Citations

Background/Objectives: Locoregional anal squamous cell carcinoma (ASCC) is usually cured with chemoradiotherapy; however, some patients relapse, require salvage abdominoperineal resection or develop metastatic disease. Approximately 90% of cases are driven by high-risk human papillomavirus, most commonly HPV16. Conventional surveillance using clinical examination and imaging may have limited sensitivity and specificity and is not individualized by recurrence risk. Circulating biomarkers (CBs), particularly circulating tumor DNA (ctDNA), have emerged as promising methods for real-time disease monitoring. We systematically reviewed available evidence evaluating CBs across treatment timepoints in localized ASCC. Methods: A PROSPERO-registered review (ID: 1133987) was conducted according to PRISMA guidelines. PubMed, EMBASE, Cochrane CENTRAL, Web of Science, and major conference proceedings (ASCO, ESMO, ASTRO) were searched on 30 November 2025. We included prospective or retrospective studies (≥10 patients) with stage I–III disease treated with curative-intent chemoradiotherapy that reported CBs, assay characteristics, and at least one clinical outcome. Studies with predominantly localized cohorts were included even if small proportions of metastatic patients were present, provided results relevant to curative-intent populations could be interpreted. Data were synthesized narratively by timepoint (baseline, mid-treatment, end of treatment, post-treatment/surveillance) and assay type given methodological heterogeneity. Results: Fifteen studies were included. CB assays comprised four categories: viral HPV ctDNA assays, tumor-informed ctDNA assays, non-specific total cell-free DNA (cfDNA) quantification, and circulating tumor cell (CTC)-based assays. Baseline detection rates varied by assay type. Viral HPV ctDNA assays demonstrated detection rates of 59–100%, while tumor-informed ctDNA assays showed rates of 79–89%. Across studies, higher CB detection rates and levels were generally associated with greater tumor burden, including more advanced T and N stage disease. Mid-treatment ctDNA clearance identified patients with excellent locoregional control and progression-free survival, whereas persistent ctDNA was associated with treatment failure. End-of-treatment and surveillance ctDNA positivity predicted recurrence within individual cohorts, with reported sensitivities of 80–90%, specificities of 95–99%, and molecular lead times preceding clinical or radiographic detection. In contrast, non-tumor-specific cfDNA dynamics showed more variable prognostic associations and were less consistently linked to tumor burden. Conclusions: Across heterogeneous assays, CB dynamics provide clinically meaningful prognostic information in localized ASCC, particularly when measured during treatment and early surveillance. Viral HPV and tumor-informed ctDNA may have the potential to guide follow-up intensity and inform future escalation or de-escalation strategies; however, prospective, standardized trials are needed to define actionable thresholds and test ctDNA-guided management.

PURPOSE For patients with advanced biliary tract cancer (BTC), cancer-related time spent in health care systems, time toxicity, represents a critical but understudied burden affecting quality of life. This study aimed to quantify time toxicity in patients receiving first-line systemic therapy and evaluate whether the addition of durvalumab to gemcitabine plus cisplatin (GC) increases health care contact time. METHODS This international, multicenter, retrospective cohort study included patients with advanced BTC seen between January 2019 and April 2024 at Mayo Clinic Enterprise (US), and between January 2021 and April 2024 at Kyorin University Hospital (Japan), and Hospital Israelita Albert Einstein (Brazil). Patients received GC plus durvalumab (GCD) or GC. Time toxicity was recorded from treatment initiation until discontinuation or last follow-up during first-line systemic therapy. Multiple regression analysis identified factors associated with high time toxicity. RESULTS Among 193 patients (102 GCD, 91 GC; median age 65 years; 50% male; 49% Eastern Cooperative Oncology Group performance status [PS] 0), median time on treatment (TOT) was 156 days (95% CI, 122 to 190). The median proportion of total time toxicity was 14.4% (IQR, 10.9-20.6). Planned visits accounted for 11.9%, while unplanned visits were infrequent (1.8%). Time toxicity strongly correlated with TOT ( r = 0.824) and progression-free survival ( r = 0.827). Despite longer treatment in the GCD group than the GC group (212 v 134 days; P = .027), total time toxicity was similar (27 v 18 days; P = .19). Younger age and poor PS were independent factors of higher time toxicity. CONCLUSION Time toxicity represents a meaningful metric that allows for more comprehensive integration of the net benefit in patients with advanced BTC with a limited lifespan.

Background: Metastatic squamous cell carcinoma of the anus (SCCA) carries a poor prognosis, with systemic therapy remaining the standard of care. While metastasis-directed therapy improves outcomes in select gastrointestinal malignancies, the role of liver-directed intervention in metastatic SCCA remains undefined. We evaluated clinicopathologic features and oncologic outcomes of patients with liver-limited metastatic SCCA treated with curative-intent hepatic local therapy at a tertiary academic center. Methods: We conducted a retrospective cohort study of adults with histologically confirmed SCCA and liver-only metastatic disease who underwent curative-intent hepatic resection or ablation at Mayo Clinic between 1993 and 2023. Patients with extrahepatic disease or incomplete records were excluded. Demographic, tumor, treatment, and outcomes data were abstracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method. Prognostic factors were assessed using univariate Cox proportional hazards models. Results: Twenty-five patients met inclusion criteria. Median age was 56.7 years, and 92% were female. Most patients had metachronous metastases (76%), a single hepatic lesion (56%), and unilobar disease (76%). Pre-intervention systemic therapy was administered in 52% of patients, with radiographic complete or partial responses observed in all treated patients. Liver-directed therapy consisted of surgical resection in 80% and thermal ablation in 20%. Among surgical patients, 90% achieved microscopically negative margins. With a median follow-up of 22 months, disease recurrence occurred in 80% of patients, most commonly within the liver. Median DFS was 7.27 months. Median OS from the date of liver-directed therapy was 51.3 months. On univariate analysis, poorly differentiated tumor histology was associated with inferior OS (hazard ratio 4.67, p = 0.018). No other clinicopathologic variables were significantly associated with DFS or OS. Conclusions: In this single-institution experience, carefully selected patients with liver-limited metastatic SCCA undergoing curative-intent hepatic-directed therapy achieved prolonged overall survival, substantially exceeding historical outcomes with systemic therapy alone. Despite frequent recurrence, the observed median OS exceeding four years supports consideration of liver-directed therapy within a multidisciplinary framework for patients demonstrating favorable disease biology and response to systemic treatment. Prospective studies are needed to better define patient selection and optimal integration of local and systemic therapies in the modern treatment era.

Liver transplantation has emerged as a curative treatment option for selected patients with unresectable hepatic malignancies beyond hepatocellular carcinoma, marking a paradigm shift in transplant oncology. For colorectal cancer liver metastases (CRLM), prospective trials have demonstrated that highly selected patients achieve 5-year OS rates of 60–83%, with the Oslo score identifying optimal candidates for transplantation. Perihilar cholangiocarcinoma (pCCA) has been successfully treated using strict patient selection criteria combined with neoadjuvant therapy, achieving 5-year OS rates of 50–68%, though emerging data suggests chemotherapy-based approaches may be preferable to radiation in selected cases. Intrahepatic cholangiocarcinoma (iCCA), previously considered a contraindication to transplantation, can now achieve excellent long-term outcomes (79.5% 5-year OS) in patients demonstrating sustained response to neoadjuvant chemotherapy and radioembolization, with metabolic tumor volume < 70 cm3 serving as an objective prognostic marker. Across these three emerging indications, successful outcomes depend on strict patient selection based on tumor biology, intensive multimodal neoadjuvant therapy, multidisciplinary evaluation in high-volume centers, and careful observation during treatment to exclude patients with aggressive disease. This evolution in transplant practice offers curative intent therapy to patients that previously only had palliative therapeutic options, fundamentally transforming hepatobiliary and oncologic surgery.

OBJECTIVE To assess whether initiating metformin at 25 weeks' gestation influences exclusive breastfeeding at 12 weeks postpartum in gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS We performed a prespecified secondary analysis of the Effectiveness of Metformin in Addition to Usual Care in the Reduction of Gestational Diabetes Effects (EMERGE) trial, a multicenter, double-blind, placebo-controlled randomized study. A total of 535 pregnant women (510 with newly diagnosed GDM) were allocated 1:1 to metformin (titrated to 2.5 g/day) or placebo alongside usual care. Infant feeding was prospectively documented at birth and at 4 and 12 weeks postpartum. The primary outcome was exclusive breastfeeding at 12 weeks (intention to treat). Multivariable logistic regression adjusted for race, education, smoking, booking BMI, health care access markers, and diagnostic oral glucose tolerance test (OGTT) glucose levels. RESULTS Twelve-week feeding data were available for 476 pregnancies (236 in the metformin group and 240 in the placebo group). Exclusive breastfeeding at 12 weeks was 27% with metformin and 26% with placebo (absolute difference +1.3%; 95% CI –6.3 to 8.7; P = 0.75). The adjusted odds ratio (OR) for metformin versus placebo was 1.24 (95% CI 0.79–1.96; P = 0.36). Feeding patterns shifted from breastfeeding to formula temporally in both groups (P &lt; 0.001), with no treatment-by-time interaction (P = 0.61). Non-Caucasian ethnicity independently predicted exclusive breastfeeding (adjusted OR 2.37; 95% CI 1.27–4.42). CONCLUSIONS Starting metformin treatment at 25 weeks in the GDM group was not associated with differences in exclusive breastfeeding at 12 weeks postpartum. Where metformin was discontinued at delivery, the results support compatibility of antenatal metformin with breastfeeding objectives. Breastfeeding outcomes were more linked to sociodemographic factors than metabolic ones, highlighting the need for culturally appropriate postpartum support.

Abstract Background: PALLAS (PALbociclib CoLlaborative Adjuvant Study, NCT02513394) is a randomized phase III trial comparing two years of the CDK4/6 inhibitor palbociclib combined with the physician’s choice of adjuvant endocrine therapy, versus endocrine therapy alone for patients with Stage II-III hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. Molecular residual disease (MRD) detection via circulating tumor DNA (ctDNA) testing was a predefined biomarker analysis to identify patients at highest risk of recurrence. Methods: PALLAS participants with available tumor block, at least a baseline (pre-study treatment) plasma sample, and either whole blood or buffy coat were randomly selected from the overall study population. Plasma samples on cycle 1 day 1 (C1D1), cycle 6 day 1 (C6D1), and at the end of treatment (EOT) were collected, processed, and stored. Nucleic acids were extracted from primary tumor tissue or, when primary tissue was insufficient, from post-neoadjuvant tumor tissue, provided the sample had sufficient material and tumor cellularity (&gt;25 mm2 tissue area with ≥20% tumor nuclei). Data from next generation sequencing of tumor tissue and matched normal DNA were used to create a personalized ctDNA SignateraTM assay (Natera, Inc.) for MRD assessment in the peripheral blood. ctDNA was reported as mean tumor molecules/mL (MTM/mL) of plasma. The primary endpoint was distant recurrence-free interval (DRFI) based on ctDNA status. Cox Proportional Hazards models were used to evaluate prognosis and predictive interactions. To minimize bias, the biorepository and laboratory teams were blinded to participant identity. Results: In total, 1280 participants were randomly selected for inclusion in this preplanned ctDNA sub-study. WES and WGS are being conducted on tissue, and Signatera results will be generated. Results for association of MRD status (positive/negative) and MTM/mL with DRFI in the context of 7 year median follow up of this study cohort will be reported. Conclusions: The planned analysis is ongoing and the presented work will provide data from the first randomized phase 3 adjuvant study in HR+/HER2- breast cancer to report MRD status by treatment arm. Citation Format: H. A. Parsons, K. Ballman, E. Heitzer, M. Watson, M. Balic, D. Hlauschek, D. Renner, E. Kalashnikova, G. Steger, J. M. Balko, Y. Novik, M. Martin, A. A. Rodriguez, Z. Dayao, A. Chan, E. Nili Gal-Yam, M. C. Liu, C. Isaacs, M. Los, M. Gil Gil, B. Felder, C. Denkert, P. Fasching, F. Liu, T. O'Donnell, E. L. Mayer, M. Gnant, W. F. Symmans, A. DeMichele. Tumor-informed circulating tumor DNA analysis to assess molecular residual disease for prognosis and prediction of benefit from palbociclib in the PALLAS trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF3-04.

Anal squamous cell carcinoma (ASCC) is a rare malignancy of the lower gastrointestinal tract, with distant metastases typically involving the liver and lungs. Metastasis to the kidneys is uncommon, and only one prior case has been reported in the literature. Herein, we report a rare presentation of a patient with biopsy-confirmed metastatic ASCC presenting as bilateral renal lesions. We then provide a review of the literature for rare metastatic presentations of ASCC, highlighting all the cases described in the literature. Clinicians should maintain a high index of suspicion for unusual metastatic sites, perform targeted imaging and biopsy when indicated, and consider systemic therapies to optimize outcomes in rare metastatic presentations.

Abstract Background Pregnancies complicated by gestational diabetes mellitus (GDM) are associated with increased risks of adverse perinatal outcomes, and with long-term metabolic and cardiovascular consequences for both mother and child. The original EMERGE randomized controlled trial (RCT) evaluated the effectiveness of early metformin in addition to usual care in women with GDM on glycaemic control and perinatal outcomes. The EMERGE Mothers and Kids study is a longitudinal follow-up of the EMERGE trial participants, designed to investigate the long-term metabolic, cardiovascular, and neurodevelopmental outcomes in mothers and their offspring. Methods This is a prospective, observational cohort study of participants and their children from the EMERGE trial (NCT06327191). A single follow-up visit will be conducted up to 6 years after the index pregnancy. Maternal assessments include anthropometric data, glucose tolerance, and metabolic parameters. Child assessments include growth metrics, adiposity measured via skinfold thickness, and neurodevelopmental status assessed through validated questionnaires. Additional data on quality of life, mental health, breastfeeding, and health economics will also be collected. Discussion This study aims to provide insights into the long-term safety and efficacy of metformin use during pregnancy and its potential impact on the long term maternal and child health outcomes, contributing to evidence-based management of GDM. Trial registration: ClinicalTrials.gov; Identifier: NCT06327191

837 Background: A recent randomized trial suggested that CR may influence ICI activity in patients with lung cancer. However, the same has not been established in GI cancers, where reports have shown mixed results with variable definitions of 'early' vs 'late' IT. We evaluated multiple approaches to assess the impact of CR on first-line ICI in GI malignancies. Methods: This retrospective study included patients from three Mayo Clinic sites (N=455). Both previously reported IT cutoffs and a new cutoff derived from ROC analysis were evaluated. Patients were categorized by the median of all ITs, the median of the first four ITs, and whether ≥20% of ITs occurred before the identified cutoff. Univariate and multivariate Cox regression (adjusting for age, MSI status, type of cancer, metastasis status, number of cycles, and receipt of chemotherapy with ICI) assessed associations with OS. KM analyses were performed to illustrate survival differences. The primary endpoint was OS. Results: When patients were categorized based on whether ≥20% of infusions occurred before 14:00 (ROC-derived cutoff), a significant association with OS was observed. On univariate analysis, early infusion timing was associated with improved survival (HR 2.30, 95% CI 1.58–3.32, p <0.001). This remained significant after multivariable adjustment (HR 2.11, 95% CI 1.41–3.16, p < 0.001). Median OS was 14.2 months in the early group vs 3.8 months in the late group (log-rank p < 0.001). Using previously defined cutoffs, categorization by the median IT of all infusions or the median of the first four infusions did not demonstrate a significant association with OS in either univariate or multivariate Cox regression analyses. Conclusions: These findings highlight the potential role of infusion timing as a chronotherapy factor in GI cancers. Given the retrospective design and heterogeneous population, prospective studies are warranted to validate this signal and clarify its clinical relevance. Baseline demographics of patients by infusion timing (early vs late). Variables Early N=412 (%) LateN=43(%) Total N=455(%) p-value Age <70 249(60.4) 21(48.8) 270 (59.3) 0.1 >70 163(39.6) 22(51.2) 185 (40.7) Gender F 118(28.6) 16(37.2) 134 (29.5) 0.3 M 294(71.4) 27(62.8) 321 (70.5) Cancer Type Gastroesophageal 109 (26.5) 8 (18.6) 117 (25.7) 0.1 Hepatocellular 159 (38.6) 24 (55.8) 183 (40.2) Biliary 86 (20.9) 4 (9.3) 90 (19.8) MSI-H 58 (14.1) 7 (16.3) 65 (14.3) Metastasis No 150 (36.4) 22 (51.2) 172 (37.8) 0.1 Yes 262 (63.6) 21 (48.8) 283 (62.2) Immunotherapy Cycle Number <6 189 (45.9) 33 (76.7) 222 (48.8) <0.001 >6 223 (54.1) 10 (23.3) 233 (51.2)

83 Background: Colon cancer is among the leading causes of cancer-related morbidity and mortality globally, with an increasing incidence observed in younger populations. Lifestyle and metabolic risk factors seem to play an important role in this rising incidence. Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the treatment of type 2 diabetes and obesity. Emerging evidence suggests that these agents may have potential anti-tumor activity as GLP-1 signaling may influence pathways involved in cell proliferation and inflammation. Our study aims to evaluate the impact of GLP-1 receptor agonists on outcomes among patients with colon cancer with comorbid obesity, exploring potential interactions between metabolic modulation and disease behavior. Methods: A retrospective cohort study was conducted using the US Collaborative Network TriNetX, covering January 2000 to December 2023, encompassing data from 105 global healthcare organizations. Adult patients aged 18 and above with colon cancer and comorbid obesity were identified and then stratified into two groups based on treatment with GLP-1 agonists or not. The two groups were then propensity-matched based on age, sex, race, and common comorbidities. We followed these patients for 5 years to assess outcomes, including overall mortality, myocardial infarction, sepsis, acute pancreatitis, need for mechanical ventilation and hemodialysis. Results: We identified 1986 patients with colon cancer and obesity who received GLP-1 receptor agonists, and 16384 patients with colon cancer and obesity who did not receive GLP-1 therapy. The average age was 68.8 years in the first cohort and 74.3 years in the second cohort. After propensity matching, each cohort consisted of 1983 patients with similar baseline characteristics and ethnicity distribution. Our analysis found that over 5 years, patients with colon cancer and obesity who received GLP-1 receptor agonists had a significantly lower risk of overall mortality (Hazard Ratio (HR): 0.461, 95% CI: 0.401 to 0.532, p-value < 0.001), myocardial infarction (HR: 0.827, 95% CI: 0.668 to 0.993, p-value =0.005), sepsis (Risk Difference: -3.48%, 95% CI: -4.774 to -2.185, p-value < 0.001), and need for mechanical ventilation (HR: 0.486, 95% CI: 0.321 to 0.739, p-value = 0.037). There was no statistically significant difference in the risk of acute pancreatitis and need for hemodialysis between the two subgroups. Conclusions: Our study revealed that patients with colon cancer and obesity who received GLP-1 receptor agonists had a significantly lower risk of mortality, myocardial infarction, sepsis, and need for mechanical ventilation. Further longitudinal cohort studies are imperative to better understand these associations and guide evidence-based clinical practice in this population.