Quality of life (QoL) is important for patients with metastatic breast cancer (MBC). We examined QoL in daily life among patients with MBC using ecological momentary assessment (EMA).

From 2023 to 2024, patients with MBC were recruited from 5 Mid-Atlantic sites. Eligible patients were English- or Spanish-speaking, with a life expectancy > 6 months and access to a smartphone. Participants were invited to complete 12 EMAs over 4 weeks. EMAs assessed global QoL, symptom severity (depression, anxiety, pain, fatigue, slowed cognition, appetite loss, nausea, gastrointestinal distress, decreased libido), and positive affect (social connection, peace, joy). Multilevel mixed-effects models analyzed the relationships between QoL and between-person and within-person variations in symptom severity and positive affect. We also explored associations between QoL and years since MBC diagnosis at the time of study entry.

Participants (N = 108; Mean age 57.8 years) were a mean of 4.4 years post-diagnosis (range = 0.06-20.65 years). Between-person effects indicated QoL was worse among individuals reporting more nausea (β = -0.109, p = 0.035) and less joy (β = 0.593, p < 0.001). Within-person effects indicated individuals' QoL was lower at times when they had more depression (β = -0.177, p < 0.001), anxiety (β = -0.049, p = 0.023), fatigue (β = -0.052, p = 0.009), appetite loss (β = -0.053, p = 0.028), and decreased libido (β = -0.058, p = 0.036) and less social connectedness (β = 0.091, p = 0.001), joy (β = 0.055, p = 0.047), and peace (β = 0.107, p < 0.001) than their personal average. QoL was not associated with years since MBC diagnosis (β = 0.106, p = 0.956). Age (β = 0.482, p = 0.013) and being partnered (β = 13.356, p = 0.005) at baseline were positively associated with estimated QoL at MBC diagnosis. Changes in QoL per year since MBC diagnosis were positively associated with being employed at baseline (β = 2.453, p < 0.001) and negatively associated with HR positive disease (β = -1.334, p = 0.001).

Both within-person and between-person variations in symptom severity and positive affect are associated with QoL, highlighting the need for adaptive, targeted intervention strategies to optimize QoL for all patients.

The optimal chemotherapy strategy after progression on cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer remains a matter of controversy. This study evaluated the efficacy of metronomic chemotherapy compared with other post-CDK4/6i treatment strategies in a real-world setting.

This retrospective multicenter study included patients with HR+/HER2- metastatic breast cancer progressing on CDK4/6i plus endocrine therapy and subsequently treated with systemic therapy. Progression-free survival (PFS) was the primary endpoint. Secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety. Propensity score matching (1:2) was performed to reduce selection bias.

A total of 177 patients were included, of whom 52 (29.4%) received metronomic chemotherapy. Among treatment strategies, metronomic chemotherapy achieved the longest median PFS (9 months; 95% CI: 5.46-12.53; p = 0.003). In multivariable analysis, metronomic chemotherapy was independently associated with prolonged PFS (HR 0.46, 95% CI: 0.30-0.69; p < 0.001). Median OS did not significantly differ across treatment groups. ORR was 48.0%, and CBR was 60.0% with metronomic chemotherapy. After propensity score matching, metronomic chemotherapy maintained a significant association with improved PFS (HR 0.49, 95% CI: 0.31-0.78; p = 0.003). Toxicities were predominantly Grade 1-2, with no severe adverse events reported in the metronomic cohort.

In this real-world study, metronomic chemotherapy was associated with improved disease control and a favorable safety profile in patients with HR+/HER2- metastatic breast cancer progressing after CDK4/6i-based therapy.

Protocol Number 0037558/23.

Estrogen receptor (ER)-positive/HER2-positive breast cancer demonstrates significantly lower rates of pathological complete response (pCR) to neoadjuvant HER2-targeted therapies compared to ER-negative/HER2-positive disease. However, the optimal ER positivity cutoff for clinically meaningful patient stratification remains undefined.

We analyzed a retrospective cohort of 741 HER2-positive breast cancer patients treated with neoadjuvant chemotherapy plus dual HER2 blockade (trastuzumab and pertuzumab) at Sun Yat-sen University Cancer Center. The optimal ER cutoff for predicting pCR was determined by ROC analysis with Youden index and validated by bootstrap resampling (1000 iterations). Transcriptomic data from TCGA and SCAN-B cohorts were analyzed to characterize biological differences between ER subgroups. Drug response was predicted using the oncoPredict algorithm, and cancer dependency was assessed using DepMap CRISPR screening data.

ER ≥ 50% positivity was identified as the optimal predictive cutoff (bootstrap 95% CI: 25.0%-77.5%) and was an independent predictor of significantly lower pCR rates in multivariate analysis (OR = 0.27; 95% CI: 0.19-0.40; p < 0.001). Transcriptomic analysis revealed that ER ≥ 50% tumors are characterized by activated estrogen response signaling, downregulated cell cycle and immune pathways. Predicted resistance to trastuzumab, T-DM1, and T-DXd was consistently enriched in this subgroup, consistent with lower HER2 and CD16A expression observed in ER ≥ 50% tumors. CCND1, a canonical transcriptional target of ESR1, was significantly upregulated in ER ≥ 50% tumors across both cohorts, and ER + /HER2 + cell lines exhibited significantly higher CCND1 and CDK4 dependency scores in DepMap CRISPR screening (p < 0.05), supporting activation of the ESR1-CCND1-CDK4/6 axis in this subgroup.

ER ≥ 50% positivity defines a clinically and biologically distinct HER2-positive subgroup with poor response to standard neoadjuvant therapy and predicted resistance to ADCs, consistent with lower HER2 and CD16A expression in this subgroup. The convergent transcriptomic and functional evidence for ESR1-CCND1 axis activation provides mechanistic support for combining CDK4/6 inhibitors with endocrine and anti-HER2 therapies to improve outcomes in this resistant subgroup.

CD169+ cells represent a distinct subset of macrophages with potential immunomodulatory roles, but their function in colorectal cancer (CRC) progression remains unclear. This study focuses on the spatial profiling and prognostic significance of CD169+ macrophages in adjacent nontumor mucosa (NM), primary CRC (pCRC), and synchronous or metachronous liver metastases (LM).

We enrolled into this retrospective cohort study patients who underwent resection of both pCRC with adjacent NM and synchronous LM (N = 55) or metachronous LM (N = 44). We applied immunohistochemical staining and computer-assisted image analysis to quantify CD169+ cell density in the NM, pCRC, synchronous, and metachronous LM. Correlations between CD169+ macrophages and T cells were evaluated. Associations between CD169+ cell density and overall survival (OS) of the patients were assessed.

CD169+ cell density was greater in NM than in the tumor center (TC) of pCRC and in the peritumor (PT) region of LM compared to pCRC. The synchronous group exhibited a higher density of CD169+ cells than the metachronous group in the inner margin (IM) of pCRC, the TC, and the outer margin (OM) of LM. CD169+ cells were more abundant in the exterior than in the interior tumor areas in both pCRC and LM. Positive correlations were observed between densities of CD169+ macrophages with CD3+ and CD8+ lymphocytes. In the synchronous group, a high density of CD169+ macrophages in the TC of pCRC was associated with longer OS, whereas a high density in the PT of LM was associated with shorter OS. High density of CD169+ macrophages in the OM of metachronous LM was associated with poor survival.

Our study highlights context-dependent prognostic associations of CD169+ macrophages in CRC. While high CD169+ macrophage density in the TC of pCRC was linked to favorable survival in the synchronous group, increased density in both synchronous and metachronous LM was associated with adverse outcomes. Further prospective studies and functional investigations are needed to validate these observations.

Head and neck cancer (HNC) trials have demonstrated pathological complete response (pCR) in patients receiving neoadjuvant treatment prior to surgery; however, systematic reviews have reported marked variation in pCR rates. This scoping review was designed to determine the definition, criteria, and assessment methodologies for pCR in interventional neoadjuvant HNC clinical trials. The review was conducted in accordance with the JBI Manual for Evidence Synthesis and the protocol prospectively registered. Medical databases, trial registries, and grey literature were systematically searched, and eligibility criteria applied. Study characteristics and pCR assessment methodologies were extracted and described. A total of 4,931 sources were identified, and screening identified 114 trials. Only 22 studies had publicly accessible protocols for assessment. Trials were initiated between 1989 and 2025, and the majority were phase II investigating chemotherapy + immunotherapy regimens (51%). pCR was most frequently classified as a secondary endpoint (55%), and reported pCR rates ranged from 0% to 100%. There was heterogeneity and incomplete documentation in both specimen preparation and pCR assessment. Where specified, most included assessment at both primary tumour and lymph nodes (50 of 69; 72%), and quantitative assessment calculating percentage residual viable tumour was common. While no formal guidelines for pCR assessment in HNC were identified, one trial outlined an immune-related pathological response criteria for oral squamous cell carcinoma, and another included a detailed 'pathological response assessment' proforma. Citation of methodologies used in other cancers, for example, lung and breast cancer, was a recurring theme. Based on these findings, we propose pragmatic definitions, assessment considerations, and a structured reporting proforma to support increased transparency and reproducibility in pCR reporting. While these proposed elements are not consensus based, they provide a foundation for harmonisation efforts and highlight priorities for development of international consensus guidelines to enable meaningful comparison of interventions and determine the validity of pCR as a surrogate endpoint in HNC.

Cellular senescence and regulated cell death represent two fundamental but intricately connected biological programs that govern tumor cell fate. Cellular senescence can suppress tumor growth by inducing stable cell-cycle arrest and promoting immune clearance, but persistent senescent cells may also drive tumor progression through the senescence-associated secretory phenotype (SASP). Concurrently, multiple modalities of regulated cell death-including apoptosis, ferroptosis, cuproptosis, necroptosis, pyroptosis, parthanatos, and autophagy-dependent cell death-have emerged as critical determinants of therapeutic response. The crosstalk between senescence and cell death is orchestrated by key molecular hubs including p53, mitochondria, autophagy machinery, and epigenetic regulators. In this review, we summarize the hallmarks and classification of cellular senescence in cancer, outline major cell death modalities, discuss the cross-regulatory networks linking senescence and death, and highlight emerging therapeutic strategies that target these interconnected processes for cancer treatment.

Cancer-associated fibroblasts (CAFs) act as key drivers of cancer progression and therapeutic resistance within the tumor microenvironment, but their diverse and context-dependent functions complicate therapeutic targeting. The limited clinical efficacy of CAF-targeting therapeutics has prompted a critical reassessment of CAF biology, therapeutic development, and emerging CAF-directed strategies. Unlike prior reviews that predominantly focused on CAF heterogeneity or isolated therapeutic modalities, this review systematically compares pharmacological and biologic CAF-targeting therapeutics, multifunctional nanomedicines, and biologically inspired and living platforms in terms of their underlying mechanisms of action and translational bottlenecks. Drawing on clinical evidence from CAF-targeting therapeutics, we identify several interconnected barriers to successful translation, including CAF heterogeneity and plasticity, patient-selection and biomarker limitations, preclinical-clinical mismatch and combination-treatment dependency, insufficient tumor penetration and systemic toxicity, and signaling redundancy and pathway compensation. Importantly, lessons from unsuccessful clinical trials are used to critically reassess whether current CAF-targeting nanomedicines and platforms adequately address these barriers. In parallel, we evaluate platform-specific translational challenges, particularly those related to biosafety and manufacturing feasibility. These analyses highlight the persistent gaps between the evolving understanding of CAF functional states, existing design rationales for nanomedicine and platforms, and real-world clinical practice. Future directions should therefore prioritize the identification of functionally defined CAF states, the optimization of clinically relevant models of advanced disease, and the development of therapeutic platforms tailored to clearly defined clinical needs. Finally, we propose an iterative translational roadmap and a hypothesis-generating sequential cancer cell/CAF dual-targeting framework to guide the development of clinically translatable CAF-directed therapies.

Genetic counseling and germline genetic testing are essential components of ovarian cancer care; however, their implementation in routine clinical practice remains inconsistent. This study aimed to evaluate the utilization of genetic counseling and testing among patients with ovarian cancer and identify barriers to implementation within routine care.

A single-center, retrospective questionnaire-based study was conducted among patients who underwent surgical treatment for ovarian malignancies between January 2021 and June 2025. Patient-reported data on information provision, referral pathways, organizational access, satisfaction, and barriers were linked with clinical and demographic characteristics. Descriptive analyses were performed, reflecting the exploratory nature of the study. A problem frequency (PF) framework, defined as the proportion of responses indicating a problem, was applied to identify and rank patient-reported barriers.

Of 321 identified patients, 61 were deceased prior to study initiation. Among 256 successfully contacted patients, 132 responded (51.6%). Overall, 115/132 (87.1%) reported receiving information regarding genetic counseling, primarily from hospital-based physicians (106/132; 80.3%). Among the 132 questionnaire respondents, 96/132 (72.7%) attended genetic counseling and 93/132 (70.5%) proceeded to genetic testing; pathogenic variants were identified in 26/93 tested patients (28.0%). Genetic counseling among respondents increased from 37.5% in 2021 to 94.7% in 2025. The majority of appointments were self-initiated. The most frequently reported barriers were limited information provision, appointment scheduling difficulties, and travel-related barriers, whereas emotional burden at the time of diagnosis was reported less frequently. Uptake was significantly associated with family history of breast and/or ovarian cancer, higher educational attainment, and parity. Notably, nearly half of the participants who had not attended genetic counseling (17/36;47.2%) reported reconsidering uptake after completing the questionnaire.

Despite recommendations for universal genetic counseling in ovarian cancer care, gaps in implementation remain evident in routine clinical practice. Organizational and informational barriers represent prominent obstacles to uptake. Our findings highlight the potential value of standardized referral pathways, proactive information provision, and repeated patient engagement to facilitate access to genetic services.

Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat due to heterogeneous antigen expression and an immunosuppressive tumor microenvironment. The epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific splice form with no detectable protein expression in normal tissues. Nevertheless, its low and often heterogeneous expression in HNSCC has limited its utility as target antigen for immunological therapies using chimeric antigen receptor (CAR) T-cells. In contrast, full-length EGFR is frequently overexpressed in HNSCC, but its expression in normal tissues prevents its use as a directly activating CAR target. Thus, we investigated here whether EGFR can instead provide additional target antigen engagement as a non-signaling CAR (nsCAR) for EGFRvIII CARs. The nsCAR was derived from Cetuximab, an EGFR-binding monoclonal antibody whose epitope is retained in EGFRvIII and was co-expressed with different EGFRvIII-specific signaling CAR to investigate whether additional receptor engagement could enhance target-cell recognition and cytotoxicity.

Primary human T-cells were engineered to express EGFRvIII-specific CARs alone or in combination with EGFR-directed nsCARs. Functional activity was evaluated using in vitro cytotoxicity assays, time-resolved killing dynamics, and fluorescence microscopy to assess immunological synapse (IS) formation in HNSCC cell lines with defined levels of EGFRvIII expression.

EGFRvIII CAR T-cells exhibited clear target antigen density-dependent cytotoxicity. Co-expression of the EGFR nsCAR specifically enhanced tumor cell killing in selected CAR and target antigen combinations, with the strongest effects observed under conditions of limited baseline CAR activity, whereas the nsCAR alone was non-cytotoxic. Fluorescence imaging revealed co-localization of CAR and nsCAR molecules at the T-cell-target-cell contact interface.

EGFR nsCAR co-expression can provide a modular strategy to enhance EGFRvIII CAR T-cell cytotoxicity under conditions of limited target antigen availability. These findings provide an in vitro proof of concept for additional target engagement through a non-signaling receptor and warrant further evaluation in more complex preclinical models.

Low anterior resection syndrome (LARS) frequently occurs following sphincter-preserving rectal cancer surgery. Although recent studies have reported the effects of digital health interventions for LARS management, no systematic review and meta-analysis has been conducted.

We searched five English databases and three Chinese databases from inception to 18 December 2025, supplemented by gray literature sources and reference checking. Randomized and non-randomized controlled studies involving adults who had undergone sphincter-preserving rectal surgery were eligible. Risk of bias was assessed using RoB 2 for randomized trials and ROBINS-I for non-randomized studies. When at least two studies reported similar outcomes, meta-analysis was performed using mean difference or standardized mean difference with 95% confidence intervals, with the I² statistic used to measure heterogeneity. Narrative synthesis was used when pooling was not appropriate. Certainty of evidence was assessed using GRADE. The protocol was registered in PROSPERO.

Eight studies published between 2021 and 2025 were included, and seven contributed to the meta-analysis. Digital health interventions were associated with reductions in LARS scores compared with usual care (MD = - 3.00, 95% CI - 4.17 to - 1.83; P < 0.00001; I² = 28%) and with improvements in health-related quality of life, although heterogeneity for this outcome was substantial (SMD = 0.75, 95% CI 0.17 to 1.34; P = 0.01; I² = 89%). No statistically significant between-group effect was observed for self-efficacy, with substantial heterogeneity (SMD = 0.43, 95% CI - 0.15 to 1.01; P = 0.15; I² = 79%). Anxiety and depression outcomes, assessed in a small number of trials, did not show meaningful between-group differences. Evidence for self-management, activation, satisfaction, feasibility, and other implementation outcomes was suggestive but inconsistently reported and often study-specific.

Digital health interventions show promising potential to reduce LARS symptom burden and may improve quality of life after sphincter-preserving rectal surgery. Nonetheless, confidence in these findings is limited by the small number of available trials, clinical and methodological heterogeneity, and inconsistent outcome measurement and reporting, particularly for psychological and intermediate pathway outcomes. Further well-designed, adequately powered studies are needed to confirm effectiveness and inform implementation in routine care.

PROSPERO Registration: CRD420251250663.