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3554 Background: Approximately 30% of patients (pts) diagnosed with colorectal cancer (CRC) develop liver metastases (LM). Liver is the most common organ of metastasis of CRC. The ARCAD database contains individual patient data of randomized trials that included CRC pts with initially unresectable metastases treated with systemic therapy. The aim of this study was to assess the response and survival outcomes in non-LM (NLM) vs LM across different lines of treatment. Methods: We analyzed survival outcomes of mCRC pts with either single site (SS) or multiple sites (MS) according to LM status in the following treatment groups: A: chemotherapy (CT) alone, B: CT + VEGF-antibodies, C: CT + EGFR-antibodies in KRAS wild-type tumors, within first-line (1L) and second line (2L) of therapy and D: pts enrolled on third line (≥3L) trials treated with trifluridine/tipiracil or regorafenib and placebo. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) which were assessed using Kaplan-Meier estimates and adjusted Cox models on ECOG PS, age, and gender. Results: We included 26 trials with 17924 pts. 14066 pts had LM. Pts with LM had a higher rate of colon vs rectum as primary tumor (72 vs 62%; P < .001) and less SS (31 vs 47%; P < .001) than those with NLM. OS and PFS results in subgroups are reported in the table. In groups A and B, we found better OS and PFS outcomes in NLM pts as either SS or MS in 1L and 2L. In group C from 1L, we found better survival outcomes in pts with SS LM. In pts with MS, NLM superiority was observed in OS but not in PFS. However, these results were influenced by primary tumor sidedness. In group D, better OS and PFS was observed in pts without LM than those with LM whether in pts with SS or MS. Response rates were higher in LM than in NLM in most 1L and 2L subgroups. Conclusions: LM is a poor prognostic factor for mCRC increasing from the 1L to ≥3L. Survival with CT alone and CT + anti-VEGF according to LM and NLM differs significantly in 1L and 2L but not with CT + anti-EGFR. This data justifies using LM as a stratification factor at least in ≥3L trials. [Table: see text]

3542 Background: Solid tumors can be characterized by distinct immune phenotypes based on the level of T cell infiltration in the tumor microenvironment (TME) which may provide prognostic information and also inform strategies to restore the anti-tumor immune response. Immune phenotypes were determined using an artificial intelligence (AI) algorithm in digitized whole-slide images (WSI) of tumors with deficient (d) mismatch repair (MMR) vs proficient (p) MMR. Methods: Stage III colon carcinomas (N = 401; 393 met QC) from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy were analyzed including all available tumors with dMMR (n = 196) and a randomly selected cohort of pMMR tumors (n = 195). Using an AI algorithm (Lunit SCOPE) previously trained on solid tumors, digitized tumors were categorized into three immune phenotypes based on epithelial and stromal TIL data-driven cutpoints in dMMR and pMMR (inflamed: TIL high in epithelium (> upper 25%); excluded: TIL high in stroma (>lower 25%), low in epithelium; and desert: TIL low in epithelium and stroma). Phenotypes were then examined in relationship to disease-free survival (DFS) using Kaplan-Meier methodology. Results: Of the 3 immune phenotypes in dMMR tumors, 25% were inflamed, 50% were immune-excluded, and 25% were immune-desert. Based on univariate results, multivariable modeling was performed incorporating immune phenotype in addition to age, histological grade, N stage, T stage, performance status, treatment arm, BRAF and KRAS status and identified immune phenotypes and N stage to be significantly associated with DFS. Among dMMR tumors, immune desert phenotype was associated with the poorest DFS (Desert: HR adj 1.95, 95%CI (1.01, 3.80); Excluded: HR adj 0.89, 95%CI (0.47, 1.69); Inflamed: ref; p:0.01). When compared to immune desert tumors, immune-excluded tumors had significantly better DFS (HR adj 0.49, 95%CI (0.27, 0.88), p:0.01). At a median follow-up of 60 months, 3-year DFS of patients with dMMR was 71.2% with Immune inflamed, 78.5% with Excluded, and 54.5% with Desert phenotypes. In contrast to dMMR, univariate analyses of data-driven cutpoints in pMMR tumors was not prognostic. Using a different data-driven cutpoint (15%), the revised immune phenotypes remained non-significant for DFS within pMMR tumors. Conclusions: Distinct AI-derived immune phenotypes in the TME were identified that were significantly prognostic in patients with dMMR, but not pMMR colon cancers. A data-driven immune-desert phenotype was identified in dMMR tumors that was associated with significantly poorer survival. Further investigation of the potential predictive utility of these phenotypes for immunotherapy are planned. Support: https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00079274 .

3536 Background: Early-onset colorectal cancer (eoCRC, initial CRC diagnosis at age < 50 years) has been increasing in the past two decades especially in Western countries. This study evaluates somatic and germline profiles in eoCRC compared to average-onset CRC (aoCRC, initial CRC diagnosis at age ≥ 50 years). Methods: This is a retrospective, cross-sectional study utilizing data from de-identified records of colorectal cancer patients tested with the Tempus xT assay from 2017 to 2022. Briefly, the assay is a targeted panel that detects single nucleotide variants, insertions and/or deletions, and copy number variants in 598-648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Baseline characteristics and immunologic markers were compared between eoCRC and aoCRC by Wilcoxon Rank Sum or Chi-squared test (reporting p-values). Somatic and germline mutations were compared between two age groups with false discover rate adjustments (reporting q-values). Results: In this study, 2,379 eoCRC and 8,627 aoCRC patients were included, with the majority diagnosed with stage IV disease. Additionally, germline alterations were assessed on a subset of 6,311 patients with tumor/normal match testing (eoCRC = 1,413 and aoCRC = 4,898). Left-sided primaries were more common in eoCRC (85% left/rectum in eoCRC vs. 75% left/rectum in aoCRC (p < 0.001), and rates of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) were lower compared to aoCRC (4.2% vs. 6.8%, p < 0.001). eoCRC has a unique somatic mutation profile compared to aoCRC. A higher prevalence of germline mutations was observed in eoCRC overall (6.9% vs. 5%, p = 0.006); however, no statistically significant differences were observed in individual germline genes compared to aoCRC, likely due to relatively small numbers. Conclusions: eoCRC has a unique mutational profile and presence of germline mutations in 6.9% of eoCRC, indicating a potential role for universal germline testing in CRC. [Table: see text]

3527 Background: Advances in deep learning may improve the ability to evaluate and quantify pathological features in solid tumors to improve prediction of patient disease-free survival (DFS). We used an artificial intelligence (AI) algorithm to quantify morphological features in the tumor microenvironment of stage III colon cancers. Methods: We analyzed digitized stage III colon carcinomas (N = 402; 382 met QC) from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy that included all available tumors with dMMR and a randomly selected cohort of pMMR tumors (median follow-up 60 months) [NCCTG N0147; Alliance for Clinical Trials in Oncology]. Fifteen morphological features were extracted using the QuantCRC algorithm that segments images into carcinoma (low-grade, high-grade, signet ring cell), stroma (immature, mature, and inflammatory), mucin, tumor/stroma ratio, tumor budding/poorly differentiated clusters (TB/PDC), necrosis, smooth muscle, fat, and tumor-infiltrating lymphocytes (TILs) and tumor area (mucin, epithelium and TB/PDC). Analysis of AI-derived features with clinical variables, molecular alterations ( BRAF/KRAS), and DFS were examined using Kaplan-Meier methodology and multivariable Cox regression. Results: Among the 15 AI-derived morphological features, the following differed significantly between dMMR (n = 191) and pMMR (n = 189) whereby dMMR tumors had lower mature stroma, but higher inflammatory stroma and tumor, higher tumor grade and increased mucin, TB/PDCs, signet ring cells, and TILs (all p< 0.05). Among dMMR tumors, multivariable analysis revealed that tumor area [mucin, epithelium and TB/PDC] (HR adj 0.45, 95%CI (0.24, 0.84), p:0.01, [Q2/3 vs Q1]) and N stage were the only significant and independent prognostic variables. Among pMMR tumors, multivariable analysis identified that tumor budding/poorly differentiated clusters (TB/PDCs) (HR adj 0.20, 95%CI (0.06, 0.61), p:0.01, [Q1 vs Q4]) was the strongest prognostic variable and the only morphological feature that was significantly associated with DFS along with age, N stage and T stage. Conclusions: Using AI, we can extract and quantify distinct morphological features in tumor sections that differ between dMMR and pMMR and multivariately, can significantly and robustly enhance prognostication within each MMR group. Among pMMR tumors, tumor budding/poorly differentiated clusters was the strongest predictor of DFS. Support: NIH U10CA180821, U10CA180882, U24CA196171, R01 CA210509 (to FAS). Study NCCTG N0147 received funds from Sanofi https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00079274 Key words Artificial Intelligence; Tumor Microenvironment; Colonic Neoplasms; Disease-free survival.

2049 Background: Glioblastoma (GBM) has a poor prognosis. Standard treatments are associated with systemic toxicity, further increasing the disease burden in this patient population. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell processes which affect cancer cell viability, and are generated by a portable, wearable device which is locoregional and noninvasive. TTFields therapy was approved by the FDA for the treatment of newly diagnosed (nd) and recurrent (r) GBM based on the phase 3 EF-14 (TTFields therapy 200 kHz + temozolomide) and EF-11 (TTFields 200 kHz) studies, respectively. TTFields therapy is also approved for pleural mesothelioma. We report an updated global, post-marketing surveillance (PMS) safety analysis of patients with CNS malignancies treated with TTFields therapy over an 11-year timeframe. This analysis represents the largest dataset of TTFields therapy use to date. Methods: Unsolicited safety data were collected from routine post-marketing activities for patients (N = 25,898) in North America, Europe, Middle East and Africa and Japan, from October 2011 to March 2022. AEs were stratified by diagnosis, age, and sex and categorized using MedDRA version 25.1. Results: Diagnoses were ndGBM (68%), rGBM (26%), anaplastic astrocytoma/oligodendroglioma (4%) and other (2%). Baseline demographics were reflective of real-world practice: median (range) age was 59 (3–103) years; two-thirds of patients were male. Most (69%) patients were 18–65 years; 0.4% were < 18 years, and 30% were > 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%), patients, respectively. The most common device-related AE was skin reaction (43% patients overall). There were no major differences in occurrence of this AE between pediatric, adult, and elderly groups (39%, 42%, and 45%, respectively), or between males and females (41% and 46%, respectively). The incidence of device-related skin reactions was higher in ndGBM than rGBM (46% vs 34%, respectively), in line with previous reports. Only 405 (2%) of patients overall reported an AE of treatment-related ‘quality-of-life decreased’. In line with the phase 3 studies, there were no treatment-related systemic AEs. Conclusions: In this updated global PMS safety analysis, TTFields therapy demonstrated a tolerable safety profile in patients with CNS malignancies, with no new safety findings. In line with previous real-world and clinical data, most AEs were localized, non-serious skin events, which were consistent between age groups. Such events can typically be managed easily using prophylaxis and topical therapies, together with optimization of caregiver techniques. Importantly, no TTFields therapy-related systemic AEs were detected.

1535 Background: Ambulatory management of select patients with febrile neutropenia (FN) may substantially decrease patients’ burden of illness and improve their quality of life, and is recommended by American Society of Clinical Oncology (ASCO) guidelines. However, in the United States, inpatient management remains the universal standard. We hereby report the health care utilization associated with the DEFeNDR remote patient monitoring (RPM) program, which leverages technology and virtual centralized nurse monitoring to facilitate ambulatory management of FN as an alternative to hospital-based care. Methods: Adult patients with cancer hospitalized with FN were assessed daily for eligibility to participate in the DEFeNDR program. Eligibility criteria included MASCC score >21 (per ASCO guidelines), and clinical judgment of the attending provider. Patients receiving cellular therapy (CAR-T, BMT) in the prior 100 days were excluded. Eligible patients agreeing to participate in the 30-day program were provided a kit containing cellular-enabled, pre-connected devices to facilitate monitoring, including twice-daily vital signs and electronic symptom questionnaires. Data were EHR-integrated in real-time and embedded decision trees facilitated alerts for adverse trends. RPM nurses responded to alerts and escalated care as indicated by pre-specified care pathways. Program assessment was performed at 20 weeks after full implementation. The primary outcome was the mean proportion of evaluable days spent inpatient (mPEDI) within 30 days of eligibility compared between those who participated in the program vs. those who declined. Results: 35 patients were offered participation in the DEFeNDR program. Of these, 17 participated and 18 declined. Baseline characteristics are provided. Participating patients experienced mPEDI of 6.9% (Standard Error [SE], 3.7%), compared with 17.7% (SE, 3.6%) for patients who declined participation. Due to small sample size, this difference (10.8%) did not reach statistical significance (Wilcoxon Rank Sums p-value, 0.15). 30-day mortality did not differ between groups. Mean inpatient days were also lower for patients participating in the program. Additionally, when readmitted, patients participating in RPM experienced a trend toward shorter length of stay and lower rates of intensive care unit utilization. Conclusions: A trend towards decreased burden of inpatient care is evident among patients participating in the DEFeNDR program. Further studies are warranted to assess comparative effectiveness of this model vs usual care.[Table: see text]

1509 Background: Medicaid expansion under the Affordable Care Act has been shown to increase insurance coverage and early-stage cancer diagnoses for young adults (YAs), the age group with the highest uninsured rate. We examined whether Medicaid expansion was associated with increased receipt of timely, guideline-concordant treatment and survival among YA women newly diagnosed with breast cancer, the most common YA cancer diagnosis. Methods: Using the National Cancer Database, we identified 51,675 women aged 18-39 years who were diagnosed with breast cancer in 2011-2018. We applied the difference-in-differences (DD) method to estimate outcome changes pre vs. post Medicaid expansion, in expansion- vs. non-expansion states. Linear probability models estimated associations of Medicaid expansion with receipt of guideline-concordant treatment – including any endocrine therapy among women with ER-positive or PR-positive breast cancer, and any chemotherapy or targeted therapy among women with ER-negative and PR-negative breast cancer – and initiation of guideline-concordant treatment (surgery, chemotherapy, or targeted therapy for stage I-III diagnoses, and systemic therapy for stage IV diagnoses) <60 days after diagnosis. Flexible parametric survival models were used to estimate 2-year overall survival. DD models also adjusted for age, race/ethnicity, rurality, zip code-level income, comorbidity, and diagnosis year, with standard errors clustered at the state level. Analyses were stratified by stage at diagnosis (stage I-III vs. IV). Results: Of the subset of women with stage I-III ER-positive or PR-positive breast cancer, the percentage receiving endocrine therapy increased in expansion states (85.20% pre-expansion to 86.46% post-expansion), but decreased in non-expansion states (84.32% to 82.79%), resulting in a net increase of 2.42 percentage points (ppt; 95% CI = 0.56 to 4.28) associated with Medicaid expansion in the adjusted DD model. Among all women with stage I-III breast cancer, the percentage with treatment initiation <60 days after diagnosis decreased less in expansion states (84.10% pre-expansion to 82.36% post-expansion) than in non-expansion states (86.95% to 83.98%), resulting in a net reduction of 1.61 ppt (95% CI = 0.05 to 3.18) in treatment delays associated with Medicaid expansion. Notably, the 2-year overall survival increased in expansion states (96.84% pre-expansion to 96.99% post-expansion), but decreased in non-expansion states (97.24% to 96.30%), resulting in a net survival increase of 1.00 ppt (95% CI = 0.21 to 1.79) associated with Medicaid expansion. Conclusions: Among YA women with stage I-III breast cancer, Medicaid expansion was associated with increased receipt of guideline-concordant treatment, reduced delays in treatment initiation, and improved 2-year survival.

PURPOSE The standard of care for locally advanced rectal cancer in North America is neoadjuvant pelvic chemoradiation with fluorouracil (5FUCRT). Neoadjuvant chemotherapy with fluorouracil and oxaliplatin (FOLFOX) is an alternative that may spare patients the morbidity of radiation. Understanding the relative patient experiences with these options is necessary to inform treatment decisions. METHODS PROSPECT was a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX versus 5FUCRT, which enrolled adults with rectal cancer clinically staged as T2N+, cT3N–, or cT3N+ who were candidates for sphincter-sparing surgery. Neoadjuvant FOLFOX was given in six cycles over 12 weeks, followed by surgery. Neoadjuvant 5FUCRT was delivered in 28 fractions over 5.5 weeks, followed by surgery. Adjuvant chemotherapy was suggested but not mandated in both groups. Enrolled patients were asked to provide patient-reported outcomes (PROs) at baseline, during neoadjuvant treatment, and at 12 months after surgery. PROs included 14 symptoms from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Additional PRO instruments measured bowel, bladder, sexual function, and health-related quality of life (HRQL). RESULTS From June 2012 to December 2018, 1,194 patients were randomly assigned, 1,128 initiated treatment, and 940 contributed PRO-CTCAE data (493 FOLFOX; 447 5FUCRT). During neoadjuvant treatment, patients reported significantly lower rates of diarrhea and better overall bowel function with FOLFOX while anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting were lower with 5FUCRT (all multiplicity adjusted P < .05). At 12 months after surgery, patients randomly assigned to FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function versus 5FUCRT (all multiplicity adjusted P < .05). Neither bladder function nor HRQL differed between groups at any time point. CONCLUSION For patients with locally advanced rectal cancer choosing between neoadjuvant FOLFOX and 5FUCRT, the distinctive PRO profiles inform treatment selection and shared decision making.

e16259 Background: Patients with KRAS mutant (mt) pancreatic ductal adenocarcinoma (PADC) have worse survival outcomes compared to KRAS wild-type (wt) PDAC patients. However, the prognostic implication of the KRAS mutation subtype (e.g. G12D, G12R, G12V and Q61) remains unclear. Furthermore, the clinical and molecular characteristics associated with these mutation subtypes remain not well defined. Methods: A retrospective review was conducted on patients with KRAS PDAC who underwent Next Generation Sequencing at Mayo Clinic between December 1, 2018 and December 1, 2021. Their somatic mutations, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcomes were collected via chart review. Results on KRAS wt were reported previously; KRAS mt are reported here. Results: A total of 158 KRAS mt patients (at diagnosis: average age 63.8 years, 57% male, 88 (56%) Stage IV) were included. 10% of patients had KRAS Q61 mutation, 14% G12R, 30% G12V and 46% G12D. G12R had a longer overall survival (OS) compared to the others (median 24.8 vs 17.5 months, unadjusted hazard ratio (HR) 0.68, p=0.05), particularly in patients with localized disease at diagnosis (median 35.4 vs 28.3 months, p=0.08). Among patients with metastatic disease at diagnosis, G12V had the lowest OS (median 9.8 vs 12.4 months, unadjusted HR 1.8, p=0.02). 137 (87%) patients had at least one pathogenic somatic variant, with statistically significant differences in SMAD4, TP53, MYC, RB1, KMT2D, RBM10, RNF43, KDM6A, KMT2C, RBM10, LRP1B, PIK3CA, and SMARC among the KRAS mt subtypes. 82 (52%) patients had at least one RNA expression variant, with statistically significant differences in CCND1, CCNE1, HRAS, MET, EGFR, and ERB3 among KRAS mt subtypes. Between these subtypes, there were no statistically significant differences in TMB value, location of PDAC or subsequent metastasis, lines of treatment (average 2.3), age at diagnosis, or gender. Conclusions: KRAS mt subtypes may confer different PDAC phenotypes. In our cohort, G12R is associated with improved OS while G12V correlates with worse prognosis in de novo metastatic disease. Additionally, there are differences in genomic variations and RNA expression between the KRAS mt subtypes. To further examine this, transcriptomic analysis is underway. [Table: see text]