Showing papers by "Karla V. Ballman published in 2020"

Association of Radial Artery Graft vs Saphenous Vein Graft With Long-term Cardiovascular Outcomes Among Patients Undergoing Coronary Artery Bypass Grafting: A Systematic Review and Meta-analysis.

Abstract: Importance Observational studies have suggested that the use of radial artery grafts for coronary artery bypass grafting may improve clinical outcomes compared with the use of saphenous vein grafts, but this has not been confirmed in randomized trials. Objective To compare clinical outcomes between patients receiving radial artery vs saphenous vein grafts for coronary artery bypass grafting after long-term follow-up. Design, Setting, and Participants Patient-level pooled analysis comparing radial artery vs saphenous vein graft in adult patients undergoing isolated coronary artery bypass grafting from 5 countries (Australia, Italy, Serbia, South Korea, and the United Kingdom), with enrollment from 1997 to 2009 and follow-up completed in 2019. Interventions Patients were randomized to undergo either radial artery (n = 534) or saphenous vein (n = 502) grafts for coronary artery bypass grafting. Main Outcomes and Measures The primary outcome was a composite of death, myocardial infarction, or repeat revascularization and the secondary outcome was a composite of death or myocardial infarction. Results A total of 1036 patients were randomized (mean age, 66.6 years in the radial artery group vs 67.1 years in the saphenous vein group; 376 [70.4%] men in the radial artery group vs 351 [69.9%] in the saphenous vein group); 942 (90.9%) of the originally randomized patients completed 10 years of follow-up (510 in the radial artery group). At a median (interquartile range) follow-up of 10 (10-11) years, the use of the radial artery, compared with the saphenous vein, in coronary artery bypass grafting was associated with a statistically significant reduction in the incidence of the composite outcome of death, myocardial infarction, or repeat revascularization (220 vs 237 total events; 41 vs 47 events per 1000 patient-years; hazard ratio, 0.73 [95% CI, 0.61-0.88];P Conclusions and Relevance In this individual participant data meta-analysis with a median follow-up of 10 years, among patients undergoing coronary artery bypass grafting, the use of the radial artery compared with the saphenous vein was associated with a lower risk of a composite of cardiovascular outcomes.

Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity

Abstract: Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10-20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors.

Alveolar Macrophage Immunometabolism and Lung Function Impairment in Smoking and Chronic Obstructive Pulmonary Disease.

Abstract: Metabolic plasticity involving shifts between mitochondrial respiration and glycolysis is emerging as a crucial component of innate immune cell function. The number of alveolar macrophages (AMs), the most abundant antigen-presenting cells in the lung, is increased in the lungs of individuals with chronic obstructive pulmonary disease (COPD), associating with disease severity and areas of lung destruction (1, 2). However, COPD AMs exhibit dysfunctional responses to infection and have lower phagocytic and bactericidal activity (3–5). Metabolism is a key determinant of immune cell function and is a vital component governing macrophage adaptation and responses. Metabolic reprogramming involving a shift from ATP production via the mitochondrial electron transport chain, toward anaerobic respiration via glycolysis, is an important proinflammatory effector function of macrophages (6). The presence and nature of any functional shifts in AM metabolic activity in COPD has not been determined. In this study, healthy nonsmokers, smokers, and individuals with COPD, all >8 weeks free of an acute exacerbation, underwent bronchoscopy with BAL and collection of AMs, as previously described (4). In BAL adherence-purified AMs, we first assessed the mitochondrial-related transcriptomic profile of AMs from 22 individuals with COPD, 42 smokers and 24 healthy control individuals, by HG-U133 Plus 2.0 microarray (Affymetrix; deposited as GSE130928, some of whom participated in a prior study [4]), normalized using the Robust Multi-Array method and filtered on the 1,938 mitochondrial-related probesets (Mitocarta2.0). Agecorrected analysis of covariance with Benjamini-Hochberg–corrected P, 0.05 considered significant, followed by grouping based on gene ontology biological processes, revealed significant alterations in mitochondria-related gene expression in response to cigarette smoke exposure and in COPD. A total of 105 genes (9%) were significantly differentially expressed in smokers versus nonsmoker control individuals with an enrichment of genes related to glutathione metabolism, mitochondrial transport, protein localization and translation, pyruvate metabolism, the tricarboxylic acid cycle, the electron transport chain, and fatty acid oxidation (false discovery rate–adjusted P, 0.05). A total of 129 genes (11%) were significantly altered in smokers with COPD versus nonsmoker control individuals, whereas 149 genes (13%) were significantly differentially expressed in smokers with COPD versus healthy smokers and were enriched for processes related to intrinsic apoptotic signaling pathways, mitochondrial fission, calcium transport, mitochondrial biogenesis, the NLRP1 inflammasome, pyruvate metabolism, complex I biogenesis, and fatty acid oxidation (false discovery rate– adjusted P, 0.05; Figure 1A). To assess function, we prospectively assessed mitochondrial and glycolytic metabolic activity in the AMs of 12 individuals with COPD, 18 smokers, and 23 healthy control individuals, using a Seahorse Bioanalyzer. Basal oxygen consumption rates and extracellular acidification rates (ECAR) of AMs were similar among nonsmoker control individuals, smokers, and patients with COPD; however, the coupling efficiency in AMs from smokers and individuals with COPD was significantly lower when compared with that of control individuals. Although ATP production was similar between phenotypes, proton leak was significantly higher in AMs from smokers and individuals with COPD versus nonsmoker control individuals. Maximal respiration and the spare respiratory capacity (reserve capacity) were significantly lower in AMs from patients with COPD than in those from smokers. The Bioenergetic Health Index (representing the composite mitochondrial profile) of AMs from both smokers and individuals with COPD was also significantly lower than that of healthy control individuals (Figure 1B and Table 1). If the spare respiratory capacity is decreased and the threshold activity cannot be met, glycolysis may be stimulated to meet cellular energetic needs. In this study, the rate of glycolysis-specific proton efflux (GlycoPER) was significantly higher in AMs from smokers versus those from healthy control individuals, and smokers had significantly higher post-2G-GlycoPER (the nonglycolytic, nonmitochondrial cellular ECAR) versus healthy control individuals. In contrast, patients with COPD had significantly lower compensatory glycolysis, post–2DG-GlycoPER, and mitochondrial-specific glycolysis versus smokers (Figure 1C and Table 1). Finally, we examined whether the above AM characteristics associated with clinical parameters including FEV1% predicted and DLCO by implementing a linear model that also included age, sex, and subject number. Maximal respiration, spare respiratory capacity, Bioenergetic Health Index, compensatory glycolysis, and post-2DG correlated with spirometric impairment, as defined by FEV1% predicted (Figures 1D and 1E). In addition, the expression of 219 (19%) mitochondrial-related genes significantly correlated with FEV1% predicted in control individuals, healthy smokers, and COPD smokers (Figure 1F). A low DLCO in individuals with normal FEV1% predicted has been linked to the development of COPD (7). Here, AM proton leak was numerically higher (mean, 7.38 vs. 4.44 pmol/min/ng DNA; P= 0.21), and coupling efficiency was lower (0.82 vs. 0.87 pmol/min/ng DNA; P= 0.21), in smokers with a low DLCO than in healthy smokers. Smokers with a low DLCO also had significantly lower Bioenergetic Health Index when Supported by NIH grants R00-20 HL125899 (S.M.C.), HL113443 (R.G.C.), HL1189541 (R.G.C.), and HL094284 (M.R.R.).

Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort

Abstract: BACKGROUNDMitochondrial dysfunction, a proposed mechanism of chronic obstructive pulmonary disease (COPD) pathogenesis, is associated with the leakage of mitochondrial DNA (mtDNA), which may be detected extracellularly in various bodily fluids. Despite evidence for the increased prevalence of chronic kidney disease in COPD subjects and for mitochondrial dysfunction in the kidneys of murine COPD models, whether urine mtDNA (u-mtDNA) associates with measures of disease severity in COPD is unknown.METHODSCell-free u-mtDNA, defined as copy number of mitochondrially encoded NADH dehydrogenase-1 (MTND1) gene, was measured by quantitative PCR and normalized to urine creatinine in cell-free urine samples from participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Urine albumin/creatinine ratios (UACR) were measured in the same samples. Associations between u-mtDNA, UACR, and clinical disease parameters - including FEV1 % predicted, clinical measures of exercise tolerance, respiratory symptom burden, and chest CT measures of lung structure - were examined.RESULTSU-mtDNA and UACR levels were measured in never smokers (n = 64), smokers without airflow obstruction (n = 109), participants with mild/moderate COPD (n = 142), and participants with severe COPD (n = 168). U-mtDNA was associated with increased respiratory symptom burden, especially among smokers without COPD. Significant sex differences in u-mtDNA levels were observed, with females having higher u-mtDNA levels across all study subgroups. U-mtDNA associated with worse spirometry and CT emphysema in males only and with worse respiratory symptoms in females only. Similar associations were not found with UACR.CONCLUSIONU-mtDNA levels may help to identify distinct clinical phenotypes and underlying pathobiological differences in males versus females with COPD.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov ( NCT01969344).FUNDINGUS NIH, National Heart, Lung and Blood Institute, supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici S.p.A., Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Novartis Pharmaceuticals Corporation, Nycomed GmbH, ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, Sunovion, Takeda Pharmaceutical Company, and Theravance Biopharma and Mylan.

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Abstract: Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in ∼10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data suggest a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

A pooled analysis of the cardiac events in the trastuzumab adjuvant trials

Abstract: Trastuzumab-associated cardiotoxicity remains an issue for patients with HER2-positive breast cancer. This pooled analysis of 3 adjuvant trials investigated the incidence, timing, impact on treatment completion, and risk factors for trastuzumab-associated cardiotoxicity. This is an individual patient data level pooled analysis of HERA, NSBAP B-31, and NCCTG 9831 (Alliance Trials). Definitions of cardiac events were as per each individual study. A total of 7445 patients enrolled in the 3 trials were included in the analysis, of which 4017 were in the trastuzumab and 3428 in the control (observation) arms, respectively. Median follow-up exceeded 10 years (119.2–137.2 months). Nearly all patients (97.4%) in the trastuzumab arms received anthracycline-based chemotherapy. In total, 452 patients in the trastuzumab arms experienced a cardiac event (11.3%), with most being mildly symptomatic or asymptomatic left ventricular ejection fraction (LVEF) decrease (351 patients, 8.7%). Severe congestive heart failure was more common in the trastuzumab arm (2.3%) than in the control arm (0.8%). Most cardiac events occurred during trastuzumab treatment (78.1%) and cardiac events were the main cause of discontinuation across the sample (10.0%); nevertheless, a large majority of patients completed trastuzumab treatment (76.2%). Baseline risk factors that were significantly associated with the development of cardiac events were baseline LVEF 25, age ≥ 60 and, non-Caucasian ethnicity. One year of trastuzumab increases the risk of cardiac events, though most consist of asymptomatic or mildly symptomatic LVEF drops. Adjuvant trastuzumab should be considered a safe treatment from a cardiac standpoint for most patients. Trastuzumab-associated cardiotoxicity is the main cause of discontinuation and further research is needed to individualize prevention and management.

Efficacy of osimertinib against EGFRvIII+ glioblastoma.

Abstract: Epidermal Growth Factor Receptor variant III (EGFRvIII) is an active mutant form of EGFR that drives tumor growth in a subset of glioblastoma (GBM). It occurs in over 20% of GBMs, making it a promising receptor for small molecule targeted therapy. We hypothesize that poor penetration of the blood-brain barrier by previously tested EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as afateninb, erlotinib, gefitinib, and lapatinib played a role in their limited efficacy. The present study examined the effects of osimertinib (previously known as AZD9291) on EGFRvIII+ GBM models, both in vitro and in vivo. Therefore, a panel of six GBM stem cells (GSCs) expressing EGFRvIII+ was evaluated. The EGFRvIII+ GSC differed in the expression of EGFRvIII and other key genes. The GSC line D317, which expresses high levels of EGFRvIII and has robust tyrosine kinase activity, was selected for assessing osimertinib's efficacy. Herein, we report that osimertinib inhibits the constitutive activity of EGFRvIII tyrosine kinase with high potency (<100 nM) while also inhibiting its downstream signaling. Further, osimertinib inhibited D317's growth in vitro and in both heterotopic and orthotopic xenograft models. Additional preclinical studies are warranted to identify EGFRvIII+ GBM's molecular signature most responsive to osimertinib.

Final report from Intergroup NCCTG 86-72-51 (Alliance): a phase III randomized clinical trial of high-dose versus low-dose radiation for adult low-grade glioma.

Abstract: Background The optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma. Methods Between 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Results For all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2-10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3-6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter 27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. Conclusions Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.

Dose-escalation results of a phase I study of 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC).

Abstract: 114Background: Prostate-specific membrane antigen (PSMA) can be targeted by antibodies (Ab) or small molecule ligands labeled with potent α emitters (e.g. 225Ac). Unlike ligands, Ab biodistribution...

PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).

Abstract: TPS4596Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunothera...

Increased airway iron parameters and risk for exacerbation in COPD: an analysis from SPIROMICS

Abstract: Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) bronchoscopy sub-study (n = 195) BALF Iron parameters were compared to systemic markers of iron availability and tested for association with FEV1 % predicted and exacerbation frequency Exacerbations were modelled using a zero-inflated negative binomial model using age, sex, smoking, and FEV1 % predicted as clinical covariates BALF iron and ferritin were higher in participants with COPD and in smokers without COPD when compared to non-smoker control participants but did not correlate with systemic iron markers BALF ferritin and iron were elevated in participants who had COPD exacerbations, with a 2-fold increase in BALF ferritin and iron conveying a 24% and 2-fold increase in exacerbation risk, respectively Similar associations were not observed with plasma ferritin Increased airway iron levels may be representative of a distinct pathobiological phenomenon that results in more frequent COPD exacerbation events, contributing to disease progression in these individuals

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Regorafenib Versus Placebo in Advanced/Metastatic, Treatment-Refractory Liposarcoma: Results from the SARC024 Study

Abstract: Lessons learned The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. Background Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. Methods Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. Results Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92-3.67) months for regorafenib versus 2.07 (95% CI, 1.64-3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16-23.48) months for regorafenib and 4.89 (95% CI, 3.02-9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31-1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. Conclusion Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.

Cosmetic Outcomes Following Breast-Conservation Surgery and Radiation for Multiple Ipsilateral Breast Cancer: Data from the Alliance Z11102 Study.

Abstract: Diagnoses of multiple ipsilateral breast cancer (MIBC) are increasing. Historically, the primary treatment for MIBC has been mastectomy due to concerns about in-breast recurrence risk and poor cosmetic outcome. The Alliance Z11102 study prospectively assessed cosmetic outcomes in women with MIBC treated with breast-conserving therapy (BCT). Z11102 was a multicenter trial enrolling women with two or three separate sites of biopsy-proven malignancy separated by ≥ 2 cm within the same breast. Cosmetic outcome was a planned secondary endpoint. Data were collected with a four-point cosmesis survey (1 = excellent, 4 = poor) and the BREAST-Q (scored 0–100). All patients undergoing successful breast-conserving therapy were treated with whole-breast radiation. Associations were assessed with Chi square or Fisher’s exact tests as appropriate. Cosmetic outcome data for 216 eligible women who completed therapy are included in this analysis. Of the 136 patients who completed the survey 2 years postoperatively, 70.6% (N = 96) felt the result was good or excellent, while 3.7% (N = 5) felt the result was poor. We found no significant differences in patient-reported cosmetic outcomes when stratifying by patient age, number of lesions (two or three), number of incisions, number of lumpectomies, or size of largest area of disease. Mean satisfaction score on the BREAST-Q was 77.2 at 6 months following whole-breast radiation and 73.7 at 3 years following surgery. BCT performed for MIBC results in good or excellent cosmesis for the majority of women. From a cosmetic perspective, BCT is a valid surgical approach to women with MIBC. ClinicalTrials.gov Identifier: NCT01556243.

Clinical significance of circulating tumor cells in hormone receptor-positive metastatic breast cancer patients who received letrozole with or without bevacizumab

Abstract: Multiple studies have identified transcriptome subtypes of high-grade serous ovarian carcinoma (HGSOC), but their interpretation and translation are complicated by tumor evolution and polyclonality accompanied by extensive accumulation of somatic aberrations, varying cell type admixtures, and different tissues of origin In this study, we examined the chronology of HGSOC subtype evolution in the context of these factors using a novel integrative analysis of absolute copy number analysis and gene expression in The Cancer Genome Atlas complemented by single-cell analysis of six independent tumors Tumor purity, ploidy, and subclonality were reliably inferred from different genomic platforms, and these characteristics displayed marked differences between subtypes Genomic lesions associated with HGSOC subtypes tended to be subclonal, implying subtype divergence at later stages of tumor evolution Subclonality of recurrent HGSOC alterations was evident for proliferative tumors, characterized by extreme genomic instability, absence of immune infiltration, and greater patient age In contrast, differentiated tumors were characterized by largely intact genome integrity, high immune infiltration, and younger patient age Single-cell sequencing of 42,000 tumor cells revealed widespread heterogeneity in tumor cell type composition that drove bulk subtypes but demonstrated a lack of intrinsic subtypes among tumor epithelial cells Our findings prompt the dismissal of discrete transcriptome subtypes for HGSOC and replacement by a more realistic model of continuous tumor development that includes mixtures of subclones, accumulation of somatic aberrations, infiltration of immune and stromal cells in proportions correlated with tumor stage and tissue of origin, and evolution between properties previously associated with discrete subtypes

Phase I dose-escalation study of PSMA-targeted alpha emitter 225Ac-J591 in men with metastatic castration-resistant prostate cancer (mCRPC).

Abstract: 5560Background: Antibodies (Abs) or small molecules can target PSMA with different biodistribution. Certain sites of PSMA expression (e.g. salivary/lacrimal glands, kidneys, small bowel) are not ac...

Prognostic value of the SPOP mutant genomic subclass in prostate cancer

Abstract: Background Speckle-type POZ protein (SPOP) mutation defines one of the dominant prostate cancer genomic subtypes, yet the impact of this mutation on clinical prognosis is unknown. Methods We defined SPOP mutation status either by DNA sequencing or by transcriptional signature in a pooled retrospective multi-institutional cohort, the Decipher retrospective cohort, the Decipher Genomics Resource Information Database prospective cohort, and The Cancer Genome Atlas. Kaplan-Meier survival analysis and multivariable Cox models were used to assess the independent impact of SPOP mutation on survival, biochemical recurrence and time to metastasis. The Decipher retrospective cohort was also used to assess the impact of the addition of SPOP mutation status to a model predicting adverse pathology at prostatectomy which was then validated in the Decipher prospective cohort. Results A fixed-effect model incorporating results from multivariable Cox regression including 5,811 subjects demonstrated that SPOP mutation was associated with a lower rate of adverse pathology at radical prostatectomy (odds ratios 0.57, 95% confidence interval 0.34–0.93), independent of preoperative prostate-specific antigen, age, and pathologic Gleason score. SPOP was not associated with biochemical recurrence, metastasis-free survival, or cancer-specific survival independent of pathologic information. The addition of SPOP status to prognostic models reclassified a large proportion of patients with the mutation (55%) into a favorable risk group when used to predict adverse pathology. Conclusion While the clinical utility of delineating any single molecular alteration in prostate cancer remains unclear, these results illustrates the importance of genomic subtypes in prostate cancer behavior and potential role in prognostic tools.

Role of Specialized mSWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Abstract: Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in ~10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data suggest a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

Codel: phase iii trial of rt alone, rt plus tmz, or tmz alone for newly-diagnosed, 1p/19q codeleted anaplastic oligodendroglioma. analysis from the initial study design. (ncctg n0577, alliance)

Abstract: The original 3-arm CODEL design included a radiotherapy (RT)-alone control arm, an RT plus temozolomide (TMZ) arm, and an exploratory TMZ-alone arm. We report the analysis involving patients treated per the initial design. Adults (18+ years) with newly-diagnosed 1p/19q codeleted WHO grade III oligodendroglioma were randomized to RT (5940 cGy) alone (Arm A); RT with concomitant and adjuvant TMZ (Arm B); or TMZ alone (Arm C). Primary endpoint was OS, Arm A vs. B. Secondary comparisons were performed for OS and PFS, comparing pooled RT arms with the TMZ-alone arm. 36 patients were randomized equally to the three arms. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients had progressed, versus 37.5% (9/24) patients on the RT arms. PFS was shorter in TMZ-alone patients compared to RT-treated patients (HR=3.12; 95% CI: 1.26, 7.69; p=0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) of RT-treated patients. OS did not statistically differ between arms, although this comparison was underpowered. After adjustment for IDH status (mutated vs. wildtype) in a Cox regression model, with IDH status and RT treatment status as co-variables (Arm C vs pooled A and B), PFS remained shorter for patients not receiving RT (HR= 3.33; 95% CI: 1.31, 8.45; p=0.011), and OS differences remained non-significant ((HR = 2.78; 95% CI 0.58, 13.22, p=0.20). Grade 3+ adverse events occurred in 25%, 42% and 33% patients (Arms A, B and C, respectively). Neurocognitive assessments, comparing baseline and 3 month timepoints, showed no significant differences between arms. TMZ-alone treated patients experienced significantly shorter PFS than patients treated on the pooled RT arms, which remained significant when adjusting for IDH status. CODEL has been redesigned to compare the efficacy and toxicity of RT+PCV versus RT+TMZ. Clinicaltrials.gov Identifier: NCT00887146. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org.

Correction to: Nomogram-based estimate of axillary nodal involvement in ACOSOG Z0011 (Alliance): validation and association with radiation protocol variations.

Abstract: A substantial proportion of patients enrolled on ACOSOG Z0011 received protocol-deviant radiation treatment. It is currently unknown whether these deviations involved the use of more extensive fields in patients at higher nomogram-predicted risk. We used the M.D. Anderson (MDA) and Memorial Sloan-Kettering (MSK) nomograms to estimate risk of additional positive axillary nodes using surgical pathology information. In the control arm, we compared axillary dissection (AD) findings to nomogram-predicted estimates for validation. We used logistic regression to evaluate whether nomogram-estimated higher risk of nodal involvement was associated with high tangent (HT) or supraclavicular (SCV) radiation fields for patients with known radiation field design. 552/856 (64.5%) had complete details for the MDA nomogram. Mean MDA risk estimate in both treatment arms was 23.8%. Estimated risk for patients on the AD arm with positive nodes was 25.9%. Higher risk estimate was associated with additional positive nodes in the AD arm (OR 1.04, 95% CI 1.02–1.06, p < 0.0001). We observed significant association with higher MDA nomogram-estimated risk and SCV radiation (OR 1.07, 95% CI 1.04–1.10, p < 0.0001) but not HT (OR 0.99, 95% CI 0.96–1.02, p = 0.52) The MSK nomogram had similar associations. MDA and MSK nomogram risk estimates were associated with lymph node risk in ACOSOG Z0011. Radiation oncologists’ use of differing radiation fields were associated with treating higher risk patients. ClinicalTrials.gov id: NCT00003855.

Temporal trends in the number of men electing for conservative management for low-risk prostate cancer in the United States.

Abstract: Concurrent with the decrease in the number of men diagnosed with prostate cancer (PCa), the proportion of men with low-risk PCa managed conservatively (active surveillance or watchful waiting) has increased in the United States. We aimed to determine whether this increase is a result of more men being managed conservatively or rather a higher proportion of the diminishing number of low-risk PCa managed this way. The SEER “Prostate Watchful Waiting Database” identified men managed initially with conservative management between 2010 and 2016. Men > 40 years old who were diagnosed with low-risk (Gleason score 3 + 3, T1–T2a, PSA level < 10 ng/mL) PCa were included. Age-standardized and age-specific PCa incidence and conservative management rates were calculated per 100,000 man-years. The annual percent change in rates for the entire time period was also calculated. The incidence of low-risk PCa declined by 11.8% per year (95% confidence interval [CI] −15.4% to −8.0%), whereas the number of men assigned to conservative management for low-risk disease did not increase significantly, rising by +3.7% per year (95% CI −0.7% to 8.4%). In age-specific analysis, the number of men < 60 years and those who were 60–69 years managed conservatively increased by +9.6% per year (95% CI 2.7% to 16.9%) and 4.5% per year (95% CI 0.1% to 9.1%), respectively, whereas the number of men ≥ 70 years electing conservative management remained stable at −4% per year (95% CI −11.2% to 3.7%). The number of men electing conservative management has remained largely stable between 2010 and 2016, despite an increase in the proportion of low-risk PCa managed in this manner.