PARP inhibitors should be described as improving progression-free survival or disease-control outcomes in selected BRCA-mutated metastatic PDAC rather than as having established a statistically significant overall survival benefit.
Targeting HER2 in urothelial carcinoma: from pathway inhibition to antibody-drug conjugates.
Wafa H, van Creij NCH, Guenther M … +7 more , Noeparast M, Subiela JD, Terbuch A, Niedersuess-Beke D, Culig Z, Ormanns S, Pichler R
Cancer Treat Rev · 2026 Jun · PMID 42341369 · Publisher ↗
Urothelial carcinoma (UC) is a biologically and clinically heterogeneous malignancy with persistently poor outcomes in locally advanced or metastatic disease. Although platinum-based chemotherapy and immune checkpoint in...
Urothelial carcinoma (UC) is a biologically and clinically heterogeneous malignancy with persistently poor outcomes in locally advanced or metastatic disease. Although platinum-based chemotherapy and immune checkpoint inhibitors have improved survival, durable disease control remains limited, and therapeutic resistance is common. Antibody-drug conjugates (ADCs) targeting Nectin-4 and Trop-2 have further expanded the therapeutic landscape, yet the need for additional biomarker-driven strategies remains pressing. Human epidermal growth factor receptor 2 (HER2), encoded by ERBB2, has emerged as a therapeutically relevant target in a subset of UC. HER2 expression in UC is highly heterogeneous and varies across histological and molecular subtypes, with the highest expression rates reported in the micropapillary subtype. Early attempts to target HER2 in UC yielded disappointing results, largely due to biological heterogeneity, lack of standardized HER2 assessment and an incomplete understanding of HER2 pathway dependence in UC. Recent advances in molecular profiling and the development of HER2-directed ADCs have fundamentally reshaped the therapeutic relevance of HER2 in UC, enabling activity even in tumors with heterogeneous or low expression of HER2. This comprehensive narrative review synthesizes current knowledge on HER2 biology in UC, addresses challenges in biomarker assessment, critically appraises the evolving clinical trial landscape of HER2-directed ADCs, explores the interaction between HER2 and other oncogenic alterations and discusses mechanisms of resistance with future directions for HER2-targeted strategies in UC.
Cyclotherapy: exploiting cell-cycle decoupling for selective cancer cytotoxicity and normal-tissue protection.
Izzo D, Marsicano RM, Trapani D … +1 more , Curigliano G
Cancer Treat Rev · 2026 Jun · PMID 42335582 · Publisher ↗
The therapeutic index of cytotoxic anticancer agents remains intrinsically constrained by the vulnerability of normal proliferating tissues. Unlike antibiotics, whose selectivity transformed infectious disease prognosis,...
The therapeutic index of cytotoxic anticancer agents remains intrinsically constrained by the vulnerability of normal proliferating tissues. Unlike antibiotics, whose selectivity transformed infectious disease prognosis, most chemotherapeutics exert non-discriminatory effects on malignant and healthy cycling cells, resulting in dose-limiting toxicities that curtail clinical efficacy. Cyclotherapy represents a strategy first conceptualized in the early 2000s, that seeks to pharmacologically widen this therapeutic window by transiently arresting normal cells in specific phases of the cell cycle, thereby shielding them from phase-specific cytotoxic agents while leaving checkpoint-defective tumor cells susceptible. This review revisits the biological rationale, preclinical foundations, and clinical trajectory of cyclotherapy. Early approaches leveraging p53 activation and MDM2 inhibition demonstrated proof-of-principle but faced translational limitations. More recently, the development of short-acting CDK4/6 inhibitors, particularly trilaciclib, has provided the first clinically approved example of pharmacologic myeloprotection in small-cell lung cancer. However, inconsistent results across tumor types underscore the context-dependency of cyclotherapy, highlighting the critical importance of tumor-specific cell-cycle vulnerabilities, such as RB1 loss and precise pharmacologic scheduling. We propose a mechanistically informed framework for cyclotherapy development based on three determinants: tumor sensitivity to the protective agent, the cell-cycle dependency of treatment-related toxicities, and the phase specificity of the partnered targeted drug. Reframing adverse events according to cycle-dependent versus cycle-independent mechanisms may enable more rational therapeutic pairings and potentially support safe dose escalation. Cyclotherapy should not be regarded as a failed hypothesis prematurely tested, but as an evolving paradigm requiring refined biological stratification and temporal optimization. Properly implemented, it may redefine cytoprotection and expand the therapeutic latitude of modern oncology.
Re-challenge strategies in neuroendocrine tumours: adding another arrow in the quiver?
Benini L, Ciardiello D, Spada F … +5 more , Cella CA, Gervaso L, Mulargiu C, Zampino MG, Fazio N
Cancer Treat Rev · 2026 Jun · PMID 42314247 · Publisher ↗
Retreatment strategies in neuroendocrine tumours have shown promising clinical activity, yet evidence to guide patient selection and optimal treatment modalities remains limited. In this narrative review, we summarise th...
Retreatment strategies in neuroendocrine tumours have shown promising clinical activity, yet evidence to guide patient selection and optimal treatment modalities remains limited. In this narrative review, we summarise the currently available data on systemic retreatment approaches (retreatment and reintroduction strategies) and highlight biological and clinical key factors - such as the role of MGMT expression, tumour grade, and treatment-free interval - that may inform clinical decision-making. We also outline critical priorities for future clinical trial design, including the integration of predictive biomarkers and the development of standardized retreatment protocols. Further prospective, biomarker-driven studies are required not only to refine patient selection but also to establish whether rechallenge strategy may represent a biologically reasonable and clinically meaningful strategy.
The antibiotic-immunotherapy interaction in NSCLC: a systematic review and meta-analysis of 54,250 patients across three outcomes.
Stylianakis D, Bertaglia V, Sangiolo D … +9 more , Podda M, Saba G, Stylianakis I, Denaro N, Pisanu A, Agelaki S, Scartozzi M, Novello S, Solinas C
Cancer Treat Rev · 2026 Jun · PMID 42269396 · Publisher ↗
BACKGROUND: Approximately 20-28% of NSCLC patients receiving ICIs also receive systemic antibiotics. Whether this reflects a true microbiome-mediated pharmacological interaction or confounding by indication remains unres...
BACKGROUND: Approximately 20-28% of NSCLC patients receiving ICIs also receive systemic antibiotics. Whether this reflects a true microbiome-mediated pharmacological interaction or confounding by indication remains unresolved. METHODS: We searched PubMed, Scopus, and CENTRAL (2013-2025) for NSCLC studies reporting OS, PFS, or ORR by antibiotic exposure. Random-effects meta-analysis was performed, with mostly non-pre-specified subgroup analyses by study design, ICI class, antibiotic timing, and line-of-therapy, plus leave-one-out, exposure-window, and adjustment-status sensitivity analyses and meta-regression of heterogeneity sources. Risk of bias was assessed with ROBINS-I and ROB 2, and certainty of evidence was rated with GRADE. RESULTS: Forty-one studies including 54,250 patients were analyzed, 27.8% of whom were antibiotic-exposed. Antibiotic exposure was associated with worse OS (HR 1.47, 95% CI 1.30-1.66; p < 0.00001; I = 79%) and PFS (HR 1.32, 95% CI 1.18-1.47; p < 0.00001; I = 65%), but not ORR (OR 0.95, 95% CI 0.67-1.35; p = 0.77; I = 88%). RCT post-hoc estimates were non-significant (OS HR 1.20, p = 0.07; PFS HR 1.09, p = 0.41; I = 0%), whereas observational estimates were larger and driven by less-adjusted cohorts. Subgroup, sensitivity, and meta-regression analyses indicated that heterogeneity was explained mainly by study design and line of therapy. In chemo-free ICI analyses, only mixed ICI regimens remained significant for OS and PFS. GRADE certainty was very low for observational outcomes and low for RCT-based estimates. CONCLUSIONS: The strongest available evidence does not support a clear antibiotic-related reduction in ICI efficacy in NSCLC. The observational signal is more compatible with confounding and exposure heterogeneity than with a uniform pharmacological interaction, although a context-specific biological effect cannot be excluded.
Clinical efficacy and immunological aspects of neoadjuvant and perioperative therapy in resectable head and neck carcinoma.
Hattenhauer T, Mispelbaum R, Bauernfeind FG … +5 more , Feldmann G, Baumjohann D, Brägelmann J, Heine A, Brossart P
Cancer Treat Rev · 2026 May · PMID 42259189 · Publisher ↗
Checkpoint inhibitor (CPI) therapy has emerged as treatment option in selected patients with resectable head and neck squamous cell carcinoma. Recent phase III data have led to approval of perioperative pembrolizumab for...
Checkpoint inhibitor (CPI) therapy has emerged as treatment option in selected patients with resectable head and neck squamous cell carcinoma. Recent phase III data have led to approval of perioperative pembrolizumab for patients with PD-L1-positive (CPS ≥ 1). With emerging data on adjuvant checkpoint inhibitor therapy the selection of the optimal treatment strategy is becoming increasingly complex. Several clinical phase II/III trials have evaluated neoadjuvant immunotherapy in resectable head and neck cancer, demonstrating both clinical and immunological benefits. This review summarizes current data on neoadjuvant and perioperative checkpoint inhibitors in resectable head and neck cancer and addresses main immunological advantages. In addition, potential strategies to optimize treatment efficacy and to overcome resistance mechanisms of CPI therapy are discussed. Further trials are needed to define optimal treatment protocols, determinate the best timing of surgery, and identify reliable biomarkers for patient selection, to guide evidence-based therapeutic decision-making in routine clinical practice.
Adjuvant chemotherapy in stage I triple-negative breast cancer: A systematic review and meta-analysis of survival outcomes.
Jacobs F, Polymeropoulos A, Monte M … +19 more , Ligorio F, Provenzano L, Armani G, Fotia G, Mazzoli G, Coppola G, Bottelli A, Iacobucci A, Bianchessi V, Abate A, Bianchi GV, Capri G, Ferraris C, Martelli G, Folli S, Vingiani A, Pruneri G, Miceli R, Vernieri C
Cancer Treat Rev · 2026 May · PMID 42235455 · Publisher ↗
BACKGROUND: The benefit of adjuvant chemotherapy in patients with surgically-resected, stage-I TNBC remains controversial, especially when tumors are smaller than 10 mm in maximum diameter. We conducted a meta-analysis t...
BACKGROUND: The benefit of adjuvant chemotherapy in patients with surgically-resected, stage-I TNBC remains controversial, especially when tumors are smaller than 10 mm in maximum diameter. We conducted a meta-analysis to evaluate the impact of adjuvant chemotherapy on survival outcomes in this setting, with prespecified subgroup analyses by pathological tumor size (pT1a/b/c). METHODS: This study followed PRISMA guidelines and was registered in PROSPERO. Literature search from PubMed, EMBASE, Cochrane (2000-2025) and recent conference proceedings was reviewed for studies comparing overall survival (OS) and/or breast cancer-specific survival (BCSS) in stage I TNBC patients receiving adjuvant chemotherapy versus no chemotherapy. Hazard ratios (HR) were pooled using fixed- or random-effects models according to prespecified heterogeneity criteria (Q statistic, P < 0.10 and/or I > 25%). Small-study effects and robustness were evaluated with Egger's test and influence diagnostics. RESULTS: Twenty-seven studies including 98,499 patients were analysed. Adjuvant chemotherapy resulted in significantly improved OS (HR 0.53, 95%CI 0.42-0.68; p < 0.001) and BCSS (HR 0.70, 95%CI 0.62-0.79; p < 0.001). In pT1a tumors, we found no benefit in terms of OS (HR 0.97, p = 0.91) or BCSS (HR 1.49, p = 0.12). In pT1b disease, chemotherapy use was associated with improved OS (HR 0.68, p < 0.0001), while no BCSS benefit was observed (HR 1.01, p = 0.94); this subgroup analysis should be interpreted cautiously. Finally, in pT1c tumors, adjuvant chemotherapy was associated with improved OS (HR 0.46, p < 0.0001) and BCSS (HR 0.68, p < 0.001). CONCLUSIONS: In surgically-resected stage I TNBC, the association between adjuvant chemotherapy and better survival appears to vary according to tumor-size, with more consistent benefit in patients with tumors > 5 mm and no significant survival advantage observed in pT1a disease. These findings support a tailored, size-based approach, although the OS results should be interpreted cautiously given the observational nature of the evidence and the substantial heterogeneity of the pooled OS analysis.
Treatments for human epidermal growth factor receptor 2 (HER2)-altered cancers evaluated using a tumor‑agnostic approach: A narrative review.
Harada G, Chaft JE, Schram AM … +2 more , Pavlakis N, Wu YL
Cancer Treat Rev · 2026 Jun · PMID 42229315 · Publisher ↗
Human epidermal growth factor receptor 2 (HER2) is a critical driver of tumorigenesis across a wide range of cancers, positioning it as a key target for tumor-agnostic therapies. Advances in HER2 therapies have shifted t...
Human epidermal growth factor receptor 2 (HER2) is a critical driver of tumorigenesis across a wide range of cancers, positioning it as a key target for tumor-agnostic therapies. Advances in HER2 therapies have shifted the treatment paradigm from histology-driven toward biomarker-driven, pan-tumor approaches. This review discusses the outcomes of approved and emerging HER2 therapies, highlighting the variability in efficacy across tumor types due to a combination of factors, such as HER2 heterogeneity, co-alterations, and tumor-specific resistance mechanisms. Although tumor-agnostic basket trials offer opportunities to evaluate HER2 therapies efficiently across multiple cancer types, challenges such as small patient populations, non-randomized designs, and heterogeneous tumor types can limit the reliability of their findings. Here, we review the available data on HER2 therapies in tumor-agnostic studies, with the goal of informing future clinical research and promoting greater appreciation of the nuances of HER2-altered cancers.
PD-(L)1 containing rechallenge strategies in patients with advanced NSCLC previously treated with immunotherapy: A systematic review and meta-analysis across resistance phenotypes.
Marinelli D, Citarella F, Torchia A … +26 more , Pannu S, Aijaz A, Sisca L, Russano M, Fujiwara Y, Takada K, Nassar AH, Banna GL, Ricciuti B, Brunetti L, Santo V, Passaro A, Saw SPL, Li MSC, Addeo A, Ferrara R, Di Maio M, Mountzios G, Santini D, Maugeri-Saccà M, Vincenzi B, Acker F, Reckamp KL, Cappuzzo F, Naqash AR, Cortellini A
Cancer Treat Rev · 2026 Jun · PMID 42224849 · Publisher ↗
INTRODUCTION: Even though PD-(L)1 inhibitors have dramatically changed the prognosis of patients with advanced non-small-cell lung cancer (NSCLC), resistance to treatment remains common. Rechallenge with PD-(L)1 based re...
INTRODUCTION: Even though PD-(L)1 inhibitors have dramatically changed the prognosis of patients with advanced non-small-cell lung cancer (NSCLC), resistance to treatment remains common. Rechallenge with PD-(L)1 based regimens has been explored in this context, but clinical benefit remains uncertain. METHODS: Two independent reviewer teams performed parallel searches of MEDLINE and EMBASE from 2019 to 2025 to identify clinical trials evaluating PD-(L)1 inhibitor based rechallenge strategies in patients with advanced NSCLC previously treated with PD-(L)1-based regimens. Randomised controlled trials (RCTs) were included in quantitative meta-analysis, while non-randomised single-arm studies were synthesised descriptively. The primary endpoint was overall survival (OS). Sensitivity analyses examined outcomes according to resistance pattern. All analyses used fixed-effects models. FINDINGS: A total of 10 RCTs (n = 3,081) and 106 non-randomised interventional trials were included. Across RCTs, PD-(L)1 based rechallenge strategies yielded modest improvements in both OS (HR 0.91, 95%CI: 0.82-0.99) and PFS (HR 0.89, 95%CI: 0.81-0.99) compared with the control arms, with no improvement in objective response rate (ORR). In sensitivity analyses, no benefit was observed in patients with primary resistance, whereas those with acquired resistance features (i.e., clinical benefit to prior immunotherapy) demonstrated a more favourable effect for OS (HR 0.86, 95%CI: 0.77-0.97). A more restrictive analysis excluding patients with < 3 months of prior PD-(L)1 exposure confirmed this pattern. Across the 106 single-arm trials, ORR varied widely, with only speculative signals of higher activity in regimens incorporating VEGF-targeting or chemotherapy. CONCLUSIONS: In the largest synthesis of rechallenge strategies to date, PD-(L)1 rechallenge produced statistically significant but clinically marginal improvements in OS and PFS compared with standard treatments, with no benefit in patients with primary resistance. A signal of benefit was observed in patients with acquired resistance to prior immunotherapy although this exploratory analysis was limited by heterogeneous resistance definitions across trials and a non-significant interaction test.
The role of the 21-gene assay in the neoadjuvant setting for hormone receptor-positive HER2-negative breast cancer: Impact on systemic and surgical treatment decisions.
Zotano ÁG, Allweis TM, Foerster R … +5 more , Palmieri C, Gluz O, Chia S, Sotiriou C, Bianchini G
Cancer Treat Rev · 2026 Jun · PMID 42218834 · Publisher ↗
In breast cancer, one of the main objectives of neoadjuvant treatment, regardless of the specific breast cancer subtype, is to downstage the disease in both the breast and the lymph nodes, thereby allowing surgical de-es...
In breast cancer, one of the main objectives of neoadjuvant treatment, regardless of the specific breast cancer subtype, is to downstage the disease in both the breast and the lymph nodes, thereby allowing surgical de-escalation. In patients with inoperable disease, downstaging could lead to a feasible surgical resection; whereas, in patients presenting with operable disease, it could increase the eligibility for breast-conserving surgery (i.e., lumpectomy) instead of a mastectomy as well as spare some patients an axillary lymph node dissection. In patients with hormone receptor-positive (HR + ) human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer, neoadjuvant treatment modalities include chemotherapy (NCT) and endocrine therapy (NET). The 21-gene Oncotype DX Breast Recurrence Score® assay is a multigene assay that determines a Recurrence Score® (RS) result (range, 0-100) based on gene expression profile within the primary tumor. The RS is a validated prognosticator and predictor of benefit from adjuvant CT. Beyond its validation, it has shown clinical utility in 3 prospective randomized clinical trials in the adjuvant setting (TAILORx, RxPONDER, and WSG PlanB). In these studies, all assays were performed on surgical excision samples. This review focuses on the utility of the 21-gene assay in patients with HR + HER2-negative early-stage breast cancer in the neoadjuvant setting. It discusses the analytical validation of performing the assay on core biopsies, its clinical validation as a tool to guide neoadjuvant treatment decisions (primary surgery, NET, or NCT), the association of the RS result with clinical outcomes, the impact of the RS results on neoadjuvant treatment decisions in real-life clinical practice, the inclusion of the assay in the neoadjuvant setting in clinical-practice guidelines, access of patients worldwide to this approach, and potential directions for additional studies examining the role of the RS in other steps in the clinical pathway of HR + HER2-negative early-stage breast cancer.
Prognostic role of postoperative circulating tumor DNA in metastatic colorectal cancer treated with curative intent: A systematic review and meta-analysis.
Cardone C, Facchini S, de Oliveira Ascef B … +4 more , Cassata A, Stefano A, Chiodini P, Avallone A
Cancer Treat Rev · 2026 Jun · PMID 42217424 · Publisher ↗
BACKGROUND: Postoperative circulating tumor DNA (ctDNA) is an emerging biomarker for molecular residual disease (MRD) detection in early-stage colorectal cancer (CRC). However, its prognostic value in patients with resec...
BACKGROUND: Postoperative circulating tumor DNA (ctDNA) is an emerging biomarker for molecular residual disease (MRD) detection in early-stage colorectal cancer (CRC). However, its prognostic value in patients with resected metastatic disease has not been comprehensively assessed. This study aimed to evaluate the association between postoperative ctDNA detection and survival outcomes, including after completion of adjuvant chemotherapy (post-ACT), in patients with metastatic CRC (mCRC) treated with curative intent. METHODS: A systematic search of PubMed/MEDLINE, Scopus, and Embase was conducted up to March 17, 2025. Eligible studies included adults with mCRC undergoing curative intent treatment, reporting hazard ratios (HRs) for time-to-event outcomes according to postoperative ctDNA status. Random-effects meta-analyses were performed to pool HRs for recurrence-free survival (RFS) and overall survival (OS). Risk of bias was assessed using the QUIPS tool. The study followed PRISMA guidelines and was registered in PROSPERO (CRD42024528320). RESULTS: Sixteen studies (N = 1048) were included. Postoperative ctDNA positivity was detected in 409 patients (39.0%) and was associated with significantly worse RFS (16 studies; HR = 4.45, 95% CI, 3.44-5.75; P < 0.0001) and shorter OS (9 studies; HR = 6.23; 95% CI, 3.15-12.33, P = 0.0003). Notably, post-ACT ctDNA positivity (N = 96, 41.4%) remained associated with recurrence (5 studies; HR, 6.08; 95% CI, 4.04-9.16; P < 0.001). CONCLUSIONS: Postoperative ctDNA positivity in mCRC treated with curative intent is strongly associated with increased risk of recurrence and mortality. These findings support its role as a consistent prognostic biomarker and highlight the need for biomarker-guided clinical trials in this setting.
Central nervous system and leptomeningeal metastases in patients with HER2-positive breast cancer: A comprehensive review and therapeutic algorithm proposal.
Caltavituro A, Buonaiuto R, Longobardi A … +18 more , Trasacco P, Martinelli C, Grazia GD, Pacelli R, Arpino G, Angelis C, Caputo R, Laurentiis M, Laakmann E, de Matos LV, Fontes-Sousa M, van Ramshorst M, Mueller V, Agostinetto E, Linn S, Angelis M, Schettini F, Giuliano M
Cancer Treat Rev · 2026 Jun · PMID 42172868 · Publisher ↗
Breast cancer (BC) is the second leading cause of brain metastases (BMs). The incidence of BMs has increased over the last decades as results of both the improvement in imaging detection power and the longer life expecta...
Breast cancer (BC) is the second leading cause of brain metastases (BMs). The incidence of BMs has increased over the last decades as results of both the improvement in imaging detection power and the longer life expectancy of patients with metastatic disease. In human epidermal growth factor receptor 2-positive (HER2 + ) advanced BC, the incidence of BMs is especially high and is associated with poor prognosis. The central nervous system (CNS) has historically been considered a sanctuary site since the blood-brain barrier prevents the penetration of most therapeutic agents. Therefore, loco-regional therapies, such as surgery or radiotherapy, have largely represented the only effective strategies for treating intracranial disease. However, the development of several anti-HER2 agents with proven CNS efficacy has resulted in unprecedented disease control, raising the question of the optimal strategy to adopt in the management of both extracranial and intracranial disease. Here, we provide a comprehensive narrative review of the therapeutic management of HER2 + BMs and leptomeningeal disease, highlighting recent advances in the efficacy of both locoregional and systemic strategies and briefly discuss brain imaging screening and biomarkers for BMs risk stratification. Building on this evidence, we propose an updated, integrated treatment algorithm designed to optimize clinical decision-making.
KRAS G12C-mutant non-small cell lung cancer: A practical guide for clinicians.
Remon J, La-Cava G, Borgeaud M … +3 more , Saw SPL, Hendriks LE, Ricciuti B
Cancer Treat Rev · 2026 Jun · PMID 42114275 · Publisher ↗
KRAS G12C-mutant non-small cell lung cancer (NSCLC) occurs in approximately 15% of NSCLC with historically limited targeted treatment options. Both KRAS "OFF"" G12C inhibitors, sotorasib and adagrasib, are considered sta...
KRAS G12C-mutant non-small cell lung cancer (NSCLC) occurs in approximately 15% of NSCLC with historically limited targeted treatment options. Both KRAS "OFF"" G12C inhibitors, sotorasib and adagrasib, are considered standard second-line therapy, albeit with a modest progression-free survival benefit over standard chemotherapy. Emerging next-generation KRAS "OFF" G12C inhibitors, as well as KRAS "ON", dual "ON/OFF", and pan-(K)RAS "ON" inhibitors, show promising early efficacy and safety profiles in second-line, though confirmatory phase III trials are pending. In the first-line setting, KRAS inhibitor-immunotherapy combinations appear particularly promising in tumors with high programmed death-ligand 1 (PD-L1) expression. However, incorporating KRAS inhibitors into chemoimmunotherapy regimens may yield more consistent and clinically meaningful benefit across patient populations, irrespective of PD-L1 expression. Critical clinical questions remain open regarding the optimal patient population for combinations, the influence of co-occurring genomic alterations, intracranial activity of KRAS inhibitors and dose optimization. This review synthesizes current evidence on the biology, clinical efficacy, safety, and practical considerations for treating KRAS G12C-mutant NSCLC, providing clinicians with an up-to-date, evidence-based framework for therapeutic decision-making and highlighting areas requiring further investigation.
Circulating tumor DNA for predicting recurrence and mortality in patients with resected Melanoma: A systematic review and meta-analysis.
Abrahão Reis PC, Noronha MM, Oliveira JP … +5 more , Ponte Conrado JE, Buonopane IR, Holanda Lopes CD, Araujo DV, Saldanha EF
Cancer Treat Rev · 2026 Jun · PMID 42107274 · Publisher ↗
BACKGROUND: Resectable melanoma remains associated with substantial relapse risk despite adjuvant therapy, and prognostic biomarkers for better risk stratification are urgently needed. We evaluated the prognostic and dia...
BACKGROUND: Resectable melanoma remains associated with substantial relapse risk despite adjuvant therapy, and prognostic biomarkers for better risk stratification are urgently needed. We evaluated the prognostic and diagnostic performance of circulating tumor DNA (ctDNA) in patients with resectable melanoma. METHODS: PubMed, Embase, and Cochrane databases were systematically searched through July 2025 for studies evaluating ctDNA detection in patients with resected melanoma and reporting outcomes of interest. All ctDNA data were assessed at three timepoints: baseline (pre-surgery), landmark (≤12 weeks post-surgery), and longitudinal surveillance. Random-effects models estimated hazard ratios (HR) with 95% confidence intervals (CI) for relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Diagnostic performance was evaluated using both univariate and bivariate models. RESULTS: Twenty-four cohorts comprising 3,032 patients were included, with a median follow-up of 38.5 months. Baseline ctDNA positivity was associated with worse RFS (HR 3.14; 95% CI 1.82-5.41) and DMFS (HR 2.25; 95% CI 1.50-3.36), but not OS. At the landmark timepoint, ctDNA positivity predicted worse RFS (HR 3.42; 95% CI 2.51-4.65), DMFS (HR 5.38; 95% CI 3.09-9.37), and OS (HR 3.55; 95% CI 2.63-4.79). Longitudinal ctDNA detection showed the strongest prognostic association with RFS (HR 3.76; 95% CI 2.83-4.99). Diagnostic performance demonstrated modest sensitivity (31-53%) but high specificity (>90%) at landmark and longitudinal timepoints, with no significant differences in accuracy between these timepoints. CONCLUSION: Detectable ctDNA in resectable cutaneous melanoma is a negative prognostic marker associated with significantly higher rates of relapse, distant metastasis, and mortality. Diagnostic metrics revealed that plasma ctDNA has high specificity with suboptimal sensitivity.
Targeting key epigenetic regulators in solid tumors: focus on EZH2, PRMT5, and BET inhibitors.
de Córdoba Sánchez IH, Ruidiaz MA, Moreno V … +2 more , Long H, Cejas P
Cancer Treat Rev · 2026 Jun · PMID 42096787 · Publisher ↗
Epigenetic dysregulation is a hallmark of cancer and a promising therapeutic target in solid tumors. This review highlights key advances in targeting epigenetic regulators such as EZH2, PRMT5, and BET proteins. EZH2 inhi...
Epigenetic dysregulation is a hallmark of cancer and a promising therapeutic target in solid tumors. This review highlights key advances in targeting epigenetic regulators such as EZH2, PRMT5, and BET proteins. EZH2 inhibition has achieved the first clinical approval in SMARCB1-deficient epithelioid sarcoma, whereas PRMT5 inhibitors exploit synthetic lethality through MTAP loss, representing a biomarker-driven therapeutic strategy in solid tumors, with next-generation selective compounds showing early activity in MTAP-deleted tumors and improved tolerability. BET inhibitors, though biologically promising, currently face challenges of toxicity and limited efficacy as monotherapy but demonstrate potential in combination strategies, particularly in glioblastoma. We analyze recent advances and ongoing investigations, as well as future directions in the development of epigenetic therapies in solid tumors. Overall, epigenetic inhibitors are poised to become an expanding pillar of precision oncology, bridging chromatin biology with clinical benefit.
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