5053 Background: Genomic aberrations associated with resistance/response to AA/P are not known. In a prospective study we assessed whole-exome/RNA-seq based aberrations in CRPC metastatic biopsies for identifying molecular markers associated with primary resistance and response duration. Methods: Sequencing of metastatic biopsies was performed for analyzing molecular aberrations that predict primary resistance (defined as progression at 12-weeks of therapy (non-responders) using PSA, RECIST, bone scan criteria per PCWG2). Gene network analysis was performed in genes mutated more frequently in non-responders and in genes differentially expressed between non-responders and responders using a “risk ratio” (RR) of ≥2. Cox regression models with multiple gene network pathways were used for determining association with time to treatment change (TTTC). Results: Of 92 enrolled pts 82 had complete whole-exome, RNA-seq & 12-week outcome data available for analysis. At 12-weeks 33/82 had progressed. Using a RR of ≥2, 113 genes were more frequently mutated in non-responders & 292 in responders. In non-responders, gene network analysis revealed frequent mutations in Wnt/β-catenin pathway genes; frequent deletion of negative regulators of Wnt pathway ( DKK4, SFRP2, LRP6). Gene expression analyses revealed significantly reduced expression levels of Wnt/β-catenin pathway inhibitors and increased expression levels of cell cycle proliferation (CCP) genes in non-responders. Median study follow up was 32 months during which time 58/82 pts progressed and switched treatments. Median TTTC was 10.1 months (IQR:4.4-24.1). In multivariate analysis CCP scores of ≥50 predicted shorter TTTC (HR = 2.11, 95% CI: 1.17-3.80; p = 0.01). Conclusions: In metastases Wnt/β-catenin pathway activation is associated with primary AA/P resistance and increased CCP with acquired drug resistance. These findings offer molecular based predictive biomarkers in CRPC stage treatment. Clinical trial information: NCT#01953640.
Moments of meeting and parting, in Shakespeare as elsewhere, are powerfully charged. Each joining or separation is a unique event. The coming together or parting of two characters is invariably a moment of great uncertainty at which there is the potential for something new (whether destructive or creative): however familiar the other may be, new possibilities unfold with each meeting; however short the interval between this meeting and the projected next one, new dangers subtend any separation. No-one can ever be sure that something unexpected will not take place in the interim; this might be the last time these two characters will meet on these precise terms (if at all).
249 Background: Serum CGA has been identified as a candidate prognostic biomarker for mCRPC. In a two cohort study, we compared the prognostic value of serum CGA with a validated CTC assay. Methods: In the discovery cohort (DC), blood samples were collected from 256 men with mCRPC. In an independent validation cohort (VC), 92 men with mCRPC were enrolled in a biospecimen collection study. In both cohorts, men receiving proton pump inhibitors and those with non-castrate levels of testosterone ( > 50ng/dl) were excluded. Serum CGA was measured in a homogeneous automated immunofluorescent assay using time-resolved amplified cryptate emission. In the VC, CTC enumeration was performed using the FDA cleared CELLSEARCH CTC test prior to treatment with abiraterone acetate/ prednisone. Cox proportional hazard regression and Kaplan-Meier analysis were performed for associations with elevated CGA (above reference range), unfavorable (≥ 5) CTCs, and overall survival (OS). Results: In the DC, 200 men were eligible for analysis. The median age was 72 years (yrs), 81/200 pts had a Gleason score (GS) ≥ 8, 34/200 had an elevated CGA. At a median follow up of 2.2 yrs, 156/200 were deceased. In the subset of men with GS ≥ 8, elevated CGA was associated with shorter OS [hazard ratio (HR) 2.19, p = 0.017]. In the VC, 71 men were eligible for analysis. The median age was 71 yrs, 36/71 tumors were GS ≥ 8, 31/71 pts had an elevated CGA, 26/66 had unfavorable CTCs (≥ 5). At a median follow up of 1.8 yrs, 31/71 were deceased. Elevated CGA (HR 1.91, p = 0.043) and unfavorable CTC counts (HR 2.97, p = 0.0012) were adversely associated with OS. In the high GS group, both CTCs and CGA had the same area under the curve (AUC) of 0.72. Pts with elevated CTC and CGA had the poorest OS (HR 3.76, p = 0.008). Conclusions: Elevated serum CGA was negatively associated with OS in men with mCRPC. Serum CGA represents a prognostic biomarker that may complement CTC enumeration. Clinical trial information: NCT#01953640.
Abstract Background: Multiple studies have confirmed the central role of preexisting immune response measured by stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). Emerging studies showed that not only the number of TILs but also the location of TILs is important. There are 3 distinct immune architectures described based on the amount and locations of TILs, namely immune enriched (IN), immune excluded (IE), and immune desert (ID). Here we evaluated outcomes and characteristics associated with each immune landscape. Methods: NanoString Digital Spatial Profiling (DSP) and CosMx, a spatial multi-omics single-cell imaging platform, were performed in 75 samples from the Mayo Clinic (MC) TNBC cohort (Leon-Ferre BCRT 2018). NanoString IO360 was performed in 114 samples from the FinXX trial ( NCT00114816) . Firstly, tumors with sTIL quantified by H&E ≤ 30% were classified as ID. The rest of the tumors with high sTIL > 30% were categorized according to the intratumoral CD8 protein expression by DSP, with IE having intratumoral CD8 in the lower median and IN having intratumoral CD8 in the upper median. Chi-square test, gene set enrichment, Cox regression, and Kaplan-Meier analysis were used. Differential expression listed as log 2-fold change (FC) was estimated from the linear mixed model with significance defined as two-sided p< 0.05. Results: ID is associated with low Ki67 < 5% (23.3% vs. 9.6% ID, p 0.02) as well as apocrine (11/13, 84.6%) and metaplastic histology (10/12, 83%). In both univariate and multivariate analysis, patients with IN had significantly improved recurrence-free survival (RFS) compared to those with ID (HR 0.37, 95%CI 0.18-0.74, p 0.005). Despite having high sTILs, IE had poor outcomes similar to ID (HR 0.84, 95%CI 0.36-1.98). Strikingly, we identified that IE patients had significantly lower plasmacytoid dendritic cells (pDCs) compared to IN (mean 0 vs. 0.26/100 tumor cells, 95%CI 0.08-0.43 , p 0.01). Using Gene Set Enrichment Analysis to evaluate differential hallmarks between IN and IE, we identified IF Nɑ and IFNγ (FDR < 0.001) responses as significantly enriched in IN group, consistent wi th the function of pDCs, which are a subset of dendritic cells specialized in secreting high levels of type I interferon. To validate this finding, we further evaluated the 11 leading edge gene IFNɑ signature in the FinXX trial. A high IFNɑ signature score was associated with significantly improved outcomes in the FinXX trial (HR 0.21, 95%CI 0.09-0.51 , p < 0.001). Similar findings were observed using Kaplan-Meier analysis in the FinXX trial with significantly improved RFS (p 0.0006) and overall survival (p 0.0001) in patients with high IFNɑ signature scores. Furthermore, we evaluated the differential gene expression unique to IN tumors in the Mayo cohort. Expressions of MHC class I and class II in tumor cells, including HLA-A, HLA-B, HLA-C, HLA-DRA, HLA-DRB1, HLA-DPA1, and HLA-E, were associated with IN and significantly improved outcomes (p < 0.05) compared to ID and IE. Conclusions: Highlighting the importance of spatial context, we identified that patients with IE tumors had poor outcomes despite having high TILs. Moreover, u sing an in-depth analysis with spatially defined context, we identified the central role of pDC and the significance of IF Nɑ in TNBC. Support: Breast Cancer Research Foundation, Mayo Clinic Breast Cancer SPORE (P50CA116201-17) W81XWH-15-1-0292, P50CA015083, R35CA253187 Citation Format: Saranya Chumsri, Yi Liu, Yaohua Ma, Jodi Carter, Mark Gregory, Sarah Church, Jason Reeves, Heather Ann Brauer, Sarah Warren, Heikki Joensuu, Edith Perez, Roberto Leon-Ferre, David Hillman, Judy Boughey, James Ingle, Krishna Kalari, Fergus Couch, Matthew Goetz, Keith Knutson, E. Thompson. The spatially resolved single-cell atlas of the tumor immune architecture revealed the central role of IFN-alpha and plasmacytoid dendritic cells in triple-negative breast cancer in the Mayo Clinic cohort and FinXX trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS03-03.
