Yildirim S, Sever ON, Turkoglu E
… +30 more, Sariyar Busery N, Dogan A, Baydas T, Sakin A, Akdag Topal G, Topal A, Alan O, Bayhan AZ, Uzun M, Canaslan K, Ünek İT, Akbas S, Sever N, Sahin E, Oğuz A, Elçiçek ÖF, Özkan FE, Demir H, Şanci PC, Uygun K, Arpaci E, Sakalar T, Surmeli H, Isik D, Ay Ersoy S, Basoglu T, Odabas H, Artaç M, Turan N, Gumus M
Clin Med Insights Oncol
· 2026 · PMID 42131419
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BACKGROUND: Gastric cancer remains one of the most common malignancies and a leading cause of cancer-related mortality worldwide. Human epidermal growth factor receptor 2 (HER2) status is a key biomarker influencing both...BACKGROUND: Gastric cancer remains one of the most common malignancies and a leading cause of cancer-related mortality worldwide. Human epidermal growth factor receptor 2 (HER2) status is a key biomarker influencing both prognosis and treatment selection. While HER2-positive patients benefit from trastuzumab, outcomes for HER2-low and HER2-zero groups remain less clearly defined. METHODS: In this retrospective cohort study, we reviewed 507 patients diagnosed with metastatic gastric adenocarcinoma between 2015 and 2023. Patients were classified as HER2-zero (n = 134), HER2-low (n = 303), or HER2-positive (n = 70) based on immunohistochemistry and in situ hybridization results. Clinicopathologic features, treatment strategies, and survival outcomes were analyzed. Kaplan-Meier methods estimated progression-free survival (PFS) and overall survival (OS), whereas Cox regression identified independent prognostic factors. RESULTS: The HER2-positive group achieved a median PFS of 9.0 months and OS of 20.0 months, superior to HER2-zero patients (PFS: 6.1; OS: 14.5; < .001). HER2-low patients demonstrated intermediate outcomes (PFS: 6.7; OS: 16.6 months). Group distribution was HER2-zero 26.4%, HER2-low 59.8%, and HER2-positive 13.8%. All HER2-positive patients received trastuzumab-based therapy. Multivariate analysis confirmed HER2-positive status as an independent predictive factor for both progression (hazard ratio [HR] = 0.65) and mortality (HR = 0.62). CONCLUSIONS: HER2 status is a strong predictive determinant in metastatic gastric cancer. Trastuzumab provided significant real-world benefit for HER2-positive patients, validating the impact of targeted therapy. Notably, HER2-low patients had better outcomes than HER2-zero, supporting the recognition of HER2-low as a distinct subgroup with potential eligibility for future HER2-directed treatments.
Daquinag AC, Ghosh SC, AghaAmiri S
… +7 more, Farmer SM, Zhang S, Vargas SH, Ramesh AK, An Z, Azhdarinia A, Kolonin MG
Mol Ther Oncol
· 2026 Jun · PMID 42124952
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There is a lack of approaches to detect and kill metastatic cells. As an agent for metastasis targeting, a cyclic peptide BLMP6 has been previously characterized. As a step toward translation, we designed AZDye555-labele...There is a lack of approaches to detect and kill metastatic cells. As an agent for metastasis targeting, a cyclic peptide BLMP6 has been previously characterized. As a step toward translation, we designed AZDye555-labeled BLMP6 and demonstrated its homing to metastases of human MDA-MB-231 cells in mice. We show that Ga-radiolabeled BLMP6 can be used for the detection of MDA-MB-231 metastases. We designed a peptide-drug conjugate consisting of monomethyl auristatin E (MMAE) and BLMP6. We show that MMAE-BLMP6 kills MDA-MB-231 cells in cell culture and . In mouse models of lung metastases, treatment with MMAE-BLMP6 suppressed metastasis growth and improved survival. Based on BLMP6 similarity to latent transforming growth factor β binding protein 4 (LTBP4), we identified fibulin-4 as a BLMP6 target. We show that BLMP6 mimics the LTBP4 domain binding to fibulin-4 and selectively binds to fibulin-4 . Fibulin-4 knockout in cancer cells abrogated BLMP6 homing to lung metastases in mice. Fibulin-4 expression was found to be increased in invasive and metastatic human breast cancer and correlated with the binding of AZDye555-BLMP6 in human tissue sections. Our results suggest that fibulin-4 and BLMP6 may be further developed for the detection and targeting of metastatic human cancers.
The digitisation of histopathology has accelerated the application of artificial intelligence (AI) to cancer diagnosis and precision oncology; however, most deployed AI systems remain narrowly task-specific and difficult...The digitisation of histopathology has accelerated the application of artificial intelligence (AI) to cancer diagnosis and precision oncology; however, most deployed AI systems remain narrowly task-specific and difficult to translate across diverse clinical environments. Pathology foundation AI models are emerging as a unifying paradigm, enabling the learning of generalisable representations of tissue morphology through large-scale pre-training and supporting a broad range of downstream tasks. In this narrative review, we examine the development, methodological foundations and current landscape of pathology foundation models in oncological pathology. We outline the evolution and principal trends in the field, classify the major model types and modalities and evaluate their capabilities and advantages in comparison with conventional pathology AI systems. We also examine the transition from foundation models to agentic AI systems and its implications for integrated, workflow-aware pathology practice. In addition, we review relevant regulatory and governance frameworks, with particular attention to requirements for validation, accountability, transparency and oversight.
BACKGROUND: Therapeutic response in patients with unresectable hepatocellular carcinoma (HCC) receiving multikinase inhibitors is associated with changes in liver function. However, limited data are available for patient...BACKGROUND: Therapeutic response in patients with unresectable hepatocellular carcinoma (HCC) receiving multikinase inhibitors is associated with changes in liver function. However, limited data are available for patients treated with atezolizumab plus bevacizumab (ATZ/BEV). METHODS: We retrospectively enrolled 151 patients with unresectable HCC who received ATZ/BEV as first-line systemic therapy. Liver function was assessed using albumin-bilirubin (ALBI) score at baseline (pre-ALBI) and 6 weeks after the initiation of ATZ/BEV (6W-ALBI). We evaluated the dynamic relationship between initial therapeutic response and changes in ALBI score (6W-ALBI - pre-ALBI), and examined the prognostic impact of pre-ALBI, 6W-ALBI, and ALBI score changes. RESULTS: Patients achieving an initial complete or partial response (CR+PR) showed a significantly higher rate of improvement in ALBI score from baseline to 6W after the initiation of ATZ/BEV than those with stable or progressive disease (SD+PD) at the initial treatment response (46% vs. 25%, respectively, P = 0.018). Among patients with baseline ALBI grade ≥2, changes in ALBI score differed significantly between the groups (median change: CR+PR vs SD+PD, -0.03 vs. 0.18, respectively, P = 0.048). Time-dependent receiver operating characteristic analysis demonstrated 6W-ALBI had the best predictive ability for overall survival (OS) at 12 months after the ATZ/BEV initiation (optimal cut-off -1.95, area under the curve: 0.763). Using this cut-off, 6W-ALBI was independently associated with OS in multivariate analysis (hazard ratio: 2.40, P = 0.004). CONCLUSIONS: Initial therapeutic response to ATZ/BEV was associated with changes in liver function. The ALBI score during ATZ/BEV may serve as a prognostic indicator.
Gondaliya P, Luo Y, Sayyed AA
… +8 more, Zinn DA, Qie Y, Yan IK, Driscoll J, Patel PB, Li S, Qin H, Patel T
Mol Ther Oncol
· 2026 Jun · PMID 42110477
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An immunosuppressive microenvironment driven by tumor and stromal cells expressing programmed death-ligand 1 (PD-L1) contributes to immune evasion and poor prognosis in cholangiocarcinoma. Although antibodies to PD-L1 ar...An immunosuppressive microenvironment driven by tumor and stromal cells expressing programmed death-ligand 1 (PD-L1) contributes to immune evasion and poor prognosis in cholangiocarcinoma. Although antibodies to PD-L1 are used clinically, their benefit is limited by immune exclusion within the local microenvironment. To overcome this, we evaluated engineered T cells directed toward PD-L1 that simultaneously target tumor cells and the immunosuppressive microenvironment. Human donor T cells were transduced with a lentiviral vector encoding a chimeric antigen receptor (CAR) consisting of an anti-PD-L1 scFv, CD4 transmembrane domain, and 4-1BB/CD3ζ signaling domain. The antitumor efficacy of these CAR-T cells was assessed in a murine orthotopic tumor model, and their specificity and effect were validated in human malignant cholangiocytes with varying PD-L1 expression. PD-L1 CAR-T cells retained T cell identity, demonstrated antigen-specific cytotoxicity, and effectively reduced tumor burden . Cytotoxicity was abrogated in PD-L1 knockout cells, confirming target specificity. PD-L1 CAR-T cells significantly reduced tumor cell viability within multicellular spheroids. Gemcitabine pretreatment upregulated PD-L1 expression and enhanced CAR-T-mediated cytotoxicity. These findings demonstrate the feasibility of second-generation PD-L1 CAR-T cells, demonstrating preclinical efficacy and specificity, and validating a therapeutic strategy that targets the tumor microenvironment for these challenging cancers.
Bouillon M, Lapoujade C, Basset L
… +4 more, Fontaine A, Hollenstein M, Garcion E, Rousseau A
Mol Ther Oncol
· 2026 Jun · PMID 42110475
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Glioblastoma, the most common primary central nervous system tumor, is the leading cause of death in neuro-oncology. Gene fusions, caused by chromosomal rearrangements, may act as drivers of tumorigenesis in glioblastoma...Glioblastoma, the most common primary central nervous system tumor, is the leading cause of death in neuro-oncology. Gene fusions, caused by chromosomal rearrangements, may act as drivers of tumorigenesis in glioblastoma. These fusions result from the juxtaposition of two genes, leading to the production of a chimeric protein and, in most cases, constitutive activation of a tyrosine kinase receptor. Despite the use of tyrosine kinase inhibitors to block the oncogenic activity of gene fusions, clinical responses in glioblastoma remain poor compared to those in other cancers, highlighting the need for innovative therapeutic strategies. RNA interference, using small interfering RNAs or micro-RNAs, offers a promising approach to target these oncogenic fusions. Through specific silencing, small interfering RNAs spare healthy cells, avoiding the adverse effects associated with tyrosine kinase inhibitors. Recent advances in biotechnology (e.g., antisense oligonucleotides and aptamers) and delivery systems have improved small interfering RNA stability, specificity, and ability to cross the blood-brain barrier. This review discusses these advances and their potential applications to target oncogenic gene fusions in glioblastoma. RNA interference-based therapy represents a critical area of research that could improve the survival of patients with glioblastoma.
Wu A, Dumo CJ, Cook WH
… +8 more, Richards I, Macapagal Foliaki J, Cooper E, Fong DM, Mouravlev A, Park TI, Dragunow M, Young D
Mol Ther Oncol
· 2026 Jun · PMID 42110474
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Glioblastoma (GBM) is a highly aggressive type of brain cancer associated with poor prognosis due to limited effective treatment options. Adeno-associated viral (AAV) vector-based gene therapy strategies have demonstrate...Glioblastoma (GBM) is a highly aggressive type of brain cancer associated with poor prognosis due to limited effective treatment options. Adeno-associated viral (AAV) vector-based gene therapy strategies have demonstrated promise in preclinical models of GBM, but inter- and intratumor cellular heterogeneity poses a challenge for tumor-specific targeting. Here, we screened a panel of 15 AAV serotypes against the widely used human GBM cell line U-87 MG, and five primary patient-derived GBM cell lines to characterize their transduction efficiencies. AAV1, AAV2, AAV1/2, AAV6, and AAV6.2 were the most efficient and consistent serotypes across cell lines, capable of differentially transducing CD44-expressing cells in culture, albeit non-selectively. Interestingly, we observed a reduction in cell number and proliferation in certain cell lines, which correlated with AAV transduction efficiency. This phenomenon was shown to be a cytostatic rather than cytotoxic effect on GBM cells, occurring independently of promoter sequence and transgene expression. The anti-proliferative effect was particularly pronounced in two patient-derived cell lines, where cell proliferation decreased by nearly 80%. Altogether, our results provide a foundation for future studies optimizing AAV-mediated transduction in the diverse GBM cell population and demonstrate the potential to harness the natural properties of AAV in treatment development for brain cancers.
Curr Treat Options Oncol
· 2026 May · PMID 42105144
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Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor. Although patient survival has been significantly improved by immune checkpoint inhibitors combined with chemotherapy, three major unmet needs rem...Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor. Although patient survival has been significantly improved by immune checkpoint inhibitors combined with chemotherapy, three major unmet needs remain in SCLC management. First, while prophylactic cranial irradiation (PCI) can reduce the risk of brain metastases, its neurotoxicity limits its use, particularly in elderly patients or those with neurological deficits. Whole-brain radiotherapy (WBRT) remains the primary approach for brain metastases, and hippocampal-avoidance WBRT (HA-WBRT) combined with neuroprotective agents can significantly reduce cognitive risks. Stereotactic radiosurgery (SRS) has shown survival benefits and less cognitive damage for patients with up to 10 brain metastatic lesions. Emerging therapies, such as antibody-drug conjugates targeting B7-H3/DLL3 (I-Dxd, ZL-1310) and bispecific antibody tarlatamab, have demonstrated intracranial response rates of 62.5%-71%. Regardless of whether the brain metastases had previously undergone radiation therapy, the novel drugs showed consistent activity, indicating promising improvements in the prognosis of brain metastases. Second, the rapid progression and severe treatment-related toxicity of SCLC greatly affect patients' physical and mental well-being. Therefore, quality of life (QoL) should be prioritised. Strategies to improve QoL include early palliative care, proactive symptom management, application of HA-WBRT or SRS to preserve neurocognitive function, and novel agents such as tarlatamab to alleviate symptoms including cough and dyspnoea. Third, real-world evidence (RWE), which complements clinical trial data by reflecting treatment efficacy and safety in routine clinical practice, is gaining increasing recognition but faces challenges due to data heterogeneity, bias, and lack of methodological standardization. Future directions involve developing new drugs with high blood-brain barrier penetration, such as radioligand therapy, conducting prospective studies to optimize HA and SRS applications, establishing high-quality RWE databases to support personalized treatments, exploring molecular subtypes (SCLC-A/N/P/I) and leveraging AI technologies to advance precision radiotherapy. SCLC management needs to be patient-centered, integrating precise treatment of brain metastases, QoL improvement, and the application of RWE to achieve a balance between survival benefits and QoL.
Vazaios K, Tallon-Cobos AC, van Oosterhout LPJ
… +11 more, Waranecki P, Cornel AM, Dautzenberg NMM, van Hoesel M, Forbes C, Nierkens S, Kemp V, Hoeben RC, van der Lugt J, Calkoen FG, Hulleman E
Mol Ther Oncol
· 2026 Jun · PMID 42100144
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Despite the success of CAR (chimeric antigen receptor) T cells in hematological malignancies, their effectiveness against solid or brain tumors, such as pediatric diffuse midline gliomas (DMGs), is limited. CAR T cell su...Despite the success of CAR (chimeric antigen receptor) T cells in hematological malignancies, their effectiveness against solid or brain tumors, such as pediatric diffuse midline gliomas (DMGs), is limited. CAR T cell success is hampered by factors including immunosuppression from DMGs and their surrounding tumor microenvironment (TME). Oncolytic viruses (OVs) can reverse this immunosuppression, suggesting a potential combination with CAR T cells. Here, we show that infection with Goravir adenovirus and R124 reovirus induced DMG cell lysis ( = 6 cultures), with minimal effect on the viability of B7H3- or GD2-targeted CAR T cells, even at high virus concentrations. In addition, RNA sequencing of infected tumor cells revealed altered gene expression in cell cycle and antiviral response pathways. Furthermore, co-cultures of CAR T cells with OV-infected DMGs enhanced CAR T-specific anti-tumor killing in 14 out of 24 cases. The successful combinations exhibited enhanced cytokine and chemokine release, coupled with an increased cytotoxic phenotype. These findings highlight the benefit of DMG pre-infection with OVs to boost CAR T cell activity and suggest that immune stimulation is a key driver of enhanced combination responses.
Background Elderly patients or those with poor performance status are underrepresented in clinical trials of pancreatic ductal adenocarcinoma (PDAC), and optimal treatment strategies for this frail population remain uncl...Background Elderly patients or those with poor performance status are underrepresented in clinical trials of pancreatic ductal adenocarcinoma (PDAC), and optimal treatment strategies for this frail population remain unclear. In real-world practice, gemcitabine, S-1, and stereotactic ablative radiotherapy (SABR) are used as first-line options in patients unfit for intensive combination chemotherapy. We compared these strategies in frail patients with advanced PDAC. Methods This single-center retrospective cohort study included frail patients with histologically confirmed PDAC diagnosed between February 2014 and February 2024. Frailty was defined as age ≥80 years or an Eastern Cooperative Oncology Group performance status ≥2. Patients with resectable disease were excluded. Eligible patients received first-line gemcitabine, S-1, or SABR. Overall survival (OS) was the primary endpoint. Propensity score-based overlap weighting was applied, and survival was analyzed using Kaplan-Meier methods and Cox regression. Results Among 63 patients, including 36 with metastatic disease and 27 with borderline resectable or locally advanced PDAC, median OS in metastatic PDAC was 7.70 months with gemcitabine and 4.33 months with S-1, with no significant difference after overlap weighting (HR, 1.31). In borderline resectable or locally advanced PDAC, SABR was not associated with inferior OS compared with systemic chemotherapy (HR, 1.78). Gemcitabine was associated with improved survival compared with S-1 in patients with tumor size ≥4 cm or peritoneal metastasis. Hematologic adverse events were more frequent with chemotherapy, whereas non-hematologic events were more common with SABR. Conclusions In frail patients with PDAC, gemcitabine and S-1 showed comparable survival in metastatic disease, and SABR showed no statistically significant difference in overall survival compared with systemic chemotherapy in borderline resectable or locally advanced disease, supporting individualized treatment.
Choi MJ, So EY, Akosman B
… +7 more, Lee YE, Raufi AG, Reginato AM, Chen CC, Lawler SE, Wong ET, Liang OD
Mol Ther Oncol
· 2026 Jun · PMID 42094336
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Recent clinical trials show that CAR T cell therapies can initially blunt tumor growth in patients with glioblastoma (GBM). However, therapeutic efficacy remains limited by the immunosuppressive tumor microenvironment an...Recent clinical trials show that CAR T cell therapies can initially blunt tumor growth in patients with glioblastoma (GBM). However, therapeutic efficacy remains limited by the immunosuppressive tumor microenvironment and restricted immune cell trafficking across the blood-brain barrier (BBB). To counteract these challenges, we have utilized the oncolytic adenovirus (OV) Ad5-Δ24-RGD as a platform to overexpress a bispecific T cell engager (BiTE) targeting both CD3 on T cells and the GBM-specific tumor associated antigen IL-13Rα2. We first demonstrated that OV-BiTE can significantly increase the recruitment of T cells to GBM, both and . Moreover, OV-BiTE treatment also markedly enhanced CAR T cell infiltration and tumor cytotoxicity in a GBM-BBB spheroid model, possibly through downregulation of endothelial junction protein expression. We then showed that intratumoral injection of OV-BiTE followed by infusion of combined EGFR and EGFRvIII CAR T cells was more effective than OV-BiTE supplemented with either CAR T therapy alone and led to significant tumor reduction in a GBM xenograft mouse model. In conclusion, our multimodal OV-BiTE plus CAR T cell immunotherapy is capable of overcoming the immunosuppressive tumor microenvironment and GBM resistance to treatment.
OBJECTIVE: Unlike survival measures, life expectancy readily illustrates the burden of cancer on society and the average impact on individuals diagnosed with cancer. Cancer stage at diagnosis is a key prognostic factor a...OBJECTIVE: Unlike survival measures, life expectancy readily illustrates the burden of cancer on society and the average impact on individuals diagnosed with cancer. Cancer stage at diagnosis is a key prognostic factor and hence it is important to obtain stage-specific life expectancy estimates. However, completeness of recording for cancer stage at diagnosis is often historically poor in cancer registries. Therefore, it can be challenging to obtain the long-term stage-specific survival estimates required for estimating stage-specific life expectancy. We provide the first stage-specific life expectancy estimates using whole population data in England. METHODS AND ANALYSIS: Multiple imputation was used to impute values of cancer stage at diagnosis for patients with missing stage at diagnosis information. The simultaneous application of period analysis to obtain up-to-date estimates restricts the contribution of patients with historical diagnoses and hence improves the overall completeness of stage at diagnosis information. For each of the 10 cancer sites in this study, we fit a flexible parametric excess hazard model for each cancer stage on the cumulative excess hazard scale and estimated stage-specific life expectancy using the relative survival framework. RESULTS: The differences in stage-specific and sex-specific life expectancy were evaluated from 40 to 90 years of age. Colorectal cancer, prostate cancer and bladder cancer yield much lower estimates of life expectancy for patients diagnosed with stage IV cancer compared with stages I-III. For example, female patients diagnosed with stage IV colorectal cancer at 70 years of age have a life expectancy of 72.3 years, while those with stages I-III can expect to live beyond 82.0 years. The remaining cancer sites yield approximately equal reductions in life expectancy with each increase in stage at diagnosis from I to IV. CONCLUSION: We offer the first stage-specific life expectancy estimates for a range of cancer sites in England using data from the National Cancer Registration and Analysis Service, with follow-up until February 2020. Estimates of stage-specific life expectancy provide a real-world, intuitive metric to evaluate the impact of cancer stage at diagnosis on prognosis up to a lifetime horizon. Stage-specific life expectancy estimates also provide key information regarding the potential benefits of early diagnosis initiatives in terms of gains in life years.
OBJECTIVE: To examine the extent to which epididymo-orchitis or urinary tract infections (UTI) may precede testicular cancer (TC) in Sweden. METHODS AND ANALYSIS: We conducted a nationwide, open-cohort study including 8...OBJECTIVE: To examine the extent to which epididymo-orchitis or urinary tract infections (UTI) may precede testicular cancer (TC) in Sweden. METHODS AND ANALYSIS: We conducted a nationwide, open-cohort study including 8 382 433 men between 1964 and 2018. Standardised incidence ratios (SIR) with 95% CIs were calculated to compare TC incidence rates in men diagnosed with epididymo-orchitis or UTI-either in the same calendar year as TC or in preceding calendar years (mean follow-up: 6.85 years, ±8.31 SD)-with those in men without these infections. Analyses were controlled for potential confounders and a sensitivity analysis on cystitis was also conducted. RESULTS: A total of 11 903 men were diagnosed with TC during the study period; of these, 400 (3.36%) had been diagnosed with epididymo-orchitis and 122 (1.02%) with UTI. The TC incidence rate per 100 000 person-years was 5.09 (95% CI 4.99 to 5.18) for the entire study period and increased from 2.84 (2.68 to 3.02) in 1964-1973 to 8.37 (7.99 to 8.77) in 2014-2018. Among men with epididymo-orchitis (n=89 596), TC was diagnosed in 0.45%, with an overall SIR of 6.34 (95% CI 5.73 to 7.00) in the full model. For TC diagnosed in the same calendar year as epididymo-orchitis (289 cases), the SIR was 85.97 (76.33 to 96.50). For TC diagnosed in subsequent calendar years (111 cases) the SIR was 1.86 (1.53 to 2.24), with most cases diagnosed within 1-4 calendar years of follow-up (65 cases). Among men with UTI (n=294 201), TC was diagnosed in only 0.04%, with an overall SIR of 1.74 (1.44 to 2.08). The associations were not significant for TC diagnosed 1-4 years after UTI, nor between cystitis and subsequent TC. CONCLUSION: The association between epididymo-orchitis and TC was strong and persisted for several years after the infection. The findings support clinicians maintaining a heightened awareness of TC in patients with epididymo-orchitis, particularly when in diagnostic doubt or if symptoms persist, and could be a foundation for more detailed clinical studies on epididymo-orchitis as a potential TC risk factor. Although a potential link between UTI and TC was identified, the absolute risk was almost negligible.
OBJECTIVE: To assess whether changes in behavioural risk factors could explain rising cancer incidence in younger adults in England, and to evaluate the extent to which established and suspected risk factors contribute t...OBJECTIVE: To assess whether changes in behavioural risk factors could explain rising cancer incidence in younger adults in England, and to evaluate the extent to which established and suspected risk factors contribute to these trends. METHODS AND ANALYSIS: Cancer incidence data from national registries (2001-2019) for 22 sites in women and 21 in men identified cancers with increasing incidence in adults aged 20-49 years. Trends in smoking, alcohol, diet, body mass index (BMI) and physical inactivity were examined using national health surveys. Annual percentage changes (APCs) quantified trends by age and sex. Population attributable fractions (PAFs) estimated the proportion of cancers attributable to risk factors and disaggregated attributable from non-attributable incidence rates. RESULTS: Eleven cancer sites (three female-specific) with established behavioural risk factors showed rising incidence in younger adults. Similar trends were observed in older adults, except for colorectal and ovarian cancer, which increased only in younger adults. For some cancers, incidence increased more rapidly in younger than older adults. PAFs for younger adults ranged from 7% to 65% depending on cancer type. All risk factors except obesity showed stable or declining prevalence. For BMI-related cancers, both BMI-attributable and BMI-non-attributable incidence increased, though more slowly for the latter. For example, BMI-attributable colorectal cancer in younger women increased from 0.9 to 1.6 per 100 000 (APC 4.3%), while non-attributable rates rose from 6.4 to 9.6 (APC 3.2%). CONCLUSIONS: Behavioural risk factors account for a substantial share of cancer burden but, apart from BMI, are unlikely to explain the rising incidence in younger adults. The present findings underscore the urgent need to investigate emerging risk factors, while strengthening prevention efforts targeting known factors across all ages.