Cancer Treat Rev
· 2026 Mar · PMID 41762530
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Over the past decade, placebo-controlled phase III trials have remained central to therapeutic development in oncology, despite the rapid expansion of effective systemic treatments. In modern practice, placebo rarely rep...Over the past decade, placebo-controlled phase III trials have remained central to therapeutic development in oncology, despite the rapid expansion of effective systemic treatments. In modern practice, placebo rarely represents the absence of therapy; rather, it serves as a methodological tool that preserves blinding, isolates the incremental effect of investigational agents, and minimizes assessment bias. Between 2015 and 2025, placebo-controlled designs underpinned many landmark trials across solid tumors and hematologic malignancies. In add-on first-line studies, placebo combined with standard-of-care therapy enabled accurate attribution of benefit to immune checkpoint inhibitors and targeted agents, including CDK4/6 inhibitors in hormone receptor-positive breast cancer. In the adjuvant setting, where observation historically constituted standard management, placebo provided an ethically appropriate comparator, supporting practice-changing trials in resected lung cancer, melanoma, renal cell carcinoma, and early breast cancer. Maintenance strategies, particularly in ovarian cancer, pancreatic cancer with germline BRCA mutations, and acute myeloid leukemia, relied on placebo to reflect real-world surveillance and to validate prolonged disease control in molecularly selected populations. In refractory disease, placebo-controlled trials remained acceptable when no effective standard therapies existed, allowing the identification of new agents with survival benefit. Across these contexts, placebo use has been essential for reducing bias in time-to-event endpoints, validating surrogate measures, and ensuring regulatory rigor. Collectively, evidence from the last decade indicates that placebo-controlled trials have facilitated, rather than hindered, major advances in oncology and will continue to play a critical role as treatment strategies become increasingly complex and precision driven.
McCracken A, Grafinger OR, Leong HS
… +3 more, Lohmann AE, Jerzak KJ, Das S
Cancer Treat Rev
· 2026 Mar · PMID 41734562
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Distant recurrence remains a significant cause of mortality in patients with breast cancer (BC). While metastasis was once considered a late event, current evidence suggests that metastatic seeding occurs early. There is...Distant recurrence remains a significant cause of mortality in patients with breast cancer (BC). While metastasis was once considered a late event, current evidence suggests that metastatic seeding occurs early. There is thus significant interest in neoadjuvant therapy (NAT) as a window of opportunity to decrease metastatic risk. While NAT has classically consisted of chemotherapy, targeted therapies, such as human epidermal growth factor 2 (HER2)-targeted therapies and immune checkpoint inhibitors (ICIs), are now offered to patients with HER2-positive and triple-negative (TN) BC, respectively. As therapies evolve, there is a growing need to identify reliable biomarkers to predict NAT response and monitor microscopic disease post-NAT. This review explores the interplay between metastasis biomarkers and NAT for HER2-positive and TNBC. Circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), disseminated cancer cells (DCCs), and tumour-infiltrating lymphocytes (TILs) provide longitudinal insights into residual disease, immune dynamics, and genomic alterations. This review critically examines the established and emerging prognostic, predictive, and response-adaptive roles of these biomarkers in the neoadjuvant setting and beyond. Clinical adoption of novel biomarker approaches has been challenging due to reliance on tissue biopsy during an already challenging treatment journey. However, liquid biopsy approaches like CTC and ctDNA analyses provide minimally invasive means of monitoring metastatic risk. Technological advancements, such as methylome sequencing and variant-based ctDNA detection, offer promise for improved sensitivity and validity. While further trials are required to establish their clinical utility, integrating these biomarker-informed assays may inform precise metastasis risk assessment and improve patient outcomes.
Lin X, Liu B, Wu J
… +8 more, Shi L, Zhang Y, Yang Q, Tang H, Xu S, Gao Y, Cui J, Zhang Y
Cancer Treat Rev
· 2026 Mar · PMID 41702297
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Circulating tumor DNA (ctDNA)-based liquid-biopsy has emerged as a transformative tool in breast cancer management, offering non-invasive, real-time insights across the clinical continuum. By capturing tumor-specific gen...Circulating tumor DNA (ctDNA)-based liquid-biopsy has emerged as a transformative tool in breast cancer management, offering non-invasive, real-time insights across the clinical continuum. By capturing tumor-specific genetic and epigenetic alterations-such as mutations, copy number variations, and methylation patterns-ctDNA enables applications in early screening, evaluation of treatment response, minimal residual disease monitoring, and tracking of resistance mechanisms. Technological advances in PCR-based methods, next-generation sequencing, and biosensor-based profiling have significantly enhanced detection sensitivity and specificity, supporting personalized therapeutic guidance and dynamic adaptation of treatment strategies. However, clinical implementation faces challenges related to assay standardization, variable detection sensitivity, high costs, and limited large-scale prospective validation. Future efforts should focus on technological refinement, multi-omics integration, and evidence generation through large-scale multicenter clinical trials to position ctDNA as a cornerstone of precision oncology in breast cancer.
Cancer Treat Rev
· 2026 Mar · PMID 41687350
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Breast cancer remains the most common malignancy among women globally, and postoperative radiotherapy (PORT) is essential for improving local control and overall survival. Proton therapy (PT) is emerging as an alternativ...Breast cancer remains the most common malignancy among women globally, and postoperative radiotherapy (PORT) is essential for improving local control and overall survival. Proton therapy (PT) is emerging as an alternative to conventional radiotherapy due to its ability to reduce dose exposure to healthy tissues. It could be of particular use in patients requiring radiotherapy to the internal mammary chain, a population that is likely to also be undergoing systemic therapy as part of their breast cancer treatment. This review evaluates current preclinical and clinical data on the integration of PT with systemic treatments in the setting of breast cancer, highlighting its potential role to improve therapeutic outcomes while reducing toxicity. The findings of this review highlight PT's potential to minimize side effects, particularly cardiotoxicity and potentially to enhance the efficacy of systemic treatments such as immunotherapy.
Cancer Treat Rev
· 2026 Mar · PMID 41653497
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Antibody-drug conjugates (ADCs) are a new class of targeted therapies that have demonstrated clinical benefit across various tumor types and disease stages. In breast cancer, following their success in the metastatic set...Antibody-drug conjugates (ADCs) are a new class of targeted therapies that have demonstrated clinical benefit across various tumor types and disease stages. In breast cancer, following their success in the metastatic setting, ADCs show improved antitumor activity with potentially reduced systemic toxicity, making them a promising option in the neoadjuvant treatment of early breast cancer. This review examines the evolving role of ADCs in early breast cancer, highlighting emerging clinical trial data, innovative trial designs, and the integration of biomarkers, all aimed at optimizing patient outcomes and personalizing neoadjuvant strategies across different breast cancer subtypes.
Cancer Treat Rev
· 2026 Feb · PMID 41604872
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Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumour with a poor prognosis. Although treatment regimens such as first-line immunochemotherapy have shown clinical benefits in extensive stage SCLC (ES...Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumour with a poor prognosis. Although treatment regimens such as first-line immunochemotherapy have shown clinical benefits in extensive stage SCLC (ES-SCLC), patients still face disease recurrence and drug resistance. Antibody-drug conjugates (ADCs) are new therapeutic compounds made up of a monoclonal antibody (mAb) attached to a cytotoxic drug (payload) using a linker. They achieve precise killing of tumour cells by conjugating highly cytotoxic drugs with monoclonal antibodies targeting specific tumour antigens. In recent years, antigens such as B7-H3, Trop-2, SEZ6, DLL3, and EGFR-HER3 have become primary targets for ADC development in ES-SCLC. Although some ADCs have been limited due to toxicity-related issues, numerous other ADCs have entered clinical trial phases and demonstrated encouraging efficacy, with ORRs of 33.3 %-68.0 % and median PFS of 4.0-7.6 months. In this review, we systematically summarize ADCs currently in clinical trials and preclinical research for SCLC, and comprehensively discuss their pharmacodynamic characteristics, therapeutic effects, adverse effects, and strategies for optimising treatment.
Chatziioannou E, Lallas K, Sinnberg T
… +4 more, Niessner H, Stratigos AJ, Flatz L, Amaral T
Cancer Treat Rev
· 2026 Feb · PMID 41576808
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NRAS mutations are present in 15-25 % of cutaneous melanomas, predominantly affecting codon 61 (Q61R > Q61K). Mutations at codons 12 and 13 are rare although they appear to be relatively enriched in mucosal subtype. KRAS...NRAS mutations are present in 15-25 % of cutaneous melanomas, predominantly affecting codon 61 (Q61R > Q61K). Mutations at codons 12 and 13 are rare although they appear to be relatively enriched in mucosal subtype. KRAS alterations, while rare in cutaneous melanomas, are more frequently observed in melanoma brain metastases as well as in acral and mucosal subtypes, where NRAS mutations are less prevalent. For advanced RAS-mutant melanoma, systemic therapy currently relies on anti-PD-1-based immune checkpoint inhibition. MEK inhibitors have demonstrated only modest clinical benefit due to the development of resistance and are not approved outside of China for this subtype. Ongoing combination strategies include MEK inhibition with type II RAF inhibitors (naporafenib plus trametinib in phase III trial), ERK1/2 or ERK5 inhibitors, PI3K/mTOR pathway blockade, or CDK4/6 inhibition. Additional investigational approaches include mutation-specific RAS inhibitors (G12C inhibitors already approved for other cancers), NRAS-specific or pan-RAS inhibitors (daraxonrasib in phase III trial for other cancers), targeted protein degradation, RAS-directed peptide and mRNA vaccines (mRNA-4157). NRAS Q61K-derived neoepitopes bound to HLA-A*01:01 have been recognized as immunogenic, suggesting that mutation-specific immunotherapies could represent a promising future strategy. In conclusion, the advent of promising and emerging therapies is set to transform the management of RAS-driven melanoma, making a personalized, biomarker-informed treatment strategy essential for optimizing patient outcomes.
Snäkä T, Friedlaender A, Graciotti M
… +4 more, Hernandez M, Rossier L, Kirchner V, Kandalaft L
Cancer Treat Rev
· 2026 Feb · PMID 41570551
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Cancer vaccines have matured significantly with advances in antigen discovery, delivery platforms, and personalized design driven by breakthroughs in genomics and artificial intelligence - yet they remain underutilized i...Cancer vaccines have matured significantly with advances in antigen discovery, delivery platforms, and personalized design driven by breakthroughs in genomics and artificial intelligence - yet they remain underutilized in clinical oncology. A growing body of evidence now demonstrates that the key to unlocking their full potential lies not in using them in isolation, but in strategically combining them with other treatment modalities. Vaccines exert their greatest efficacy when administered during defined immunologic windows-periods in which the patient's immune system is most amenable to activation and durable antigen-specific priming. Crucially, combination with standard-of-care (SOC) therapies such as chemotherapy, radiotherapy, and immune checkpoint inhibitors can generate synergistic effects that reshape the tumor-immune interface. Cytotoxic and targeted agents can enhance antigen release, modulate the tumor microenvironment, and promote immune infiltration, thereby creating a more permissive milieu for vaccine-induced responses. In reciprocity, vaccination can potentiate the efficacy of SOC regimens by amplifying tumor-specific immunity, counteracting resistance mechanisms, and sustaining immune surveillance. Thus, the emerging paradigm positions cancer vaccines not as standalone interventions, but as integral components of a multimodal therapeutic architecture. Strategic co-deployment of vaccines within SOC frameworks represents a scientifically grounded and clinically actionable approach to achieving durable tumor control and long-term remission in patients with solid malignancies. This review delineates the mechanistic rationale and clinical evidence supporting such integration across the continuum of disease stages.
Persano I, Licata L, Piras M
… +18 more, Ata-Shiroshita A, Naldini MM, Bosi C, Notini G, Mariani M, Chiavassa A, Patanè F, Zanibelli C, Rognone A, Sica L, Zambelli S, Zucchinelli P, Guarino A, Pasetti M, Di Micco R, Gentilini OD, Bianchini G, Viale G
Cancer Treat Rev
· 2026 Feb · PMID 41570550
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The recognition that axillary surgery in early breast cancer primarily serves as a staging tool rather than a curative treatment, along with the shift from axillary lymph node dissection (ALND) to sentinel lymph node bio...The recognition that axillary surgery in early breast cancer primarily serves as a staging tool rather than a curative treatment, along with the shift from axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB) as the standard procedure for clinically node-negative patients, has paved the way for further de-escalation of axillary treatment. This strategy aims to reduce treatment-related morbidity while preserving survival outcomes. Multiple studies have provided compelling evidence that ALND can be safely omitted in cases of limited SLN involvement. Moreover, even the omission of SLNB in selected low-risk cohorts has been shown not to increase recurrence rates. On the other side, from the oncological perspective, research has moved toward an escalation of adjuvant treatments, aiming to reduce recurrence rates and improve overall survival. Thus, while residual axillary disease does not affect patient outcomes, limited axillary staging may hinder access to certain adjuvant therapies. Here, we aim to critically assess the potential impact of recent advances in axillary surgical de-escalation on adjuvant systemic therapy decision-making especially in hormone receptor positive/HER2 negative early breast cancer, with a particular focus on the appropriate selection of patients for adjuvant chemotherapy, CDK4/6 inhibitors, and PARP inhibitors. We argue that decisions on surgical de-escalation should be carefully tailored, balancing its potential benefits with the need for accurate staging to guide adjuvant therapies. A patient-centered, multidisciplinary approach remains essential to ensure that de-escalation does not impact negatively on adjuvant treatment decision making and long-term survival.
Lin HJ, Wu SG, Lo Y
… +3 more, Feng PH, Wu YW, Chen KY
Cancer Treat Rev
· 2026 Feb · PMID 41564805
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INTRODUCTION: Kinase inhibitors (KIs) play an important role in targeted therapy for lung cancer. Lorlatinib as a third-generation anaplastic lymphoma kinase (ALK) inhibitor, provided unprecedentedly prolonged survival f...INTRODUCTION: Kinase inhibitors (KIs) play an important role in targeted therapy for lung cancer. Lorlatinib as a third-generation anaplastic lymphoma kinase (ALK) inhibitor, provided unprecedentedly prolonged survival for patients with advanced non-small cell lung cancer harboring ALK rearrangements. However, this benefit comes at a cost of hyperlipidemia with possible implications for cardiovascular disease (CVD) in long-term survivors. This review aims to provide multidisciplinary evidence-based recommendations for managing hyperlipidemia related to KIs. METHODS: We established a collaborative study group comprising cardiologists, thoracic oncologists, and a pharmacist. The working group conducted a comprehensive literature search to identify KIs investigated or approved for lung cancer treatment and associated with hyperlipidemia. In addition, the most recent clinical trials and atherosclerotic CVD guidelines for the general and cancer patient populations were also reviewed. RESULTS: Among KIs, ALK inhibitors, mammalian target of rapamycin inhibitors, Janus kinase inhibitors, and multikinase inhibitors demonstrated clinical benefits for patients with lung cancer but are also associated with hyperlipidemia. Optimal target levels for total cholesterol, low-density lipoprotein cholesterol, and triglycerides in managing KI-associated hyperlipidemia for the primary and secondary prevention of CVD were recommended. Furthermore, we proposed strategies that include baseline risk assessment, regular blood lipid monitoring, and timely pharmacological interventions. Dose adjustments and discontinuation, evaluation for drug-drug interactions, patient education, and lifestyle modifications were also detailed. CONCLUSIONS: A multifaceted approach is proposed for lung cancer patients receiving KI therapy to manage hyperlipidemia, minimize CVD risks, optimize treatment outcomes, and improve quality of life.
Cancer Treat Rev
· 2026 Feb · PMID 41546915
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Despite dramatic advances in cancer genomic medicine over the past decade, the complex and diverse nature of cancer makes it difficult to identify biomarkers for predicting treatment and prognosis in personalized medicin...Despite dramatic advances in cancer genomic medicine over the past decade, the complex and diverse nature of cancer makes it difficult to identify biomarkers for predicting treatment and prognosis in personalized medicine. The epigenome is a universal system that regulates genomic information and its expression and is involved in the development and progression of cancer. DNA methylation is a key epigenetic modification in cancer, leading to the inactivation of tumor suppressors and the activation of oncogenes through aberrant gene expression patterns. Therefore, epigenomic information may contain robust cancer biomarkers, suggesting that the development of epigenetic diagnostics will enable accurate disease stratification, prediction of treatment response and prognosis. However, in managing advanced colorectal cancer, as in other cancers, gene mutations and the expression of their products, but not epigenomic information, have been used to guide treatment or predict prognosis. This review explores the significance of DNA methylation in advanced colorectal cancer, focusing on its role in carcinogenesis and as a biomarker for predicting the efficacy of anti-EGFR antibody and prognosis. It also reviews the clinical application of recently developed genome-wide DNA methylation diagnostics and predicts the future of epigenomic diagnostics in cancer treatment.
Kirmani N, De León-Fernández N, Rodriguez-Parra JD
… +4 more, Ghanem L, Hakkeem B, Briceño-Morales C, Briceño-Morales X
Cancer Treat Rev
· 2026 Feb · PMID 41539087
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BACKGROUND: Endocrine therapy (ET) plus CDK4/6 inhibitors (CDK4/6i) remains first-line (1 L) standard for ER+/HER2- metastatic breast cancer (mBC). However, ESR1 mutations lead to ET resistance and subsequent disease pro...BACKGROUND: Endocrine therapy (ET) plus CDK4/6 inhibitors (CDK4/6i) remains first-line (1 L) standard for ER+/HER2- metastatic breast cancer (mBC). However, ESR1 mutations lead to ET resistance and subsequent disease progression (PD). Limitations of intramuscular fulvestrant have led to the development of novel oral selective estrogen receptor degraders (SERDs). We aim to evaluate efficacy and safety of novel oral SERDs for ER+/HER2- mBC. METHODS: PubMed, Embase, and Cochrane were systematically searched for randomized controlled trials (RCTs) comparing oral SERDs with standard treatment. Primary outcomes were progression-free survival (PFS) overall and by subgroups (ESR1 mutation, menopausal status, age, prior CDK4/6i use, visceral metastases), PFS comparing oral SERDs versus fulvestrant in ESR1-mutated patients, and grade ≥ 3 or discontinuation due to treatment-related adverse events (TRAEs). Hazard and risk ratios (HRs/RRs) were pooled using random-effects models (RStudio 2025.09.2 + 418). RESULTS: Eight RCTs (n = 3,978) were included. Overall, PFS did not differ significantly between groups (HR 0.80; 95 % CI 0.62-1.04; p = 0.09). Statistically significant PFS subgroups included: ESR1 mutation (HR 0.57; 95 % CI 0.45-0.73; p < 0.01); prior CDK4/6i use (HR 0.68; 95 % CI 0.49-0.95; p = 0.03); visceral metastases (HR 0.78; 95 % CI 0.63-0.97; p = 0.03); age < 65 years (HR 0.75; 95 % CI 0.60-0.92; p = 0.01); and oral SERDs versus fulvestrant (HR 0.55; 95 % CI 0.46-0.66; p < 0.01). Grade ≥ 3 TRAEs were higher with SERDs (RR 1.64; 95 % CI 1.07-2.50; p = 0.03), while treatment discontinuation was not significant. CONCLUSIONS: Novel oral SERDs may represent a paradigm shift in managing PD after 1 L therapy, showing potential to improve PFS in selected patients.
de Torres CS, Elias E, Vaghi C
… +10 more, González NS, García A, Alcaraz A, Rodríguez-Castells M, Baraibar I, Ros J, Salvà F, Tabernero J, Élez E, Sanz-Garcia E
Cancer Treat Rev
· 2026 Feb · PMID 41534185
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Colorectal cancer (CRC) with mismatch-repair deficiency (dMMR) or high microsatellite instability (MSI-H) represents a distinct molecular subtype highly sensitive to immune checkpoint inhibitors (ICIs). Landmark clinical...Colorectal cancer (CRC) with mismatch-repair deficiency (dMMR) or high microsatellite instability (MSI-H) represents a distinct molecular subtype highly sensitive to immune checkpoint inhibitors (ICIs). Landmark clinical trials have established ICIs as standard-of-care in this setting, demonstrating durable responses and improved survival. However, up to one-third of patients will exhibit primary or acquired resistance, highlighting the urgent need for predictive biomarkers and novel therapeutic strategies. This review summarizes the clinical evidence supporting ICIs in dMMR/MSI-H CRC, explores mechanisms of resistance-including intrinsic and extrinsic modulators-and evaluates the role of potential predictive biomarkers of response. Finally, we discuss innovative therapeutic approaches to overcome resistance, including combination strategies, DNA repair pathway inhibitors, immune-oncology drugs beyond checkpoint inhibitors and microbiome-targeted interventions. Together, these insights aim to refine patient selection, optimize therapeutic benefit, and guide the development of next-generation therapies for dMMR/MSI-H CRC.
Patel SP, Gadgeel S, Mino-Kenudson M
… +2 more, Naidoo J, Sethakorn N
Cancer Treat Rev
· 2026 Feb · PMID 41512604
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Lung cancer remains the leading cause of cancer-related death in the United States, with non-small cell lung cancer (NSCLC) accounting for most lung cancer cases. Improvements in first-line treatment with immuno-oncology...Lung cancer remains the leading cause of cancer-related death in the United States, with non-small cell lung cancer (NSCLC) accounting for most lung cancer cases. Improvements in first-line treatment with immuno-oncology and targeted therapies have been observed in patients with NSCLC, but benefits may be limited for those with advanced or metastatic NSCLC (mNSCLC). Following progression on frontline therapies, later-line therapies offer modest benefits and are associated with pronounced adverse effects. Accordingly, there is a need for new, more effective options to improve survival and quality of life. Trophoblast surface antigen 2 (TROP2) antibody-drug conjugates (ADCs) are a novel approach to address unmet treatment needs in NSCLC. There are 5 TROP2-directed ADCs currently under investigation for treatment of NSCLC: datopotamab deruxtecan, sacituzumab govitecan, sacituzumab tirumotecan, DB-1305, and SHR-A1921. Here, we provide an overview of the properties of each ADC as well as efficacy and safety data from clinical trials of patients with NSCLC with or without actionable genomic alterations (AGAs). The unique characteristics of each ADC and its components, particularly the linker chemistry and payload attributes, define the mechanism of action and subsequently influence dosing, efficacy, and safety. TROP2 ADCs have shown antitumor responses with a manageable safety profile in patients with mNSCLC in several ongoing and completed trials. Additional studies are required to understand how these agents can be effectively integrated into the treatment paradigm for lung cancer, taking into consideration sequential use of multiple ADCs, resistance mechanisms, combination therapies, and use in special populations.
Yucel KB, Ilhan Y, Almuradova E
… +3 more, Bardakci M, Dinckal C, Ergun Y
Cancer Treat Rev
· 2026 Feb · PMID 41512603
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BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression defines a distinct breast cancer (BC) subtype that is highly sensitive to anti-HER2 therapy. However, the predictive and prognostic value of vary...BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression defines a distinct breast cancer (BC) subtype that is highly sensitive to anti-HER2 therapy. However, the predictive and prognostic value of varying HER2 expression levels-specifically immunohistochemistry (IHC) 3 + versus IHC 2+/in situ hybridization (ISH)-positive-tumors remains uncertain. This systematic review and meta-analysis compared pathological complete response (pCR) between these subgroups in early-stage HER2-positive BC treated with anti-HER2-based neoadjuvant chemotherapy (NACT). METHODS: Following PRISMA guidelines (PROSPERO: CRD420251066320), PubMed, EMBASE, Cochrane Library, and ClinicalTrials databases were searched up to June 2025. Eligible studies compared HER2 (3 + ) and HER2 (2 + )/ISH + early-stage BC receiving anti-HER2-based NACT. Data extraction was performed independently by two reviewers. Pooled odds ratios (ORs) and hazard ratios (HRs) were calculated using fixed- or random-effects models according to heterogeneity. RESULTS: Thirteen retrospective studies involving 7,206 patients were included. Among 6,081 HER2-positive cases, 76 % were HER2 (3 + ) and 24 % were HER2 (2 + )/ISH + . The pooled pCR rate was significantly higher in HER2 (3 + ) tumors than in HER2 (2 + )/ISH + tumors (55.1 % vs. 21.6 %; OR = 5.38, 95 % CI: 3.72-7.80; p < 0.00001). The difference persisted in dual-targeted regimens (66.0 % vs. 32.9 %; OR = 4.31, 95 % CI: 2.70-6.88; p < 0.00001). No significant difference was observed in 3-year invasive disease-free survival (HR = 0.71, 95 % CI: 0.32-1.57; p = 0.40). CONCLUSION: HER2 IHC 3 + tumors are substantially more likely to achieve pCR following anti-HER2-based NACT than HER2 (2 + )/ISH + tumors, indicating that HER2 expression intensity has predictive relevance. Quantitative HER2 assessment should be integrated into therapeutic planning and trial stratification to optimize outcomes in early-stage HER2-positive BC.
Fabbroni C, Johnston EW, Sanfilippo R
… +43 more, Strauss DC, Bonvalot S, Spalek M, Van Houdt WJ, Ford SJ, Lee KW, Salawu A, Swallow CJ, Bae S, Gyorki DE, Raut CP, Mullinax JE, Albertsmeier M, Cananzi F, Konieczkowski D, Grignol VP, Pennacchioli E, Solli P, Napolitano A, Blasi ED, Wilkinson M, Stacchiotti S, Tzanis D, Rutkowski P, Bouhadiba T, Schrage YM, Sherriff J, Wang J, Callegaro D, Farma JM, Fiore M, Gervais MK, Gladdy RA, Nessim C, Roland CL, Cranmer LD, Lee TY, Patel S, von Mehren M, Wagner AJ, Sicklick JK, Gronchi A, Tseng WW
Cancer Treat Rev
· 2026 Feb · PMID 41506129
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BACKGROUND: Retroperitoneal sarcoma (RPS) encompasses a heterogenous group of rare malignancies that develop in the back of the abdomen. For localized primary disease, the mainstay of treatment is surgery. Beyond the pri...BACKGROUND: Retroperitoneal sarcoma (RPS) encompasses a heterogenous group of rare malignancies that develop in the back of the abdomen. For localized primary disease, the mainstay of treatment is surgery. Beyond the primary site, patterns of disease manifestation vary by histologic type and include visceral organ metastasis, as well as intraabdominal multifocal disease. Although cure is extremely rare, some patients may still derive significant benefit from treatment. METHODS: A comprehensive literature search was performed and international, key opinion leaders for RPS met together to discuss principles of practice for multifocal and metastatic disease, summarized in 45 statements, each given a level of evidence and grade of recommendation. RESULTS: Patients should be evaluated in a multidisciplinary sarcoma center with experience in RPS and recognition of histologic type is critical to guide management. After pretreatment assessment that includes imaging and pathology review, the goals of treatment should be clarified upfront and aligned with the anticipated ability for the patient to tolerate treatment. Disease biology (e.g., disease-free interval) should be thoroughly understood. Treatment modalities can include a combination of surgery, non-surgical local therapy (radiation therapy, percutaneous tumor ablation and embolization) and systemic therapy. CONCLUSIONS: This updated consensus document gives comprehensive and practical clinical guidance to providers for the management of multifocal and metastatic RPS. The current document also serves as the foundation for future clinical and translational investigation, as we continue to optimize patient care in these complex and challenging cases.
Jatan N, Talo S, Azar AJ
… +2 more, Adrian TE, Kellett CF
Cancer Treat Rev
· 2026 Feb · PMID 41506128
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BACKGROUND: Aromatase inhibitors anastrozole and letrozole (non-steroidal, reversible), and exemestane (steroidal, irreversible) are approved standard therapies (Food and Drug Administration) for hormone receptor-positiv...BACKGROUND: Aromatase inhibitors anastrozole and letrozole (non-steroidal, reversible), and exemestane (steroidal, irreversible) are approved standard therapies (Food and Drug Administration) for hormone receptor-positive breast cancer. Their use is limited by Aromatase Inhibitor-induced Musculoskeletal Signs and Symptoms (AIMSS). METHODS: Articles on AIMSS mechanisms and biomarkers published between January 1, 1990, and October 31, 2024, in PubMed, EMBASE, and Cochrane Library were identified. Included study designs were randomized and non-randomized trials, observational cohorts, cross-sectional studies, and preclinical animal models. Risk of bias was assessed using the Critical Appraisal Skills Programme tool for observational studies and Risk of Bias 2 for randomized trials. RESULTS: Fifty studies were included (43 human and seven animal). Estrogen deprivation was the central mechanism, affecting immune function, bone remodeling, and nociceptive sensitivity. Genetic variants in Estrogen Receptor 1, CYP19A1, and T-cell Leukemia/Lymphoma 1A were frequently associated with AIMSS. Vitamin D deficiency, polymorphisms in RANKL and Osteoprotegerin contributed to bone-related symptoms. Imaging studies identified tenosynovial thickening, tendon sheath fluid, and subclinical inflammation. Systemic inflammatory markers C-Reactive Protein and Interleukin 6 were elevated in human and animal studies. Transient Receptor Potential Ankyrin 1 and Transient Receptor Potential Vanilloid 4 ion channels were implicated in peripheral sensitization. Insulin-like Growth Factor 1 during AI therapy was independently associated with symptoms. CONCLUSION: AIMSS involves intersecting hormonal, genetic, inflammatory, and neural pathways. Identification of mechanistic biomarkers may support AIMSS risk stratification and targeted interventions. Further research should validate multi-omic models and explore new strategies to reduce AIMSS and improve treatment compliance. REGISTRATION: PROSPERO Registration: CRD42025642540.
Skrzypiec B, Żółciak-Siwińska A, Pietrzak L
… +1 more, Bujko K
Cancer Treat Rev
· 2026 Feb · PMID 41500029
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INTRODUCTION: To enable cross-trial comparisons of the benefit-risk ratio of the watch-and- wait strategy, two endpoints are required: a primary to assess the benefit and a co-primary to assess the main risk, i.e. regrow...INTRODUCTION: To enable cross-trial comparisons of the benefit-risk ratio of the watch-and- wait strategy, two endpoints are required: a primary to assess the benefit and a co-primary to assess the main risk, i.e. regrowth. MATERIAL AND METHODS: We performed a literature search to identify and critically analyse endpoints used to evaluate the watch-and-wait strategies. RESULTS AND DISCUSSION: The review identified four watch-and-wait strategy-specific primary endpoints assessing benefit and four methods for calculating regrowth rate across nine prospective studies, indicating the need for standardisation. To initiate a debate on this topic, we discuss shortcomings of the following commonly used endpoints: 1) "The clinical complete response (cCR) rate" is flawed for demonstrating benefit, as it combines patients who ultimately achieve sustained cCR ('winners') with those who eventually experience regrowth ('losers'); 2) "the organ preservation rate" combines two procedures with different outcomes: watch-and-wait strategy and local excision; 3) calculating "the regrowth rate" only among patients achieving cCR-while excluding those with near-cCR who pursue watch-and-wait but later require surgery for persistent or progressive abnormalities-leads to an underestimation of the risk associated with deferring surgery. The following endpoints do not share these limitations and are therefore proposed for consideration in the debate on standardisation: 1) proportion of patients with sustained cCR among those who start radio(chemo)therapy; 2) the calculation of regrowth rate among pooled patients with cCR and all with near-cCR pursuing watch-and-wait surveillance.
Cancer Treat Rev
· 2026 Feb · PMID 41483736
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Antibody-drug conjugates (ADCs) represent a rapidly evolving class of therapeutics in non-small cell lung cancer (NSCLC), offering targeted delivery of cytotoxic payloads to tumor cells while minimizing off-target toxici...Antibody-drug conjugates (ADCs) represent a rapidly evolving class of therapeutics in non-small cell lung cancer (NSCLC), offering targeted delivery of cytotoxic payloads to tumor cells while minimizing off-target toxicity. Although ADCs have demonstrated promising results in NSCLC, their efficacy in treating central nervous system (CNS) metastases has been uncertain due to concerns over blood-brain barrier (BBB) penetration and the lack of dedicated CNS-specific evaluations in clinical trials. However, emerging evidence challenges this paradigm. While earlier-generation ADCs such as T-DM1 exhibited limited CNS efficacy, newer ADCs employing optimized linkers and cytotoxins demonstrate more favorable efficacy and toxicity profiles. Selected agents, including trastuzumab deruxtecan, datopotamab deruxtecan and patritumab deruxtecan, have all shown intracranial responses in patients with advanced NSCLC with brain metastases (BM). Proposed mechanisms facilitating CNS activity include BBB disruption by BM, membrane-permeable and highly potent cytotoxic payloads, and bystander effects that enable tumor cell killing beyond the target antigen. Nevertheless, several limitations remain, including variability in trial designs, limited number of patients with untreated CNS disease, and a lack of CNS-specific endpoints. Given the high incidence of BM in NSCLC and their significant impact on patient outcomes, there is an urgent need to better understand the intracranial activity of ADCs and whether they can prevent the development of CNS metastases, especially as some of these ADCS are being tested in the curative-intent setting. This review synthesizes current evidence and highlights ongoing trials, with a focused examination of the evolving role of ADCs in the management of BM.