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Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children. Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations. There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors. However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults. Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous system–penetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation. This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.

PURPOSE The 17-gene Onco type DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a predictor of outcomes in a multicenter active surveillance cohort. MATERIALS AND METHODS Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group [GG] ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models. RESULTS GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio [HR]/5 GPS units, 1.18; 95% CI, 1.04 to 1.44; P = .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19; P = .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade ( P = .48). CONCLUSION In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.

To compare the ability of loss of phosphatase and tensin homolog (PTEN) and Genomic prostate score assay (GPS) in predicting the biochemical-recurrence (BCR) and clinical-recurrence (CR) after radical prostatectomy (RP) for clinically localized prostate cancer (PCa).Three hundred seventy seven patients with and without CR were retrospectively selected by stratified cohort sampling design from RP database. PTEN status (by immunohistochemistry [IHC] and fluorescence in situ hybridization [FISH]) and GPS results were determined for RP specimens. BCR was defined as Prostate Specific Antigen (PSA) ≥ 0.2 ng/mL or initiation of salvage therapy for a rising PSA. CR was defined as local recurrence and/or distant metastases.Baseline mean age, PSA, and GPS score for the cohort were 61.1 years, 8 ng/dL, and 32.8. PTEN loss was noted in 38% patients by FISH and 25% by IHC. The concordance between FISH and IHC for PTEN loss was 66% (Kappa coefficient 0.278; P.001). On univariable analysis, loss of PTEN by FISH or IHC was associated with BCR and CR (P.05). However, after adjusting for GPS results, PTEN loss was not a significant predictor for CR or BCR (P.1). The GPS result remained strongly associated with CR and BCR after adjusting for PTEN status (P.001). PTEN status and GPS results only weakly correlated. GPS was widely distributed regardless of PTEN status indicating the biological heterogeneity of PCa even in PTEN-deficient cases.GPS is a significant predictor of aggressive PCa, independent of PTEN status. After adjustment for GPS results, PTEN was not independently associated with recurrence for PCa.

A 17-gene biopsy-based reverse transcription polymerase chain reaction assay, which provides a Genomic Prostate Score (GPS-scale 0-100), has been validated as an independent predictor of adverse pathology and biochemical recurrence after radical prostatectomy (RP) in men with low- and intermediate-risk prostate cancer (PCa).To evaluate GPS as a predictor of PCa metastasis and PCa-specific death (PCD) in a large cohort of men with localized PCa and long-term follow-up.A retrospective study using a stratified cohort sampling design was performed in a cohort of men treated with RP within Kaiser Permanente Northern California. RNA from archival diagnostic biopsies was assayed to generate GPS results.We assessed the association between GPS and time to metastasis and PCD in prespecified uni- and multivariable statistical analyses, based on Cox proportional hazard models accounting for sampling weights.The final study population consisted of 279 men with low-, intermediate-, and high-risk PCa between 1995 and 2010 (median follow-up 9.8 yr), and included 64 PCD and 79 metastases. Valid GPS results were obtained for 259 (93%). In univariable analysis, GPS was strongly associated with time to PCD, hazard ratio (HR)/20 GPS units=3.23 (95% confidence interval [CI] 1.84-5.65; p0.001), and time to metastasis, HR/20 units=2.75 (95% CI 1.63-4.63; p0.001). The association between GPS and both end points remained significant after adjusting for National Comprehensive Cancer Network, American Urological Association, and Cancer of the Prostate Risk Assessment (CAPRA) risks (p0.001). No patient with low- or intermediate-risk disease and a GPS of20 developed metastases or PCD (n=31). In receiver operating characteristic analysis of PCD at 10 yr, GPS improved the c-statistic from 0.78 (CAPRA alone) to 0.84 (GPS+CAPRA; p0.001). A limitation of the study was that patients were treated during an era when definitive treatment was standard of care with little adoption of active surveillance.GPS is a strong independent predictor of long-term outcomes in clinically localized PCa in men treated with RP and may improve risk stratification for men with newly diagnosed disease.Many prostate cancers are slow growing and unlikely to spread or threaten a man's life, while others are more aggressive and require treatment. Increasingly, doctors are using new molecular tests, such as the17-gene Genomic Prostate Score (GPS), which can be performed at the time of initial diagnosis to help determine how aggressive a given patient's cancer may be. In this study, performed in a large community-based healthcare network, GPS was shown to be a strong predictor as to whether a man's prostate cancer will spread and threaten his life after surgery, providing information that may help patients and their doctors decide on the best course of management of their disease.

Background: Relapsed and refractory myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a clinical challenge due to high mortality, morbidity, and lack of effective therapeutic agents. PLX2853 is an orally available, non-benzodiazepine bromodomain and extraterminal domain (BET) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second of the double bromodomains of the BET proteins. By regulating genes (e.g., BCL2 and MYC) central to leukemic cell proliferation and survival, PLX2853 has demonstrated broad anti-leukemic activity both as a single agent and in combination with other agents in preclinical models. The pharmacokinetic (PK) profiles in patients with solid tumors revealed high peak plasma concentrations, a short terminal half-life (T 1/2 < 3 hour), and nearly complete elimination from the plasma by 9 hours post dose. This PK profile is hypothesized to improve tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: This is an open-label, Phase 1b dose-escalation study of PLX2853 as a single agent, administered with oral daily dosing for 21-day cycles in adult patients with relapsed or refractory (R/R) AML or high risk MDS. A modified continuous reassessment model with overdose control was used to guide dose escalation decisions and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamic biomarker assessments. Results: Fourteen patients with R/R AML and 8 patients with high risk MDS (median age 69 years, range 47 - 79 years; median number of prior therapies 2, range 1-7) received PLX2853 in escalating doses from 20 to 180 mg QD. Through the data cut-off of 30 Jun 2021 (n=22), the most common treatment emergent adverse events (AEs) regardless of causality occurring in ≥20% of patients (n≥5) are: fatigue (n=14), nausea (n=13), decreased appetite (n=13), anemia (n=10), diarrhea (n=10), vomiting (n=9), hypokalemia (n=9), international normalized ratio increased (n=8), hyperglycemia (n=8), hypophosphatemia (n=8), peripheral edema (n=7), blood bilirubin increased (n=7), dyspnea (n=7), febrile neutropenia (n=6), constipation (n=6), sepsis (n=6), hypoalbuminemia (n=6), hyponatremia (n=6), insomnia (n=6), proteinuria (n=6), and hypertension (n=6). Two dose limiting toxicities (DLTs) were observed at the two highest doses: G3 and G4 hyperbilirubinemia at 180 mg QD and 140 mg QD respectively. The MTD is 140 mg QD and the RP2D, determined on the totality of data in this study and the companion phase 1 study in solid tumors (NCT03297424), is 80 mg QD. The median time to reach maximal PLX2853 plasma concentration (T max) is 1 hour, with no accumulation observed at steady state, consistent with the short T 1/2 (< 3 hours). Dose-dependent increases in exposures were observed across the dose range tested (20-180 mg daily). Fifteen of 22 patients completed at least 1 cycle of treatment. Median duration of treatment was 49 days (range 8 - 232 days). Best Overall Response: 1 patient with a confirmed marrow CR (MDS), 2 x partial remission (1 AML and 1 myeloid sarcoma), 12 x stable disease (7 AML and 5 MDS), 2 x progressive disease (1 AML and 1 MDS), and 5 x not evaluable (4 AML and 1 MDS). Conclusions: Daily dosing of PLX2853 was well tolerated as a monotherapy and showed early signs of clinical activity in some patients with relapsed or refractory AML or high risk MDS, with potential for combination with other agents. The RP2D is 80 mg QD continuous dosing. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Solh: Jazz Pharmaceuticals: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Partner Therapeutics: Research Funding; BMS: Consultancy. Saultz: IKENA: Research Funding. Borate: Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Jazz Pharma: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Pemmaraju: CareDx, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Affymetrix: Consultancy, Research Funding; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Sager Strong Foundation: Other; DAVA Oncology: Consultancy; Springer Science + Business Media: Other; Aptitude Health: Consultancy; MustangBio: Consultancy, Other; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Celgene Corporation: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Borthakur: Protagonist: Consultancy; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Roboz: Actinium: Consultancy; Jasper Therapeutics: Consultancy; AbbVie: Consultancy; Mesoblast: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Blueprint Medicines: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Daiichi Sankyo: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Jazz: Consultancy; Bayer: Consultancy; Agios: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Astex: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Janssen: Research Funding; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Powell: Plexxikon Inc.: Current Employment. Matusow: Plexxikon Inc.: Current Employment. Halladay: Plexxikon Inc.: Current Employment. Vali: Plexxikon Inc.: Current Employment. Hope: Plexxikon Inc.: Current Employment. Kundu: Daiichi Sankyo: Current Employment. Hsu: Daiichi Sankyo: Current Employment. Watkins: Plexxikon Inc.: Current Employment. Zhang: Plexxikon Inc.: Current Employment. Walling: Plexxikon Inc.: Consultancy; Aduro Biotech: Consultancy; Ambagon Therapeutics: Consultancy; Arch Oncology: Consultancy; CytomX: Consultancy; Flag Therapeutics: Consultancy; Harpoon Therapeutics: Consultancy; January Therapeutics: Consultancy; Myovant Sciences: Consultancy; Nurix Therapeutics: Consultancy; Propella Therapeutics: Consultancy; Prothena: Consultancy; Que Oncology: Consultancy; Shape Therapeutics: Consultancy; Aminex Therapeutics: Consultancy; Proximagen Neurosciences: Consultancy; Sesen Bio: Consultancy; Sunesis Pharmaceuticals: Consultancy; TRex BioSciences: Consultancy; Upsher-Smith: Consultancy; Nuvation Bio: Consultancy; Oryzon: Consultancy. Tsiatis: Plexxikon Inc.: Current Employment. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Importance Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors. Objective To assess whether combining a type II KIT inhibitor with a conformation-complementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control. Design, setting, and participants A highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020. Interventions Participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 together with 25 or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal. Main outcomes and measures Pharmacokinetics, safety, and tumor responses were assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA. Results A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000 mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5 mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500 mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14% (0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively. Conclusions and relevance In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile. Trial registration ClinicalTrials.gov Identifier: NCT02401815.

Background: Relapsed and refractory myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a clinical challenge due to high morbidity and mortality as well as a paucity of effective therapeutic agents. PLX2853 is an orally available, non-benzodiazepine bromodomain and extraterminal domain (BET) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g., MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 has demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profiles in patients with AML or MDS revealed high peak plasma concentrations, a short terminal half-life (T1/2 < 3 hour), and nearly complete elimination from the plasma by 9 hour post dose. This PK profile is hypothesized to enable improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: This is an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily for 21 day cycles in adult patients with relapsed or refractory AML or high risk MDS. A modified continuous reassessment model with escalation with overdose control is employed to determine the recommended phase 2 dose (RP2D). Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments. Enrollment through Cohort 5 (140 mg QD) is ongoing as of July 2020. Results: 9 subjects with relapsed or refractory AML and 7 subjects with high risk MDS (median age 65.7 years, range 47-77 years old; median number of prior therapies 2.3, range 1-5 prior therapies) have received PLX2853 in escalating doses from 20 to 140 mg QD. Through the data cut-off of 19 Jul 2020 (n=16), the most common treatment emergent adverse events (AEs) regardless of causality occurring in ≥20% of patients (n≥4) are: decreased appetite (n=9), (n=8), fatigue (N=8), hyperbilirubinemia (N=8), nausea (n=7), constipation (n=6), hypokalemia (n=6), leukopenia (n=6), vomiting (n=5), international normalised ratio increased (n=5), proteinuria (n=5), and dyspnea (n=5). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patients are: anemia (n=7), leukopenia (n=5) hyperbilirubinemia (n=4), febrile neutropenia (n=4), sepsis (n=3), thrombocytopenia (n=3), hypertension (n=2), lymphocyte count decreased (n=3), and neutrophil count decreased (n=3). No dose limiting toxicity (DLT) has been observed. Following a daily dose of PLX2853 the median time to reach maximal plasma concentration (Tmax) is 1 hour, and no accumulation observed at steady state, which is consistent with the short T1/2 (< 3 hours). Dose-dependent increases in exposures were observed across the dose range tested (20-80 mg daily). Fifteen of 16 subjects have completed at least 1 cycle of treatment. The following best overall responses have been observed: 1 subject with a confirmed marrow complete remission, 1 subject with a partial remission (myeloid sarcoma), 10 subjects with stable disease, 1 subject with progressive disease, and 3 subjects not evaluable. Conclusions: In an ongoing Ph1b study of PLX2853, four cohorts have been completed with continuous, once daily dosing in patients with relapsed or refractory AML or high risk MDS, and no DLTs have been observed yet. As dose escalation continues, PK, PD, preliminary safety, and efficacy data will be reviewed further to determine the clinical significance of this BET inhibitor and identify the RP2D. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Mims: Agios: Consultancy; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Novartis: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board. Borate:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Blueprint Medicines: Honoraria; MustangBio: Honoraria; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria. Borthakur:BioTherix: Consultancy; BioLine Rx: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; BMS: Research Funding; Jannsen: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Consultancy; AstraZeneca: Research Funding. Roboz:Agios: Consultancy; Amphivena: Consultancy; MEI Pharma: Consultancy; Helsinn: Consultancy; Epizyme: Consultancy; Jasper Therapeutics: Consultancy; Cellectis: Research Funding; Trovagene: Consultancy; Takeda: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; AstraZeneca: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Argenx: Consultancy; Actinium: Consultancy; Sandoz: Consultancy; Astex: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy. Powell:Plexxikon Inc.: Current Employment. Severson:Plexxikon Inc.: Current Employment. Matusow:Plexxikon Inc.: Current Employment. Halladay:Plexxikon Inc.: Current Employment. Hsu:Daiichi Sankyo Inc.: Current Employment. Watkins:Plexxikon Inc.: Current Employment. Zhang:Plexxikon Inc.: Current Employment. Walling:Plexxikon Inc.: Consultancy; Aduro Biotech: Consultancy; Arch Oncology: Consultancy; CytomX Therapeutics: Consultancy; Harpoon Therapeutics: Consultancy; ImmuNext: Consultancy; Myovant Sciences: Consultancy; Nurix Therapeutics: Consultancy; Que Oncology: Consultancy; Sesen Bio: Consultancy; Amgen: Consultancy; Aminex: Consultancy; Crown Bio: Consultancy; Leap Therapeutics: Consultancy; Prothena Corporation: Consultancy; Puma Biotechnology: Consultancy; Rhizen Pharmaceuticals: Consultancy; Shanghai Pharmaceuticals: Consultancy; Stealth Biotherapeutics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Upsher-Smith Laboratories: Consultancy; Flag Therapeutics: Consultancy; January Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Current Employment. DeZern:Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy; MEI: Consultancy.

3018 Background: PLX2853 is a potent, orally active small molecule BET inhibitor. Its unique pharmacokinetic (PK) profile is associated with less thrombocytopenia and improved tolerability by allowing transient target engagement with a prolonged pharmacodynamic (PD) response and time for recovery after dosing. Methods: We conducted a first-in-human 3+3 Ph1b/2a study of PLX2853 in adults with relapsed or refractory solid tumors and lymphoma to determine the safety, PK and recommended phase II dose (RP2D) (NCT03297424). Secondary endpoints included efficacy and PD. Results: As of 2 February 2021, 44 subjects (median age 65, range 39 - 84) received PLX2853 in escalating doses from 5mg to 120mg QD and 40mg to 60mg BID. Ovarian cancer (n = 11), uveal melanoma, colorectal, and prostate (n = 5 each) were the most represented tumor types. Adverse events (AE) occurring in ≥15% of subjects included nausea (41%), decrease appetite (39%), fatigue (27%), vomiting (25%), diarrhea (25%), dysgeusia (25%), dehydration (23%), anemia (20%), dry mouth (18%), dizziness (16%), abdominal pain (16%), and pyrexia (16%). Thrombocytopenia occurred in 11% of subjects. Most AEs ( > 85%) were grades (G) 1-2. Of all AEs, 40% were related. There were 5 treatment-related serious AEs in 2 subjects (n = 1 G4 thrombocytopenia, G4 ischemic stroke, G3 subarachnoid hemorrhage [SAH], and G3 thromboembolic event; n = 1 G3 vomiting). Dose-limiting toxicities were observed at 120mg QD (G4 thrombocytopenia, G4 ischemic stroke, G3 thromboembolic event, and G3 SAH; asymptomatic G4 thrombocytopenia), 60mg BID (G3 thrombocytopenia with recovery > 7 days), and 40mg BID (dose reduction for transient G3 fatigue). PLX2853 systemic exposure was dose-proportional up to 120mg with a short terminal half-life ( < 3.5 hr). Plasma concentrations were above the IC90 in the MYC-responsive reporter assay for 9 hr at 80mg or higher doses. RNA-seq analyses of peripheral blood mononuclear cells showed a dose-dependent modulation of BET target gene expression. One complete response (ongoing 9+ months) was seen in a patient with DLBCL, two patients had partial responses (1 uveal melanoma, 1 primary peritoneal cancer), and 14 patients had stable disease. The median PFS was 82.5 days (range: 51 – 209 days). Conclusions: PLX2853 shows encouraging signs of clinical activity and is well tolerated at the anticipated RP2D of 80 mg/day. PLX2853 is being evaluated as monotherapy and in combination. Clinical trial information: NCT03297424.

Summary Background The likelihood of tumour recurrence after nephrectomy in localised clear cell renal cell carcinoma is well characterised by clinical and pathological parameters. However, these assessments can be improved and personalised by the addition of molecular characteristics of each patient's tumour. We aimed to develop and validate a prognostic multigene signature to improve prediction of recurrence risk in clear cell renal cell carcinoma. Methods In the development stage, we investigated the association between expression of 732 genes, measured by reverse-transcription PCR, and clinical outcome in 942 patients with stage I–III clear cell renal cell carcinoma who had undergone a nephrectomy at the Cleveland Clinic (OH, USA). 516 genes were associated with recurrence-free interval. 11 of these genes were selected by further statistical analyses, and were combined with five reference genes (ie, 16 genes in total), from which a recurrence score algorithm was developed. The recurrence score was then validated in an independent cohort of 626 patients from France with stage I–III clear cell renal cell carcinoma who had also undergone nephrectomy. The association between the recurrence score and the risk of recurrence and cancer-specific survival in the first 5 years after surgery was assessed using Cox proportional hazard regression, stratified by tumour stage (stage I vs stage II vs III). Findings In our primary univariate analysis, the continuous recurrence score (median 37, IQR 31–45) was significantly associated with recurrence-free interval (hazard ratio 3·91 [95% CI 2·63–5·79] for a 25-unit increase in score, p Interpretation Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I–III clear cell renal cell carcinoma, providing a more accurate and individualised risk assessment beyond existing clinical and pathological parameters. Funding Genomic Health Inc and Pfizer Inc.

Background Prostate tumor heterogeneity and biopsy undersampling pose challenges to accurate, individualized risk assessment for men with localized disease. Objective To identify and validate a biopsy-based gene expression signature that predicts clinical recurrence, prostate cancer (PCa) death, and adverse pathology. Design, setting, and participants Gene expression was quantified by reverse transcription-polymerase chain reaction for three studies - a discovery prostatectomy study (n = 441), a biopsy study (n = 167), and a prospectively designed, independent clinical validation study (n = 395) - testing retrospectively collected needle biopsies from contemporary (1997-2011) patients with low to intermediate clinical risk who were candidates for active surveillance (AS). Outcome measures and statistical analysis The main outcome measures defining aggressive PCa were clinical recurrence, PCa death, and adverse pathology at prostatectomy. Cox proportional hazards regression models were used to evaluate the association between gene expression and time to event end points. Results from the prostatectomy and biopsy studies were used to develop and lock a multigene-expression-based signature, called the Genomic Prostate Score (GPS); in the validation study, logistic regression was used to test the association between the GPS and pathologic stage and grade at prostatectomy. Decision-curve analysis and risk profiles were used together with clinical and pathologic characteristics to evaluate clinical utility. Results and limitations Of the 732 candidate genes analyzed, 288 (39%) were found to predict clinical recurrence despite heterogeneity and multifocality, and 198 (27%) were predictive of aggressive disease after adjustment for prostate-specific antigen, Gleason score, and clinical stage. Further analysis identified 17 genes representing multiple biological pathways that were combined into the GPS algorithm. In the validation study, GPS predicted high-grade (odds ratio [OR] per 20 GPS units: 2.3; 95% confidence interval [CI], 1.5-3.7; p < 0.001) and high-stage (OR per 20 GPS units: 1.9; 95% CI, 1.3-3.0; p = 0.003) at surgical pathology. GPS predicted high-grade and/or high-stage disease after controlling for established clinical factors (p < 0.005) such as an OR of 2.1 (95% CI, 1.4-3.2) when adjusting for Cancer of the Prostate Risk Assessment score. A limitation of the validation study was the inclusion of men with low-volume intermediate-risk PCa (Gleason score 3 + 4), for whom some providers would not consider AS. Conclusions Genes representing multiple biological pathways discriminate PCa aggressiveness in biopsy tissue despite tumor heterogeneity, multifocality, and limited sampling at time of biopsy. The biopsy-based 17-gene GPS improves prediction of the presence or absence of adverse pathology and may help men with PCa make more informed decisions between AS and immediate treatment. Patient summary Prostate cancer (PCa) is often present in multiple locations within the prostate and has variable characteristics. We identified genes with expression associated with aggressive PCa to develop a biopsy-based, multigene signature, the Genomic Prostate Score (GPS). GPS was validated for its ability to predict men who have high-grade or high-stage PCa at diagnosis and may help men diagnosed with PCa decide between active surveillance and immediate definitive treatment. © 2014 European Association of Urology.

Background: PLX2853 is an orally available, non-benzodiazepine BET (bromodomain and extraterminal domain) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g. MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profile in solid tumor patients revealed a short half-life (< 3 hour) enabling high peak plasma concentrations and nearly complete elimination from the plasma 9 hour post dose. Since strong and prolonged suppression of BET proteins have often untoward effects in normal tissues, the PLX2853 PK profile is hypothesized to be associated with improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: We are conducting an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily in adult patients with relapsed or refractory acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) using a modified continuous reassessment model (mCRM) with escalation with overdose control (EWOC) to determine the recommended phase 2 dose (RP2D). Up to 36 patients are expected to enroll. The dosing cycle and dose limiting toxicity window (DLT) is 21 days. Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments in various tissues. Enrollment through Cohort 2 (40 mg QD) is ongoing as of July 2019. Results: Five subjects with relapsed or refractory AML (median age 65 years) have received PLX2853 in escalating doses from 20 to 40 mg QD. Among these first 5 patients treated, the most common treatment emergent adverse events (AEs) regardless of causality in > 1 patient: decreased appetite (n=3), nausea (n=2), diarrhea (n=2), peripheral edema (n=2), cough (n=2), oropharyngeal pain (n=2), blood bilirubin increase (n=2), anemia (n=2), febrile neutropenia (n=2), fatigue (n=2), bacteremia (n=2), headache (n=2), dyspnea (n=2), and hypertension (n=2). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patient included: anemia (n=2), febrile neutropenia (n=2) and hypertension (n=2). No treatment-related serious AEs or DLTs have been observed. Following a 20 mg daily dose of PLX2853, median time to reach maximal plasma concentrations (Tmax) is 1 hour and the absorption half-life (T1/2) is < 3 hours. Conclusions: In an ongoing Ph1b study, PLX2853 has now completed its first dosing cohort for patients with relapsed or refractory AML or high risk MDS, and no DLT has been observed yet. As dose escalation continues, PK, PD, preliminary safety and efficacy data will be assessed further to determine the clinical significance of target engagement. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Pemmaraju: mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Borthakur:Polaris: Research Funding; Arvinas: Research Funding; Agensys: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Merck: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; NKarta: Consultancy; Incyte: Research Funding; Janssen: Research Funding; GSK: Research Funding; PTC Therapeutics: Consultancy. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Zhang:Plexxikon Inc.: Employment. Powell:Plexxikon Inc.: Employment. Severson:Plexxikon Inc.: Employment. Inokuchi:Plexxikon Inc.: Employment. Matusow:Plexxikon Inc.: Employment. Halladay:Plexxikon Inc.: Employment. Hsu:Daiichi Sankyo, Inc.: Employment. Watkins:Plexxikon Inc.: Employment. Walling:Myovant Sciences: Consultancy; Nurix: Consultancy; Aduro Biotech: Consultancy; Plexxikon: Consultancy; CytomyX: Consultancy; Flag Therapeutics: Consultancy; Aminex: Consultancy; Immunext: Consultancy; SensenBio: Consultancy; Harpoon Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Employment. Mims:PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

262 Background: The 17-gene Genomic Prostate Score (GPS) test (scale 0-100) predicts adverse surgical pathology (AP) and recurrence in newly diagnosed low- and intermediate-risk PCa. Studies of the predictive value of the GPS test in men initially managed with AS are limited. Methods: Diagnostic biopsy tissue was obtained from 634 men enrolled at 8 sites in PASS. Time to AP (Gleason Grade Group (GG) ≥3, ≥pT3a, or N1) in men who underwent radical prostatectomy (RP) was the primary endpoint. All diagnostic biopsies and RP specimens were centrally reviewed. Multivariate regression models for interval censored data were used to evaluate the association between time to AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Association between GPS and time to Gleason score upgrade on surveillance biopsy was also evaluated using a Cox Proportional Hazards model. Results: GPS results were obtained for 432 men (median follow-up 4.6 [IQR: 2.9-6.2] years); 374 and 58 with GG 1 or 2 cancer, respectively; median PSA density (PSAD) was 0.11 [IQR: 0.08-0.15]; 101 men underwent RP with central pathology after a median of 2.1 [IQR: 1.3-4.3] years surveillance, and 52 (52%) men undergoing RP had AP. 167 men upgraded at a subsequent biopsy. No clinico-pathologic covariates were significantly associated with AP other than PSAD. GPS was significantly associated with time to AP (hazards ratio [HR]/20 GPS units: 1.96 [95% CI = 1.17-4.28]; p = 0.030), when adjusted for diagnostic GG, or for dichotomous PSAD ( < vs ≥ 0.15; HR: 1.83, 95% CI = 1.04-3.62; p = 0.046). GPS was not significantly associated with AP (HR: 1.61, 95% CI = 0.87-2.98; p = 0.12) when adjusted for continuous PSAD. No association, either univariable or multivariable, was observed between GPS and subsequent biopsy upgrade. Conclusions: In a cohort of men on AS, GPS was associated with time to AP when adjusted for diagnostic GG or dichotomous PSAD. GPS was not associated with surveillance biopsy GG upgrading or AP at surgery after adjustment for continuous PSAD, although a trend was seen for AP, suggesting an association may be seen in a larger study.

Identification of microsatellite instability (MSI) in colorectal cancer (CRC) patients can have prognostic, therapeutic, and family planning implications. MSI is a term that describes a shift in the length of microsatellite repeats because of mismatch repair gene deficiency secondary either to DNA methylation or genetic mutation. MSI testing is frequently performed on patients with suspected hereditary nonpolyposis CRC, and MSI is found in CRC samples from patients who eventually go on to be genotyped and confirmed to have Lynch syndrome. Other indications for MSI testing include prognosis determination, since MSI cancer patients do better than those with microsatellite stable cancers, and for chemotherapy selection, where some data indicate the lack of benefit to patients with microsatellite unstable CRCs treated with 5-Fluorouracil. During the histologic review of either a biopsy or a resection specimen, a pathologist's increased familiarity with the revised Bethesda criteria and awareness of the histopathological features commonly seen in colorectal tumors harboring MSI can increase the rate of clinically appropriate testing and improve patient care. Molecular analysis for MSI is performed routinely by a number of clinical laboratories on formalin-fixed paraffin-embedded tissue. Immunohistochemical stains can also be performed to assess for the absence of mismatch repair protein in a tumor cell. A representative case will be detailed to review the histology and the molecular data commonly observed in CRC showing MSI.

Mutations in codons 12 and 13 of the KRAS oncogene are relatively common in colorectal and lung adenocarcinomas. Recent data indicate that these mutations result in resistance to anti-epidermal growth factor receptor therapy. Therefore, we assessed Sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS codon 12/13 mutations in formalin-fixed paraffin-embedded samples, including 58 primary and 42 metastatic colorectal adenocarcinomas, 63 primary and 17 metastatic lung adenocarcinomas, and 20 normal colon samples. Of 180 tumor samples, 62.2% were KRAS mutant positive, and 37.8% were negative. Melting curve analysis yielded no false positive or false negative results, but had 10% equivocal calls. Melting curve analysis also resulted in 4 cases with melting curves inconsistent with either wild-type or codon 12/13 mutations. These patterns were generated from samples with double mutants in codons 12/13 and with mutations outside of codons 12/13. Pyrosequencing yielded no false positive or false negative results as well. However, two samples from one patient yielded a pyrogram that was flagged as abnormal, but the mutation subtype could not be determined. Finally, using an electronic cutoff of 10%, Sanger sequencing showed 11.1% false positives and 6.1% false negatives. In our hands, the limit of detection for Sanger sequencing, pyrosequencing, and melting curve analysis was approximately 15 to 20%, 5%, and 10% mutant alleles, respectively.

Purpose: The prognostic significance of capsular incision (CPI) at radical retropubic prostatectomy remains to be defined. To evaluate this we compared prostate specific antigen recurrence for with CPI to that with established pathological groups. Materials and Methods: From January 1998 to December 2000, 409 men underwent radical retropubic prostatectomy at our medical center. CPI was defined as a positive posterior, lateral or posterolateral surgical margin without documented extraprostatic extension (EPE). Excluding patients with preoperative androgen ablation, positive lymph nodes or seminal vesicle involvement there were 129 with organ confined disease and negative surgical margins (pT2/−M), 18 with CPI, 29 with EPE and negative surgical margins (pT3a/−M), and 24 with EPE and positive surgical margins (pT3a/+M). We compared time to biochemical recurrence among these 4 groups using Kaplan-Meier estimates. Cox proportional hazard regression was performed to determine the HR of CPI vs the other groups, while controlling for age, prostate specific antigen, tumor volume and Gleason score. Results: The 3-year likelihood of freedom from biochemical recurrence in the CPI group was 65%, for pT2/−M it was 96%, for pT3a/−M it was 91% and for pT3a/+M it was 58%. The adjusted HR with the 95% CI showed that the risk of biochemical recurrence with CPI was 8.4 times higher than that with pT2/−M (p = 0.002), 5.9 times higher than that with pT3a/−M (p = 0.046) and the same as that with pT3a/+M (p = 0.840). Conclusions: Isolated posterior, lateral and posterolateral CPI by our definition occurs not uncommonly and it may represent true incision of the capsule and/or difficulty in diagnosing EPE due to a lack of extraprostatic tissue in the surgical specimen. However, the prognostic significance of CPI as defined appears similar to that of pT3a with positive margins.

41 Background: Validated biomarkers can improve risk stratification for men with prostate cancer (PCa). A biopsy-based RT-PCR assay that provides a GPS (scale 0-100) has been validated as an independent predictor of adverse surgical pathology and BCR after RP in men with low-risk and low-volume intermediate-risk PCa. We sought to confirm that GPS is a predictor of BCR across the full spectrum of clinical risk (low, intermediate and high) in a large cohort of men with long term follow up within Kaiser Permanente Northern California (KPNC). Methods: From the KPNC clinical database of 6,184 RP treated men diagnosed with NCCN very low, low, intermediate and high-risk PCa between 1995- 2010, we performed a retrospective cohort study using stratified cohort sampling. BCR was defined as either 2 successive post-RP PSAs ≥ 0.2, or initiation of salvage therapy after a rising PSA ≥ 0.1. Archival biopsy tissue was assayed to yield a GPS. Univariable and multivariable Cox proportional hazards models were used to estimate the association, accounting for sampling weights and covariates. Results: Tissue was retrieved for 334 patients. 279 met all eligibility criteria and 259 (93%) generated a valid GPS. The cohort consisted of 117 BCR and 142 non-BCR events. GPS was strongly associated with BCR - HR/20 GPS units = 2.5; p < 0.0001 in univariable analysis, and after adjusting for PSA, clinical T stage and central biopsy Gleason Score (HR/20 units = 2.1; p = 0.002). The association between GPS and BCR was similar within different racial groups. Each of the 4 gene groups in GPS contributed to the prediction of BCR. Conclusions: GPS was associated with BCR independently of other clinical factors in surgically treated men with PCa, and may provide improved risk stratification beyond clinical risk assessment.

25% at 5 and 10 years post RP. The GC had a c-index of 0.79 (95% CI 0.71-0.86) for predicting metastasis and this was significantly better than any single clinical variable (c-indices: 0.49 0.65). Decision curve analysis showed that the GC model had higher overall net benefit compared to clinical variables over a wide range of ?decision-to-treat? thresholds for risk of metastasis. In multivariable modeling with clinicopathologic variables, GC remained the only significant independent predictor of metastasis (HR 1.51, for each 0.1 unit increment p 0.001). CONCLUSIONS: Our results suggest that GC can better predict metastatic disease progression compared with clinical variables and may help identify both patients at higher risk to progress and those more likely to have an indolent course. This may enable optimization of multimodal therapy for high risk prostate cancer patients.

e16570Background: The overtreatment of prostate cancer and underutilization of active surveillance in men with Gleason 6 (GS6) cancer stems from uncertainty with current risk instruments such as vo...

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a cystic precursor lesion of infiltrating pancreatic adenocarcinoma characterized by mucin production, a dilated main pancreatic duct and/or ectasia of one of its side branches, and intraductal (usually papillary) growth.1,2 Since its description nearly 3 decades ago,3 there have been numerous advances made in understanding the histopathology and natural history of solitary IPMNs.1,2,4–6 The apparent incidence of IPMNs, and in particular, asymptomatic lesions, has increased somewhat dramatically in recent years, largely paralleling the increasing use of abdominal imaging technologies.2,7,8 In contrast to the other common cystic precursor lesion of pancreatic adenocarcinoma, such as mucinous cystic neoplasms (MCNs), which are essentially always solitary in nature, a subset of IPMNs, are multifocal. The reported prevalence of multifocality in IPMNs—either as synchronously diagnosed cysts or in a metachronous setting—varies widely, from 0% to 83% (Table 1).9,10 These highly discrepant rates are largely a reflection of variations in methodologies used for assessing multifocality, particularly in the synchronous setting, with many of the reports relying solely on imaging criteria for assigning multifocality. Histopathological assessment remains critical to establishing that preoperatively suspected multifocal IPMN lesions are not extensions of a solitary IPMN or even pancreatic cysts of an entirely different histogenesis (ie, pseudocysts, retention cysts, serous cystadenomas, among others). Comparable uncertainties vis-a-vis multifocal IPMNs also extend to their natural history and optimal clinical management, a conundrum that is reflected in the absence of clearly defined recommendations in the recent guidelines from the working group of the International Association of Pancreatology on management of pancreatic cystic lesions (a.k.a., “Sendai criteria”).11–14 TABLE 1 Published Studies on the Prevalence of Multifocal IPMNs Another prevailing enigma regarding multifocal IPMNs pertains to the molecular pathogenesis of these lesions, for which 2 competing hypotheses have been proposed. On the one hand it has been suggested that multifocal IPMNs are clonally related neoplasms arising from a single or few progenitor cells that exhibit shared genetic alterations. The haphazard intraductal growth of a single neoplasm could mimic true multifocality. Multifocal IPMNs could also be the result of the entire ductal epithelium having an increased risk of developing a neoplasm as may be seen in the familial setting.15 In these cases, a common germline inactivating mutation is shared by all cells in the pancreas, with a “second hit” on the remaining allele likely to be observed within each independent lesion. Finally, multifocal IPMNs might also arise because of entirely unrelated independent genetic events in anatomically distinct areas of the pancreas. To date, the molecular pathogenesis of multifocal IPMNs remains poorly understood. The goals of this study were to characterize multifocal IPMNs with respect to their clinicopathologic features and to forge a better understanding of genetic relatedness among synchronous lesions. We rigorously defined multifocal IPMNs on the basis of histological confirmation of surgically resected cysts, which allowed us to delineate a prevalence at the lower detection end with some degree of certainty. As a result of this study, we have established that the overwhelming majority of multifocal IPMNs are branch duct lesions that demonstrate gastric-foveolar type epithelium, and typically harbor low to intermediate grades of epithelial dysplasia. Not unexpectedly, a significant minority of cases in our series arise in familial pancreatic cancer kindreds, and this history needs to be elucidated in any index case presenting with multifocal cysts. Furthermore, we provide evidence of discordant molecular aberrations among noninvasive IPMNs arising in the same individual, including between synchronous cysts with no more than low or intermediate grades of dysplasia. Finally, the potential for IPMNs to be multifocal mandates that clinicians should be cognizant of the need for lifelong surveillance of the residual pancreas after partial pancreatectomy—even if histology of the primary IPMN reveals a noninvasive lesion.16

Sarcina organisms were first observed in and recorded from the stomach contents of a patient suffering from vomiting by John Goodsir in 1842. Since that time, their fine structure, phylogenetic classification, and biochemical characteristics have been described. Although numerous cases of fatal disease have been attributed to this organism in the veterinary literature, only a few human cases have been documented. As a result, whether this organism causes disease in humans has not been definitively established. We report the clinicopathologic findings in a series of 5 patients with Sarcina-like organisms identified in upper gastrointestinal endoscopic biopsies with molecular confirmation. Our findings have shown that the organism is most commonly found in patients with a history of gastric outlet obstruction or delayed gastric emptying. Although many of the patients do not demonstrate direct mucosal injury from the organism, the presence of a concurrent gastric ulcer puts the patient at increased risk for complications such as emphysematous gastritis or perforation. The finding of Sarcina organisms should prompt further investigation for functional causes of gastric outlet obstruction and delayed gastric emptying, such as occult malignancy.

Cyclooxygenase 2 (COX2) expression is up-regulated and associated with adverse prognosis in select types of carcinoma. Although not extensively studied in skeletal or soft tissue sarcoma, expression of COX2 has been described in a variable number of gynecological and non-gynecological leiomyosarcomas. In this study, the prevalence and prognostic implications of COX2 expression in leiomyosarcoma were evaluated further.Immunohistochemical stains for COX2 were performed on 33 samples of soft tissue leiomyosarcoma and tested for their association with clinicopathological parameters and patient outcome.COX2 staining was limited to tumor cells surrounding areas of tumor necrosis in 6 cases. There were no statistically significant correlations with the clinicopathological parameters studied, including local recurrence, distant metastasis, or disease-specific death.The low frequency, restricted distribution and absence of prognostic implications of COX2 expression soft tissue leiomyosarcoma suggest that this enzyme may not be a useful pharmacological target in this clinical setting.

The biological potential of soft tissue leiomyosarcoma is difficult to predict using current standard prognostic parameters, and control of systemic disease is challenging with current chemotherapeutic protocols. Additional prognostic markers and alternative treatment options are very much required. Previous studies implicate upregulation of the oncogenic nuclear transcription factor c-Myc with aggressive behavior of many solid tumors. Therefore, this oncoprotein was evaluated as a prognostic marker for overall and metastasis-free survival in leiomyosarcoma. Immunohistochemical stains for c-Myc were performed on 28 cases of leiomyosarcoma occurring in the deep somatic soft tissues. Comparisons of Kaplan-Meier survival curves stratified by c-Myc status and conventional prognostic factors (histological grade, tumor size, and tumor stage) were evaluated using standard univariate statistical methods. A subsequent multivariate survival analysis was carried out according to the Cox proportional hazards regression model adjusting for potential confounding prognostic factors. A total of 15 cases (54%) were positive for nuclear c-Myc expression. Patients with c-Myc-positive tumors had significantly shorter metastasis-free survival intervals compared with those with c-Myc-negative tumors (median, 9 months vs. >94 months; P=0.014). c-Myc positivity also correlated with decreased overall survival (median, 23 months vs. >94 months; P=0.017). Histological grade was the only other prognostic marker predictive of poor outcome in the univariate analyses. In the multivariate survival analysis, only c-Myc status reached statistical significance, suggesting that it is an important and independent predictor of prognosis in leiomyosarcoma. Detection of nuclear c-Myc in leiomyosarcoma predicts decreased overall and metastasis-free survival, independent of standard prognostic variables, tumor size, histological grade, and TNM stage. The expression of this oncoprotein may represent a useful prognostic marker and potential therapeutic target in leiomyosarcoma.

Sarcomas of the adult liver are unusual neoplasms, and can sometimes pose a difficult differential diagnosis. The authors report a myxoid spindle cell tumor arising in the liver of a 26-year-old woman. Histopathologic, immunohistochemical, and ultrastructural analysis demonstrated features of smooth muscle differentiation. Neoplastic nuclei were positive for estrogen receptor-beta and androgen receptor, but not estrogen receptor-alpha or progesterone receptor. Based on the large size of the tumor and the presence of conspicuous mitotic activity, the diagnosis of myxoid leiomyosarcoma was made. This case represents the third documented example of this tumor in the liver. The differential diagnosis in relation to this particular site of origin is discussed.

e16124 Background: The 17-gene prostate cancer assay is clinically validated as a biopsy-based gene expression assay that, combined with clinical features, provides an estimate of PCa disease aggre...

86 Background: Molecular assays can improve risk assessment for newly diagnosed PCa, but it is imperative to characterize assay performance in different racial groups, since tumor biology and clinical outcomes may vary. A racially diverse cohort of men (20% AA) with PCa in the Center for Prostate Disease Research multi-center national database was used to determine the association of GPS with outcomes in men treated with radical prostatectomy (RP) for localized PCa. Methods: Biopsy specimens from 431 men treated with RP for NCCN very low, low or intermediate risk PCa at 2 U.S. military medical centers were tested with a 17-gene RT-PCR assay to validate the association between GPS (scale 0-100) and 1) biochemical recurrence (BCR) following RP, and 2) adverse pathology (AP) at RP. BCR was defined as 2 successive PSA levels > 0.2 ng/mL. AP was defined as high-grade (primary Gleason pattern 4 or any pattern 5) and/or pT3 disease. Cox proportional hazards and logistic regression models were used. Results: GPS was obtained in 402 cases (93%), including 82 AA men. A broad range of GPS results was observed in both AA and CA men; GPS distributions were similar between AA (median GPS = 30.3; inter-quartile range (IQR): 23-38) and CA (median GPS = 30.3; IQR: 23-40); no correlation was observed between GPS and race (r = -0.04, p = 0.45). No differences in expression of individual genes or gene groups in the assay were observed between the two groups. In univariable analysis, PSA, biopsy GS and NCCN risk group were associated with BCR and AP, but race was not. The associations between GPS and clinical outcomes were similarly strong and statistically significant in both AA and CA men - BCR HR/20 GPS units = 3.0 (95% CI: 2.0-4.3) for CA vs. 3.5 (95% CI: 1.0-11.7) for AA; AP OR/20 units = 4.0 (95% CI: 2.6-6.6) for CA vs. 2.9 (95% CI: 1.2-7.6) for AA (p < 0.05 for all). Conclusions: In this cohort of patients treated in a health care system with equal access, clinical outcomes and the tumor biology measured by GPS were similar between AA and CA patients. GPS is a significant predictor of BCR and AP in men treated with RP for localized PCa in both AA and CA men.

455 Background: The Renal Cancer assay is a clinically validated RT-PCR assay developed to estimate the risk of recurrence in stage I-III clear cell renal cell carcinoma (ccRCC) patients (pts) treated with nephrectomy. The assay measures expression of 16 genes that are combined to calculate the Recurrence Score result (RS). The RS is associated with recurrence, renal cancer-specific survival and overall survival (all p7cm), grade, and presence/absence of invasion (all interaction p>0.29). Within-patient variability in the score (std. dev. of 1.73 and 4.74 RS units for within- and between-tumor block, respectively) was lower than patient-to-patient variability (std. dev. of 15.6 in validation study). Conclusions: The 16-gene signature remains strongly associated with risk of recurrence after adjustment for the Leibovich score and performs consistently across clinically relevant subgroups. Examination of within-patient and between-patient variability indicates that the score is robust to tumor heterogeneity.

4502 Background: New molecular diagnostics are needed to improve assessment of recurrence risk after nephrectomy in ccRCC. The 16-gene (11 cancer-related, 5 reference) Recurrence Score (RS) was pre...

5082 Background: The 17-gene Genomic Prostate Score, GPS (Genomic Health, Inc., Redwood City, CA), has been analytically (Knezevic et al. BMC Genomics 2013) and clinically validated as a biopsy-bas...

11 Background: Classic lobular carcinoma is characterized by a distinctive morphology, loss of E-cadherin commonly due to mutation or deletion of CDH1 on chromosome 16q, and a variable clinical course. Variants (pleomorphic, solid and alveolar) with distinct morphologies and potential differences in outcome have been described (Rosen 2009). Herein we provide an 8-year update of the patterns of quantitative gene expression as measured by the 21 gene Oncotype DX assay observed between ductal NOS (DC) and classic and variant lobular carcinomas. Methods: All tumors analyzed in the Genomic Health laboratory from 6/1/04-5/31/12 were included. Central path used WHO criteria for classification of classic lobular (CL), solid and alveolar lobular (SAL), and pleomorphic lobular (PL) carcinomas. Quantitative expression of 16 cancer related genes was measured on a scale from 2 to 15 (relative to reference genes) where a 1 unit increment is associated with an ~2-fold change in expression. Descriptive statistics for RS & individual genes [ER, PR, invasion gene group (IGG) and proliferation gene group (PGG)] among the subtypes were obtained. Comparisons of means among the subtypes were adjusted to control the overall error rate under any complete or partial null hypothesis. Results: DC accounted for 81.8% of 286,726 cases, CL 7.3%, SAL 0.4% and PL 0.4%. For all types a continuous range of RS was observed. DC had the greatest percentage of high risk RS followed by SAL, PL and CL. DC had the highest mean RS and PL and CL had the lowest RS. SAL had the highest mean ER expression and CL and PL had the lowest ER expression. These results may reflect a submission bias and are not population based. The proportion with ER+/PR- phenotype was slightly different among the subtypes: SAL (24.0%) and PL (19.4%) had a higher incidence compared to DC (14.1%) and CL (15.2%). SAL had the highest PGG expression; CL had the lowest. DC had the highest IGG; CL had the lowest. Conclusions: CL and the lobular carcinoma variants are characterized by differential patterns of gene expression. Outlier cases are not infrequent within each of the special subtypes in this large observational cohort. The variation in gene expression, noted by histologic subtype, will be presented in detail.

Introduction: Loss of heterozygosity (LOH) of chromosome arms 1p and 19q in gliomas has diagnostic, prognostic, and therapeutic implications. The deletion of 1p and the codeletion of chromosome arms 1p and 19q correlate with the diagnosis of oligodendroglioma, increased chemosensitivity and improved prognosis. Clinically, LOH is most frequently determined by Fluorescent In Situ Hybridization (FISH) and short tandem repeat (STR) analysis. Each approach suffers from the limitation that the probes/primers interrogate only a small portion of the chromosomes. Small deletions can be misinterpreted as LOH of the entire chromosome arm. We have investigated the use of a single nucleotide polymorphism (SNP) array for identifying LOH in gliomas. Methods: Genomic DNA was extracted from 5 formalin-fixed paraffin-embedded tissue samples following microdissection, and from peripheral blood. Samples were run on an ABI 3100 following multiplex PCR amplification of 5 STRs on chromosome 1p (D1S199, D1S186, D1S162, D1S312, D1S226) and 3 STRs on chromosome 19q (D19S918, D19S112, D19S206). Array analysis was performed using the Affymetrix genome-wide human SNP array 6.0 platform (906,600 SNPs) according to protocol. Data were analyzed with Partek Genomics Suite. Results: Cases 1 and 4 showed no LOH on chromosomes 1p and 19q by STR analysis and SNP array. Cases 2 and 5 showed LOH on chromosomes 1p and 19q by STR analysis and SNP array. Case 3 showed partial centromeric LOH on chromosome 1p by STR analysis which was confirmed by SNP array. Case 1 was a 48 year old male with anaplastic mixed oligoastrocytoma. Additional SNP array findings included a deletion of chromosome arm 13q. Case 4 was a 31 year old female with a low grade glioneural tumor, and no additional findings were made by SNP array. Case 2 was a 47 year old female with anaplastic oligodendroglioma. Additional SNP array findings included losses on chromosomes 5, 6, 9,15, and whole gain of chromosome 11. Case 5 was a 12 year old male with anaplastic oligodendroglioma. SNP array found additional losses on chromosomes 2, 3, 6, 8, 9, 10, and 20. Case 3 was a 47 year old female with an astrocytoma. Analysis of the 3 most centromeric STR loci on 1p demonstrated allelic imbalance that was consistent with LOH. The 2 most telomeric STR loci demonstrated allele ratios consistent with heterozygosity (negative for LOH). SNP array confirmed partial centromeric LOH on 1p and identified losses on chromosomes 2, 6, 10, 13, 16, and 22. Conclusion: Analysis of LOH on chromosome arms 1p and 19q by STR analysis and SNP array were concordant. SNP array identified additional gains or losses in each sample that were not detected by the STR assay. Interestingly, SNP array analysis also identified LOH on chromosome 13q, which contains the BRCA2 gene locus, in cases 1 and 3. If a second-hit can be identified, this may present a novel approach for identifying glioma patients who may potentially benefit from Poly (ADP-Ribose) Polymerase (PARP) inhibitor therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1781.