Citations

TPS256 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 9-4-2025): 967/1,912. Drs. Lieu and Dasari contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

210 Background: ERBB2/HER2 amplification defines a rare but clinically distinct subtype of colorectal cancer (CRC), associated with favorable responses to HER2-targeted therapies. In contrast, ERBB2/HER2 -mutant CRCs show limited therapeutic benefit, and their clinical and molecular features remain poorly defined. This study investigated the molecular and clinical features of ERBB2/HER2 -mutant CRCs to provide insight into the molecular basis of their differential therapeutic vulnerabilities compared to amplified CRC. Methods: CRC cases were identified from cBioPortal studies with available clinical and ERBB2/HER2 genomic data. After quality control and deduplication, the cohort included 4407 unique cases: 97 with driver mutation(s) only (2.2%), 86 with amplification only (2%), and 4224 wild-type (95.9%). Demographic, clinical, and molecular features, including microsatellite instability (MSI), tumor mutational burden (TMB), and alterations in 94 oncogenic pathway genes, were compared across groups. Statistical analyses used chi-square/Fisher’s exact tests for categorical data, Kruskal-Wallis tests for continuous variables, and the Benjamini-Hochberg correction for multiple comparisons. Odds ratios and FDR-adjusted p-values were calculated to assess associations. Results: Across groups, the distributions of gender, race, and primary cancer site (colon or rectal cancer) were comparable. However, significant differences were observed in age (mean 58.7 ± 15.0 years for ERBB2/HER2 -mutant, 55 ± 13.9 for amplified, and 59 ± 14.8 for wild-type; p = 0.035) and tumor sidedness (among ERBB2/HER2 -mutant cases: right-colon 30.8%, left-colon 15.2%; among ERBB2/HER2 -amplified: right-colon 12.1%, left-colon 37.9%, p = 0.011). KRAS alterations were significantly more common in ERBB2/HER2 -mutant CRCs (50.5%) compared with both amplified (19.8%) and wild-type (37.6%). MSI-H was detected in 34.5% of ERBB2/HER2 -mutant cases, whereas no MSI-H was observed among amplified tumors (p < 0.001). Expectedly, ERBB2/HER2 -mutant tumors exhibited a hypermutated phenotype, with significantly higher TMB (30.3 ± 45.5) and total mutation count (232.8 ± 926.0), compared to amplified (6.1 ± 9.7 and 15.3 ± 28.4) and wild-type (10.5 ± 20.3 and 126.3 ± 424.5; both p < 0.001). Conversely, ERBB2/HER2 -amplified tumors had the highest fraction of overall genomic alterations including chromosomal changes (0.24 ± 0.17 in amplified vs 0.14 ± 0.17 in mutants and 0.20 ± 0.16 in wild-type; p < 0.001). Hierarchical clustering demonstrated that ERBB2/HER2 -mutant tumors form a distinct molecular cluster, whereas amplified tumors cluster closely with wild-type CRC. Conclusions: ERBB2/HER2 - mutant and amplified CRCs show highly distinct genomic and clinical features, supporting the need for tailored treatment approaches.

Stereotactic radiosurgery was associated with a higher obliteration rate compared with embolization in patients with eloquent brain arteriovenous malformations, whereas there was no evidence of a difference in functional outcomes or complications after adjustment.

Background and objectives Arteriovenous malformations (AVMs) with perinidal aneurysms and single draining vein are associated with an elevated risk of rupture and increased procedural complexity. The role of preoperative embolization in this high-risk anatomical subset remains unclear. This study aimed to evaluate the safety and efficacy of microsurgery with preoperative embolization, compared with microsurgery alone in patients with such AVMs. Methods We conducted a multicenter retrospective analysis of an AVM registry from the MISTA (Multicenter International Study for Treatment of Brain AVMs) consortium and included AVMs with perinidal aneurysms and a single draining vein. Baseline characteristics, angiographic outcomes, functional outcomes, and complication rates were compared. Propensity score weighting (PSW) using the covariate balancing method was applied to adjust for baseline differences. Results Out of a total of 1919 patients, 65 met the inclusion criteria; 45 patients underwent preoperative embolization followed by microsurgery, and 20 underwent microsurgery alone. After adjustment, complete obliteration rates were similar between groups (OR 0.87, 95% CI 0.04 to 16.33, P=0.92), as were rates of functional independence at discharge and follow-up. Overall complication, symptomatic complication, and mortality rates did not differ significantly between groups. However, permanent complications were significantly lower in patients with preoperative embolization (OR 0.06, 95% CI 0.004 to 0.84, P=0.03). Discussion In patients with AVMs featuring perinidal aneurysms and single draining vein, preoperative embolization followed by microsurgery was associated with fewer permanent complications and no increase in adverse outcomes compared with microsurgery alone. However, given the small number of events, this finding should be interpreted cautiously.

TPS3644 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera™, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 1-27-2025): 647/1,912. NCT: 05174169. Support: U10 CA180868, -180822; -180888; UG1 CA189867; Natera, Inc. Clinical trial information: NCT05174169 .

BACKGROUND: Data registries lack a definitive classification system that distinguishes different locations of colon cancer from one another. OBJECTIVE: To establish an international consensus on the definition of primary colon cancer segment locations. DESIGN: Between December 2022 and June 2023, Delphi survey study was conducted to seek opinions from relevant international experts and eventually develop a consensus definition of each colon cancer segment. SETTING: Three-round online-based Delphi survey study. INTERVENTIONS: Online survey included 17 questions. In the first two rounds, participating experts were asked to rank each statement on a scale of 1–9 (9 is the most relevant). Consensus statements and definitions were revised according to results, obtaining a consensus score of 7–9. During the third round and online meeting, definitions and statements reached a moderate or high consensus(above 4 in more than 70% of participants) were included. MAIN OUTCOME AND MEASURE: Primary goal of our project was focused on precisely localizing the specific segment affected by primary colon cancer, rather than to identify surgical treatment or type of resection needed for particular segment. RESULTS: The first round included 331 experts, 301 (91%) completed the second round, and 295 (98%) completed the final round. Experts strongly supported the use of a “10 cm rule” to describe colon cancer sites at the flexures and anatomical landmarks for other segments. Regarding the definition of rectosigmoid cancer, experts from America and Europe reached a high consensus that the term rectosigmoid as a colon cancer location must be abolished in contrast to experts from Asia. Description of cancers overlapping segments achieved a consensus of 64%. LIMITATIONS: Subjective decisions are based on individual expert clinical experience. CONCLUSIONS: This Delphi survey, the first internationally conducted consensus study, achieved a remarkable level of consensus among a panel of global experts. Ambiguity still exists regarding overlapping lesions. See Video Abstract .

Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray–excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y 2 O 3 fluorescing at 611 nanometers and decorated with SiO 2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y 2 O 3 :Eu@SiO 2 -methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression ( P < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8 + cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically “cold” tumor to an immunologically “hot” tumor.

ImportanceImmune checkpoint inhibitors (ICIs) have been approved for treatment of microsatellite instable (MSI-H) metastatic colorectal cancer (mCRC), but factors associated with receipt and efficacy of ICIs in routine clinical practice remain largely unknown.ObjectiveTo identify factors associated with receipt of ICIs and associated survival outcomes among patients with mCRC in routine clinical practice.Design, Setting, and ParticipantsThis population-based cohort study used deidentified data from a nationwide electronic health record–derived database to include 18 932 patients diagnosed with mCRC between January 2013 and June 2019. Population-based patients were diagnosed with de novo mCRC and had at least 2 documented clinical visits on or after the date of diagnosis. The study analyses were performed between September 2020 and April 2021.ExposurePatients received ICI therapy and/or chemotherapy as part of a systemic treatment for mCRC.Main Outcomes and MeasuresThe outcomes were receipt of ICI therapy, overall survival (OS), and time to treatment discontinuation (TTD).ResultsIn this cohort study of 18 932 patients diagnosed with mCRC (10 537 [55.7%] male; 546 [2.9%] Asian, 2005 [10.6%] Black or African American, 1674 [8.8%] Hispanic, 12 338 [65.2%] White, 4043 [21.4%] unknown race or ethnicity; median [IQR] age at metastatic diagnosis, 64.6 [55.0-73.3] years), patients with MSI-H tumors had a significantly higher probability of receiving ICIs than those with microsatellite stable (MSS) tumors (odds ratio [OR], 22.66 [95% CI, 17.30-29.73]; P &amp;lt; .001), whereas patients initially diagnosed with synchronous mCRC had significantly lower odds of receiving ICIs than patients with metachronous mCRC (OR, 0.57 [95% CI, 0.45-0.73]; P &amp;lt; .001). Patients with MSI-H tumors who received ICIs as first line of therapy had significantly longer OS than those receiving chemotherapy only (HR, 0.37 [95% CI, 0.25-0.56]; P &amp;lt; .001). Among patients with MSS tumors, ICI-based therapy was associated with significantly longer OS for patients with high albumin level (vs low: HR, 0.28 [95% CI, 0.18-0.45]; P &amp;lt; .001) and antibiotic use (vs nonuse: HR, 0.43 [95% CI, 0.27-0.67]; P &amp;lt; .001), but a significantly shorter OS for patients with synchronous mCRC (vs metachronous: HR, 1.90 [95% CI, 1.24-2.89]; P = .003). In addition, 29 out of 235 patients with MSS tumors (12.3%) experienced durable responses on ICI-based therapy. Similar patterns of associations with TTD were observed.Conclusions and RelevanceIn this cohort study of patients with mCRC, clinical characteristics were associated with different survival outcomes in patients treated with ICI-based therapy, with important clinical implications for patients with MSS tumors who are generally unresponsive to immunotherapy.

Background: Arteriovenous malformations (AVMs) are complex vascular anomalies with a high risk of hemorrhage and neurological deficits, especially when located in eloquent brain regions. The eloquence of an AVM location is a critical factor in the treatment planning, influencing both the risk of complications and long-term functional outcomes. This study aims to compare outcomes between eloquent and non-eloquent AVMs. Methods: This multicenter, retrospective study utilized data from the Multicenter International Study for Treatment of Brain AVMs (MISTA) consortium. Patients with eloquent and non-eloquent AVMs were compared on baseline characteristics, angiographic outcomes, and functional outcomes using the modified Rankin Scale (mRS). Propensity score weighting (IPTW) was applied to adjust for confounding variables. Results: The study included 1013 patients, with 498 (49.2%) AVMs located in eloquent regions and 515 (50.8%) in non-eloquent regions. In unadjusted analysis, eloquent AVMs had lower complete obliteration rates (67.6% vs 79.5%, OR: 0.53, 95% CI: 0.39–0.72, p < 0.001) and higher complication rates (24.5% vs 19.0%, OR: 1.38, 95% CI: 1.02–1.86, p = 0.03) compared to non-eloquent AVMs. After IPTW adjustment, eloquent AVMs continued to show significantly higher odds of overall complications (OR: 1.68, 95% CI: 1.12–2.52, p = 0.01) and symptomatic complications (OR: 1.77, 95% CI: 1.12–2.80, p = 0.01). Secondary analysis within the eloquent group indicated that embolization was linked to an elevated risk of complications. Surgery and radiosurgery showed comparable functional outcomes at last follow-up and complications rates with higher complete obliteration rates in surgery. Conclusion: AVMs in eloquent brain areas present higher risks of complications and lower obliteration rates, emphasizing the need for cautious, individualized treatment planning. Within the eloquent group, embolization increased the risk of complications, while surgery and radiosurgery showed comparable functional outcomes at last follow-up and complication rates with higher complete obliteration rates in surgery. These findings highlight the importance of location in AVM management and support further research focusing on comparing treatment strategies for AVMs in eloquent brain areas.

TPS310 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 9-20-2024): 500/1,912. Clinical trial information: NCT05174169 .