AIM:Sunitinib has marked pharmacokinetic (PK) and pharmacodynamic (PD) interpatient variability. This study evaluated the utility of extensive excretory/metabolic/PD pharmacogenomics (PGx) with hepatic functional imaging (HNI) to explore their associations with sunitinib PK/PD (toxicity/response) and progression-free survival (PFS), respectively. METHODS:Eligible patients (pts) suitable for sunitinib therapy. At baseline: (i) PGx: blood analysed by the Affymetrix DMET™ Plus Array (1936 variants/225 genes) and Sanger sequencing (HNF1A, FLT3, VEGFR2, VEGFR3, RET, PDGFRα, TNFα). (ii) HNI: pts given IV 800 MBq 99mTc-MIBI, imaging data analysed for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). In cycles 1 and 2, bloods taken for sunitinib parent (SU), metabolite (SU12662) and total SU (metabolite + parent) PK. Associations evaluated between (i) HNI parameters and (2) PGx, with sunitinib PK, toxicity/response and PFS. RESULTS:N = 15 pts. The two most significant associations in either direction between PGx variants or HNI parameters (p < .05) for: (i) PK included: (a) SU logAUC0-14days with HEF, ATP7B (rs1801246) and UGT8 (rs4148254); (b) SU logAUC0-28days, with Td1/2, SLC15A1 (rs8187832) and SLC10A2 (rs188096); (c) SU12662 logAUC0-14days with HEF, ABCC3 (rs11568591), PPARD (rs1003973) and SLC15A1 (rs8187840); and (d) SU12662 logAUC0-28days with SULT1A2 (rs1059491) and SLC10A2 (rs188096). (ii) Toxicity: (a) Diarrhoea grade 1+ with HEF, VEFGR3 (rs307826) and AKAP9 (rs7785971); (b) ≥grade 3 AEs with CBR1 (rs998383); (iii) overall response rate with SULT1E1 (rs1881668) and GSTA2 (rs2180314); and (iv) PFS with CYP4Z1 (rs4926802) and CYP2A6 (rs28399442). CONCLUSIONS:Exploratory associations were observed between sunitinib PK/PD with hepatic functional imaging with extensive pharmacogenomics. Further validation is required.

Introduction Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, even after curative-intent resection. Tumor-infiltrating lymphocytes (TILs) assessed by immunohistochemistry have prognostic value, but standardized assessment on routine H&E sections is not established, particularly in Australian cohorts. This pilot study evaluated stromal TIL density in resected PDAC on H&E sections using the International Immuno-Oncology Biomarker Working Group (ITWG) guidelines and explored its association with survival and key clinicopathological metrics. Methods We conducted a retrospective cohort study of 21 consecutive patients who underwent curative-intent resection for histologically confirmed PDAC at an Australian tertiary center between September 2016 and January 2025. Stromal TIL density was quantified on H&E sections and categorized a priori as low (<15%) or high (≥15%) lymphocytic infiltration of the tumor stroma. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan-Meier methods and log-rank tests. Univariable Cox regression was performed, followed by an exploratory multivariable Cox model incorporating stromal TIL category, lymph node ratio (LNR), and vascular invasion. Results Median follow-up was 17 months (range, 3-99), with 11 deaths (52%) and 12 recurrences (57%). Using the prespecified threshold of 15% stromal TIL density, 10 patients had low stromal TILs, and 11 had high stromal TILs. Compared with low TILs, high TILs were associated with improved OS (median not reached vs. 16 months; log-rank p = 0.029) and DFS (median not reached vs. nine months; log-rank p = 0.026). In the exploratory multivariable model, high TILs remained associated with improved OS (HR 0.15, p = 0.033) and DFS (HR 0.18, p = 0.024). A higher LNR was associated with poorer OS (HR 3.42 per 10% increase, p = 0.005) and DFS (HR 2.41 per 10% increase, p = 0.010). When analyzed as a continuous variable (per 5% increase), stromal TIL density showed a consistent direction of effect without statistical significance for OS (HR 0.94, p = 0.155) or DFS (HR 0.94, p = 0.115). Conclusions In this single-center Australian pilot cohort, high stromal TIL density assessed on routine H&E sections was associated with improved OS and DFS following PDAC resection. These findings support the feasibility and potential prognostic utility of stromal TIL assessment using ITWG guidelines and warrant validation in larger multicenter studies.

OBJECTIVE:To leverage the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (an Australian cancer database) to explore the ideal timing and sequence of therapies and the factors influencing these decisions in colorectal cancer (CRC) patients with liver-only metastases to inform contemporary decision-making and future trials. STUDY TYPE:Retrospective registry-based cohort study using the TRACC registry. SETTING AND PARTICIPANTS:Consecutive patients with liver-only metastatic CRC enrolled in the TRACC registry. MAIN OUTCOME MEASURES:To explore cancer biology, intended treatment at presentation, actual treatment received and the resultant outcomes for early-onset CRC (EOCRC) (≤ 50 years) and late-onset CRC (LOCRC) (> 50 years) patients with liver-only metastases from a real-world perspective. RESULTS:Between 14 January 2009 and 2 September 2024, 1691 patients with liver-only metastatic CRC were enrolled in TRACC. These included 276 EOCRC patients (16.3%) and 1415 LOCRC patients (83.7%). In the EOCRC subset, there were more females (48.2% vs. 34.5%, p < 0.001), less comorbidity (Charlson comorbidity index score 0, 90% vs. 59%, p < 0.001), more left-sided primaries (76.1% vs. 65.7%, p < 0.001), more synchronous disease (53.3% vs. 42.1%, p < 0.001) and BRAF V600E mutations (13.9% vs. 8.1%; p = 0.010). Overall, EOCRC patients had a longer median survival compared with LOCRC patients (3.20 vs. 2.38 years, p < 0.001). For the 662 patients (39.1%) undergoing liver resection, median survival was 5.99 years in EOCRC patients and 5.88 years in LOCRC patients. For all patients and for those undergoing resection, respectively, B-Raf proto-oncogene, serine/threonine kinase (BRAF) (hazard ratio, 1.97 [p < 0.001] and hazard ratio, 2.25 [p < 0.001]) and Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations were associated with worse outcomes (hazard ratio, 1.29 [p < 0.001] and hazard ratio, 1.34 [p = 0.003]). CONCLUSION:Differences in sex distribution, BRAF mutation rates, primary tumour site and overall survival suggest biological differences between EOCRC and LOCRC. Liver resection was associated with improved survival in LOCRC, with the benefits of all therapies varying depending on age, primary tumour site and whether patients presented with synchronous or metachronous liver-only metastases.

AIM:We aim to provide an overview of treatment patterns and outcomes in high-risk rectal cancer patients with a particular focus on total neoadjuvant therapy (TNT) use. METHODS:Patients with locally advanced rectal cancer who commenced pre-operative treatment at the Royal Brisbane and Women's Hospital, the Princess Alexandra Hospital, and Redcliffe Hospital between 2020 and 2023 were included in this retrospective cohort study. Data collected included demographics, cancer stage, tumour details, treatment undertaken, disease progression, and survival. Data were analyzed using R Studio version 1.4.1717. RESULTS:124 patients were included, with 47 having undergone TNT and long-course chemoradiotherapy (LCCRT) and 77 having undergone LCCRT alone ± adjuvant chemotherapy. Those who received TNT were significantly more likely to have high-risk features such as extramural venous invasion, T4 tumor, and N2 disease. 89.5% of TNT patients across our centres received FOLFOX chemotherapy, and 77.1% received ≥6 cycles. 14.7% of TNT patients went on to receive adjuvant chemotherapy compared to 35.5% of non-TNT patients, with the most common adjuvant chemotherapy in the TNT group being FOLFOX (85.7%). 15% of TNT patients achieved a pathological complete response compared with 13.8% in the non-TNT group. Disease-free survival favored the non-TNT group with a median value of 39.4 months versus 36.9 months, though this was not statistically significant. CONCLUSION:This retrospective cohort study undertaken across multiple metropolitan centres shows increased uptake of TNT, particularly in high-risk patient cohorts, consistent with changes in international guidelines for treatment of rectal adenocarcinoma.

IntroductionThe 5-year follow-up results of KEYNOTE-177 [1] established pembrolizumab as a standard first-line (1L) treatment for deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC), demonstrating improved response rates, progression-free survival (PFS) and tolerability over chemotherapy. Pembrolizumab became available as a 1L option in Australia following government reimbursement in August 2021. Real-world treatment patterns and outcomes since then have not previously been reported. Patients and methodsPatients with dMMR mCRC diagnosed 1/8/2021-30/5/2025 were analysed using data from TRACC and TRACC-SELECT, Australian multi-site prospective registries. Clinicopathologic characteristics, treatment patterns, and outcomes were examined. Survival outcomes for 1L pembrolizumab-treated patients were analysed using Kaplan-Meier. ResultsFrom 36 sites, 120 dMMR mCRC patients were identified; 109 (91%) received any systemic treatment. 1L treatment included pembrolizumab (n=103, 94%), clinical trial enrolment (n=4,4%), and chemotherapy (n=2,2%). Among pembrolizumab-treated patients, the median age was 76 years, 49% had a BRAFV600E mutation, and 17% had an ECOG performance status ≥ 2. Median follow-up was 25.8 months. The clinician-assessed response rate was 58%, while 17% had progressive disease as best response. Median duration of therapy was 15.2 months. Of 74 patients who discontinued pembrolizumab, 21 (28%) completed the 2-year course, 28 (38%) had progressive disease, 11 (15%) discontinued due to toxicity, 6 (8%) had a complete response before 2 years, and 8 (11%) had other reasons. Median PFS was 37.9 months. Median overall survival (OS) was not reached; 12- and 24-month OS rates were 88% and 77%, respectively. ConclusionIn this real-world cohort, patients were older and had higher rates of BRAFV600E mutation and poorer ECOG performance status than those in KEYNOTE-177. There has been rapid and wide uptake of pembrolizumab as a new standard of care, with promising outcomes. Ongoing data collection and analyses will evaluate predictors of immunotherapy response and real-world second-line treatment patterns and outcomes.

Introduction:The prognosis in pancreatic ductal adenocarcinoma (PDAC) remains poor with 2-year recurrence rates around 80% despite curative-intent surgery. This study evaluated factors associated with early recurrence in a contemporary, multi-center, Australasian population. A better understanding of patients at risk of early recurrence (ER) could improve selection of operative candidates. Methods:De-identified data were extracted from 23 hospitals participating in the PURPLE pancreatic cancer registry between 2016 and 2024. Clinicopathological features, treatment, recurrence patterns, and survival were examined. ER was defined as cancer recurrence within 12 months of surgery. Results:Of 3041 patients identified, 539 completed curative intent surgery. At a median follow-up of 21.8 months, 74% of resected cases had recurred. The median recurrence free survival was 14.3 months. ER occurred in 41% of patients and was associated with advanced age (P = 0.04), worse performance status (P < 0.01), T3-T4 stage (P = 0.01), CA19-9 > 300 U/ml (P < 0.01), involvement of more than two lymph nodes (P < 0.01), lymphovascular invasion (P = 0.01), and no neoadjuvant and/or adjuvant treatment (P < 0.01). There was a significant association between the primary tumor location and recurrence site (P = 0.046). The median OS of those with isolated lung (31.4 months) and locoregional (29.2 months) recurrences was longer than those with liver (21.3 months) or peritoneal (20.7 months) recurrences (P = 0.01). The use of neoadjuvant and adjuvant therapy was associated with lower ER rates (P < 0.01). Conclusion:A high proportion of resected PDAC patients experienced ER. Multiple pathological factors can predict ER. Primary tumor location was associated with site of recurrence. Neoadjuvant and adjuvant therapy significantly reduced ER and increased OS.

This report details the long-term follow-up of a patient previously reported from our centre with recurrent acute pancreatitis and episodic jaundice in the setting of three rare anatomic variants: gallbladder agenesis, ansa pancreatica, and a santorinicele. The index report described progressive main pancreatic duct dilatation and endoscopic findings consistent with intraductal papillary mucinous neoplasm (IPMN) despite non-diagnostic cross-sectional imaging. We now present the subsequent clinical course, including elective pancreaticoduodenectomy, definitive histopathology, and surveillance outcomes. Histopathology demonstrated a 30 mm grade 2 pancreatic colloid carcinoma arising in association with an intestinal-type IPMN involving both main and branch ducts (pT2N1). This occurred despite the absence of a discrete mass or guideline-defined high-risk features on cross-sectional imaging. The postoperative course was complicated, and later remnant duct dilatation raised concern for a late pancreaticojejunostomy stricture. The patient's symptoms subsequently improved, and duct calibre decreased on surveillance imaging, with computed tomography (CT) imaging in February 2025 confirming no recurrence of malignancy. This longitudinal case demonstrates that guideline-negative cross-sectional imaging does not exclude invasive carcinoma in suspected IPMN, particularly when pancreatitis and ductal variants confound interpretation. It supports individualised management, multidisciplinary assessment, and timely consideration of resection in selected patients.

Abstract Background: Standard of care treatment for patients with locally-advanced rectal cancer includes neoadjuvant chemoradiotherapy followed by surgery. However, this treatment is toxic affecting the patient’s quality of life. Additionally, 20% of patients achieve a complete response, 15% show no response and 30-40% may develop metastasis post treatment. Therefore, predicting patient response to treatment would be beneficial to inform clinicians if treatment is not optimal. 3D patient-derived tumor organoids (PDTOs) have been used to predict patient response to treatment due to their ability to replicate the biology and drug responsiveness of the original tumor. My project aims to use rectal cancer PDTOs to develop a personalized medicine strategy to accurately predict patient clinical response prior to therapy to inform clinicians of their treatment options. Patient-derived normal organoids (PDNOs) will also be used for toxicity assessment. Methods: Rectal cancer patients that meet the required criteria were recruited. Biopsies were collected via flexible-sigmoidoscopy and processed immediately in the laboratory for PDO establishment. Post establishment, patient-derived organoids (PDOs) were tested using a chemoradiation assay to determine sensitive, partial and resistant responders. On day 0, PDOs were seeded on a 384 well plate in 5% matrigel. On day 2, PDOs were exposed to Fluorouracil (0.412uM) followed by radiation (2 and 4 Grays). On day 7, live cells were measured using CellTiter Glo 3D Cell Viability Assay (Promega) on the Cytation 5 multiplate reader. Treatment sensitivity was investigated by calculating 50% growth rate (GR50) using Graphpad Prism. Results: To date, 14 patients have been recruited and 11 (78.5%) patient biopsy samples have been collected. Out of the collected biopsy samples, 7 out of 10 (70%) have been established with one currently in progress. Chemoradiation assays have been completed for 5 of the 7 established PDOs (RC-001, RC-003, RC-006, RC-008 and RC-010). RC-001 PDTOs exhibited a cytotoxic effect indicating complete response to treatment. The remaining PDTOs illustrated a partial effect indicating partial response to treatment. RC-001, 003, 008 and 010 PDNOs achieved GR50 at 4Gy whereas RC-006 PDNOs achieved GR50 at 2.2Gy. These results indicate that the complete responder could potentially benefit from chemoradiation treatment and the partial responders and could potentially benefit from additional treatment strategies with one partial responder potentially more susceptible to adverse treatment effects. Conclusion: This project is the first of its kind in Australia to predict patient response to chemoradiotherapy using PDOs. We demonstrate varied patient response to treatment and the important information that could potentially be garnered. Our work has the potential to inform selection of optimal therapy for patients and improve rectal cancer outcomes. Citation Format: Kiki Lianos, Kelly Olsen, Aleksandra Edmundson, Danielle Siganto, Matthew Burge, David Clark, Vicki Whitehall. Development of personalized medicine strategies for rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7549.

Metastatic colorectal cancer (mCRC) remains a major clinical challenge, particularly for patients with disease progression after multiple lines of therapy. Advances in molecular profiling have transformed the therapeutic landscape, enabling personalized treatment selection and expanding third- and later-line options. Targeted therapies such as BRAF inhibitors, anti-HER2 agents, and KRASG12C inhibitors are utilized in patients whose tumors harbor specific molecular alterations, with their use increasingly being explored across various lines of therapy. Agents such as trifluridine/tipiracil, regorafenib, and fruquintinib offer additional benefit in heavily pretreated mCRC. The integration of broad molecular testing, including emerging rare biomarkers, further supports individualized management. Despite these developments, prognosis in late-line mCRC remains poor, underscoring the need for ongoing research and clinical trial participation. This review summarizes contemporary evidence supporting third- and later-line therapies, highlights key clinical trial data, and discusses practical considerations in treatment sequencing. Potential treatment algorithms designed to aid clinicians in the selection and sequencing of therapies for refractory mCRC are also proposed. Anticipated paradigm shifts with novel agents may further refine management strategies and improve outcomes for these patients. As the landscape evolves, ongoing multidisciplinary collaboration will be essential in optimizing both patient selection and therapy sequencing as new options become available.

The incidence of early-onset colorectal cancer (CRC), commonly defined as diagnosis prior to age 50, is increasing. Studies of patients diagnosed prior to age 35 as a distinct subset of all early-onset patients have yielded inconsistent results. We extracted prospectively collected data from consecutive patients with metastatic colorectal cancer (mCRC) entered in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australasian registry. We focused on comparing demographic and clinicopathologic characteristics of those diagnosed < 35Y with remaining early-onset patients (35-49Y) whilst including a comparison to older patients (≥ 50Y) as a reference point. Molecular data were examined from 2015 when testing became reflexive. From July 2009 to December 2023, we identified 4399 patients with mCRC, including 133 (3.0%) < 35Y, and 537 (12%) 35-49Y. The proportion of < 35Y among newly diagnosed mCRC increased per calendar year (odds ratio 1.07, 95% CI 1.02-1.11). Gender, ECOG performance status and primary tumour location were similar for < 35Y and 35-49Y. Compared to 35-49Y, < 35Y had more de novo metastatic disease (79% vs. 70%; p = 0.04), BRAF V600E mutations (32% vs. 10%, p < 0.001) and deficient mismatch repair (dMMR) tumours (9.8% vs. 2.8%, p = 0.008). Rates of chemotherapy, rates of liver resection and overall survival (OS) were similar between < 35Y and 35-49Y. Multiple differences were observed between < fand 35-49Y, most notably a higher rate of BRAF V600E mutations and dMMR cancers. Collectively, these findings may inform the interpretation of clinical outcomes, refine screening approaches and advance understanding of CRC tumorigenesis in younger patients.

BACKGROUND & AIMS:Accurate risk stratification in Stage II colorectal cancer is essential for treatment decision-making, as current guidelines recommend adjuvant chemotherapy only for patients with a high risk of relapse. We aimed to develop and validate an artificial intelligence-based approach for automated invasive front assessment to improve prognostic stratification in this population. METHODS:We developed Semantically-Enhanced Multiple Instance Learning (SÉMIL), integrating vision-language foundation models with attention-based multiple instance learning for automated invasiveness assessment from H&E-stained whole slide images. We trained and validated SÉMIL on 1608 H&E-stained whole slide images from 3 cohorts (Austin n = 697, MCO n = 478, DYNAMIC n = 433). We compared SÉMIL performance against manual pathologist assessment and nonsemantic MIL approaches. RESULTS:For binary classification, SÉMIL outperformed nonsemantic MIL across all cohorts (external validation: AUC 0.713-0.821 vs 0.686-0.803). For survival prediction, SÉMIL demonstrated validated prognostic stratification in both the internal (Austin: hazard ratio [HR] = 4.73; P = .0012) and the 2 external (MCO: HR = 2.84; P = .0032; DYNAMIC: HR = 2.10; P = .0396) Stage II validation cohorts. Critically, among National Comprehensive Cancer Network guideline-defined high-risk Stage II patients, SÉMIL successfully stratified outcomes across all 3 cohorts (HRs, 2.96-3.50; all P < .05), demonstrating consistent reproducible performance. In multivariate analysis of the combined Stage II cohort (n = 1220), SÉMIL retained independent prognostic significance (HR = 1.98; P = .005) after adjusting for conventional clinicopathologic features including T stage, MMR status, and lymph node examination adequacy. Concordance analysis between SÉMIL and manual assessment showed concordant infiltrative classification identified the highest-risk group (HR = 3.96; P < .0001), with discordant cases showing intermediate risk. CONCLUSIONS:SÉMIL demonstrates validated prognostic stratification in Stage II colorectal cancer, with potential utility for refining risk assessment within National Comprehensive Cancer Network guideline-defined high-risk categories where treatment decisions are most challenging.

Adjuvant chemotherapy in stage III colon cancer provides uncertain benefit at the individual level. Circulating tumor DNA (ctDNA) may help refine risk-adjusted treatment selection. In this multicenter, randomized, phase 2/3 trial, patients with stage III colon cancer underwent ctDNA testing 5-6 weeks after surgery and were assigned (1:1) to ctDNA-guided or standard management. In the ctDNA-guided arm, patients negative for ctDNA received de-escalated therapy, whereas ctDNA-positive patients received escalated therapy. Clinicians prespecified the standard regimen. Primary endpoints were 3-year recurrence-free survival (RFS) for ctDNA-negative patients and 2-year RFS for ctDNA-positive patients. Secondary endpoints included treatment-related hospitalization and ctDNA clearance. Among 968 evaluable patients, 702 (72.5%) were ctDNA negative. With a median follow-up of 47 months, ctDNA-negative patients experienced significantly fewer recurrences than ctDNA-positive patients (3-year RFS 87% versus 49%; P < 0.001). In ctDNA-negative patients, de-escalation reduced oxaliplatin use (34.8% versus 88.6%) and hospitalizations (8.5% versus 13.2%) but yielded slightly lower RFS than standard management (85.3% versus 88.1%), not meeting the non-inferiority margin. In ctDNA-positive patients, higher ctDNA burden correlated with recurrence risk (3-year RFS 77% to 23% across quartiles; P < 0.001). Escalated therapy did not improve outcomes over standard management (2-year RFS 51% versus 61%). There was no unexpected toxicity. Persistent ctDNA after treatment predicted markedly worse prognosis (3-year RFS 14% versus 79%). ctDNA is validated as a strong prognostic classifier. ctDNA-guided de-escalation reduced oxaliplatin exposure and adverse events with outcomes approaching standard of care, whereas exploratory chemotherapy intensification conferred no RFS benefit, suggesting a need for novel strategies in ctDNA-positive disease.Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617001566325 .

Background: BRAFV600E-mutated metastatic colorectal cancer (mCRC) is a biologically distinct and clinically aggressive subtype associated with poor outcomes. Real-world data on this population remains limited, particularly within the Australian health care setting. Patients and methods: The COALA study is a national, prospective registry-based observational analysis of patients with mCRC across 21 Australian institutions. Data were extracted from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) and TRACC-Select registries and included demographics, molecular profiles, treatment patterns and overall survival (OS). Uptake and impact of encorafenib plus cetuximab (EC), since being available in Australia from May 2019, were examined. Results: Of 2976 patients tested for BRAF, 374 (13%) harboured BRAFV600E mutations, including 53 (24%) of the 217 ‘very-young’ subset (<40 years of age). Overall, compared with wild-type (BRAF-wt) tumours, BRAFV600E-mutated tumours were more likely to occur in females (55% versus 39%), and right-sided primaries (60% versus 28%) occur with deficient mismatch repair (dMMR) (24% versus 3%), and/or peritoneal metastases (36% versus 20%). Only 42% of BRAFV600E patients received second-line (2L) treatment. OS was significantly shorter in BRAFV600E versus BRAF-wt patients [hazard ratio (HR) 1.75, 95% confidence interval 1.5-2; median 16.6 versus 32.3 months]. Among BRAFV600E patients receiving 2L therapy, EC use versus chemotherapy was associated with a trend for improved OS (HR 0.70, median 8.6 versus 6.8 months). Conclusions: The COALA study provides the first Australian real-world profile of BRAFV600E-mutated mCRC. These findings underscore the importance of early and effective therapeutic strategies, and identify a novel, disproportionately affected very-young subgroup requiring targeted research and clinical focus.

3503 Background: Despite adjuvant chemotherapy (ACT) a proportion of patients (pts) with stage III colon cancer (CC) will recur. Most at risk are those with detectable ctDNA, whereas those with undetectable ctDNA have a reduced recurrence risk. The DYNAMIC-III study explored the impact of ACT de-escalation or escalation as informed by post-surgery ctDNA results. Here, we report the primary analysis on the impact of treatment escalation in ctDNA-positive pts. Outcome data for treatment de-escalation in ctDNA-negative pts is immature. Methods: DYNAMIC-III is a multi-center, randomized, phase II/III trial. Eligible pts had resected stage III CC and were fit for ACT. Pts were randomly assigned 1:1 to ctDNA-informed or standard of care (SOC) management. Clinicians nominated the selected SOC ACT regimen prior to randomization. For ctDNA-informed management, a ctDNA-positive result at 5-6 weeks after surgery with a tumor-informed assay prompted an escalation ACT strategy (from single agent fluoropyrimidine [FP] to oxaliplatin-based doublet, from 3 months doublet to 6 months doublet or FOLFOXIRI [clinician choice], or from 6 months doublet to FOLFOXIRI). The primary efficacy endpoint for the ctDNA-positive cohort was 2-year RFS. The target sample size of 250 provided 80% power with 90% confidence to confirm superiority of ctDNA-informed treatment escalation compared to SOC with a HR of 0.746. Results: Of 961 eligible pts randomized between Oct 2017 and Apr 2023, 259 (27%) were ctDNA-positive. Of these, 113 (44%) had clinical low risk disease (non-N2 + non-T4). Median follow-up was 42.2 months (range 0.78 – 63.0). 115 (89%) of 129 ctDNA-informed pts received ACT escalation, with 65 (56%) receiving FOLFOXIRI. Of 130 SOC pts, 14 (11%) and 112 (86%) received single agent FP and oxaliplatin doublet, respectively. 2-year RFS for ctDNA-informed treatment escalation was 52% (90% CI: 44 - 59%) vs 61% (90% CI: 54 - 68%) for SOC (HR 1.11, 90% CI: 0.83 - 1.48; P = 0.6). The 3-year RFS for ctDNA-positive pts receiving FOLFOXIRI and FOLFOX/CAPOX was similar (47% vs 51%, HR 1.09, 90% CI 0.78 to 1.53; P = 0.7). In a pre-specified correlative analysis of all ctDNA positive pts, recurrence risk increased with ctDNA burden, with 3-year RFS of 78%, 63%, 36% and 22% for tumor-derived mutant molecules/mL quartiles < 0.06, 0.06 – 0.17, 0.18 – 1.31, and > 1.31, respectively (P < 0.01). Treatment-related hospitalisation was similar for escalated and SOC pts (OR 1.21, P = 0.58). Analysis of post-ACT ctDNA is underway. Conclusions: In this first randomised study of ctDNA-informed management in stage III CC, we confirm the prognostic significance of detectable ctDNA, with the novel finding of recurrence risk increasing markedly with ctDNA burden. Treatment escalation, including to FOLFOXIRI, did not improve RFS. Future studies in ctDNA positive pts should explore other escalation strategies. Clinical trial information: ACTRN12617001566325 .

The management of malignant insulinoma (MI) presents dual management challenges of hypoglycaemia and tumour control. This study aims to analyse long-term outcomes of PRRT for the treatment of MI. We retrospectively reviewed consecutive patients with MI treated with [177Lu]Lu-DOTATATE (LuTATE) at two Australian NET centres between 2004 and 2022. Follow-up for hypoglycaemia, molecular imaging, radiologic and biochemical responses, treatment-related side-effects, progression-free and overall survival were assessed. Of 15 patients (seven female; median age 60, range 26–82) treated for intractable hypoglycaemia, WHO grade (G) was known in 12 patients (three G1, six G2 and three G3). PRRT was administered in a median of seven cycles (range 1–15), with a median cumulative activity of 42 GBq (range 4–117 GBq) and radiosensitizing chemotherapy in 9/15 (60%) patients. Resolution of hypoglycaemia was observed in 14/15 (93%) patients after a median of 2.5 months (range 0.2–23.5), but recurred in 7/14 cases after a median of 17.7 months (range 7.6–48.3). Patients with recurrent hypoglycaemia had a longer time to hypoglycaemia resolution (median 3.0 vs 0.5 months), were more likely G3 (57 vs 0%) and experienced higher mortality (86 vs 29%). In all seven cases, PRRT re-treatment was successful. The mean duration of hypoglycaemia remission was 23.8 months (range 9.2–101). The median progression-free and overall survival was 17.9 months (95% CI, 8.5–43.2) and 50.1 months (95% CI, 23.0-ND), respectively. Side-effects included G3/4 myelosuppression in 4/15 patients and hypoglycaemia flare (hospitalisation >48 h) in 7/15 patients. PRRT provides durable hypoglycaemic and oncologic disease control of MI with manageable toxicity including hypoglycaemia flare requiring multidisciplinary care.

11125 Background: ctDNA detection following curative intent treatment is highly prognostic, with potential to impact patient fear of cancer recurrence (FCR). In 3 separate randomized trials (DYNAMIC II, III, rectal), pts with early-stage CRC were randomly assigned to treatment decision guided by ctDNA results (adjuvant chemotherapy escalation if ctDNA positive, de-escalation or no treatment if ctDNA negative), or according to standard clinicopathological features. The relationship between being informed of a high recurrence risk, or treatment de-escalation, and FCR is unclear. This study aims to explore the relationship between biomarker-informed adjuvant chemotherapy (ACT) decision making and FCR, including changes over time. Methods: A subset of pts from the 3 DYNAMIC studies completed validated self-report questionnaires measuring FCR, anxiety, depression and quality of life. Data were collected at three time points: after surgery (T1), at the time of the ACT decision (T2), and 9-12 months later (T3). Pts randomized to the ctDNA-guided group received a ctDNA test result (positive or negative) at T2, while those in the standard of care (SOC) group did not. The primary endpoint was the FCR Inventory Short Form score (FCRI-SF). FCR patterns over time were analyzed using a mixed model 2 (Randomization) x 3 (Time) ANCOVA. A 2 (Randomization) x 2 (Chemotherapy Status) ANCOVA was used to assess ACT’s impact on FCR at follow-up. Gender, age, and cancer stage were included as covariates. Results: 317 pts from 35 Australian sites participated in the FCR substudy (74% response rate for all timepoints). Two-thirds were male, and the mean age was 60 years. Of the ctDNA-guided group (n=176), 73% had a negative ctDNA result. At baseline, 63% of patients exhibited clinically significant levels of FCR (FCRI-SF >13). Younger age, female gender, anxiety, and higher cancer stage all predicted higher baseline FCR. FCR significantly decreased over time for all pts ( F (2,176) = 3.64, p = .03). This reduction was more pronounced in the ctDNA-guided group compared to the SOC group ( F (2, 176) = 3.83; p = .02), although the effect size was small (Cohen’s d =0.24). In the ctDNA-guided group, no differences in FCR were found between pts based on ctDNA result (positive vs. negative). High baseline anxiety was the only independent predictor of FCR at 12 months. Chemotherapy receipt, cancer stage, depression, and quality of life scores were not predictive of FCR over time. Conclusions: In pts with early-stage CRC, neither a positive nor negative ctDNA result impacted FCR. ctDNA-guided approach to determining ACT was associated with a greater reduction in FCR over time compared to SOC. This biomarker-guided treatment approach has potential to improve ACT selection as well as psychosocial outcomes. Temporal reduction in FCR is likely driven by increased prognostic certainty over time. Clinical trial information: 12615000381583 .