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4584 Background: EVP is the preferred frontline regimen in pts with aUC. Despite initial response to treatment, many pts treated with EVP ultimately have progression. We hypothesized that recurrence patterns would differ between pts with and without baseline liver metastases. Methods: UNITE is a multi-institutional retrospective database capturing clinical and treatment characteristics of pts with aUC receiving systemic therapies. We queried this database to identify pts who achieved an observed response (OR) to EVP. Pts were grouped by initial metastatic sites using a non-mutually exclusive approach. Descriptive statistics were used to summarize observed response rates (ORR) and recurrence patterns at time of progression. Progression-free survival (PFS) from start of EVP was estimated using the Kaplan-Meier method. The effect of liver metastases on PFS was assessed via multivariable Cox regression. Median-follow up time was estimated using the reverse Kaplan-Meier method. Statistical analyses were conducted in RStudio. Results: We identified 464 pts treated with EVP (median age 72; 74% male, 80% White). Best ORR in pts with baseline liver metastases (n=77) were complete response 9%, partial response 35%, stable disease 18%, and progressive disease 21%, compared with 18%, 37%, 27%, and 18%, respectively, in pts without baseline liver metastases (n=325). The estimated median follow-up time was 52 weeks (95% CI 48-62). Among pts with initial OR to EVP, those with baseline liver metastases showed a non-significant trend toward shorter PFS (HR 1.35; 95% CI 0.67–2.75; p=0.40) versus those without baseline liver metastases. Among pts with initial OR to EVP and subsequent progression the distribution of sites of recurrences at progression for those with (n = 10) and without (n = 40) baseline liver metastases were: liver (50% vs. 10%), lymph nodes (60% vs. 55%), lungs (50% vs. 38%), bone (20% vs 20%), and primary tumor (20% vs 25%). EVP responders with baseline liver metastases had a numerically higher rate of site-specific metastasis resolution at progression versus those with lymph node or lung metastases (Table). Conclusions: Our analysis suggests that liver metastases may be associated with shorter PFS among EVP responders, though these pts frequently do not retain liver metastases at time of progression. Study limitations include retrospective analysis, investigator-assessed response, small sample size, selection and confounding biases. Patterns of recurrence following EVP merits further evaluation. Metastatic Site Pts with Site-Specific Baseline Metastases (n) Pts with Resolution of Site-Specific Metastases at Progression, n (%) Pts without Baseline Metastases at Site (n) Pts who Remained Free of Site-Specific Metastases at Progression, n (%) Liver 10 5 (50%) 40 36 (90%) Lymph Nodes 37 12 (32%) 13 10 (77%) Lungs 26 8 (31%) 24 22 (92%)

4565 Background: EVP is the preferred 1 st -line regimen for patients (pts) with aUC. EV-related toxicities are often managed with dose adjustments, such as reductions and holds. Analysis of EV monotherapy trials showed consistent survival outcomes despite dose adjustments. We hypothesized that on-treatment EV dose adjustments would not impact survival in these pts. Methods: Pts with aUC treated with EVP in the multisite UNITE study were analyzed. Early dose reductions (DR) and holds were defined as occurring < 9 weeks from EVP start, with the remainder classified as late. Pts with DR at treatment start were excluded. Survival endpoints were progression-free survival (PFS) and overall survival (OS) from EVP start, assessed by Kaplan-Meier analysis and Cox models. Multivariable Cox analysis (MVA) included age (≥ 75 vs < 75), ECOG performance status (0-1 vs 2-3), Hgb level (< 10 vs ≥ 10) and liver metastases (present vs not). A time-dependent covariate was used to reduce immortal time bias. Complementary MVA landmark analyses were performed, aligned to the total number of treatment cycles received, with six analyses from cycles 2 to 7. Results: 360 pts from 17 sites were included (median age 70; 78% Caucasian; 76% male; 27% upper tract primary; 35% histology subtype component; 17% with liver metastasis; 78% frontline); median follow-up was 11.7 months (95% CI [10.79, 13.08]). Median number of cycles was 6 in pts with DR and 3 with no DR. Early DRs (100 pts [28%]) and holds (18 pts [5%]) were most commonly due to rash (28% of all early DRs and holds). Late DR (75 pts [21%]) and holds (50 pts [14%]) were most commonly due to neuropathy (52% of all late DRs and holds). Pts with early or late DR had longer PFS and OS vs those who did not (Table); however, there was no significant PFS or OS difference with dose hold vs no hold (PFS HR 0.65, 95%CI (0.40, 1.05), p = 0.08; OS HR 0.70, 95%CI (0.39, 1.27), p=0.24). In landmark analyses, about 50% of pts had DR; no significant difference in PFS or OS was observed at most landmarks, except for longer OS in the DR cohort at cycle 4 (HR 0.53, 95% CI (0.29, 0.98), p = 0.042) and cycle 5 (HR 0.43, 95% CI (0.19, 0.99), p = 0.048). Conclusions: In this real-world retrospective analysis, EVP efficacy was maintained despite DR and dose holds. Survival difference noted in the time-dependent analyses were not consistently reproduced in landmark analyses, suggesting exposure-related selection bias rather than causal effect. Prospective studies are warranted to validate these hypothesis-generating findings. Association of EV DR with PFS/OS (time-dependent analyses). Early DR Late DR DR vs no DR outcomes UVAHR (95% CI), p MVAHR (95% CI), p UVAHR (95% CI), p MVAHR (95% CI), p PFS 0.50 (0.35, 0.72), <.001 0.56 (0.38, 0.84), 0.005 0.32 (0.21, 0.49), <.001 0.36 (0.23, 0.57), <.001 OS 0.51 (0.32, 0.79), 0.003 0.57 (0.35, 0.92), 0.022 0.26 (0.15, 0.45), <.001 0.31 (0.17, 0.55), <.001

4515 Background: Adenocarcinomas of the urinary tract are rare malignancies with limited prospective data. Outcomes of triplet chemotherapy remain poorly defined. Methods: This was a prospective, single-arm, phase II study (NCT00082706) conducted at MD Anderson. Between 2005 and 2010, patients (pts) aged ≥18 years with ECOG 0–2 and metastatic or unresectable urachal (UA) or non-urachal adenocarcinoma (NUA) received frontline GemFLP (5-fluorouracil 200 mg/m² continuous infusion ×5 days with leucovorin 23 mg IV daily ×5; cisplatin 20 mg/m² IV daily ×5; gemcitabine 200 mg/m² IV on days 1 and 5). Best overall response (BOR) was assessed by imaging. Primary endpoints were objective response rate (ORR) and overall survival (OS); secondary endpoint was toxicity. PFS was calculated from treatment initiation and duration of response (DoR) from first CR/PR to progression or death; time-to-event endpoints were estimated by Kaplan–Meier (KM). Post hoc analyses evaluated baseline tumor markers (CEA, CA19-9, CA125, β-hCG) Treatment-related adverse events (TRAEs) were graded per CTCAE v5. Results: Forty-six pts were enrolled (28 UA, 18 NUA). Median age was 58 years; 41% were de novo metastatic, and 78% had visceral metastases. ORR was 44% (20/46). Among responders, median DoR was 8.6 months (95% CI 4.6–30.8). median PFS was 3.3 months (95% CI 2.3–8.4) and median OS (mOS) was 21.0 months (95% CI 15.9–35.3) There was no difference in PFS (p=0.39) or OS (p=0.99) between UA and NUA. Baseline CEA, CA19-9, CA125, and β-hCG were not associated with ORR or PFS. Higher baseline CA125 was associated with inferior OS (HR 1.33, 95% CI: 1.12–1.58; p =0.001) Subsequent systemic therapy was administered to 28 pts (60.9%); median number of subsequent treatment lines was 2 (range 1–5). The most common hematologic TRAEs were anemia (28.1%; grade ≥3 [G3] 12.5%), thrombocytopenia (21.9%; G3 12.5%), and neutropenia (12.5%; G3 9.4%). The most frequent non-hematologic TRAEs were dehydration (21.9%; G3: 6.2%), diarrhea (9.4%; G3 6.2%) and catheter-related thrombosis (9.4%; G3 9.4%). No grade 5 events occurred. Conclusions: In this prospective phase II study, frontline GemFLP achieved a 44% ORR with durable responses (mDoR 8.6 mo) and 21 mo mOS in advanced UA and NUA. Survival did not differ between UA and NUA subtypes. Baseline CA125 was associated with OS. Toxicity was manageable. These data provide a prospective benchmark for this rare disease. Clinical trial information: NCT00082706 . Variable UA (n=28) NUA (n=18) Characteristics Age, median [ICR] 58 [54– 62] 58 [54– 62] 67 [ 62-72] Race, n (%) White 22 (79) 11 61) Black 6 (21) 6 (33) Other 0 1 (6) Prior surgery for localized disease, n (%) 18 (64) 5 (28) Mets at baseline Any 24 (86) 7 (39) Lung 6 (21) 4 (22) Liver 3 (11) 0 Peritoneum 17 (61) 0 Bone 3 (11) 3 (17) Nodal-only mets 1 (3) 2 (10) Outcomes ORR (%) 43.5 35.7 55.6 BOR n (%) CR 4 (14) 2 (11) PR 6 (21) 8 (44) SD 11 (39) 4 (22) PD 6 (21) 3 (17) NE 1 (4) 1 (6)

Triple-negative breast cancer (TNBC) represents a biologically aggressive subtype with limited therapeutic targets; however, tumor-infiltrating lymphocytes (TILs) have emerged as the most robust immune biomarker with compelling prognostic and predictive significance. This comprehensive review synthesizes current evidence on TIL assessment methodology; the immunobiological landscape of TNBC, including regulatory T cell populations and PD-L1 correlations; gene expression underpinnings of the tumor immune microenvironment; and systematic evidence from meta-analyses and clinical trials. Meta-analytic estimates demonstrate that high TIL levels are associated with improved overall survival (HR 0.58, 95% CI 0.48–0.71) and disease-free survival (HR 0.66, 95% CI 0.57–0.76), with each 10% TIL increment conferring incremental benefit. High TILs predict superior pathologic complete response to neoadjuvant chemotherapy (OR 2.14, 95% CI 1.43–3.19), with lymphocyte-predominant breast cancer achieving pCR rates exceeding 80% with pembrolizumab-based chemoimmunotherapy. Future directions include prospective TIL-guided treatment trials, artificial intelligence-enabled standardization, and emerging adoptive TIL cellular therapies for metastatic disease.

PURPOSE Remote symptom monitoring using patient-reported outcomes (PROs) has been shown to improve symptom control and physical function among patients with advanced cancer. However, it is unclear whether these benefits are similar across demographic groups. This exploratory analysis of the PRO-TECT trial examined whether the effects of electronic symptom monitoring varied by race, age, sex, and educational attainment. METHODS PRO-TECT was a cluster randomized trial conducted across 52 US community oncology practices comparing weekly electronic symptom monitoring with usual care (UC). Adult patients with metastatic solid tumors receiving systemic therapy were enrolled (N = 1,191). Participants in the PRO arm completed weekly symptom surveys including the PRO-CTCAE, triggering alerts to the care team for severe or worsening symptoms. Patients chose whether to complete weekly PROs online or via telephone-based interactive voice response not requiring Internet access. Outcomes were measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 symptom control and physical function scales. Subgroup analyses were performed by race (Black v White), age (<65 v ≥65 years), sex (male v female), and educational attainment (≤high school v >high school). RESULTS From baseline to 3 months, PRO participants showed greater improvements in symptom control (+2.37 v −0.20, P = .002) and physical function (+1.54 v −0.93, P = .02) versus UC. Benefits were most pronounced among younger, female, Black, and less educated participants. Black participants in the PRO arm were more likely to report that symptom reporting made them feel more in control of their care compared with White participants. CONCLUSION Electronic symptom monitoring improved quality-of-life outcomes overall, including among groups who have historically experienced higher symptom burden or barriers to communication. Remote PRO systems may represent an equitable strategy to enhance cancer care delivery.

Abstract Background: Up to 50% of patients with breast cancer experience chemotherapy-inducednausea (CIN) and 95% experience fatigue. A comprehensive understanding of biological mechanisms remains elusive. Herein, we evaluated the association of CIN and fatigue with clinical and multi-omics features, including serum and stool metabolites before (T1) to after chemotherapy (T2). Methods: Patients with breast cancer (n=36) who were to receive chemotherapy, provided symptom assessment using the Memorial Symptom Assessment Scale, stool and blood samples at T1 and T2. Patients provided dietary intake data using a Dietary Screener Questionnaire at T1. Descriptive and univariate analyses evaluated associations of co-occurringsymptoms and diet with CIN and fatigue at T2. Gut microbiome was sequenced using shotgun metagenomics. Targeted metabolomics was performed on stool and serum. Shift in the abundance of taxonomic groups and metabolite levels from T1 to T2 were evaluated in association with CIN and fatigue. Results: Approximately 64% of the patients experienced CIN and 94% experienced fatigue atT2. Three gastrointestinal symptoms co-occurred with CIN and fatigue. Higher daily average intake of calcium (p=0.013) and dairy (p=0.035) were associated with CIN. Levels of hexosylceramides, ceramide, phosphatidylcholine and sphingomyelins were significantly perturbed in association with CIN and fatigue (p&lt;0.05). Conclusion: CIN and fatigue are associated with perturbation in the sphingolipid turnover pathway, which negatively impacts functions in the gut-liver axis that include apoptosis activity and change in bile acid levels. Confirmatory studies are warranted to support the development of interventions to alleviate CIN and fatigue in patients with breast cancer receiving chemotherapy.Keywords: breast cancer; chemotherapy-induced nausea; fatigue; metabolites; sphingolipids Citation Format: Komal Preet Singh, Brenda J. Ernst, Jun Chen, Surendra Dasari, Felipe Batalini, Cindy Tofthagen, Kathryn J. Ruddy, Keenan Pituch, Linda Chlan. Perturbations in gut liver axis functions are associated with chemotherapy induced nausea and fatigue in patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6309.

ABSTRACT Background Chemotherapy‐induced peripheral neuropathy (CIPN), characterized by loss of sensation and impaired physical function, is a prevalent and debilitating side effect of chemotherapy, affecting 30%–50% of breast cancer survivors (BCS) with effects lasting years after treatment completion. Mindfulness‐based interventions are shown to be efficacious in reducing symptoms in neuropathies. This subgroup analysis examined the effect of Mindfulness‐Based Stress Reduction on Breast Cancer (MBSR(BC)) compared to Breast Cancer Education Support (BCES) or Usual Care (UC) on CIPN among BCS who received chemotherapy or chemotherapy and radiation. Methods BCS ( n = 114) were randomly assigned to the 6‐week MBSR(BC) ( n = 48), BCES ( n = 52), or UC ( n = 14) regimen. Demographic and clinical data were assessed at baseline, and CIPN was assessed using the Chemotherapy‐Induced Peripheral Neuropathy assessment tool (CIPNAT) at baseline, 6, 12, and 26 weeks. Between‐ and within‐group differences were evaluated and change over time was compared between groups. Results BCS (mean age = 52.7 years, range: 28–81 years) were primarily White and non‐Hispanic ( n = 78, 68%). The pattern of effect sizes was similar for CIPNAT symptoms and interference with improvements in CIPN for MBSR(BC) and BCES groups overtime. For both groups, the effects were larger compared to the UC. Differences tended to increase over time with significant effects observed between MBSR(BC) and UC, and between BCES and UC at weeks 12 and 26. Conclusions The findings indicate that MBSR(BC) and BCES may effectively reduce CIPN symptoms among BCS compared to UC. MBSR(BC) and BCES programs are effective non‐pharmacological interventions for CIPN that may translate into practice.

794 Background: HER2 protein, encoded by ERBB2 gene, is the target of emerging therapies for patients (pts) with advanced urothelial carcinoma (aUC). High HER2 IHC expression (IHC 3+) is present in ~15% of pts with aUC, while >50% of pts have HER2 IHC 1+/2+/3+ expression. EVP is the preferred 1 st line regimen for pts with aUC, but the impact of HER2 status on EVP outcomes is unclear. Methods: We identified pts from the UNITE study with tumor samples tested for HER2 by IHC and another cohort with next-generation sequencing (NGS) data available. Outcomes were compared by HER2 IHC status (HER2 IHC 0/1+ vs 2+/3+) and separately based on ERBB2 status (alteration vs wild-type). X 2 test was used to compare observed response rate (ORR) and logistic regression was used to compare disease control rate (DCR). Duration of response (DOR), progression-free survival (PFS) and overall survival (OS) from EVP start were evaluated using log-rank test and Cox proportional hazards models. Multivariate analysis (MVA) included age, sex, race, ECOG PS, neutrophil:lymphocyte ratio, albumin, hemoglobin, primary tumor site, tumor histology, prior lines of treatment, and metastatic sites as covariates. Results: Among 521 pts treated with EVP from 16 sites, 112 had HER2 IHC data and 313 had NGS. Median age was 71, 74% were men, 84% Caucasian, 82% had ECOG PS 0-1, 65% pure urothelial histology, and 73% received frontline EVP. HER2 IHC distribution (n=112) was 27%/21%/37%/15% for 0/1+/2+/3+, respectively. ERBB2 alterations were present in 14% (44/313). Baseline characteristics were similar in HER2 0/1+ and 2+/3+ pts, except more primary bladder tumors in 2+/3+ pts (83% vs 63%, p=0.01). For the overall cohort (n=521), with a median follow up of 7.3 mos from EVP start, ORR was 54%, DCR 81%, median DOR (mDOR) 8.5 mos, median PFS (mPFS) 8.5 mos, and median OS (mOS) 19.8 mos. Pt outcomes by HER2 IHC status are shown (Table). In univariate analysis (UVA), pts with HER2 IHC 0/1+ had longer mOS compared to HER2 IHC 2+/3+, but this was not significant in MVA (HR: 0.5; CI: 0.2–1.3, p=0.17). No significant differences were observed in other outcomes. Evaluating clinical outcomes by ERRB2 status, no significant differences were seen for ERBB2 -altered vs wild-type pts. Conclusions: In this retrospective study, no significant differences were seen in EVP treatment outcomes based on HER2 IHC status or ERBB2 status. These findings are hypothesis-generating and require validation in larger and prospective cohorts. HER2 0/1+ (n=54)* HER2 2+/3+ (n=58) OR (95%CI, p) HR UVA (95%CI, p) HR MVA (95%CI, p) ORR 49% (23/47) 55% (27/49) 1.3 (0.6-2.9, p=0.5) - - DCR 79% (37/47) 88% (43/49) 1.9 (0.7-6.2, p=0.2) - - mDOR 11.7 mos 10.4 mos - 1.3 (0.7-2.4, p=0.4) 1.2 (0.4-3.3, p=0.8) mPFS 5.9 mos 7.1 mos - 0.8 (0.5-1.4, p=0.5) 1.1 (0.5-2.5, p=0.9) mOS 42.4 mos 18.7 mos - 2.3 (1.1-4.5, p=0.02) 2.0 (0.8-5.4, p=0.2) *HER2 0/1+ used as reference.

696 Background: EVP is the preferred 1st-line therapy for patients (pts) with aUC. Upfront EV dose reductions may be utilized to enhance tolerance and minimize treatment-related toxicities when intolerance is anticipated. Prior studies of EV monotherapy suggest that starting dose 1.25 mg/kg resulted in exposure that maximized chance of response. We hypothesize that upfront EV dose reductions would not compromise EVP efficacy. Methods: Pts with aUC treated with EVP in the multi-site UNITE database were analyzed. Upfront dose reduction was defined as starting dose < 1.25 mg/kg. Correlation between clinical features and EV dose reduction were assessed using Fisher’s Exact test. Endpoints include progression-free survival (PFS) and overall survival (OS) from EVP initiation, assessed by Kaplan-Meier analysis and Cox models. Multivariable Cox analysis (MVA) included age (< 75 vs ≥ 75), ECOG performance status (PS) (0-1 vs 2-3), hemoglobin level (< 10 vs ≥ 10), and liver metastases (present vs absent), chosen in accordance with Bellmunt criteria. Correlation with investigator-assessed observed response rate (ORR) was determined using logistic regressions. All tests were 2-sided with p < 0.05 considered significant. Results: A total of 456 pts across 17 sites were included (median age 72; 77% Caucasian; 75% male; 26% upper tract primary; 66% pure UC; 77% ECOG PS 0-1; 17% with liver metastasis; 89% 1 st line EVP). Upfront dose reduction occurred in 96 pts (21%); 76 pts (79%) started at 1.0 mg/kg and 20 pts (21%) at 0.75 mg/kg. Upfront dose reduction was significantly associated with age ≥ 75 (p = 0.002), ECOG PS 2/3 (p = 0.04), and hemoglobin < 10 (p = 0.01) but not with liver metastasis (p = 0.9). Lower starting EV dose correlated with shorter median PFS (5 vs 6 months) and OS (9 vs 10 months), and lower ORR (28% vs. 60%) when compared to full dose (Table). In MVA adjusting for prognostic factors for PFS and OS, these associations were no longer statistically significant. Conclusions: In this real-world analysis, upfront EV dose reductions were most frequently used in pts with factors associated with frailty and poor prognosis, e.g. older age and ECOG PS 2/3, and were associated with lower ORR. When adjusted for these factors, upfront EV dose reductions were not associated with shorter PFS/OS though a trend towards inferior outcomes persisted. These differences in outcomes may reflect baseline risk factors rather than dose intensity; however, prospective investigation is required to validate our hypothesis-generating results. Association of upfront EV dose reduction with outcomes. Outcome (Upfront dose reduction vs no upfront dose reduction) Univariable analysis Multivariable analysis PFS: HR (95% CI), p 1.50 (1.11 – 2.02), 0.008 1.33 (0.95-1.86), 0.09 OS: HR (95% CI), p 1.56 (1.11-2.20), 0.01 1.41 (0.96-2.06), 0.08 ORR: OR (95% CI), p 0.35 (0.21-0.60), 0.0001 0.38 (0.21-0.67), 0.0009