Florida Hospital Cancer Institute

863 Background: We previously reported that the combination of IPI-NIVO plus SG shows high efficacy with 83.3% objective response rate (ORR) as first-line treatment for cisplatin-ineligible mUC patients in a Phase I/II trial (NCT04863885). However, two grade 5 immune-mediated myocarditis events attributed to IPI-NIVO occurred, leading to early trial termination after accruing 25 patients. We evaluated serum autoantibodies (AAbs) to predict response and immune-related adverse events (irAEs) in patients receiving IPI-NIVO + SG on this trial. Methods: Using a customized 96-antigen NavigAID panel potentially linked to heart, muscle, autoimmune myositis, myasthenia gravis (MG) and checkpoint inhibitors (CPI)-induced irAEs in mUC, IgG AAbs were measured via SeroTag in pre- and post-treatment serum from mUC patients enrolled in NCT04863885. Comparative analyses included baseline vs. healthy controls, association with irAEs, best overall response (BOR), and time to progression (TTP). Top associated AAbs were selected by |log2 fold change| > 1 and |ΔMFI| > 500 between groups. P-values were calculated post-hoc using logistic regression risk modeling, ANOVA or SAM analysis. Results: Risk model analysis showed moderate evidence linking cardiac and muscle-related antigens L1CAM (OR 4.43, p = 0.08) and KCNJ8 (OR 4.31, p = 0.086) to myocarditis. KCNJ8 (KIR6.1) mutation has been previously associated with cardiac arrest. While no clear association was observed between total AAb burden and specific irAEs or response types, individual AAbs such as HMGCR (p = 0.66/0.22), TRIM28 (p = 0.43/0.058), and MYL4 (p = 0.44/0.61) showed potential predictive value for BOR/TTP. TRIM28 (TIF1β) and HMGCR AAbs are myositis-specific AAbs (MSA). HMGCR AAbs are a marker for necrotizing autoimmune myopathy (NAM), a rare but severe muscle disease. MYL4 is expressed in adult cardiac atrial tissue. Treatment-induced AAb variation was higher in responders (CR/PR). The most prominent post-treatment changes in AAbs were observed for anti-TONSL (p = 0.07). AAbs to several tumor associated antigens were elevated in mUC vs. controls including CTAG1B (NY-ESO-1) (p = 0.03) and BCL2L1 (p = 0.02). Conclusions: In patients with mUC receiving first-line IPI-NIVO+ SG, pre-treatment AAbs to cardiac and muscle-related antigens L1CAM and KCNJ8 showed a trend for association with immune myocarditis, while AAbs to HMGCR, TRIM28 and MYL4 were associated with better outcomes with the treatment. Together, these observations support further exploration of AAb profiling as a biomarker to predict efficacy and toxicities in those receiving CPI based therapies.

The datasets generated and/or analysed during the current study are not publicly available due to confidentiality agreement but are available from the corresponding author on reasonable request.

Abstract Background: Circulating tumor DNA (ctDNA) is a clinically validated biomarker in breast cancer for predicting the risk of recurrence, monitoring response to neoadjuvant treatment, and detecting molecular relapse after adjuvant therapy. Signatera™ is a tumor-informed, multiplex PCR-NGS ctDNA assay that may be developed from a backbone of whole-exome sequencing (WES) or whole-genome sequencing (WGS). Early clinical validation of Signatera Genome in a pan-cancer cohort demonstrated improved performance in certain clinical scenarios. In this study, we specifically assessed the performance of the Signatera Genome assay in the surveillance setting for breast cancer. Methods: A retrospective analysis was performed using clinically annotated residual patient samples from commercial testing with WES-based Signatera. Treatment decisions and cadence of ctDNA testing were at the provider’s discretion. Signatera Genome assays were designed, consisting of 64 high-quality tumor-specific variants, from matched tumor and normal whole genome sequencing data. These assays were then used to detect ctDNA in the corresponding patients’ plasma. ctDNA levels were quantified as mean tumor molecules per mL of plasma (MTM/mL). Longitudinal blood samples represented time points after surgery/definitive treatment until recurrence or the end of follow-up. The correlation between ctDNA status and distant recurrence-free survival (DRFS) was assessed using Cox regression analysis. Results: Clinical performance of the Signatera Genome assay was assessed in a real-world cohort of 228 patients with breast cancer [triple-negative breast cancer (TNBC), n=130; HR+/HER2-, n=85; and HER2+, n=13]. In a landmark analysis, patients with ctDNA-positivity within 3 months of surgery were significantly at a higher risk of distant disease and/or molecular recurrence (HR: 8.1, 95% CI: 3.5-8.6, P <0.001). With longitudinal testing, ctDNA-positivity at any time post-definitive treatment was associated with significantly worse DRFS (HR: 22.2, 95% CI: 11.0-44.7, P <0.0001). ctDNA detection in the surveillance setting preceded clinical recurrence as confirmed by imaging with a sensitivity and specificity of 100%. Upon analyzing ctDNA dynamics, patients with unfavorable ctDNA dynamics (persistently/converted to positive) were observed to have significantly shorter DRFS than those with favorable ctDNA dynamics (serially/converted to negative) (HR with Firth’s penalized likelihood hazard model: 97.8, 95% CI: 11.5-12768.9, P <0.001). Conclusions: These data indicate the robust clinical performance of the Signatera Genome in breast cancer for detecting recurrence after surgery or definitive treatment. Prospective clinical trials are warranted to establish the clinical utility of the assay for guiding treatment decisions for patients with molecular non-radiographic recurrence. Citation Format: W. McHayleh, C. Scalise, E. Kalashnikova, B. Sridhar, J. Feeney, W. Tan, A. Hsieh, A. Butskova, J. Ortega, S. Velichko, C. Palsuledesai, H. Sethi, G. Heilek, J. McKenzie, A. Rodriguez, M. Liu, M. George. Clinical performance of Signatera Genome assay for predicting recurrence in patients with 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 PS2-07-26.

BackgroundTriple-negative breast cancer is an aggressive breast cancer subtype, and there remains an unmet need to improve outcomes in patients with previously untreated, programmed death ligand 1 (PD-L1)–positive, locally advanced unresectable or metastatic triple-negative breast cancer.MethodsIn this phase 3, open-label, international trial, we randomly assigned patients in a 1:1 ratio to receive sacituzumab govitecan plus pembrolizumab or chemotherapy plus pembrolizumab. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included overall survival, objective response (complete or partial response) and duration of response as assessed by blinded independent central review, and safety.ResultsA total of 443 patients were randomly assigned to receive sacituzumab govitecan plus pembrolizumab (221 patients) or chemotherapy plus pembrolizumab (222 patients). The median progression-free survival was 11.2 months (95% confidence interval [CI], 9.3 to 16.7) with sacituzumab govitecan plus pembrolizumab and 7.8 months (95% CI, 7.3 to 9.3) with chemotherapy plus pembrolizumab (hazard ratio for disease progression or death, 0.65; 95% CI, 0.51 to 0.84; two-sided P<0.001). Data for overall survival were immature. The percentage of patients with an objective response was 60% (95% CI, 53 to 66) with sacituzumab govitecan plus pembrolizumab and 53% (95% CI, 46 to 60) with chemotherapy plus pembrolizumab; among patients with a response, the median duration of response was 16.5 months (95% CI, 12.7 to 19.5) and 9.2 months (95% CI, 7.6 to 11.3), respectively. Adverse events of grade 3 or higher occurred in 71% of the patients receiving sacituzumab govitecan plus pembrolizumab and in 70% of those receiving chemotherapy plus pembrolizumab; the incidence of treatment discontinuation due to adverse events was 12% and 31%, respectively. Adverse events leading to death occurred in 3% of the patients in each group.ConclusionsSacituzumab govitecan plus pembrolizumab led to significantly longer progression-free survival than chemotherapy plus pembrolizumab among patients with previously untreated, PD-L1–positive, advanced triple-negative breast cancer. (Funded by Gilead Sciences; ASCENT-04/KEYNOTE-D19 ClinicalTrials.gov number, NCT05382286.)

IntroductionCervical cancer (CC) is the third most prevalent malignancy among women worldwide. Candidate gene studies have identified multiple single nucleotide polymorphisms (SNPs) that are associated with an increased risk of CC. The objective of this study was to examine the relationship between 8 specific single-nucleotide polymorphisms (SNPs) and the risk of cervical cancer in the Georgian population.MethodsThe present study employed a prospective case-control design, with 40 patients diagnosed with CC and 45 healthy women. A total of 8 single-nucleotide polymorphisms (SNPs) were genotyped using the TaqMan genotyping assay: rs7579014, rs11263763, rs7726159, rs6897196, rs2853672, rs635634, rs231775, and rs2304204.ResultsOur analysis demonstrated that rs7579014 (BCL11A, G/A), rs7726159 (TERT, C/A), and rs6356634 (ABO, T/A) were associated with an increased risk of cervical cancer in Georgian patients. However, following the implementation of the Benjamini-Hochberg correction, only rs6356634 (ABO T/A) and rs7579014 (BCL11A G/A) remained statistically significant. A lack of statistically significant correlation was identified between the genetic variants rs11263763, rs6897196, rs2853672, rs2304204, and rs231775 and susceptibility to cervical cancer.ConclusionsThis study represents the first attempt to investigate SNP associations in women with cervical cancer in Georgia. The findings indicate that SNP-based analysis may hold promise for the early identification of susceptibility to cervical cancer, and potentially to other cancers. Nevertheless, further research involving larger sample sizes is required to validate and strengthen these preliminary observations.

The evolving treatment landscape of muscle-invasive bladder cancer (MIBC) increasingly warrants novel trial design to evaluate perioperative strategies aimed at bladder preservation. To establish standardized outcome measures for evaluating organ preservation strategies in MIBC, the International Bladder Cancer Group (IBCG) and the Global Society of Rare Genitourinary Tumors (GSRGT) assembled an international, multidisciplinary consensus panel. The IBCG and GSRGT gathered global bladder cancer experts and patient advocates to establish a framework for risk-adapted bladder-sparing treatment approaches for MIBC. Working groups reviewed the literature and developed draft recommendations, which were discussed at a live meeting in December 2024 in Milan. This was followed by voting by the members using a modified Delphi process. Recommendations achieving ≥75% agreement during the meeting were further refined and presented. Clinical complete response (cCR) definition should encompass the absence of high-grade malignancy on pathology and malignant cells on urine cytology and no evidence of local or metastatic disease on cross-sectional imaging. Although cCR remains immature as a primary or coprimary end point in registrational trials, it could serve as a suitable end point in early-phase studies and risk-adapted investigations. Event-free survival (EFS) remains the preferred primary end point as it could reliably capture the durability of clinically meaningful benefit after omittance of surgical consolidation or chemoradiation. Given the composite nature of EFS, events should be prespecified, evaluated in an intention-to-treat approach, and meticulously collected. Continuous assessment of individual patient preferences should begin at the outset of perioperative therapy discussions, with informed decision making prioritized throughout. The consensus definition of cCR and the framework presented in this study can serve as a foundation for thorough testing of risk-adapted bladder-sparing treatment paradigms for MIBC.

In this study, we evaluate the utility of ctDNA analysis in a large cohort of patients for whom ctDNA testing was ordered commercially with real-world application. Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for assessing post-surgical molecular residual disease (MRD) and response to treatment. A real-world data analysis was performed using commercial ctDNA testing (SignateraTM) from patients (N=795, n=5,971 plasma samples) with stage I-III colon cancer treated at multiple US institutions. The association of ctDNA detection within the MRD window, during surveillance, and the impact of ACT was correlated with patient outcomes. ctDNA-positive patients during the MRD window and surveillance showed significantly shorter DFS compared to ctDNA-negative patients (hazard ratio (HR): 9.85, P<0.0001; HR: 26.91, P<0.0001). Multivariate analysis of the MRD window revealed ctDNA-positivity as the most significant factor associated with inferior DFS (adjHR: 7.7, P<0.001). MRD-positive patients who received ACT showed improved DFS compared to patients observed post-surgery (adjHR: 6.1, FDR adj P=0.0007). No ACT benefit was observed in MRD-negative patients (adj HR: 1.20, FDR adj P=0.768). On evaluating ctDNA dynamics from MRD to surveillance, patients who remained ctDNA-positive or converted from negative to positive showed a significantly inferior DFS (HR: 34.40, P<0.0001; HR: 13.65, P<0.0001) compared to persistently ctDNA-negative patients. Postsurgical ctDNA detection is prognostic of relapse and potentially predictive of ACT benefit in patients with resectable colon cancer, which may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.

Opioids are known to come with some relatively benign side effects, not including their addictive potential. This review will look at some of the side effects that occur when patients, especially chronic pain patients, take opioids chronically. These side effects include both hyperalgesia and allodynia caused by opioids. Overdose and factors, including hyperalgesia and allodynia, that make a patient more likely to overdose, is the other topic that will be covered. Not much research has been done with human subjects regarding treatment of opioid induced hyperalgesia or allodynia, but some of this research will also be briefly explored throughout this review.