Tennessee Oncology

LBA639 Background: PPARG is a master regulator of luminal lineage in UC with two-thirds of adv tumors classified as luminal. FX-909 is a first-in-class oral small molecule that potently and selectively inhibits both ligand-mediated and basal PPARG activity, offering a novel approach to targeting key cancer cell-intrinsic biology. Preliminary phase 1A data have demonstrated objective responses with FX-909 monotherapy (Gao, AACR Targets 2025). Here we report updated safety, tolerability, antitumor activity and predictive biomarker discovery to identify pts most likely to benefit from FX-909. Methods: 56 pts enrolled in a phase 1A open-label dose escalation study (30-100 mg PO QD, 28-day cycles), including additional 10 adv UC patients in 30 mg PO and 50 mg PO QD backfill cohorts. Baseline archival tissue (<30 months old) or a fresh biopsy collected for PPARG IHC (SP500 clone) and NGS correlative biomarker analysis. A provisional PPARG TPS cutoff was determined using linear regression modeling leveraging molecular real-world data (RWD) (N=2609 adv UC pts, Tempus xT). Serial blood samples collected for ctDNA analysis. Results: As of Nov 10, 2025, 46 pts with adv UC have been treated across four dose levels; 30 mg (17); 50 mg (16); 70 mg (11); and 100 mg (2). Median age was 71 (range 44-86), 71.7% ECOG PS 1, and 100% had mUC. Median lines of prior therapy was 3 (range, 1-8), including prior EV and anti-PD(L)1 treatment in 69.6%. Concordance between PPARG mRNA and TPS (r = 0.88, p<0.001) supported linear regression modeling, which inferred a provisional TPS cutoff of ≥60% (PPARG high ). Among 40 efficacy-evaluable adv UC pts, 35 had PPARG IHC results. 18/26 PPARG high pts showed tumor regressions, including 5 confirmed and 1 unconfirmed partial response. Decreases in ctDNA VAF occurred in 7/8 PPARG high pts with available results at cycle 2 (3 PR, 3 SD). Additional data demonstrating the relationship between PPARG high status, luminal subtype, and specific genomic alterations (PPARG(CN≥3), RXRA S427F and FGFR3) will be presented. At 30mg and 50mg doses, the most common ≥Gr3 TRAEs were anemia (18.9%), thrombocytopenia (16.2%) and fatigue (10.8%). Other common TEAEs were diarrhea (32.4%), hypertriglyceridemia (27%) and hyperglycemia (24.3%). The 30 mg dose was associated with fewer Gr3 TRAEs (35.3%), longer time to TRAE onset (52 days, range 44, 85), and fewer dose interruptions (29.4%) and dose reductions (11.8%). Conclusions: FX-909, a first-in-mechanism orally bioavailable PPARG inhibitor, demonstrates clinical proof-of-concept for targeting the master regulator of luminal lineage in heavily pretreated adv UC pts and may offer a novel therapeutic strategy for PPARG high adv UC. A randomized phase 1B expansion study is ongoing (NCT05929235). A combination study of FX-909/anti-PD1 is planned for early 2026. Clinical trial information: NCT05929235 .

Abstract Background: Latin American (LA) women are more likely to be diagnosed with aggressive early-stage breast cancer (EBC) compared to Non-Hispanic White (NHW) women, yet population-specific tumor biology remains underexplored. Previously, we reported elevated immune gene expression in BluePrint® (BP) Luminal B tumors in LA patients (pts) with EBC and obesity compared to Black and NHW cohorts. Here, we present updated clinical comparisons between LA, NHW and Black pts with EBC and whole transcriptome analysis (WTA) between BP Luminal B and Basal BC in pts with obesity. Methods: Clinical and WT data were analyzed from 15,577 EBC pts self-identified as LA, Black, or NHW enrolled in FLEX (NCT03053193), a prospective observational study with MammaPrint® risk of recurrence and BP molecular subtyping assays, and WT profiles. ImPrint, 53-gene immune signature, results (+/-) were generated for pts with hormone receptor positive (HR+) EBC. Chi-square and t-tests were conducted on clinical groups using arsenal R package. For WT comparisons, 215 obese LA pts with BP Luminal B and 77 with BP Basal EBC were matched to corresponding NHW and Black pts by age, T and N status. Differentially expressed genes (DEGs) were evaluated using limma, and pathway enrichment was performed using gene set enrichment analysis with Hallmark gene sets. Significant results were reported with adjusted p < 0.05. Results: Compared to Black and NHW pts, LA pts were younger and more often premenopausal (Table). Both LA and Black pts had statistically significantly higher rates of obesity compared to NHW pts. Significantly higher rates of MP High Risk 2, BP Basal and ImPrint+ tumors were observed in LA and Black pts vs NHW. WT comparisons among the obese subpopulations revealed that metabolic pathways, including adipogenesis, angiogenesis, epithelial-mesenchymal transition, and oxidative phosphorylation were significantly downregulated in EBC in LA pts vs NHW and Black cohorts. Conversely, immune-related pathways such as allograft rejection and interferon gamma response were enriched among LA pts with Basal cancers compared to NHW and Black groups. These coordinated pathway alterations suggest unique metabolic and immune profiles in LA EBC subtypes with a median absolute fold change of 1.3 among DEGs. Conclusion: The data suggest that signals from metabolic pathway alterations from modest immune-related gene upregulation may contribute to more aggressive tumor behavior in obese LA pts with EBC. Clinical and transcriptomic analyses demonstrated differences in Luminal B and Basal EBC biology among self-identified LA pts compared to NHW and Black cohorts, consistent with prior research. With further research, these findings may offer treatment targets which may enhance outcomes and reflect the importance of including racially and ethnically diverse pts in clinical trials to characterize population-specific differences in EBC outcomes. Citation Format: M. Mazo Canola, A. Santillan, J. Alberty-Oller, E. Dias, V. Kaklamani, A. Elkhanany, K. Hoskins, M. Habibi, R. Hampton, J. L. Barone, N. M. Johnson, N. Gordon, N. Sookhan, T. Bah, P. John, E. Aponte, S. Diab, V. Klimberg, N. Stivers, C. Page, S. Uygun, W. Audeh, J. O'Shaughnessy. Distinct Immune and Metabolic profiles in Latin American breast cancer patients with obesity enrolled in FLEX [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 PS4-09-09.

Abstract Background Targeted therapies have transformed treatment for HR+/HER2- metastatic breast cancer (mBC), but optimal use depends on timely biomarker testing and matched therapy selection. This study evaluated national trends in PIK3CA, PTEN, AKT1 and ESR1 biomarker testing and treatment patterns among U.S. patients (pts) in community oncology clinics and examined factors associated with timely biomarker testing. Methods We conducted a retrospective cohort study of adult pts (≥18 years) with HR+/HER2- mBC treated between 01/01/2018 and 01/31/2025, using de-identified, electronic health record-derived data from the United States Flatiron Health Network. Eligible pts received at least one line of therapy at U.S. community oncology practices. Biomarker testing and treatment patterns across the first three lines of therapy (1L-3L) were analyzed descriptively. Logistic regression model evaluated associations between timely testing and baseline demographic, socioeconomic (SES), and clinical characteristics. Timely testing was defined as completing biomarker testing with results available before initiating a line of therapy for which an approved targeted treatment was available. Results Among 6,197 eligible pts who received 1L therapy, 3,550 progressed to 2L and 2,045 to 3L during the study period. Biomarker testing rates increased over time prior to 1L (from 4% in 2018 to 35% in 2024), 2L (from 9% to 69%), and 3L (from 13% to 83%). CDK4/6 inhibitors were the predominant 1L treatment regardless of biomarker status. In 2L and 3L, treatment patterns became more fragmented. Among pts with known PIK3CA mutations, the use of targeted approved therapies was 32% in 2L and 36% in 3L in 2019, compared to 27% and 29% in 2024. Among pts with ESR1+, elacestrant use rose from 22% in 2023 to 29% in 2024 in 2L and remained steady at 26-27% in 3L. In AKT1/PTEN+ pts, capivasertib use was 6% in 2L and 11% in 3L in 2024. Among pts with no test, or with negative or inconclusive biomarker results, 1% in 1L, 9% in 2L and 17% in 3L received Antibody Drug Conjugates in 2024. Treatment choices for dual-mutant (ESR1+ with either PIK3CA, AKT1 or PTEN) pts remained highly variable, with no dominant regimen: 27% received targeted therapies in 2L versus 34% in 3L. Pts were less likely to receive timely biomarker testing if they were older, lived in lower-SES areas, were treated at smaller practices, or had a worse ECOG score. However, timely testing became more common in more recent years. Conclusions Despite the availability of targeted therapies, major gaps persist in both biomarker testing and the uptake of these treatments. In 2024, nearly one-third of pts remained untested before 2L, and only 35% were tested prior to initiating 1L, limiting timely access to newly approved options. Even when actionable mutations were identified, over two-thirds of eligible pts did not receive matched therapies. Timely testing was less common in smaller practices and lower-SES settings, highlighting systemic barriers to precision oncology. To close these gaps, coordinated, equity-focused strategies are needed to improve timely testing and ensure appropriate use of targeted treatments across all pts populations. Study Number: SL46196 and PL-03044. Financial Statement: This study was sponsored by Genentech, Inc., a member of the Roche Group. Citation Format: I. M. Abbass, D. Lebovitch, N. Jain, T. Stricker, S. Nunnery, A. Pregenzer, E. Behan, R. Wang, L. Chen, P. Dhillon, Y. Liu, T. Szado, E. Yu, S. Ogale. Trends and Barriers in Biomarker Testing and Treatment Patterns in HR+/HER2- Metastatic 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 PS1-12-27.

Cancer of unknown primary (CUP) is evolving from a diagnosis of exclusion treated with empirical chemotherapy to a molecularly defined entity amenable to precision-based interventions. This heterogeneous entity, comprising 2–3% of all metastatic malignancies, encompasses diverse cancers with clinically occult primary sites at diagnosis after a thorough workup. Recent landmark trials including CUPISCO and Fudan CUP-001 have demonstrated significant survival improvements with molecularly guided therapies compared to empirical chemotherapy, fundamentally enhancing and complementing traditional organ-centric treatment paradigms. This review synthesizes the current evidence supporting molecular diagnostics, tumor-agnostic therapies, and precision-based approaches in CUP management. We examine the clinical utility of comprehensive genomic profiling, gene expression profiling, and liquid biopsy technologies, while addressing implementation challenges and future directions. The integration of molecular tumor boards and the emergence of tissue/tissue-of-origin agnostic therapies herald a new era where CUP transitions from therapeutic nihilism to personalized oncology. As molecular technologies advance and targeted therapies proliferate, CUP may no longer represent a diagnosis of exclusion but rather an opportunity for molecularly informed precision care.