Rachel Wong

Proton pump inhibitors (PPIs) are commonly prescribed in patients with cancer. Prior studies suggest concomitant PPI use may reduce the efficacy of oral capecitabine through impaired absorption, with no interaction expected with intravenous 5‐fluorouracil (5‐FU). Using the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD), we identified patients with Stage III colon cancer diagnosed between 1 January 2006 and 31 December 2023. Concomitant PPI use during adjuvant chemotherapy was determined by chart review. We evaluated the prevalence of PPI use with fluoropyrimidine‐containing adjuvant therapy and its association with recurrence‐free survival (RFS) and overall survival (OS). A total of 459 patients were included as follows: 63 (14%) received 5‐FU alone, 115 (25%) capecitabine alone, 148 (32%) FOLFOX and 133 (29%) CAPOX. High‐risk disease (T4 and/or N2) was present in 203 patients (44%). Overall, 142 patients (31%) received a PPI during adjuvant chemotherapy, with similar rates across treatment groups ( p = 0.952). Formal interaction testing did not demonstrate significant heterogeneity of PPI effect across treatment regimens (RFS: LR test p = 0.615; OS: LR test p = 0.143). However, in high‐risk patients receiving CAPOX, PPI use was associated with reduced RFS (HR 3.07, 95% CI 1.38–6.84, p = 0.006) and OS (HR 4.11, 95% CI 1.44–11.74, p = 0.008). No impact was observed with capecitabine monotherapy, 5‐FU, or FOLFOX. Concomitant PPI use is common in Australian patients with Stage III colon cancer. While formal interaction testing did not reach statistical significance, PPI use was associated with inferior survival outcomes in high‐risk patients receiving CAPOX.

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.

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.

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.

Purpose: Long-course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) achieves a pathologic complete response (pCR) in approximately 10% to 30% of cases. Radiotherapy exerts both immunostimulatory and immunosuppressive effects. Inhibition of PDL1 may augment the immunostimulatory response. We hypothesize that administering avelumab following LCCRT may enhance tumor response and reduce relapse rates. Patients and Methods: This was a phase II single-arm trial. Eligible patients had MRI stage T3b to 4/N1 to 2/M0 LARC within 12 cm from the anal verge. Treatment consisted of long-course chemoradiotherapy (LCCRT) with 50.4 Gy and 5-fluorouracil or capecitabine, followed by four cycles of avelumab (10 mg/kg every 2 weeks). Surgical resection was performed 10 to 12 weeks after completion of LCCRT. Fresh tumor biopsies/ctDNA were taken before LCCRT, before avelumab, and at surgery. The primary endpoint was pCR, reported centrally. Secondary endpoints were imaging responses and toxicity, and exploratory endpoints were translational studies (immune evaluation by multiplex IHC and biopsy-derived tumoroids), distant relapse-free survival, and relapse sites. Results: Thirty-seven patients entered the trial, of whom 33 received avelumab and 32 had surgery. The overall response rate by pelvic MRI (N = 33) was 48%. By 2-[¹⁸F]fluoro-2-deoxy-D-glucose PET, there were 10 complete metabolic responses (CMR) and 18 partial metabolic responses (PMR). Regression score 0 (modified Ryan pCR) was observed in 19% of patients (N = 6), and regression score 1 in 16% (N = 5). Overall, 34% of patients (N = 11) had a major pathologic response. Tumors with greater PDL1 expression showed superior pCR/tumor regression. Tumoroid studies indicated intact cellular machinery for PDL1/HLA class-1 expression modulated by IFNγ. No immune-related grade 3 adverse events were observed, and postoperative complications were as expected. The median follow-up was 3.1 years, the 3-year estimated time to progression was 82%, distant relapse-free survival was 80%, and disease-free survival was 80%. Conclusions: The Ave-Rec phase II study demonstrated that avelumab after LCCRT is deliverable and tolerable, with significant imaging responses and a major pathologic response rate. Tumoral immune cell subsets/checkpoint expression was predictive of pathologic response. The addition of immune checkpoint inhibitors warrants further evaluation in patients with LARC.

Early data from the DYNAMIC study of circulating tumor DNA (ctDNA)-guided adjuvant chemotherapy (ACT) versus standard approach met its primary outcome demonstrating reduced ACT use without compromising 2-year recurrence-free survival (RFS) for stage II colon cancer. We report here other prespecified analyses of overall survival, ctDNA clearance and ctDNA level. At a median follow-up of 59.7 months, 5-year RFS was 88% and 87% with ctDNA-guided and standard management, respectively (difference 1.1%, 95% confidence interval −5.8% to 8.0%), and 5-year overall survival is similar (93.8% versus 93.3%, hazard ratio (HR) 1.05; P = 0.887). For treated ctDNA-positive patients, ctDNA clearance was observed at the end of ACT (EOT) in 35 out of 40 patients (87.5%). A higher than median postoperative tumor-derived mutant molecules per milliliter plasma was associated with worse 5-year RFS (HR 10.62; P = 0.005). For treated ctDNA-positive patients, post hoc analysis of ctDNA clearance at EOT assessed by a new assay that evaluated an average of 29 tumor-derived mutations per patient predicted for a favorable 5-year recurrence-free probability of 97% versus 0% for ctDNA persistence (P < 0.001). Mature DYNAMIC outcome data support a ctDNA-guided approach to ACT for stage II colon cancer, with potential to further risk stratify ctDNA-positive patients based on ctDNA burden and EOT results. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12615000381583.

Background Pancreatic cancer incidence is increasing in younger populations. Differences between early onset pancreatic cancer (EOPC) and later onset pancreatic cancer (LOPC), and how these should inform management warrant exploration in the contemporary setting. Methods A prospectively collected multi-site dataset on consecutive pancreatic adenocarcinoma patients was interrogated. Patient, tumour, treatment, and outcome data were extracted for EOPC (≤50 years old) vs LOPC (>50 years old). Results Of 1683 patients diagnosed between 2016 and 2022, 112 (6.7%) were EOPC. EOPC more frequently had the tail of pancreas tumours, earlier stage disease, surgical resection, and trended towards increased receipt of chemotherapy in the curative setting compared to LOPC. EOPC more frequently received 1st line chemotherapy, 2nd line chemotherapy, and chemoradiotherapy than LOPC in the palliative setting. Recurrence-free survival was improved for the tail of pancreas EOPC vs LOPC in the resected setting; overall survival was superior for EOPC compared to LOPC across the resected, locally advanced unresectable and metastatic settings. Conclusions EOPC remains a small proportion of pancreatic cancer diagnoses. The more favourable outcomes in EOPC suggest these younger patients are overall deriving benefits from increased treatment in the curative setting and increased therapy in the palliative setting.