Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics, and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4 mg/m 2 . Dose escalation in cohorts of at least three patients proceeded according to the worst toxicity observed in the previous cohort. Twenty-eight patients were treated with 72 courses of ES-285 across eight dose levels. No dose-limiting toxicities were seen between 4 and 128 mg/m 2 . Two of four patients treated at 256 mg/m 2 had dose-limiting reversible grade 3 transaminitis; one patient at 256 mg/m 2 also had transient grade 3 central neurotoxicity. One of three patients subsequently treated at 200 mg/m 2 died following drug-related central neurotoxicity. Other toxicities included phlebitis, nausea, fatigue, and fever. Pharmacokinetic studies indicated dose proportionality with high volume of distribution (median V ss at 256 mg/m 2 was 2,389 liters; range, 1,615-4,051 liters) and long elimination half life (median t 1/2 at 256 m g / m 2 was 28 h; range, 21-3 2 h ) . T h e t h r e e patients with dose-limiting toxicity had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Disease stabilization for 6 to 18 weeks was recorded in nine patients. Using this schedule, 128 mg/m 2 was considered safe and feasible. At this dose, pharmacologically relevant concentrations of the drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential mechanistic relevance.
DCE MR imaging and DCE CT can depict vascular response to antiangiogenic agents with response evident at day 7. Improved reproducibility with MR imaging favors its use in trials with small patient numbers.
5016 Background: Monitoring CTCs in patients undergoing therapy for metastatic breast cancer is an effective means to predict outcome and monitor treatment. The primary endpoint of this prospective multi-center study was to demonstrate a significant relation between the presence of CTCs and survival in men treated for CRPC. Methods: 276 patients with diagnosed CRPC, PSA progression, and an ECOG score of 0–2 about to begin initial or salvage chemo and/or combination therapy were enrolled. CTCs were enumerated with the CellSearch System in blood drawn pre-treatment and monthly thereafter for up to 18 months. Patient data were collected and maintained by an independent CRO. Median overall survival (OS) was determined for patients with =5 CTC /7.5mL at baseline and specified intervals. Results: Of 240 evaluable patients, 142 (59%) are alive - mean follow-up 11.4 ± 4.4 months. Median OS (in months) and significance between the two groups (logrank p-value) at different time points after the initiation of therapy are indicated in the table . Median OS for 40 (19%) patients with a reduction of CTCs below 5 CTCs 2–5 weeks after initiation of therapy was significantly longer as compared to those 78 (38%) patients that remained above 5 CTCs (>20 vs. 9.3mth, p=0.0000) and was not significantly different from the 83 (40%) patients with 20 vs. >20mth, p=0.2725). In multivariate analyses, which included stage at diagnosis, age, ECOG, Gleason score, LDH, Alkaline Phosphotase, and PSA, CTCs remained the most significant independent predictor of outcome. Conclusions: CTC levels in CRPC patients are a strong predictor of OS. The persistence of CTCs after initiation of therapy suggests that the patients are deriving less than optimal benefit from their current therapy. CTC levels may be a valid surrogate end-point in monitoring response to chemotherapy. [Table: see text] No significant financial relationships to disclose.
8580 Background: Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. A phase I of oral Bel in patients (pts) with solid tumors found a recommended dose for day (d) 1–14, q3w, of 750 mg QD, with option for intra-patient dose escalation if limited toxicity. The current study was initiated to assess if the same dose could be utilized in pts with lymphoma. Methods: Objectives included safety and efficacy of oral Bel in cohorts of 3–6 pts (A 750; B 1000; C 1250; mg QD) treated d 1–14, q3w. Pts with relapsed/refractory non-Hodgkin lymphoma (NHL) or Hodgkin's disease (HD) with evaluable disease and acceptable organ functions were eligible. Dose limiting toxicity (DLT) assessed in cycle 1 included: related non-hem grade (gr) 3/4 tox; gr 4 neutropenia > 5 d or with fever > 100.5 °F; gr 4 thrombocytopenia > 7 d. Results: 9 pts (3 per cohort), median age 51 (range 21–92), median 5 (range 2–7) prior regimens (83% had BM transplants, including 1 pt with allogeneic) have been enrolled. Diagnoses include mantle cell lymphoma (MCL; 4 pts), HD (3 pts), other NHL (2 pts). Most frequent adverse events (regardless of attribution or gr) in 7 pts fully evaluable for tox: anorexia (7 pts), fatigue, (6 pts), diarrhea (6 pts), and constipation, fever, and cough (each in 3 pts). Non-hem gr 3 events (no gr 4 noted): diarrhea (1 pt each in cohorts A and B, both in cycle 2), fatigue, anorexia, and leg DVT (each in 1 pt; all after cycle 1). One gr 3, and 1 gr 4 (from baseline gr 2; duration gr 4 <7 d) thrombocytopenia were seen in cohort C. In 6 pts evaluable for efficacy, stable disease have been noted in 5 pts for 3 to +7 cycles, including 3 of 3 pts (one refractory) with MCL and 2 of 2 pts (both refractory) with HD. Tumor shrinkage of 43 to 49% have been found in 1 HD and 2 MCL pts after cycle 2. Conclusions: Oral Bel can be delivered safely with a d 1–14, q3w schedule in pts with lymphoma at a daily dose higher than what has been established for pts with solid tumors. No protocol defined DLTs have yet been encountered in the dose range 750 to 1250 mg QD in pts with lymphoma. Final evaluation will include additional pts and possible dose escalation. The safety profile and early tumor shrinkage noted in MCL and HD warrants continued evaluation of Bel, especially in combination with other active compounds. [Table: see text]
The significant linear relationship between percentage change in T2* as derived from UTE MRI and percentage change in HU from corresponding CT studies is indirect evidence that they are measuring effects of the same process.If the relationship between T2* and electron density holds true in further studies it offers potential for MR guided radiotherapy planning as well as attenuation correction for PET/MRI.
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