USC Norris Comprehensive Cancer Center

To evaluate the effects of ambient air pollution on rheumatoid arthritis (RA) incidence in a racially and ethnically diverse population. This analysis included 42,152 California Multiethnic Cohort participants, aged ≥65 years (>70% African American and Latino adults) who were enrolled in the Fee For Service component of Medicare (2001-2018). We employed multivariable Cox proportional hazards regression to examine the associations of time-varying air pollutants based on spatiotemporal models with RA incidence (n=2,027) after adjusting for demographics, neighborhood socioeconomic status, smoking, work, and other exposures. RA incidence increased with exposure to fine particulate matter (PM) with diameter ≤2.5 μm (PM2.5) (hazard ratio [HR] per 2 μg/m3=1.20 [95% confidence interval (CI) 1.16-1.23]) and nitrogen dioxide (NO2) (HR per 10 μg/m3=1.44 [95% CI 1.35-1.52]). Air pollutant levels and risk associations were higher in African American and Latino than in Japanese American and White adults (Pheterogeneity < 0.05). The RA-PM2.5 association was higher in men (HR 1.23 [95% CI 1.15-1.32]) than in women (HR 1.17 [95% CI 1.12-1.21]; Pheterogeneity=0.06). RA associations with PM2.5 (and NO2) did not differ by demographics, smoking, or other lifestyle factors, but the HR associated with PM2.5 was higher among those with high-risk work (longest occupation in labor/craftsman work and exposed to ≥10 years in one or more of 13 industries; HR 1.29 [95% CI 1.18-1.41]) than those without high-risk work exposures (HR 1.16 [95% CI 1.12-1.21]; Pheterogeneity=0.04). Exposure to PM and gaseous pollution associates with increased RA incidence after age 65 years, particularly among African American and Latino adults. Further characterization of air pollution's contribution to racial and ethnic disparities in RA risk is warranted.

Role of labor induction requiring cervical preparation for full-term, low-risk pregnant patients is under active investigation. The objective of this study was to describe nationwide temporal trends, characteristics, and outcomes associated with labor induction requiring cervical preparation at full-term gestation for low-risk pregnant patients in the United States. This cross-sectional study queried the Agency for Healthcare Research and Quality mechanism's Healthcare Cost and Utilization Project National Inpatient Sample. Study population included 5,003,348 hospital deliveries at 39-406/7weeks' gestation for singleton, cephalic low-risk pregnancy from 2018 to 2022, excluding historically known presumed pre-labor pregnancy risk factors. Exposure was labor induction status, defined as the performance of cervical preparation (ripening or mechanical dilation), with or without adjunctive intervention (artificial rupture of membranes or oxytocin administration). Main outcome measures were set as cesarean delivery as the primary outcome; induction failure, chorioamnionitis, umbilical cord prolapse, in-labor uterine rupture, postpartum hemorrhage, severe maternal morbidity and mortality as the secondary outcomes, assessed with multivariable generalized linear model. A total of 618,785 (12.4%) deliveries had labor induction requiring cervical preparation. The rate increased from 8.8 to 14.4% between QT1/2018-QT2/2020 (P-trend < .001), at which the rate started gradually decreasing when the COVID-19 pandemic occurred (14.4% at QT2/2020 to 13.4% at QT4/2022, P-trend = .04). The majority of cervical preparation was ripening alone (69.9%), followed by mechanical dilation alone (20.7%) and both ripening and mechanical dilation (9.4%). During the 5-year study period, cervical preparation with mechanical dilation alone (14.4% to 26.9%) and both ripening and mechanical dilation (4.6% to 11.4%) increased (both, P-trend < .001); adjunctive use of both oxytocin and artificial rupture of membranes (18.7% to 27.0%) and oxytocin alone (15.0% to 18.8%) increased while artificial rupture of membranes alone decreased (29.5% to 23.0%) (all, P-trend < .001). When compared to 4,384,563 deliveries without labor induction cervical preparation, induction was associated with cesarean delivery (17.1% vs 9.2%, adjusted-incidence rate ratio [aIR] 1.75, 95% confidence interval [CI] 1.74-1.76), chorioamnionitis (3.2% vs 1.9%, aIR 1.67, 95%CI 1.64-1.69), umbilical cord prolapse (0.2% vs 0.1%, aIR 1.67, 95%CI 1.58-1.77), in-labor uterine rupture (21.8 vs 7.8 per 100,000, aIR 2.66, 95%CI 2.17-3.25), postpartum hemorrhage (5.7% vs 3.9%, aIR 1.42, 95%CI 1.40-1.44), severe maternal morbidity (0.4% vs 0.2%, aIR 1.61, 95%CI 1.54-1.68), and maternal mortality (4.8 vs 0.7 per 100,000, aIR 7.34, 95%CI 4.37-12.33). In conclusion, this nationwide cross-sectional assessment suggests the increasing trend of full-term labor induction for study-defined low-risk pregnancy may have stopped during the COVID-19 pandemic in the United States. The observed association with cesarean delivery and adverse outcomes related to labor induction requiring cervical preparation warrant further investigation.

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TPS292 Background: Neuroendocrine differentiated prostate cancer (NED PCa) is an aggressive form of prostate cancer with few treatment options and a poor prognosis. There is evidence that NED PCa and advanced castration resistant prostate cancers (CRPC) overexpress the somatostatin receptor (SSTR), which can be targeted with Lu-177 DOTATATE, a radiopharmaceutical therapy that improves survival in neuroendocrine tumors of the midgut. We are conducting a phase II trials investigating Lu-177 DOTATATE in NED PCa. Methods: This is a phase II trial run through the National Cancer Institute’s (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN). Key inclusion criteria include evidence of neuroendocrine differentiation by histology (i.e. small cell carcinoma or positivity for synaptophysin or chromogranin A), molecular features (TP53, PTEN, and/ or RB1 loss), serum markers (chromogranin A or neuron-specific enolase), or clinical factors (progression of visceral metastases in the absence of PSA progression). Patients must have a positive Ga-68 DOTATATE PET/CT to proceed with Lu-177 DOTATATE therapy, defined as at least 1 lesion with a maximum standardized uptake value (SUV max ) greater than the mean SUV of normal liver. The primary objective for the trial is objective response rate (ORR), defined by Prostate Cancer Working Group 3 (PCWG3) criteria. Secondary objectives include 6-month radiographic progression-free survival as well as the correlation between ORR and change in fluorodeoxyglucose PET/CT signal pre- to mid-treatment. Exploratory objectives include SPECT/CT-based dosimetry of Lu-177 DOTATATE and gene expression analysis of circulating tumor cells collected prior to treatment, during treatment, and at time of progression. A pre-specified activity goal for the first 15 enrolled patients was met, and accrual of an additional 10 patients is currently in progress. Clinical trial information: NCT05691465 .

TPS897 Background: Current guidelines recommend radical cystectomy for High-Risk, BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (HR BCG-UR NMIBC). However, many patients are unwilling or unfit for this intervention due to medical risks. Thus, there is a need for effective, well-tolerated, and accessible bladder-sparing treatments. Cretostimogene grenadenorepvec is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Retinoblastoma (Rb)-E2F pathway alterations, while simultaneously amplifying an anti-tumor immune response, further mediated by the GM-CSF transgene. Results from the Phase 3 BOND-003 study led to cretostimogene receiving Fast Track and Breakthrough Therapy Designations by the US FDA for BCG-UR NMIBC with CIS. The cretostimogene Expanded Access Program (CRETO-EAP) (NCT06443944) an open-label, expanded access clinical trial provides cretostimogene to real-world patients who may not qualify for current clinical trials or are unable to access or tolerate currently available options. Methods: The eligibility criteria are pragmatic and inclusive of the at-risk population seen in real-world practice: ECOG PS 0-3, pathologically confirmed BCG-UR CIS +/- Ta/T1 after completion of adequate BCG treatment. The protocol has been amended to improve flexibility and include patients who received prior therapies for HR BCG-UR NMIBC, including investigational agents. Intravesical cretostimogene is administered in combination with n-dodecyl-β-D-maltoside (DDM), an excipient that enhances adenoviral delivery for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through Month 12, then biannually through Month 24. Re-induction is permitted. Additionally, patients with partial response, defined as persistent but improved disease at Week 25 or subsequent timepoints, may receive continued 3-weekly doses of cretostimogene at the discretion of the investigator. As per routine NMIBC surveillance, primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and bladder biopsies when clinically indicated, with pathologic samples reviewed locally. Co-primary endpoints include safety and complete response at any time. The incidence of adverse events will be reported using the Medical Dictionary for Regulatory Activities (MedDRA) and CTCAE v5.0. Secondary outcomes include Duration of Response, Progression-Free Survival, Cystectomy-Free Survival, Patient Reported Outcomes and Health-Related Quality of Life measures. A broad cross-section of geographically diverse clinical sites that serve socioeconomically diverse patients has been identified. The study is actively enrolling, with initial patients treated. Clinical trial information: NCT06443944 .

756 Background: Standard of care treatment for HR NIMBC includes TURBT followed by intravesical BCG. However, high recurrence rates and BCG shortages highlight the need for effective, well-tolerated, and readily available treatment options. Cretostimogene grenadenorepvec is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Retinoblastoma (Rb)-E2F pathway alterations, while simultaneously amplifying anti-tumor immune response, further mediated by the GM-CSF transgene. CORE-008 (NCT06567743) is a Phase 2, multi-arm, multi-cohort trial evaluating the efficacy and safety of intravesical cretostimogene in patients with HR NMIBC. Methods: Cohort A includes patients age ≥18 years, ECOG PS of 0-2, with pathologically confirmed HR NMIBC with CIS and who are BCG-naïve (no prior BCG, BCG administered &gt; 24 months ago, or receipt of only 1-2 BCG doses within the past 24 months). Patients receive intravesical cretostimogene for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through Month 12, then every six months through Month 36. Re-induction is permitted at Month 3, if persistent HG Ta and/or CIS is noted at biopsy. Response assessments included urine cytology, serial cystoscopy with directed biopsy, and axial imaging (as indicated). The primary endpoint is Complete Response (CR) at any time. Enrollment is complete. Results: As of the September 1, 2025 data cut off, 54 patients in Cohort A received treatment with intravesical cretostimogene. 88.8% of participants were 65 years of age or older, 9.3% are female, and 18.5% have an ECOG PS of 1. Baseline disease characteristics demonstrate CIS alone in 44.4%, CIS + HGTa in 31.5%, and CIS + T1 in 24.1%. 53 (98.1%) patients completed induction with 49 assessed for efficacy. Median exposure of the cohort is 15.3 weeks (range 1.1, 41.0 weeks). The CR rate at any time in evaluable patients is 83.7% (41/49) (95% CI 70.3-92.7%). No patients progressed to MIBC or metastatic disease. The safety and tolerability profile of cretostimogene is consistent with prior clinical trials with this agent. The most common adverse events are low grade and localized to the bladder. There are no related Serious Adverse Events, Grade 3+ adverse events or treatment related discontinuations. To date, only 3.7% (2/54) of patients required a dosing delay due to a related adverse event; however, none of these delays resulted in missed doses. Further, updated data will be presented. Conclusions: Cretostimogene has promising clinical efficacy and safety in patients with high-risk, BCG-naïve NMIBC. These findings support the further development of cretostimogene in other early, HR NMIBC disease states. Currently, additional treatment arms are planned for patients with BCG-naïve NMIBC. Clinical trial information: NCT06567743 .

Abstract Introduction: Many people with metastatic breast cancer (MBC) experience life-limiting side effects from MBC treatments, with most patients remaining on treatment indefinitely. While supportive medications are often used to mitigate toxicities, they may introduce additional side effects and financial cost. Individualized dosing, particularly dose reductions and frequency adjustments, is a strategy to improve tolerability with the goal of maintaining treatment efficacy. The objective of this study was to elicit MBC patient experiences with treatment toxicity, including dosing strategies and side effect management. Methods: As a follow up to a 2020 survey to characterize real-world experiences with dosing strategies (Loeser et al. 2024), the Patient-Centered Dosing Initiative (PCDI) conducted a new cross-sectional survey to elicit patient experiences and preferences related to toxicity management. The survey, distributed electronically to a convenience sample of people living with MBC in the United States, combined closed and open-ended questions. Recruitment occurred through support organization e-mail lists and newsletters, as well as closed social media groups. The survey included items associated with side effect management, knowledge and experiences of dose modifications, and supportive medication use among other topics. The survey opened April 14th 2025 and data were pulled on June 22nd for analysis, although data collection is still ongoing. Descriptive statistics, including frequency counts and percentages, were used to summarize participant responses. Associations between knowledge of dose modifications and care primarily by a breast specialist were evaluated using chi-squared tests. Results: As of the abstract submission, 340 responses were available for analysis. Surveyed patients reported all treatment drugs taken in the metastatic setting, including cytotoxic chemotherapy (35%), CDK 4/6 inhibitors (62%), HER2-targeted antibodies (24%), antibody-drug conjugates (23%), and PI3K pathway inhibitors (11%). Of the 26% who started an MBC drug at a lower dose, 69% reported that the oncologist initiated the conversation and 16% said they initiated it themselves. There was no statistically significant difference in who initiated the conversation based on whether the participant was primarily treated by a breast specialist or not (p=0.43). Overall, 57% of the respondents had their dose reduced due to side effects, whether they started at full or reduced dose, and 72% felt better on the lower dose. In addition, 27% of patients reported that their oncologist reduced the frequency of drug administration; 67% of these patients felt better with the reduced frequency. 88% of surveyed patients were aware that an MBC drug with significant side effects may have an approved dose reduction schedule. Further, 59% believed that the highest dose of a drug is not always more effective than a lower dose. Conclusions: Dose modifications are common among people with MBC, often driven by treatment toxicity and side effect management. Experiences with dose reductions did not significantly differ based on receiving care from a breast cancer specialist, suggesting broader awareness and acceptance of dose adjustments in patient and clinical communities. Notably, 83% of respondents reported starting on a lower dose, having the dose reduced, or both, indicating a need for further study into the efficacy of lower doses and for clinical trial designs in MBC that include multiple doses tested in later phases. Given that patients rarely initiated these conversations, further research is needed to understand barriers to discussing dose adjustments and to support more patient-clinician dialogue. Citation Format: A. Beumer, M. Carlson, J. Maues, J. Cowden, S. Walker, A. Veach, J. Collins, K. Shanahan, M. E. Burkard, K. Kalinsky, A. Bardia, H. Rugo, M. Lustberg, E. L. Papautsky, A. Arcuri, J. Brown, M. Roberson. Dose reductions in metastatic breast cancer patients: Frequency, strategies, and patient experience [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 PS2-03-17.

Abstract Background: The standard first-line therapy for most previously untreated locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) &amp;lt;10 is chemotherapy alone. New therapeutic options with superior efficacy are needed. Sacituzumab tirumotecan (sac-TMT; MK-2870/SKB264) is a novel antibody-drug conjugate (ADC) composed of an anti-trophoblast cell surface antigen 2 (TROP2) monoclonal antibody coupled to a cytotoxic belotecan derivative, topoisomerase I inhibitor payload via a novel linker. Sac-TMT monotherapy has shown promising efficacy with a manageable safety profile in metastatic TNBC. There is strong biologic rationale supporting combination of an ADC with pembrolizumab regardless of PD-L1 expression. The TroFuse-011 study (NCT06841354) evaluates sac-TMT ± pembrolizumab vs treatment of physician’s choice (TPC) in participants with previously untreated locally recurrent unresectable or metastatic TNBC with PD-L1 CPS &amp;lt;10. Trial design: Eligible participants (≥18 y) with centrally confirmed locally recurrent unresectable or metastatic TNBC, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and a tumor tissue sample evaluable for central PD-L1 and TROP2 testing are randomized 2:1:2 to receive sac-TMT (Arm A), sac-TMT + pembrolizumab (Arm B), or TPC (Arm C; Table). Primary endpoints are PFS per RECIST 1.1 as assessed by BICR (Arm A vs C and Arm B vs C) and OS (Arm A vs C). Secondary endpoints are PFS (Arm B vs A), OS (Arm B vs C and Arm B vs A), ORR (Arm A vs C and Arm B vs C) and DOR, patient-reported outcomes, and safety. Tumor imaging occurs at baseline, Q8W after randomization until week 48, and Q12W thereafter. Enrollment is ongoing. Citation Format: A. Bardia, X. Peng, K. L. Smith, J. A. Mejia, H. S. Rugo. Trofuse-011: a phase 3, randomized, open-label study of sacituzumab tirumotecan with or without pembrolizumab vs treatment of physician’s choice for previously untreated locally recurrent unresectable or metastatic triple-negative breast cancer [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 PS5-08-18.

Background/Objectives: Human papillomavirus (HPV) oncoproteins early (E)6 and E7 cause upregulation of the IL-6 and IL-23 cytokines in HPV16+ cancers, contributing to tumor progression through enhanced tumor cell proliferation and suppression of the tumor specific adaptive CD8 T-cell response. The IL-6 and IL-23 receptors signal through signal transducer and activator of transcription 3 (STAT3) in the tumor microenvironment. Methods: To better understand how HPV-induced STAT3 signaling contributes to tumor progression and explore its therapeutic potential, we used the platinum (IV) compound CPA-7, a specific STAT3 inhibitor. CPA-7 was tested in vitro for its ability to inhibit STAT3 signaling, alter proliferation, and cause cell death in HPV16+ C3.43 tumor cells. In vivo, CPA-7 was tested for its ability to affect the HPV specific T-cell response, tumor growth, and survival in C3.43 tumor bearing mice. Results: In vitro, CPA-7 inhibited STAT3 signaling, reduced proliferation, and caused significant cell death to HPV16+ C3.43 cells. In vivo, CPA-7 eradicated early-stage HPV16+ tumors, while therapeutic treatment of late-stage tumors led to a systemically increased presence of tumor-specific CD8 T-cells and halted tumor progression. Conclusions: These results suggest that targeting STAT3 signaling downregulates tumor cell proliferation and induces tumor cell death. In addition, targeting STAT3 increases the HPV-specific anti-tumor adaptive immune response. Combined, this results in significantly reduced late-stage HPV16+ tumor progression.