Boon Cher Goh

Purpose: MAPK pathway activation suppresses iodine-handling genes, including sodium-iodide symporter (NIS), contributing to loss of iodine avidity in radioiodine-refractory thyroid cancer. Prior BRAF/ MEK inhibitor re-differentiation trials improved iodine uptake but used empiric 4–6 week treatment. The timing of maximal NIS re-expression remains undefined. We evaluated whether short course dabrafenib plus trametinib restores iodine uptake and provides clinical benefit. Patients and Methods: In this multicentre phase II trial, patients with progressive metastatic radioiodine-refractory thyroid carcinoma harbouring BRAFV600E or RAS mutations received dabrafenib and trametinib. I-124 PET/CT dosimetry was performed at baseline and after 2 weeks, with repeat imaging at week 4 post therapy if dosimetry criteria was not met. Radioiodine was administered once criteria was met. The primary endpoint was attainment of predicted lesional absorbed dose ≥20 Gy with I-131 activity ≤300 mCi. Secondary endpoints included RECIST response, progression-free survival (PFS), thyroglobulin response, and safety. Results: Nine of 14 patients (64%) met the dosimetry criteria and received radioiodine; 6 out of 9 (67%) restored iodine uptake within 2 weeks. Among radioiodine-treated patients, best objective response rate within 6 months was 75% by RECIST. Median PFS was 10.8 months. RAS-mutant tumours demonstrated greater lesion regression than BRAFV600E-mutant tumours. Early reduction in stimulated thyroglobulin and preserved FOXE1 nuclear localisation, and higher tumour-to-normal GLIS3 nuclear expression were associated with re-differentiation response. Conclusions: Short-course dabrafenib/ trametinib can induce rapid re-differentiation within 2 weeks in a subset of patients with MAPK-driven radioiodine-refractory thyroid cancer, supporting individualized BRAF/MEK inhibition duration rather than empiric prolonged treatment.

Aims: Pre‐emptive pharmacogenomics (PPGx) testing holds promise for optimizing drug therapy, but uptake remains limited in Asia. This pilot study aimed to assess the feasibility of PPGx uptake into clinical practice and its impact on prescribing in an Asian healthcare setting. Methods: A prospective, multicentre pilot study was conducted to pre‐emptively genotype 16 pharmacogenes. Results were integrated into electronic health records, alongside deployment of clinical decision support (CDS) tools for 31 drug–gene pairs. A pharmacogenomics drug information service and digital platforms were also developed. Results: All 2492 participants carried ≥1 actionable variant (median: 5, range: 1–11). Across four institutions within one cluster, 1046 out of 2238 (46.7%) patients were prescribed ≥1 drug with pharmacogenetic association, and of those, 460 (44%) had genotypes linked to undesirable drug responses. Among 285 interruptive CDS alerts, 69 (24.2%) led to prescription modifications. Acceptance was higher for new prescriptions (50.0% vs . 17.3%, p < 0.001), in outpatient settings (31.0% vs . 7.3%, p < 0.001) and among consultants (57.1% vs . other designations 5–27.3%, p < 0.001). The drug information service received 137 enquiries, while 471 and 151 patients accessed the app and web‐based platforms respectively. Conclusions: PPGx testing and genotype‐guided prescribing are feasible in Singapore. Widespread adoption requires leadership support, robust informatics infrastructure, clinician engagement and sustainable funding.

Lutetium-177 ( ¹⁷⁷ Lu)–based Radioligand Therapy (RLT) has emerged as an important modality in precision oncology, with demonstrated clinical benefit in selected malignancies. Its clinical relevance is underscored by regulatory approvals of Lutathera® for neuroendocrine tumours and Pluvicto® for metastatic castration-resistant prostate cancer. However, despite these advances, the field faces significant challenges that limit broader clinical translation and optimisation. In this review, we provide a critical and balanced evaluation of the current ¹⁷⁷ Lu RLT landscape, integrating evidence from clinical trials, emerging targets, and translational studies. We highlight that much of the existing evidence is derived from small, non-randomised studies with inherent risk of bias, limiting the strength of clinical conclusions. Key challenges include the lack of standardised and clinically actionable dosimetry, insufficient predictive biomarkers beyond target expression, vulnerability of isotope supply chains, and the development of drug-evasive traits in malignant cells. In addition, heterogeneity in trial design and limited long-term safety data further constrain clinical implementation. We propose a strategic roadmap to advance ¹⁷⁷ Lu RLT toward a more rigorous, reproducible, and equitable precision oncology framework, emphasising the transition from empiric application to evidence-based personalisation.

Purpose:Therapeutic options beyond platinum, gemcitabine, and immunotherapy in recurrent/metastatic (R/M) nasopharyngeal carcinoma (NPC) remain limited. Median overall survival (OS) for R/M disease is 20 months. This study evaluated the efficacy and safety of trifluridine/tipiracil (FTD/TPI) in platinum-resistant R/M NPC. Patients and Methods:In this single-arm, phase II study, patients received oral FTD/TPI at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle. The primary endpoint was disease control rate (DCR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. Results:Thirty-five patients were enrolled. The median age was 56 years with a median of 2 prior lines of systemic therapy (range, 1–7). Forty five percent patients had prior fluoropyrimidine. The DCR at 12 weeks was 57.1% [95% confidence interval (CI), 39.4%–73.7%], and the ORR was 22.9% (95% CI, 10.4–40.1). The DCR was comparable with and without fluoropyrimidine exposure (55.6% vs. 58.8%). The median PFS was 6.5 months, and the median OS was 13.1 months. Treatment-emergent adverse events were predominantly hematologic, including ≥ grade 3 neutropenia (43%), anemia (26%), and thrombocytopenia (9%), with grade ≥3 events largely hematologic. Dose modifications were required in 60%, most commonly due to neutropenia, manageable with dose reduction. One patient discontinued treatment because of symptomatic anemia. Grades 3 to 4 neutropenia was significantly associated with improved ORR (P < 0.001). Exploratory plasma proteomic analyses suggested potential differences in baseline and on-treatment protein expression between responders and nonresponders, warranting further validation in larger cohorts. Conclusions:FTD/TPI demonstrated a manageable safety profile and encouraging antitumor activity. It is a convenient oral alternative to intravenous chemotherapy.

Progression free survival of patients on FTD/TPI. Median progression free survival was 6.5 months (95% CI 3.12–9.88).

Overall survival of patients on FTD/TPI. Median overall survival was 13.1 months (95% CI 6.83–19.38).

Depth of response of EBV DNA (BamHI-W) on FTD/TPI.

Log2 fold change in plasma thymidylate synthase (TYMS) expression from baseline to pre–cycle 2 following TAS-102, demonstrating upregulation of TYMS following exposure to FTD/TPI.

Relationship between neutropenia and clinical response on FTD/TPI Fisher’s exact p < 0.001.