Singapore Health Services (SingHealth) is Singapore's largest group of healthcare institutions. The group was formed in 2000 and consists of four public hospitals, three community hospitals, five national specialty centres and a network of eight polyclinics. The Singapore General Hospital is the largest hospital in the group and serves as the flagship hospital for the cluster.
Despite promising data showing that circulating tumour DNA (ctDNA) dynamics during treatment can inform real-time tumour response and recurrence risk1, how best to translate these insights into actionable clinical decision-making remains unclear. Here we report results from the EP-STAR trial-a multi-centre, ctDNA-driven, risk-adapted, non-randomized phase II study ( NCT04072107 ; ClinicalTrials.gov) testing whether a risk-adaptive treatment (RAT) strategy guided by on-treatment ctDNA dynamics can meaningfully improve survival, using nasopharyngeal carcinoma as a model. Eligible patients were enrolled and began treatment with standard-of-care gemcitabine-cisplatin neoadjuvant chemotherapy (GP-NAC; the P in this abbreviation stands for platinum)2, followed by RAT or standard-of-care chemoradiotherapy guided by ctDNA clearance trajectory during GP-NAC. Protocol-eligible patients who did not receive RAT, drawn from a prospectively registered ctDNA biomarker cohort ( NCT03855020 )3, served as a non-randomized, contemporaneous no-RAT external cohort. The primary end-point was failure-free survival (FFS) in the RAT group. After a median follow-up of 47.3 months, the 3-year FFS was 89.1% (83.2-95.0%) in the RAT group (n = 110). Patients who received RAT showed significantly improved FFS (P = 0.003, log-rank test) compared with the no-RAT external cohort (hazard ratio = 0.41 [0.23-0.75]; P = 0.004, Cox regression model). The RAT strategy was well-tolerated with no treatment-related deaths. Collectively, these data show that a ctDNA-driven RAT paradigm could be a promising strategy to improve survival, challenging the conventional fixed-course, static treatment approach.
The immune microenvironment is a crucial component of colorectal carcinoma that has been well characterized, but much less is known about the immune microenvironment of colorectal carcinoma precursors. We hypothesized that T-cell infiltrates might differ across the colorectal neoplastic spectrum. We leveraged the prospective cohort incident-tumor biobank method, which provided formalin-fixed, paraffin-embedded tumor tissue specimens (N = 1,825) from 790 colorectal carcinoma precursors (including hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, tubular adenomas, tubulovillous adenomas, and villous adenomas) and 1,035 colorectal carcinomas. We performed an in situ multispectral immunofluorescence assay for CD3, CD4, CD8, FOXP3 (negative, low, or high expression), PTPRC (CD45RO and CD45RA), MKI67 (Ki-67), and KRT (keratin) combined with supervised machine learning. CD3+CD4+ cells were more abundant than CD3+CD8+ cells in most precursors. In conventional adenomas, greater villous component correlated with fewer intraepithelial CD3+CD8+ cells. Serrated lesions, including hyperplastic polyps and sessile serrated lesions, exhibited higher densities of intraepithelial CD3+CD8+ cells compared with other precursors and carcinomas. Age strata of patients with precursors (including early-onset precursors) were not associated with differential T-cell infiltration patterns. Compared with invasive colorectal carcinoma, precursors generally showed higher densities of CD3+CD4+ cells and CD3+CD8+ cells with phenotypes of naive (CD45RA+CD45RO-), memory (CD45RA-CD45RO+), and regulatory (FOXP3+Low and FOXP3+High) in intraepithelial and lamina propria/stromal regions. In conclusion, T-cell infiltration patterns vary across different histopathologic types of the colorectal neoplastic spectrum from precursors to invasive carcinomas. Our findings shed light on how the tumor-immune microenvironment evolves during precursor development and progression to colorectal carcinoma.
171 Background: Compared to populations of European-descent, prevalence of pathogenic germline variants in cancer predisposition genes is poorly-defined in Asian populations. Here, we investigate genetic spectrum in cancer susceptibility in the Singapore real-world cancer cohort. Methods: The cancer cohort comprised patients referred to Cancer Genetics Service at the National Cancer Center Singapore (Feb 2014-Nov 2025), who underwent multi-gene panel testing. Predictive testing cases were excluded and only the probands were analyzed. Demographics, medical/family history, and genetic results were prospectively collected via REDCap (v13.1.30). Results: The cohort (N=6093) included Chinese (n=4601, 75.5%), Malay (n=516, 8.5%), and Indian (n=358, 5.9%) patients. Predominant diagnoses were breast (3477/6093, 57.1%) and ovarian (998/6093, 16.4%) cancers. Multiple cancers occurred in 11.6% (707/6093), of which 17.5% (124/707) had combined breast and ovarian cancers. Overall, 19.6% (1195/6093) were positive variant (PV) carriers, primarily in BRCA2 (17.7%), BRCA1 (16.2%), and PALB2 (4.4%). PV rates varied significantly: Chinese patients (18.1%) had lower rates compared to Malay (24.0%, p=0.0035) and Indian patients (24.6%, p=0.0078), with no significant difference between the latter two (p>0.05). Among 669 patients with variant reclassification, 61 (9.1%) novel PV carriers were identified, primarily upgraded from VUS. With a median time to reclassification of 1.55 years, upgraded PVs were most frequently observed in BRCA1 (18.0%), ATM (11.5%), MLH1 (9.8%), and POLE (9.8%). Crucially, 16 pedigrees pursued cascade testing, identifying 33 asymptomatic PV carriers who subsequently became eligible for high-risk surveillance. Conclusions: Leveraging Asia's largest multi-ethnic hereditary cancer cohort with up to 11 years of follow-up, this study highlights the clinical value of Singapore's diverse demographic. It also establishes the critical necessity of continuous VUS reassessment. Systematic, long-term VUS tracking is indispensable for optimizing timely interventions and improving cancer prevention. Reclassified variants and cascade testing outcomes. Gene Category & Key Genes Reclassified PVs, n (%) Median Time to Reclassification, yr (Range) Pedigrees with Cascade Testing, n (%) Novel PV Carriers Identified, n Lynch Syndrome ( MLH1, MSH2 ) 9 (14.8%) 1.5 (0.34-6.5) 5 (55.6%) 13 Hereditary Breast/Ovarian ( BRCA1, BRCA2 ) 12 (19.7%) 1.33 (0.22-4.99) 6 (50%) 15 Gastrointestinal Polyposis ( MUTYH, POLE ) 7 (11.5%) 1.89 (0.36-5.94) 0 (0%) 0 Other HRR / Moderate Risk ( ATM, CHEK2, RAD51C, BARD1 ) 13 (21.3%) 2.5 (0.56-6.37) 1 (7.7%) 1 Rare High-Penetrance ( TP53, VHL, NF1, SDHA, SDHB, POT1 ) 9 (14.7%) 1.1 (0.15-3.33) 4 (44.4%) 4 Other genes ( ERCC4, CFTR, RINT1, TET2, FANCA ) 11 (18.0%) 1.61 (0.54-3.13) 0 (0%) 0 Overall Cohort 61 (100%) 1.55 (0.15-6.5) 16 (26.2%) 33
307 Background: Mutations in BAP1 occur across multiple cancers and are associated with aggressive clinical phenotypes and limited therapeutic options. Although BAP1 functions as a deubiquitinase, its role in DNA damage responses and potential therapeutic vulnerabilities remains incompletely studied. We examined how BAP1 mutations affect DNA repair and explored rational combination strategies to target these vulnerabilities. Methods: Quantitative proteomics and ubiquitin profiling identified proteins whose stability is regulated by BAP1. A targeted small molecule screen was performed to discover compounds that selectively reduced survival of BAP1 mutant cells. Selected compounds were evaluated using proliferation, viability and apoptosis assays, DNA repair functional assays, and chromatin structure analyses. Drug synergy was determined using combination index modeling. Preclinical efficacy was assessed in cell-derived and patient-derived xenograft models. Results: BAP1 mutations disrupted the stability of key DNA damage response proteins, impairing damage repair efficiency. Treatment with a selected drug combination led to changes in chromatin structure, further reduced DNA repair capacity, and selectively triggered apoptosis in BAP1 mutant cells. The combination treated induced enhanced cytotoxicity, significantly reduced tumor growth, and improved survival in vivo. These effects were specific to BAP1 mutant models and were not observed in BAP1 wildtype tumors. Conclusions: BAP1 modulates DNA repair through effects on protein stability and chromatin dynamics. Our study identifies a mechanistically guided drug combination that selectively targets BAP1-deficient tumors, providing a foundation for further preclinical and clinical evaluation.
Shared treatment decision-making refers to an approach to care in which patients and their clinicians work in partnership to choose between treatment options, or delay/forgo treatment, concordant with patient values and considering the best available evidence. Research in various diseases, including cancer, has shown that patients who feel informed in treatment decisions have greater satisfaction with their medical care, better adherence to treatment, and better quality-of-life outcomes. The treatment landscape for advanced bladder cancer has evolved in recent years and several treatment options are now available, increasing the importance of shared treatment decisions. Various factors may be relevant to shared decision-making in advanced bladder cancer, including the attributes of different treatment options (e.g., efficacy, toxicity profile, or treatment regimen), patient characteristics (e.g., priorities, health status, or social factors), disease characteristics (e.g., extent of disease or treatment history), and treatment access, highlighting the need to tailor treatment to individual patients. Challenges or barriers to shared treatment decision-making include the lack of knowledge in patients newly diagnosed with cancer, and potential discordance between patients and clinicians regarding treatment goals. However, tools are available that can facilitate shared treatment decision-making and help patients prepare for discussions. In this podcast, we discuss the concept of shared treatment decision-making and the range of considerations related to its application in the management of advanced bladder cancer. With the increasing focus on patient-centered care, shared treatment decision-making can help create individualized treatment plans for patients with advanced bladder cancer, which can be facilitated by in-depth discussions between patients, carers, and clinicians about treatment goals and the benefits and risks of available treatment options. Infographic and podcast audio are available for this article.
