搜索结果：British journal of cancer

Indigenous communities in Canada have high age-standardized rates of cancer mortality. Remote communities in Canada's northern territories have a high proportion of Indigenous residents and disproportionately low utilization rates of screening services for breast, cervical, and colorectal cancers, which could contribute to delayed cancer diagnosis and less favourable clinical outcomes. Knowledge is limited regarding the under-utilization of cancer screening services. This study identified factors contributing to the underutilization of breast, cervical, and colorectal cancer screening services and documented suggestions to promote utilization in remote Indigenous communities in Northwest Territories, Canada. This qualitative study consisted of four sessions of sharing circles and two one-on-one interviews with nine healthcare professionals, eight community members including Elders, and five community leadership from two Northwest Territories communities. Data were transcribed verbatim and coded and analyzed using NVivo-10. The constant comparative method determined emergent themes. Data identified four themes of factors influencing the utilization of cancer screening services (socio-environmental, socio-cultural, socio-political, and personal themes), covering limited resources, limited cultural considerations, the legacy of colonial practices, and fear. Five themes regarding suggested approaches to encourage utilization were community outreach, collaboration, sustainability, cultural safety, and support for healthcare professionals. Factors identified to affect cancer screening service utilization and suggested approaches to improve the utilization are supported by other studies and initiatives in the region highlighting the relevance and feasibility of the findings. The findings could further inform community-based interventions for improving the utilization of cancer screening and support services in remote Indigenous communities. Main findings: This qualitative study explores socio-environmental, socio-cultural, socio-political, and personal aspects of utilizing publicly funded breast, cervical, and colorectal cancer screening services in remote Indigenous communities in Northwest Territories, Canada.Added knowledge: Addressing low rates of utilizing cancer screening services in remote Indigenous communities in Northwest Territories requires implementing community outreach, encouraging community collaboration, supporting sustainability, establishing cultural safety, and providing support for healthcare professionals.Global health impact for policy and action: The findings can inform interventions, practices, and policies to improve the utilization of cancer screening services for remote Indigenous communities, where increasing cancer mortality warrants promoting the utilization of cancer screening services and early detection.

Patients' awareness of tobacco's harms is a key driver for smoking cessation. In Brazil, unique smoking practices-such as straw cigarettes-may influence these views. We hypothesized that cancer patients who continue smoking exhibit an attenuated perception and awareness of tobacco-associated impact on treatment efficacy and survival compared to their primary caregivers. Thiscross-sectional study recruited144 active smoker patients with solid cancers and their primary caregivers at a Brazilian public academic hospital. Participants completed a structured questionnaire assessing sociodemographic characteristics, smoking history, perceptions of smoking's impact on quality of life, fatigue and treatment outcomes, and objective awareness of tobacco-related harms. Tumor information was abstracted from medical charts. Groups were compared using chi-square, t-tests, and logistic regression analyses. From 1342 patients approached; 144 (10.9%) active smokers and their caregivers were enrolled. Patients were older (median age 63 vs 51&#x2009;years), and predominantly male (69%). Among patients, 46% smoked non-manufactured cigarettes (straw, rope, or mixed types). Compared to caregivers, patients exhibited lower scores for both perception (19.8 vs. 23.6; p&#x2009;<&#x2009;0.001) and awareness (23.0 vs. 25.1; p&#x2009;=&#x2009;0.02) regarding the harms of continued smoking on both cancer and non-cancer outcomes. Notably, 50% of patients disagreed that smoking adversely affects treatment efficacy, vs. 23% of caregivers (p&#x2009;<&#x2009;0.001). Only half of both groups reported feeling adequately supported by their medical team to quit smoking. Higher nicotine dependence (Fagerstr&#xf6;m score; aOR&#x2009;=&#x2009;2.48, 95% CI: 1.10-5.20) and use of manufactured cigarettes (aOR&#x2009;=&#x2009;2.36, 95% CI: 1.10-5.10) were independently associated with an improved perception of tobacco harms. Cancer patients in the Brazilian public health system who continue smoking tend to underestimate tobacco's harms relative to their primary caregivers. Targeted educational interventions and enhanced cessation support are needed to improve cancer care outcomes.

Cancer screening can reduce late-stage diagnoses, expand treatment options, and improve cancer outcomes. We modelled how introducing a multi-cancer early detection (MCED) screening programme in England could impact cancer treatment patterns. The proportions of cancers (19 types, diagnosed 2014-2019) treated with resection, radiotherapy, and systemic anti-cancer therapy (SACT) were applied to modelled stage-specific cancer incidence data with and without addition of MCED screening to existing screening. We modelled an initial screening round (first screen for individuals aged 50-79 years) and a steady-state programme (annual screening from age 50-79 years). Assuming test parameters are accurate, if MCED screening is introduced in England, more cancers would require resection compared with current annual usage (steady-state: +8900, +10.0%). The number of cancers receiving radiotherapy would decrease overall (-1200; -2.0%) due to a decrease in palliative radiotherapy (-2100; -23.0%); the number of cancers treated with curative radiotherapy would increase slightly (+932; +2.1%). Fewer cancers would receive cytotoxic chemotherapy (-5300, -9.8%) and non-cytotoxic SACT (-530, -12.2%). Increased use of curative treatment combinations is also predicted. Changes to future service delivery and workforce planning will be needed for the full benefits of an MCED screening programme to be realised.

Cancer and mental disorders may influence one another, yet research on the risk of developing a new-onset mental disorder following cancer, other than depression, remains limited. In a nationwide register-based study, patients were followed from incident cancer diagnosis between 1995 and 2015 until end of follow-up 2023, excluding those with preexisting mental disorders. Patients were matched with cancer-free individuals on age, sex, socioeconomic position and comorbidities. We estimated incidence rates (IR) of mental disorders through psychiatric diagnoses and psychotropic medication prescriptions, as well as hazard ratios (HR) in comparison to cancer-free individuals. We included 289,391 cancer patients and 1,031,057 population-matched cancer-free comparisons. Across the cancer cohort, 116,118 developed any incident mental disorder, with a HR of 2.3 [95%-CI: 2.3-2.3] and varying rates across tumor types. IR and HR were highest in the first year after cancer diagnosis and decreased rapidly thereafter, yet the HR remained elevated exceeding ten years. Highest IRs and HRs were observed for anxiety, depression and substance use disorders. Our results were confirmed by several sensitivity analyses. The incidence and risk elevation of incident mental disorders in cancer patients vary based on sex, cancer type, time since diagnosis and type of mental disorder.

Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer (BC). However, the development of cisplatin resistance limits its antitumor effects. While, the mechanism of cisplatin resistance remains unclear. Bioinformatics techniques were used to analyse genes and pathways associated with cisplatin therapy resistance. A variety of biological techniques were used to identify the role of ITGB4 in cisplatin sensitivity in BC and its potential molecular mechanism. In this study, we demonstrated that ITGB4 plays a key role in regulating the sensitivity of p53 wild-type (WT) BC to cisplatin therapy. Our findings revealed that ITGB4 inhibits the activation of p53 by suppressing the phosphorylation at the p53-S15 site and promotes&#xa0;the degradation of p53 by facilitating the binding of MDM2 to p53, thereby reducing the sensitivity of BC to cisplatin.Additionally, we showed that ITGB4 influences the antitumor effects of MDM2 inhibitors when they are combined with cisplatin therapy. Furthermore, we found that the elevated expression of ITGB4 in cisplatin-resistant BC cells&#xa0;were mediated by STAT3 activation. The combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin in BC. ITGB4 is a key molecule influencing cisplatin sensitivity in p53 WT BC, and the combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin.

The Australian alcohol health guidelines were revised in 2020 to recommend a maximum of 10 drinks/week. We calculated estimates of cancer caused by alcohol use in Australia for the updated recommended limits. Cox regression models were used to estimate hazard ratios (HR) for cancer incidence in relation to self-reported alcohol consumption (drinks/week) among 225,805 participants aged &#x2265;45 years (2005-2009) in the New South Wales (NSW) 45 and Up Study, an Australian prospective cohort study (baseline n&#x2009;=&#x2009;267,357). Cumulative absolute risk of cancer to age 85 years was estimated using 0 to <1 drink/week as the comparator. Population attributable fractions were calculated using Australian national alcohol consumption and cancer incidence data, compared to a theoretical minimum risk exposure of no alcohol consumption. Cancer cases and deaths were ascertained through record linkage to the NSW Cancer Registry and NSW Registry of Births Deaths & Marriages to 2019. Participants diagnosed with cancer pre-baseline were excluded. Over a median 11.4 years, 34,860 cancer cases were recorded. When modelled as a continuous variable, alcohol-related cancer risk increased by 19% for every ten drinks/week increase in consumption (HR: 1.19; 95% confidence interval: 1.15-1.23). By age 85 years, those who consumed >10 drinks/week had an estimated 4.9% higher cumulative absolute risk of an alcohol-related cancer compared to those consuming 0 to <1 drink/week. An estimated 7804 cancer cases (4.6% of all cancer cases) were attributable to alcohol use in 2024. The proportion of alcohol-attributable cancers in Australia is substantial and somewhat higher than previously estimated.

Frail patients with cancer (Ca) have worse survival. Current methods of assessment of fitness (performance status) for cancer treatment, such as chemotherapy, are time -consuming and often not used by practicing oncologists. The electronic frailty index (SCARF) is derived from a cumulative deficit frailty model and provides a measure of frailty alongside pre-existing conditions. We used this methodology to investigate whether it can predict outcomes of chemotherapy in patients with Ca. The study conducted data analysis of Ca patients treated with chemotherapy in England, years 2015-2018; stage II-III breast Ca, stage III colon Ca and stage IIIB-IV non-small-cell lung Ca. The data was linked with hospital admissions to calculate 30-day chemotherapy mortality, overall survival and SCARF. The SCARF was calculated for 78,799 patients. The risk of dying within 30 days of chemotherapy in severely frail patients with colorectal cancer &#x2265;70&#x2009;y.o. was twice that of the <70&#x2009;y.o. (OR 2.04 -95% CI 1.58-2.64, mild frailty 1.07-95% CI 0.78-1.45); and 6 times higher in breast cancer (OR 5.73-95% CI 2.66-12.32, mild frailty OR 1.45 95% CI 0.78-2.71). The SCARF index predicts poor outcomes from SACT, particularly in breast and colon cancer, and it requires further evaluation.

Lung cancer survivors have a high risk of second primary lung cancer (SPLC). While air pollution is associated with the risk of initial primary lung cancer (IPLC), especially in never smokers, its effect on SPLC risk is unknown. We identified 2439 IPLC patients from the UK Biobank, followed through 2017, linking baseline addresses to 2005-2007 annual average exposures of particulate matter (PM10) and nitrogen dioxide (NO2) from the EU-wide Land Use Regression model. Associations with SPLC risk were assessed using cause-specific Cox models adjusted for co-pollutants, socioeconomic factors, smoking, and tumour characteristics. Of 2439 IPLC patients, 92 (3.7%) developed SPLC over 6561 person-years. The 10-year cumulative incidence of SPLC was 3.98% (3.11-4.85%). A dose-response relationship was observed between PM10 and SPLC risk, with an adjusted hazard ratio (aHR) of 6.43 (2.38-17.32) in the highest vs. lowest (aHR&#x2009;=&#x2009;1.69 [0.68-4.19]) quintile; a co-pollutant NO2 showed an aHR of 0.96 (0.93-0.99). The PM10 effect was pronounced in never-smoking (aHR&#x2009;=&#x2009;2.26 [1.22-4.18]) vs. ever-smoking IPLC patients (aHR&#x2009;=&#x2009;1.42 [1.21-1.68]) on the risk of non-small cell SPLC. Exposure to PM10 may increase SPLC risk in lung cancer survivors, highlighting the potential value of incorporating environmental factors into SPLC surveillance to identify high-risk individuals.

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with few biomarkers to inform treatment selection or patient prognosis. Methylation profiles of plasma circulating tumour DNA (ctDNA) accurately reflect tumour methylomes and may reveal novel biomarkers of mCRPC. To establish a novel mCRPC-associated methylation signature for detection of ctDNA, we performed plasma methylome profiling on 27 mCRPC patients and 10 controls (cohort 1). Signature-based ctDNA detection was evaluated across prostate cancer (PC) disease stages using an internal cohort of 93 PC patients and 8 controls (cohort 2), and an external cohort of 115 PC patients (cohort 3). We established a 48-region methylation signature (cfMeCaP) capable of highly sensitive detection of ctDNA in mCRPC (100%, 84% and 95% in cohorts 1, 2 and 3, respectively). cfMeCaP methylation at mCRPC diagnosis was associated with poor progression-free survival (PFS) and overall survival in all three cohorts (p&#x2009;<&#x2009;0.005), independent of routine clinical variables. Persistent serial detection of ctDNA using cfMeCaP was strongly associated with rapid mCRPC treatment failure (median PFS 4.4 vs. 65.5 months; p&#x2009;<&#x2009;0.0001), while no detection predicted continued treatment response. These results highlight cfMeCaP as a promising non-invasive biomarker for prognostication in mCRPC.

Patients with advanced gastrointestinal (GI) cancer experience a high symptom burden which frequently necessitates emergency care. Integration of early home-based specialised palliative care (SPC) with tumour-specific treatments may impact emergency healthcare use. At the initiation of palliative chemotherapy, patients with advanced GI cancer were randomised to early home-based SPC integrated with tumour-specific treatment, or tumour-specific treatment with SPC referral when needed. The aim was to compare quality of life in the two groups. Here we present secondary outcomes; number of emergency department visits, hospitalisations, days of inpatient care, the time from the last chemotherapy treatment to death, and the place of death between the study groups. A total of 118 patients were randomised. Patients in the early SPC group had significantly fewer emergency department visits (median 1 versus 3), hospitalisations (median 1 versus 2), and inpatient care days (median 1.5 vs. 11.5) compared to the control group (p&#x2009;<&#x2009;0.001). There was no significant difference between the study groups in either time between the last chemotherapy treatment and death, inpatient SPC or place of death. Early integration of home-based SPC in advanced GI cancer patients significantly reduces emergency healthcare use and hospitalisation. ClinicalTrials.gov (ref: NCT02246725).

Artificial intelligence (AI) offers a potential solution to radiologist shortages in breast cancer screening while maintaining diagnostic accuracy. Retrospective studies suggest AI performs comparably to human readers in detecting cancers, but no economic evaluations have yet used prospective trial data. We developed a de novo discrete-event simulation model to estimate the cost-effectiveness of integrating AI into the NHS screening pathway using evidence from a large prospective trial. The AI-only strategy generated a small incremental QALY gain of 0.00009 and reduced lifetime costs by &#xa3;159.55 per woman invited, and had a 100% probability of being most cost-effective at the &#xa3;20,000/QALY threshold. Replacing one human reader with AI also increased QALYs, by 0.00019, and reduced costs by &#xa3;31.07. Triple reading (two humans plus AI) produced the largest QALY gain (0.00023) but increased costs by &#xa3;72.79. All AI-based pathways reduced cancer deaths, shifted cancers from advanced (TNM stage 4) to earlier stages at detection, and increased the proportion of cancers detected by screening. Using AI in place of human readers is likely to be cost-effective, marginally improving health outcomes while reducing overall costs, with full replacement of both human readers being the most cost-effective screening strategy.

The molecular interplay between Notch and TGF-&#x3b2; signaling in colorectal cancer (CRC) metastasis remains poorly understood. Genetic ablation of RBP-J, the central transcriptional mediator of Notch signaling, was performed in CRC cells. In vitro functional assays assessed migration, invasion, and transendothelial migration. Metastatic colonization was evaluated in vivo using orthotopic, intrasplenic, and intravenous murine models. Whole-transcriptome analysis, chromatin immunoprecipitation sequencing (ChIP-seq), and luciferase reporter assays were used to analyze RBP-J-mediated transcriptional regulation of SMAD2/SMAD3. Rescue experiments reconstituted SMAD2/SMAD3 in RBP-J knockout (KO) cells to verify functional necessity. RBP-J knockout profoundly impaired CRC cell migration, invasion, and transendothelial migration in vitro, and suppressed metastatic colonization across multiple in vivo models. Transcriptomic and ChIP-seq analyses revealed RBP-J directly binds to SMAD2 and SMAD3 promoters and activates their transcription. Reconstitution of SMAD2/SMAD3 restored the migratory and metastatic capacities of RBP-J KO cells. Mechanistically, Notch signaling primes TGF-&#x3b2; responsiveness by maintaining SMAD2/SMAD3 expression and phosphorylation, establishing a feedforward loop essential for metastasis. Notch signaling orchestrates TGF-&#x3b2;-driven metastasis through direct transcriptional control of SMAD2/SMAD3, defining a hierarchical regulatory axis. This offers novel therapeutic targets for metastatic CRC.

Sex differences in cancer incidence and survival have been documented, but underlying mechanisms remain unclear. We examined sex differences in incidence and survival for non-sex-specific cancers and the role of socioeconomic factors and comorbidity. All individuals living in Denmark from 2004-2020 were included. Incidence rate ratios (IRRs) and excess mortality ratios (EMRs) for 35 cancers were estimated using Poisson regression adjusted for age and year. Modification of associations between sex and death by cohabitation, education and comorbidity was assessed. A total of 7,339,667 individuals were followed for 99,832,998 person-years, during which 355,339 were registered with a primary malignancy (197,375 males, 157,964 females). Males had a 52% higher risk of cancer and upon cancer diagnosis 10% higher mortality than females. IRRs were elevated (with confidence intervals excluding the null) for 24 cancers and EMRs for 16 cancers in males. One in six cancers and one in five cancer deaths in males could have been avoided if male rates matched female rates. Disparities were greatest among males living alone, particularly for alcohol- and smoking-related cancers. Sex differences in cancer must be addressed and translated into interventions that promote equality between sexes, specifically focusing on socioeconomically vulnerable males.

Platinum resistant ovarian cancer (PROC) is associated with poor survival. This clinical trial sought to determine whether the bispecific CD47 inhibitor and CD40 agonist, SL-172154, could be combined safely and improve the efficacy of mirvetuximab (MIRV) or pegylated liposomal doxorubicin (PLD) through enhanced tumor cell phagocytosis and antigen presentation to T cells. Patients with PROC received MIRV (21-day cycle) or PLD (28-day cycle) on day 1 and SL-172154 (3&#x2009;mg/kg) on days 8 and 15 of each cycle. Objectives included safety, anti-tumor activity, PK, and immunogenicity. 65 patients (60% folate receptor alpha (FR&#x3b1;) high and 40% medium/low) were enrolled in the MIRV cohort and 21 patients in the PLD cohort. Most common TEAEs (&#x2009;>&#x2009;40%) in the MIRV cohort were blurred vision, nausea, infusion related reaction, transaminase increase, diarrhea, and in the PLD cohort, nausea, constipation, neutropenia and fatigue. The objective response rate in the MIRV cohort was 33% (95% CI, 19%, 50%) for FR&#x3b1; high subgroup, and 15% (95% CI, 4%, 35%) for FR&#x3b1; medium/low subgroup, and in the PLD cohort was 20% (95% CI, 6%, 44%). Combination of SL172154 with MIRV did not improve upon the previously reported ORR for MIRV, while the combination with PLD resulted in a higher ORR than reported for PLD, albeit in a small number of patients. Limited tumor penetration of SL-172154, lack of durable CD47 blockade, inability to overcome T cell exhaustion and other mechanisms of resistance may explain these findings. Trial register number: NCT05483933.

Every 2&#x2009;minutes, a woman dies from cervical cancer, resulting in over 300&#x2009;000 preventable deaths globally. Nearly all cervical cancers are caused by human papillomavirus (HPV) and are preventable with HPV vaccination and screening through Papanicolaou (Pap) and HPV tests. In Canada, cervical cancer mortality rates have declined in recent decades with more accessible cervical cancer screening programmes. However, screening rates remain low, particularly among Black women and people with a cervix (WPC).Cervical cancer screening studies of Black WPC in Ontario-Canada's most populous province-are limited. These studies indicate Black WPCs are at elevated risk for under-screening, with many overdue for screening.An innovative approach to begin addressing delays is HPV self-sampling (HPVSS). Self-sampling is a cost-effective and more accurate test for detecting high-risk HPV infections associated with precancerous changes versus the Pap test. Self-sampling supports Canada's action plan-a response to WHO's global strategy-to eliminate cervical cancer by 2040.Despite Canada's plan, research on the state of Black WPCs' HPV knowledge and self-sampling interventions tailored to them is scant. These scarcities are concerning as Ontario plans to implement HPV primary screening and offer HPVSS soon.The study objective is to codevelop an HPVSS intervention tailored for and made by Black WPC in Peel region, Ontario. This protocol focuses on phase one of a two-phased study. In phase one, a qualitative, community-informed approach, co-led by community research assistants, will be used to purposively recruit 10 service providers (eg, clinicians, social workers, community care workers) and 40 Black WPC who will undergo one-on-one semistructured interviews and sociodemographic surveys to explore the state of: (1) Black WPC's level of HPV, cervical cancer and cervical cancer screening knowledge; (2) Black WPC's motivators, beliefs, attitudes and misconceptions towards HPVSS; (3) Black WPC's perceived barriers and facilitators to HPVSS and (4) service providers' perspectives on Black WPC's barriers and facilitators to HPVSS. Charmaz's grounded theory approach and intersectionality will guide data collection and analysis. Ethical approval has been obtained from the Trillium Health Partners Research Ethics Board (ID#1207). Study findings will be disseminated through community healthcare events, conference presentations, peer-reviewed publications and virtual and physical pamphlets. Additionally, summaries of the findings will be shared and tailored to collaborators, healthcare leadership and researchers and community health centres. Wide dissemination will help enhance understanding of the state of cervical cancer screening, HPV and HPVSS among Black WPC. Given Canada's commitment to eliminating cervical cancer, study findings will be used to begin developing an HPVSS intervention for Black communities.

Emerging evidence indicates that tumour innervation promotes cancer progression via a non-canonical TLR7 signalling pathway. However, its impact across breast cancer subtypes, patient populations, associated molecular pathways, and oncogenic drivers remains poorly defined. We analysed TLR7 signature scores in human breast cancer across multiple datasets and evaluated their associations with prognosis, clinical outcomes, TNBC subtypes, metastasis, molecular signatures, oncogenic signalling, and pathological complete response. We demonstrate that the TLR7score signature is significantly elevated in triple-negative breast cancer (TNBC) - the most aggressive breast cancer subtype-compared with ER&#x207a; disease. Within TNBC, high TLR7 signalling characterises basal- and mesenchymal-like tumours relative to the luminal androgen receptor (LAR) subtype. Across multiple breast cancer cohorts, including TNBC, TLR7score alone does not uniformly predict prognosis, as both high- and low-scoring tumours are associated with reduced survival. Using sequential cut-off analysis in seven independent clinical cohorts, we show that both TLR7score-high (e.g. HR&#x2009;=&#x2009;4.7, P&#x2009;=&#x2009;0.01) and TLR7score-low (HR&#x2009;=&#x2009;3.37, P&#x2009;=&#x2009;0.038) tumours are associated with unfavourable outcomes relative to intermediate-score tumours. TLR7score-high lesions are enriched for cell proliferation, neuronal, and mast cell-related pathways, as well as RB1 and TP53 loss and elevated E2F, PI3K, MET, and MYC signalling. In contrast, TLR7score-low tumours show increased ER signalling and are enriched for T cell-associated but not neuronal pathways, delineating innervated versus non-innervated TNBC phenotypes. Moreover, TLR7score correlates with pathological complete response (pCR) in a treatment-dependent manner. Collectively, these findings suggest that TNBC progression involves both TLR7-dependent and TLR7-independent mechanisms and that TLR7score may enable patient stratification for distinct therapeutic strategies.

Hormone receptor-positive (HR&#x2009;+&#x2009;), HER2-negative breast cancer comprises ~70% of all breast cancer cases and is primarily treated with endocrine therapies such as tamoxifen, aromatase inhibitors, fulvestrant, and CDK4/6 inhibitors. However, resistance arises in ~40% of patients, limiting therapeutic efficacy. We performed integrated genomic, transcriptomic, and functional analyses of 186 HR&#x2009;+&#x2009;/HER2-tumors (88 sensitive, 98 resistant), to identify key drivers of endocrine hormone therapy resistance, Findings were validated functionally using in-vitro and in-vivo models. We identify frequent CDKN1B (p27) loss-of-function mutations or deletions as a key and clinically actionable driver of endocrine resistance. CDKN1B knockdown in cell lines induces resistance to tamoxifen and fulvestrant, while its restoration re-sensitizes resistant cells. Importantly, CDKN1B-deficient tumors remain responsive to CDK4/6 inhibition, in vitro and in vivo. Immunohistochemistry and transcriptomic analysis of clinical cohorts (n&#x2009;=&#x2009;138) and TCGA-METABRIC data (n&#x2009;=&#x2009;1398) identify low p27 as an independent predictor of early relapse and poor survival. Our results highlight CDKN1B as a prognostic biomarker to guide CDK4/6-targeted therapy and a predictor of endocrine resistance in HR&#x2009;+&#x2009;/HER2- breast cancer.

Concurrent chemoradiotherapy (cCRT) is a pivotal component in locally advanced non-small cell lung cancer (NSCLC) treatment; however, exploration of factors that impact its efficacy has been limited. We analyzed individual data of 1165 patients with locally advanced NSCLC enrolled in randomized phase II/III trials of cCRT between 1999 and 2016. Least absolute shrinkage and selection operator (LASSO) regression was applied to identify factors associated with 3-year progression-free survival (PFS). Cox regression was applied to adjust for key clinical variables. The 3- and 5-year PFS rates were 19.7% and 14.3%, respectively (median PFS: 9.7 months). The 3- and 5-year overall survival rates were 56.7% and 42.9%, respectively (median OS: 25.7 months). LASSO regression identified age, lower lobe tumor location, weight loss (&#x2265;5% within 6 months), smoking index, and histology as predictors of PFS. Lower lobe tumors and weight loss independently predicted shorter PFS (lower lobe: hazard ratio 1.29; 95% CI, 1.02-1.64; P&#x2009;=&#x2009;0.036). Lower lobe tumors also had more pneumonitis (55.8% vs. 43.4%; grade &#x2265;3: 11.0% vs. 4.3%) and in-field recurrence (60.2% vs. 51.4%). Primary tumor location should be carefully considered in clinical practice and during the development of treatment strategies for locally advanced NSCLC.

Endocrine resistance remains a major challenge in hormone receptor-positive (HR+) breast cancer (BC), where up to 70% of tumours overexpress HER3, a receptor associated with poor prognosis and therapeutic resistance. HER3-DXd (patritumab deruxtecan) is currently under clinical investigation for HER3-expressing metastatic BC. However, strategies to further enhance its efficacy, particularly in endocrine therapy-resistant settings, are urgently needed. We hypothesised that targeting ATR, a key regulator of DNA damage repair (DDR), potentiates HER3-DXd in HER3+/HR+&#x2009;BC, including tamoxifen-resistant (TMR) disease. Synergistic partners for HER3-DXd were identified by whole-genome RNAi screening. Treatments' effects on cell cycle, DNA damage, and protein expression were analysed using flow cytometry, comet assay, and Western blotting, respectively. Treatments' antitumor efficacy was assessed using xenograft mouse models. TCGA and CPTAC databases were analysed for clinical relevance. HER3-DXd inhibited growth in both parental and TMR MCF7 and T47D cells. Compared to monotherapies, combining HER3-DXd with an ATR inhibitor enhanced DNA damage, sub-G1 arrest, apoptosis, downregulation of DDR and cell cycle regulatory proteins, and tumour growth inhibition. TCGA and CPTAC analyses confirmed high HER3 expression and correlation of ATR, CHEK1, and TOP1 gene expression with poor prognosis in HR+&#x2009;BC. Combining HER3-DXd with an ATR inhibitor could benefit HER3+/HR+&#x2009;BC patients with both endocrine-sensitive and -resistant diseases.