Showing papers by "Karla V. Ballman published in 2018"

Somatic mutations precede acute myeloid leukemia years before diagnosis.

Abstract: The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women’s Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the odds of developing AML. All subjects with TP53 mutations (n = 21 out of 21 patients) and IDH1 and IDH2 (n = 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered. Somatic mutations detected years before diagnosis increase the odds of development of acute myeloid leukemia in women.

Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: results of Alliance N0874/ABTC 02.

Abstract: Background Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.

An omnibus test for differential distribution analysis of microbiome sequencing data.

Abstract: Motivation One objective of human microbiome studies is to identify differentially abundant microbes across biological conditions. Previous statistical methods focus on detecting the shift in the abundance and/or prevalence of the microbes and treat the dispersion (spread of the data) as a nuisance. These methods also assume that the dispersion is the same across conditions, an assumption which may not hold in presence of sample heterogeneity. Moreover, the widespread outliers in the microbiome sequencing data make existing parametric models not overly robust. Therefore, a robust and powerful method that allows covariate-dependent dispersion and addresses outliers is still needed for differential abundance analysis. Results We introduce a novel test for differential distribution analysis of microbiome sequencing data by jointly testing the abundance, prevalence and dispersion. The test is built on a zero-inflated negative binomial regression model and winsorized count data to account for zero-inflation and outliers. Using simulated data and real microbiome sequencing datasets, we show that our test is robust across various biological conditions and overall more powerful than previous methods. Availability and implementation R package is available at https://github.com/jchen1981/MicrobiomeDDA. Contact chen.jun2@mayo.edu or zhiwei@njit.edu. Supplementary information Supplementary data are available at Bioinformatics online.

National trends in management of localized prostate cancer: A population based analysis 2004-2013.

Abstract: Purpose Recent years have brought many changes in the management of localized prostate cancer as national screening guidelines have been updated and diagnostic practice patterns evolved. We sought to better understand how the changing landscape influenced treatment utilization in the United States. Methods We used the SEER database in this retrospective analysis of patients with clinically localized prostate cancer between 2004 and 2013. We evaluated utilization of primary treatment modalities over time with descriptive and trend analyses, and examined treatment utilization by cancer risk group and age at diagnosis. Results Of 398 074 patients in the analytic data set, 38% elected radiation therapy, 38% underwent radical prostatectomy, and 24% opted for expectant management. While in 2004 radiation treatment was almost twice as common as expectant management (42% vs 23%), by 2013 approximately equal percentages of patients were treated with each of the three modalities. Expectant management use increased over time, while the proportion of patients opting for surgery decreased remarkably with increasing age at diagnosis in intermediate- and higher-risk disease. Among radiotherapy options, brachytherapy was most common among lower-risk patients in 2004 but substantially decreased over time (P < 0.001). Conclusions Management of localized prostate cancer changed substantially over time in the United States. Utilization of expectant management has increased for men with low- and intermediate risk cancer. Among those who pursue curative therapy, younger men remain more likely to elect surgery whereas older men tend to choose radiotherapy. Further studies are needed to better characterize factors contributing to treatment selection.

The Feasibility of Breast-Conserving Surgery for Multiple Ipsilateral Breast Cancer: An Initial Report from ACOSOG Z11102 (Alliance) Trial.

Abstract: Historically, multiple ipsilateral breast cancer (MIBC) has been a contraindication to breast-conserving therapy (BCT). We report the feasibility of BCT in MIBC from the ACOSOG Z11102 trial [Alliance], a single arm noninferiority trial of BCT for women with two or three sites of malignancy in the ipsilateral breast. Women who enrolled preoperatively in ACOSOG Z11102 were evaluated for conversion to mastectomy and need for reoperation to obtain negative margins. Characteristics of women who successfully underwent BCT and those who converted to mastectomy were compared. Factors were examined for association with the need for margin reexcision. Of 198 patients enrolled preoperatively, 190 (96%) had 2 foci of disease. Median size of the largest tumor focus was 1.5 (range 0.1–7.0) cm; 49 patients (24.8%) had positive nodes. There were 14 women who underwent mastectomy due to positive margins, resulting in a conversion to mastectomy rate of 7.1% (95% confidence interval [CI] 3.9–10.6%). Of 184 patients who successfully completed BCT, 134 completed this in a single operation. Multivariable logistic regression analysis did not identify any factors significantly associated with conversion to mastectomy or need for margin reexcision. Breast conservation is feasible in MIBC with 67.6% of patients achieving a margin-negative excision in a single operation and 7.1% of patients requiring conversion to mastectomy due to positive margins. No characteristic was identified that significantly altered the risk of conversion to mastectomy or need for reexcision. NCT01556243.

Axillary ultrasound identifies residual nodal disease after chemotherapy: Results from the American college of surgeons oncology group Z1071 trial (Alliance)

Abstract: OBJECTIVE The purpose of this study is to determine lymph node features on axillary ultrasound (US) images obtained after neoadjuvant chemotherapy that are associated with residual nodal disease i

Circulating RIPK3 levels are associated with mortality and organ failure during critical illness

Abstract: BACKGROUND. Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness. METHODS. Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data. RESULTS. In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure. CONCLUSIONS. Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure. FUNDING. Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

Phase I dose-escalation study of 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC).

Abstract: TPS399Background: PC is a radiosensitive disease. PSMA is overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of beta-emitting radiolabeled anti-PSMA monoclonal antibody (mAb) J591 have demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable, reversible dose-limiting myelosuppression. Alpha emitters are significantly more potent with a shorter range than beta emitters. Though there is no direct tumor-targeting, the bone-targeting alpha emitter Ra223 is approved. Anecdotal reports of PSMA small molecule targeted alpha emitters have hinted at efficacy but are limited by xerostomia and in mouse models may lead to long-term renal damage. Intact mAb J591 has comparatively no to minimal distribution in salivary glands and kidneys. Preclinical studies demonstrated purity, immunoreactivity, and stability with efficacy in a xenograft model [AACR 2017]. Metho...

SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy.

Abstract: Histone deacetylase inhibitors (HDACi) can reverse chemoresistance, enhance chemotherapy-induced cytotoxicity, and reduce sarcoma proliferation in cell lines and animal models. We sought to determine the safety and toxicity of mocetinostat and its ability to reverse chemoresistance when administered with gemcitabine in patients with metastatic leiomyosarcoma resistant to prior gemcitabine-containing therapy. Participants with metastatic leiomyosarcoma received mocetinostat orally, 70 mg per day, three days per week, increasing to 90 mg after three weeks if well tolerated. Gemcitabine was administered at 1,000 mg/m2 intravenously at 10 mg/m2/minute on days five and 12 of every 21-day cycle. Disease response was evaluated with CT or MRI. Twenty participants with leiomyosarcoma were evaluated for toxicity. Median time to disease progression was 2.0 months (95% CI 1.54–3.12). Eighteen participants were evaluated for radiologic response by RECIST 1.1. Best responses included one PR and 12 SD. Tumor size reduced in 3 patients. Most common toxicities were fatigue, thrombocytopenia, anemia, nausea, and anorexia. One patient experienced a significant pericardial adverse event. No study-related deaths were observed. Rechallenging with gemcitabine by adding mocetinostat was feasible and demonstrated modest activity in patients with leiomyosarcoma. Further studies are needed to better define the role of HDAC inhibitors in patients with metastatic leiomyosarcoma.

Targeted learning ensembles for optimal individualized treatment rules with time-to-event outcomes.

Abstract: We consider estimation of an optimal individualized treatment rule when a high-dimensional vector of baseline variables is available. Our optimality criterion is with respect to delaying the expected time to occurrence of an event of interest. We use semiparametric efficiency theory to construct estimators with properties such as double robustness. We propose two estimators of the optimal rule, which arise from considering two loss functions aimed at directly estimating the conditional treatment effect and recasting the problem in terms of weighted classification using the 0-1 loss function. Our estimated rules are ensembles that minimize the crossvalidated risk of a linear combination in a user-supplied library of candidate estimators. We prove oracle inequalities bounding the finite-sample excess risk of the estimator. The bounds depend on the excess risk of the oracle selector and a doubly robust term related to estimation of the nuisance parameters. We discuss the convergence rates of our estimator to the oracle selector, and illustrate our methods by analysis of a phase III randomized study testing the efficacy of a new therapy for the treatment of breast cancer.

Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer

Abstract: Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04). These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting. ClinicalTrials.gov, NCT00005970 . Registered on July 5, 2000.

SU2C-SARC032: A phase II randomized controlled trial of neoadjuvant pembrolizumab with radiotherapy and adjuvant pembrolizumab for high-risk soft tissue sarcoma.

Abstract: TPS11588Background: Radiotherapy (RT) and surgical resection achieve local tumor control for most large, high-grade soft tissue sarcomas (STS) of the extremity. However, many patients (pts) subsequ...

ABC trial (A011502): A randomized phase III double-blinded placebo controlled trial of aspirin as adjuvant therapy breast cancer.

Abstract: TPS597Background: In-vitro and in-vivo evidence suggest that aspirin may have an anti-tumor effect. Epidemiologic studies have reported improved breast cancer survival among regular aspirin users c...

A randomized, double-blind, placebo-controlled, phase II study of regorafenib vs placebo in advanced/metastatic, treatment-refractory liposarcoma: results from the SARC024 study.

Abstract: 11505Background: Pazopanib, a multi-targeted tyrosine kinase inhibitor, has shown activity in various soft tissue sarcomas. Activity in liposarcoma, however, is limited. Regorafenib is a multi-kina...

Meta-analysis of the cardiac events in the adjuvant trastuzumab trials.

Abstract: 10066Background: Cardiac dysfunction may occur in patients (pts) receiving adjuvant trastuzumab-based chemotherapy and long follow-up is required to better understand it. This meta-analysis of 3 ad...

Axillary vs Sentinel Lymph Node Dissection in Women With Invasive Breast Cancer-Reply.

Abstract: Author Contributions: Dr Cawley and Mr Willage had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Cawley, Frisvold. Acquisition, analysis, or interpretation of data: Cawley, Willage. Drafting of the manuscript: Cawley. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: All authors. Obtained funding: Cawley. Administrative, technical, or material support: Cawley. Supervision: Cawley.

Identification of risk factors for toxicity in patients with hormone receptor-positive advanced breast cancer treated with bevacizumab plus letrozole: a CALGB 40503 (alliance) correlative study.

Abstract: In hormone receptor-positive advanced breast cancer, a progression-free survival benefit was reported with addition of bevacizumab to first-line letrozole. However, increased toxicity was observed. We hypothesized that functional age measures could be used to identify patients at risk for toxicity while receiving letrozole plus bevacizumab for hormone receptor-positive advanced breast cancer. CALGB 40503 was a phase III trial that enrolled patients with hormone receptor-positive advanced breast cancer randomized to letrozole with or without bevacizumab. Patients randomized to bevacizumab were approached to complete a validated assessment tool evaluating physical function, comorbidity, cognition, psychological state, social support, and nutritional status. The relationship between pretreatment assessment measures and the incidence of grade ≥ 3 (National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0) adverse events was determined. One hundred thirteen (58%) of 195 patients treated with letrozole plus bevacizumab completed the pretreatment assessment questionnaire. One patient was excluded due to missing adverse event data. The median age of patients was 56. Frequently reported grade ≥ 3 adverse events were hypertension (26%), pain (20%), and proteinuria (7%). Two hemorrhagic events (one grade 5) and 1 thrombosis event occurred. Age ≥ 65 years (p < 0.01), decreased vision (p = 0.04), and poorer pretreatment physical function measures (p < 0.05) were found on univariate analysis to be significantly associated with increased incidence of grade ≥ 3 adverse events. Upon multivariate analysis, age ≥ 65 years (p = 0.01) and decreased vision (p = 0.04) remained significant. Univariable and multivariable logistic regression models demonstrated associations between age, vision, the ability to walk up flights of stairs, and grade ≥ 3 adverse events. Age (≥ 65 years), decreased vision, and impairments in physical function correlated with increased incidence of toxicity in patients receiving first-line letrozole plus bevacizumab. When evaluating therapy likely to increase toxicity, functional assessment measures can identify patients at increased risk for side effects who may benefit from closer monitoring.