Abstract Background: The standard treatment for locally-advanced rectal adenocarcinoma is trimodality therapy with neoadjuvant chemotherapy and chemoradiation, followed by surgery. A subset of these cases overexpress HER2; therapies that target HER2 signaling may improve therapeutic responses and organ preservation. Methods: We conducted a prospective investigator initiated single-arm study for patients with stage 2-3, HER2-overexpressed, RAS-wild-type, mismatch-repair-proficient rectal cancer. Patients received 6 weeks of induction HER2 targeted therapy with trastuzumab and tucatinib and then continued trastuzumab and tucatinib with the addition of 15 weeks of FOLFOX or CAPOX. Patients with a complete clinical response (cCR) transition to active surveillance without radiation or surgery. Patients with a non-cCR proceeded with SOC chemoradiation or surgery. The primary endpoint is cCR rate that exceeds 40% at completion of trastuzumab/tucatinib/chemotherapy. Overall response rate (ORR) is a key secondary endpoint. Results: Nine patients with stage II (n=2) and III (n=7) rectal adenocarcinoma with at least 2+ expression of HER2 by immunohistochemistry and Fluorescence in Situ Hybridization HER2-amplification were enrolled. Eight of nine patients completed 21 weeks of neoadjuvant therapy with combination HER2/chemotherapy. The study achieved an ORR of 78% (n=7/9) after 6 weeks of trastuzumab and tucatinib and 75% (n=6/8) after 15 additional weeks of combination HER2/chemotherapy. Four patients out of 8 exhibited a cCR after induction trastuzumab/tucatinib/chemotherapy and an additional patient achieved a cCR with subsequent radiation. All remain alive without metastatic recurrence after a median follow-up of 26 months (95% CI 15 mo - not reached). Only patients with 3+ HER2 expression achieved a cCR. Conclusion: Genomic HER2 amplification in early stage rectal adenocarcinoma predicts for complete clinical response to HER2 targeted therapy in combination with chemotherapy, which may guide non-operative management in this patient population. Citation Format: Michael B. Foote, Jinru Shia, Callahan Wilde, Marinela Capanu, Joanne Chou, Vetri Sudar Jayaprakasam, Marc Gollub, Miteshkumar Patel, Mina Ito, Leonard B. Saltz, Devika Rao, Neil Segal, Maliha Nusrat, Karuna Ganesh, Paul Romesser, Julio Garcia-Aguilar, Martin Weiser, Rona Yaeger, Luis A. Diaz, Andrea Cercek. Genomic HER2 amplification predicts for complete clinical response in a phase II study of induction tucatinib and trastuzumab combined with chemotherapy in locally advanced rectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT011.

To evaluate the relationship between mucin quantity on MRI and outcomes following total neoadjuvant therapy (TNT) in patients with rectal cancer. This retrospective, single-center study included patients with rectal adenocarcinoma who underwent TNT followed by surgery or non-operative management (NOM) from January 2018–December 2019. Two abdominal radiologists independently scored baseline and restaging MRIs for mucin quantity in the tumor or tumor bed, using two classifications: < 50

Non-Hispanic Black (NHB) patients have a 20% higher incidence of colorectal cancer (CRC) and a 40% higher CRC mortality than non-Hispanic white (NHW) patients. Disparities may be explained by socioeconomic variables (such as smoking or obesity) and access to health care. However, the role of potential biological differences remains unclear. Patient-derived organoid models (PDOs) provide an ideal model system to study biological differences and avoid confounding clinical variables by focusing on the genomic, phenotypic and functional differences in CRC cells ex vivo. There is currently a lack of patient-derived preclinical models from NHB populations. We aim to build a public biobank of NHB patients with detailed clinical annotation, chemosensitivity and biological characterization, examining intrinsic tumor cell states in different genomic backgrounds as potential variables in CRC outcomes. PDOs were established from surgically resected primary and metastatic CRC samples from NHB and NHW patients, processed through enzymatic digestion and filtration, and cultured in Matrigel in human intestinal stem cell (HISC) media. Genomic features of the corresponding patients were analyzed using the MSK-IMPACT targeted DNA sequencing assay. We assessed the responses of NHB and NHW PDOs to FOLFOX chemotherapy through drug sensitivity assays with 5-FU:oxaliplatin (concentration of 25:1). Dose-response curves were fitted using the two-parameter logistic regression model to calculate median IC50. After dissociation into single cells, PDOs were cultured in HISC and Base (media without intestine-specific growth factors) conditions for 11-14 days and analyzed by bulk RNA-sequencing to capture phenotypic differences associated with canonical intestinal (less aggressive) and non-canonical (more aggressive) cell states. We aim to establish a biobank of 10 NHB and 10 comparative NHW patients with similar clinicogenomic profiles. To date, 12 PDOs derived from 5 NHB (3 primary and 2 metastasis samples) and 7 NHW (2 primary and 4 metastasis samples) patients are characterized with further PDO collection ongoing. Four samples with KRAS missense mutations were present across the NHB and NHW patient groups (NHB: 80%, NHW: 57%). IC50 of five NHB and five NHW PDOs revealed no significant differences in sensitivity to FOLFOX (median IC50 NHB: 70.3uM; median IC50 NHW: 59.92uM). ssGSEA scores derived from bulk RNA-seq data of five PDOs, comparing three NHB and two NHW patients, exhibited greater variation across lines than within racial groups, with no significant differences between NHB and NHW patients. Ongoing work is focused on building a larger cohort for wider comparative characterization. The future completed biobank will become a public resource for scientists to access racially diverse PDOs for drug testing and further biological characterization. Xiang Han, Stefanie Gerstberger, Kathleen Luckett, Francesco Cambuli, Jaeyop Lee, Andres Rettig, Ahmed Mahmoud, Jonathan Bermeo, Asha Saxena, T.Peter Kingham, William Jarnagin, Philip Paty, Martin Weiser, Michael D’Angelica, Rona Yaeger, Julio Garcia-Aguilar, Francisco Sanchez-Vega, Karuna Ganesh. Leveraging race-informed biological models for disparities research in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7108.

BACKGROUND AND OBJECTIVES:Robotic arm surgical systems provide minimally invasive access and are commonly used in multiple surgical fields, with limited application in neurosurgery. Our institutional experience has led us to explore the benefits of a neurosurgeon trained to perform robotic surgery as part of a multidisciplinary team. The objective of this study is to evaluate the feasibility, safety, and outcomes of robotic resection for spinal nerve sheath tumors (NST). METHODS:Retrospective case series of robotic-assisted intracavitary approaches and resection of NSTs including thoracic, retroperitoneal, and transperitoneal. Surgical outcomes are compared to a historical cohort of open surgical resection of NSTs. RESULTS:Nineteen cases presented, of which 2 were combined posterior spinal followed by robotic tumor resection. One of 19 cases was converted to an open surgery. Gross total resection was achieved in all cases. There were 2 cases of postoperative Horner's syndrome, and 1 case with an intraoperative durotomy that was repaired primarily with no postoperative sequelae. Median estimated blood loss was 50 cc (range: 5-650) and median length of stay was 1 day (range: 0-6), with 9 (47.4%) patients discharged on postoperative day 1 and 3 (15.8%) patients discharged on an outpatient basis. Compared with our previously reported institutional outcomes for open resection of 25 tumors, there was a significant increase in rates of gross total resection (100 vs 60%, P = .002) and decrease in length of stay (median 1 vs 5 days, P < .0001). CONCLUSION:Robotic resection of complex paraspinal tumors appears safe and effective including for preservation of neurological function and may reduce surgical morbidity. Integration of robotic surgical platforms holds the potential to significantly affect neurological surgery.

21 March, 2025. This preprint was retracted at the authors' request due to a conflict with a conference embargo policy. Authors should verify embargo policies before posting to avoid post-publication removal.

Neoadjuvant checkpoint blockade of locally advanced mismatch repair deficient (MMRd) rectal cancers results in a high rate of complete clinical responses that can eliminate the need for surgery. MMRd occurs broadly across solid tumors but is unknown if these findings could be extended in a tumor agnostic manner. Early stage MMRd solid tumors that were eligible for curative intent surgery were enrolled to a study of six months of neoadjuvant treatment with dostarlimab, a PD-1 blocking monoclonal antibody. The study was comprised of two cohorts. The first cohort enrolled MMRd locally advanced rectal cancers and the second cohort enrolled MMRd non rectal solid tumors. In both cohorts, patients who achieved a clinical complete response could elect non-operative management. The co-primary endpoints for cohort one included response rate and durability of complete response at 12 months, the primary endpoint for cohort two was response and exploratory endpoints included genomic and circulating tumor DNA analyses for both cohorts. 110 patients were enrolled. In cohort one (MMRd rectal cancers), to date, 48 patients completed 6-months of treatment and 100% achieved a clinical complete response and did not undergo surgical resection of their primary tumor. Twenty nine of these 48 have attained 12 or more months of recurrence-free survival median 24.8 (range 15.6,48.6). In the second cohort of locally advanced MMRd non-rectal solid tumors, which included esophagogastric, hepatobiliary, genitourinary, and gynecologic tumors, at time data submission, 49 patients completed treatment and 31 patients (63%) achieved a clinical complete response and did not undergo resection surgical resection of their primary tumor. Across both cohorts, 81% of patients (79 of 97) who completed 6-months of treatment achieved a clinical complete response and 79% (77 of 97) were managed non-operatively. Baseline tumor mutational burden and MSI sensor scores in cohort one was 55.2 mutations per megabase (range 22.8, 106) and 19 (range 2.2, 37.6),and for cohort two 51.1 mutations per megabase (range 4.9, 145) and 18.6 (range 0.23, 39.4), respectively. Tumor-informed circulating tumor DNA levels were detectable at baseline in 87% of patients and on-therapy levels correlated with complete and incomplete responses especially at the completion of treatment. In the curative setting, neoadjuvant PD-1 blockade offers the option of organ preservation for most patients with early stage MMRd malignancies regardless of tumor type. Andrea Cercek, Michael B. Foote, Jinru Shia, Jenna Sinopoli, Benoit Rousseau, Jesse J. Smith, Jill Weiss, Lindsay Temple, Miteshkumar Patel, Callahan Wilde, Steven Maron, Yelena Janjigian, Daniela Molena, Gopa Iyer, Jonathan Coleman, Wassim Abida, Seth Cohen, Vivian Strong, Mithat Gonen, Marc Gollub, Vetri S. Jayaprakasham, Tae-Hyung Kim, Julio Garcia Aguilar, Martin Weiser, Luis A. Diaz. Non operative management of mismatch repair deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT003.

PURPOSE:To correlate rectal MRI findings with endoscopic margin status and depth of invasion in patients undergoing endoscopic submucosal dissection (ESD) for rectal adenomas and early rectal cancers. METHODS:Pre-treatment MRIs of patients with colonoscopy-detected polyps and early rectal cancer undergoing curative-intent ESD from 2018 to 2023 were re-interpreted by two radiologists (3- and 25-years' experience) blinded to outcomes. MRI features assessed included largest and smallest length, T2 signal intensity, degree of wall attachment, diffusion restriction and apparent diffusion coefficient values. The reference standard was histopathology. Associations between MRI features and outcomes were tested with Fisher's exact test and Wilcoxon rank sum test. Inter-rater agreement was assessed with kappa statistics and intraclass correlation coefficient. RESULTS:In 21 patients (median age, 64 years [interquartile range, 54-75]; 12 (57 %) female), final ESD histopathology showed 12 (57 %) adenocarcinomas and 9 (43 %) adenomas. R0 resections were achieved in 11/21 ESD procedures (52.3 %, 95 % CI: 30-74 %). Depth of invasion was correct in 6/21 and 5/21 cases (29 % and 24 %, 95 % CI: 11-52 % and 8-47 %), for 2 readers, respectively. Significant associations with R0 resection for both readers included: smaller mass size (long axis; p = 0.005, 0.003, short axis; p = 0.018, 0.022) and lower degree of wall attachment (p = 0.001, 0.011). Agreement on these three measures was good to low (ICC = 0.87, 0.80, and 0.39), respectively. CONCLUSIONS:In this hypothesis-generating exploration of MRI findings of adenomas and early rectal cancers undergoing ESD, MRI polyp size and degree of wall attachment showed strong negative associations with tumor-free resection margins.

3518 Background: Definitive chemoradiation (CRT) is a highly effective, organ-preserving treatment for localized anal squamous cell carcinoma (ASCC). However, a subset of patients experience locoregional failure, leading to unfavorable oncologic outcomes despite salvage surgery. Circulating tumor DNA (ctDNA) has emerged as a promising tool for monitoring treatment efficacy and predicting prognosis; however, there is a paucity of studies evaluating the baseline detectability and kinetics of tumor-informed ctDNA assays in ASCC. Methods: Patients with ASCC ( N =88) undergoing definitive CRT provided prospective consent for longitudinal ctDNA monitoring using a personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc.). ctDNA testing was assessed at three key time points: pre-treatment (any time before CRT to within 5 days after initiation), mid-treatment (from >5 days after initiation to <7 days before completion), and post-treatment (>7 days before completion to 42 days after CRT). Surveillance testing continued every three months. Changes in ctDNA levels were analyzed in relation to clinical outcomes. Locoregional failure (LRF) was assessed using competing risk regression, stratified by ctDNA status (positive vs. negative). ctDNA results were also correlated with progression-free survival (PFS). Results: Pre-treatment ctDNA was detected in 79% of patients, with 92% achieving ctDNA-negativity at post-treatment (Table 1). Over a median follow-up of 18 months (IQR 11–26), 7 patients experienced LRF, and 5 experienced distant failure. The cumulative LRF incidence was 0% among patients with ctDNA negativity by mid-treatment. Conversely, 26% of patients with ctDNA positivity at mid-treatment and 61% of patients with ctDNA positivity at post-treatment experienced LRF, respectively. Estimated one-year PFS was 100% for patients who achieved ctDNA negativity by mid-treatment. In contrast, patients who remained ctDNA-positive at mid-treatment and post-treatment had estimated one-year PFS rates of 81% and 44%, respectively, from the date of the corresponding ctDNA test. Among patients who achieved ctDNA negativity but subsequently developed molecular recurrence during the surveillance period ( N =7), all developed disease recurrence. Molecular recurrence predated clinical or radiographic evidence of recurrence in all instances. Conclusions: This tumor-informed ctDNA assay demonstrates high baseline detectability and rapid clearance during CRT, with molecular clearance correlating with favorable outcomes in ASCC. Notably, ctDNA-based detection of molecular recurrence consistently precedes conventional clinical and radiographic indicators of disease recurrence. Further validation in large, prospective cohorts is warranted. Pre -Treatment Mid -Treatment Post- Treatment Positive 61 (79%) 29 (47%) 6 (8%) Negative 16 (21%) 33 (53%) 67 (92%) Unknown 11 26 15

Primary perianal adenocarcinoma of intestinal type (PPAI) has been described in recent literature and proposed as a subtype of extramucosal anal adenocarcinoma. Whether this represents a unique entity remains to be elucidated. Herein, we analyzed the clinicopathologic and genomic features of 14 cases of PPAI. Fourteen patients, predominantly older adults with a median age of 73 years (range, 50-85), with a slight woman predilection (5 men and 9 women) were identified. All cases presented with pagetoid intraepithelial growth, and 9 were eventually found to have underlying invasive carcinoma at the site of the Paget disease. Clinical and radiographic evaluation failed to detect another primary site, either in the anorectal region or elsewhere, in all patients. By immunohistochemistry, all but 1 case showed an intestinal phenotype with cytokeratin 20 and caudal-related homeobox transcription factor 2 (CDX2) positivity and variable cytokeratin 7. Metastasis developed in 4 of 14 patients, including regional lymph node and distant bone metastasis. Patient survival for localized disease ranged from 29 to 176 months (median, 62 months), whereas for metastatic disease, it ranged from 13 to 75 months (mean, 31 months). Genomic profiling revealed a high frequency of TP53 mutations (86%, 12/14), ERBB2 alterations (57%, 8/14), and MYC amplification (36%, 5/14), with absence of genetic alterations typically seen in rectal adenocarcinomas, such as APC, KRAS, and BRAF. In contrast, a control group of primary extramammary Paget disease cases displayed distinct genomic features, including recurrent PIKC3A and KMT2C mutations. Treatment included surgical excision, radiation therapy, and systemic chemotherapy in metastatic cases, with radiation proving effective in preventing local recurrence among those with localized disease. In metastatic cases, chemotherapeutic regimens including capecitabine/oxaliplatin and folinic acid, fluorouracil, and oxaliplatin were employed. The absence of anorectal or other visceral adenocarcinomas along with distinct genomic findings supports the classification of PPAI as a distinct clinicopathologic entity.

A novel method for overbooking surgeon blocks was developed and successfully used in practice for years to improve operating room (OR) access while ensuring fairness through Mixed Integer Quadratic Programming. Implemented as a web tool, this approach optimizes OR utilization, contributing an additional 2–3.5% at two hospital campuses.

Objective: Assess the significance of enlarged lateral lymph nodes (LLN) for disease recurrence, metastasis, and organ preservation in patients with rectal cancer. Background: Optimal treatment of rectal adenocarcinoma involving LLN is subject to debate. Methods: A post hoc analysis of the OPRA trial, a multicenter study of patients with rectal cancer treated with total neoadjuvant therapy (TNT) followed by total mesorectal excision or watch-and-wait management. We analyzed the association of visible LLN (LLN+), LLN≥7 mm (short axis) on baseline MRI, and LLN≥4 mm on restaging MRI with recurrence, metastasis, and rectum preservation. Results: At baseline, 57 out of 324 (18%) patients had LLN+. In 30 (53%) of 57 patients with LLN+ on baseline MRI, the LLN disappeared after TNT. Disease recurrence in LLN was rare (3.5% of patients with LLN+ and 0.4% of patients with LLN−). All patients with recurrence in LLN also had distant metastasis. The rate of organ preservation was significantly lower in patients with LLN≥4 mm on restaging MRI (P=0.013). We found no significant differences in rates of local recurrence or metastasis between patients with LLN+ vs. LLN− and in patients with LLN≥7 vs.<7 mm on baseline MRI. LLN dissection was performed in 3 patients; 2 of them died of distant metastasis. Conclusions: LLN involvement is not associated with disease recurrence or metastasis, but persistence of LLN≥4 mm after TNT is negatively associated with rectum preservation in patients with locally advanced rectal cancer treated with TNT. Dissection of lateral nodes likely benefits few patients.