bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-05-03: Progesterone receptor antagonists as inhibitors of breast cancer stem cell activity
Authors: Alferez D , Clarke RB , Cresta C , Mnene S , Howell SJ
Published: August 2014

Background: Tamoxifen has become the standard of care for premenopausal women with hormone receptor positive breast cancer (BC). However, resistance to Tamoxifen therapy remains a major clinical problem and we have evidence that cancer stem cells (CSCs) may play a role in recurrence in these patients. The progesterone receptor (PR) is a potential therapeutic target in BC but development of steroidal PR antagonists (PRAs) has been halted due to toxicity issues, despite evidence of activity. Recent reports have linked PR activity to the expansion of adult mammary gland stem cells through paracrine effectors such as RANK-L.

Methods: To investigate the effects of PR antagonism on CSCs, we have tested 2 non-steroidal PRAs; onapristone (Schering AG/Arno Therapeutics) and AZPRA (AstraZeneca) in 2 hormone receptor positive BC cell lines (MCF-7 & T47D) and 8 patient-derived samples (PDS; from malignant pleural effusions and ascitic fluid), using a low adherence mammosphere assay. Western and gene expression array analysis of PDS samples were performed to identify predictive biomarkers.

Results: In the presence of 10nM P4 AZPRA inhibited mammosphere forming efficiency (MFE) in MCF-7 cells by 32% (p<0.0001) and in T47D by 21% (p<0.0001). Similar results were seen with onapristone (34% inhibition in MCF-7 (p<0.002) and 34% in T47D cells (p<0.0002). AZPRA or onapristone significantly reduced MFE in 7 of 8 PDS. Tamoxifen affected MFE in 4/6 PDS samples. In 5 of 7 PDS tested additive effects were seen when AZPRA was combined with tamoxifen (>80% reduction in MFE; p<0.001). A similar effect was seen with onapristone (>70% reduction in MFE (p<0.05)). Data from Western analysis of PR A and B isoforms and gene expression analysis of PDS samples will be presented at the conference.

Conclusions: Preliminary data on PR inhibition presented here support the rationale of administration of PRA in the clinic but predictive biomarkers are required to identify which patients are likely to benefit. Combination of PRA with current anti-oestrogen therapies such as Tamoxifen may be a way of overcoming resistance mechanisms by targeting CSCs.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-05-03.
Abstract S5-04: Primary results of ROSE/TRIO-12, a randomized placebo controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer
Authors: Mackey JR , Ramos-Vazquez M , Lipatov O , McCarthy N , Kraznozhon D , Semiglazov V , Manikhas A , Gelmon K , Konecny G , Webster M , Hegg R , Verma S , Gorbounova V , Abi Gerges D , Thireau F , Fung H , Simms L , Buyse M , Ibrahim A , Martin M
Published: August 2014

Background: To date, anti-angiogenic strategies in metastatic breast cancer have demonstrated benefits confined to modest improvements in progression-free survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab, an anti-VEGF receptor 2 antibody, is a human IgG1 antibody that specifically binds VEGF receptor 2 and blocks ligand stimulated activation. Early phase studies suggested anticancer effects in several solid tumors, and a phase III study demonstrated survival improvements in gastric cancer. The ROSE trial was designed to evaluate ramucirumab in the setting of HER2 negative, unresectable locally recurrent or metastatic breast cancer.

Methods: In this placebo-controlled randomized multinational phase III trial, patients with HER2 negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomized 1:2 to receive docetaxel 75 mg/m2 + placebo IV every three weeks, or to the same chemotherapy + ramucirumab 10 mg/kg IV every three weeks. Treatment was continued with each agent until investigator determined progressive disease using RECIST criteria, or until unacceptable toxicity. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographical region. An independent data monitoring committee oversaw the trial conduct, the efficacy database resides with TRIO, and this analysis was conducted by the TRIO statistical team in collaboration with Eli Lilly and Co. The primary endpoint was investigator-assessed PFS. The sample size was calculated to provide for this event-driven final PFS analysis and interim OS analysis, and a final OS analysis (to be conducted when at least 792 OS events are observed). ROSE also includes evaluation of potential predictive biomarkers.

Results: Between Aug 2008 and Dec 2011, 1144 patients were randomized. At data cut-off (March 31, 2013), median follow-up was 16.2 months. Safety, final PFS and interim OS results will be presented. Anticipated data availability is early November 2013.

Aggregated Patient CharacteristicsAge(years) 24 - 82Prior Taxane Therapy(%)No74 (%)Yes26Visceral Metastasis(%)No29  Yes71Hormonal Receptor(%)Negative/Unknown24  Positive76Geographic Region(%)Americas24  Asia/Middle East/Africa12  Europe/Australia/New Zealand64

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-04.
Abstract S5-07: SWOG S0500 – A randomized phase III trial to test the strategy of changing therapy versus maintaining therapy for metastatic breast cancer patients who have elevated circulating tumor cell (CTC) levels at first follow-up assessment
Authors: Smerage JB , Barlow WE , Hayes DF , Winer EP , Leyland-Jones B , Srkalovic G , Tejwani S , Schott AF , O'Rourke MA , Lew DL , Gralow JR , Livingston RB , Hortobagyi GN
Published: August 2014

Introduction:

CTC are detectable in approximately 75% of patients with metastatic breast cancer (MBC), and are elevated (≥5CTC/7.5 ml whole blood (WB)) in about half. Elevated CTC at baseline are associated with a worse prognosis, and a decline in CTC levels suggests response to therapy. We initiated a prospective randomized clinical trial (SWOG S0500) to test whether a change in chemotherapy after failure to clear CTC after one cycle of first line chemotherapy would improve outcomes of patients starting first line cytotoxic chemotherapy for MBC.

Methods:

Patients initiating first-line chemotherapy for MBC were enrolled. All patients had measurable or evaluable disease that included bone metastases. Patients with elevated CTC at baseline and who continued to have elevated CTC after 21 days of therapy were randomly assigned to either continue initial therapy until progression or to change to a second line chemotherapy (physician choice) immediately at cycle 2. Patients with elevated CTC at baseline, which were not elevated at the 21-day follow-up were maintained on their initial therapy. Patients without elevated CTC at baseline were followed in an observation arm. The primary endpoint was overall survival, and progression-free survival was a secondary endpoint. It was expected that approximately 500-650 patients would have to be screened to enroll 120 patients in the randomized trial. Power was 81% with 2-sided α = 0.05 to detect a 70% increase in median overall survival for patients randomized to change therapy. Three interim analyses were planned during the course of the trial.

Results:

From 10/1/2006 until 3/15/2012, 624 patients were registered of whom 612 were eligible. A baseline CTC was obtained in 593 (97%) eligible patients of whom 317 (53%) had elevated CTC at baseline. Thirty-one patients (10%) with elevated baseline CTC did not complete the follow-up CTC due to death, progression, withdrawal, or assay failure. Of the 286 remaining patients, 123 patients (43%) continued to have elevated CTCs after the first cycle of chemotherapy and were randomly assigned to either maintain original chemotherapy (n = 64) or switched to new chemotherapy (n = 59).

Final outcome results will be analyzed in October 2013 and will be reported if released by the SWOG Data Safety Monitoring Board.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-07.
Abstract A54: The association of county level characteristics with the incidence of squamous cell carcinoma of the cervix in Hispanic women.
Authors: Ward Kristy K. , Roncancio Angelica M. , Plaxe Steven C.
Published: August 2014

Purpose: To evaluate the association of county level characteristics with the incidence of invasive squamous cell carcinoma of the cervix among Hispanic women.

Methods: The Surveillance, Epidemiology, and End Results (SEER) Program's 18 registries from 2000-2009 were queried and average annual age-adjusted incidence rates per 100,000 Hispanic women for invasive squamous cell carcinoma of the cervix (SCC) were calculated. Patients were stratified by residence in a county with high versus low percent language isolation, percent of Hispanics with less than a high school education and percent of Hispanic families below the poverty level.

Results: Between 2000-2009, 5,534 Hispanic women were diagnosed with SCC in SEER. Incidence rates were highest among those living in counties with high levels of LI (8.9 v 10.7), or low levels of education (8.9 v 10.8) or income (8.7 v 11.0). The incidence of SCC was significantly less in women living in counties with higher levels of education and income and lower levels of LI than among those living in counties with lower levels of education and income and higher levels of LI (8.6 v. 11.3). Counties that have higher levels of income and education are less likely to be LI whereas counties with lower levels of income and education are more likely to be LI.

Conclusions: Among Hispanic women, county level characteristics such as LI, education, and income have a complex interaction that appears to be associated with the incidence of SCC. Community level interventions need to be evaluated to decrease the high incidence of SCC in this population.

Citation Format: Kristy K. Ward, Angelica M. Roncancio, Steven C. Plaxe. The association of county level characteristics with the incidence of squamous cell carcinoma of the cervix in Hispanic women. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A54.
Abstract B06: Rural women's decision making about cervical cancer prevention in South Carolina.
Authors: Bellinger Jessica D. , Millegan Whitney , Abdalla Azza , Creek Kim
Published: August 2014

Objective: Despite advances in screening and prevention, cervical cancer disparities have been detected in minority, rural, and underserved women. This study explored women's knowledge, attitudes, and behavior related to human papillomavirus (HPV) and cervical cancer prevention in South Carolina, which ranks fourteenth in the United States in cervical cancer incidence and mortality.

Methods: Three focus groups were conducted in two rural and urban counties as part of a community-based participatory (CBPR) project. Instrument development and participant recruitment were conducted in partnership with a community advisory board. Snowball sampling was employed to recruit twenty-eight adult women (18-70 years of age). An Institutional Review Board approved the study and informed consent was obtained.

Results: Cervical cancer prevention knowledge varied, with urban women reporting greater exposure to public health campaigns. Most participants had more positive views about screening than HPV vaccination, but were less knowledgeable about current screening guidelines. Lack of health insurance, transportation, and costs were main barriers to screening. Provider recommendations for HPV vaccination also emerged as a barrier. Lack of provider recommendations and ineffective patient-provider communication were viewed as greater barriers to HPV vaccination than cost due to expanded access vaccination programs.

Conclusions: Rural women view cervical cancer screening as an important health service; however, their health decisions are informed by cancer prevention knowledge, access to care, cost concerns. Providers are a trusted source of health information and present an opportunity to convey culturally-appropriate evidence-based messages about cervical cancer prevention and control.

Citation Format: Jessica D. Bellinger, Whitney Millegan, Azza Abdalla, Kim Creek. Rural women's decision making about cervical cancer prevention in South Carolina. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B06.
Abstract B08: Examining community-perceived cancer mortality from industrial toxins along the Houston Ship Channel through spatial-temporal analysis in a GIS environment.
Authors: Jordan Demetrice R. , King Denae Waller , Jones Lovell A.
Published: August 2014

Studies demonstrate that economically deprived minority communities are often disproportionately located in close proximity to industrial sources of pollution, and often these pollutants are known to cause cancer. Additionally, prolonged exposure to toxins such as, benzene and 1,3 butadiene, known human carcinogens and by-products of petroleum refining, can result in high premature cancer mortality. Recent studies have revealed an increased risk of cancer for port communities, similar to Galena Park, Texas located along the Houston Ship Channel; however, these studies did not investigate mortality concerns. This project seeks to investigate the community-identified concerns regarding cancer-related death clusters within the Galena Park community and other communities located along the Houston Ship Channel, between 1990 and 2010, through spatial analysis using Geographic Information Systems (GIS). Preliminary findings suggest that approximately 1 in 5 premature cancer related deaths within the study area were attributed to cancers with a known association to benzene and 1,3 butadiene exposure. Spatially the findings reveal that the historically high premature cancer mortalities occurred in the predominantly minority and economically disadvantaged areas in close proximity to the Houston Ship Channel with higher ambient air concentrations of these toxins than more affluent areas in the region.

Citation Format: Demetrice R. Jordan, Denae Waller King, Lovell A. Jones. Examining community-perceived cancer mortality from industrial toxins along the Houston Ship Channel through spatial-temporal analysis in a GIS environment. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B08.
Abstract SS01-04: Objective and perceived risk of cervical cancer risk among Appalachian women.
Authors: Paskett Electra D. , Bons Nicolas P. , Reiter Paul L.
Published: August 2014

Objectives: Appalachia is a geographic area with elevated cervical cancer incidence rates, yet little research has examined the accuracy of the cervical cancer risk perceptions of women living in this region. We examined the accuracy of Appalachian women's cervical cancer risk perceptions and identified factors correlated with accurate risk perceptions.

Methods: Completed in 2006, we surveyed women (n=411) from Appalachian Ohio for the Community Awareness Resources Education (CARE) study. We calculated women's actual cervical cancer risk using the CARE Risky Sexual Behavior Index (classified as high, medium, or low risk), and women indicated their perceived risk of cervical cancer (classified as higher than, about the same as, or lower than other women). We used multivariate logistic regression to identify factors correlated with women accurately classifying their risk.

Results: About 38% of women had high actual risk of cervical cancer, 31% had medium risk, and 31% had low risk. Most women (56%) perceived their risk of cervical cancer to be about the same as other women. About 38% of women accurately classified their cervical cancer risk. Women ages 31-50 (OR=1.77, 95% CI: 1.03-3.05; compared to women ages 51 and older) and those with a prior abnormal Pap test (OR=1.56, 95% CI: 1.01-2.39) were more likely to accurately perceive their cervical cancer risk.

Conclusions: Most Appalachian women do not accurately perceive their risk of developing cervical cancer. This may be particularly true for older women and those who have no history of abnormal Pap tests. Education efforts are needed to help Appalachian women better understand their risk for cervical cancer, which may in turn help improve cervical cancer screening rates among this population.

Citation Format: Electra D. Paskett, Nicolas P. Bons, Paul L. Reiter. Objective and perceived risk of cervical cancer risk among Appalachian women. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr SS01-04.
Inflammation and Oxidative Stress Markers and Esophageal Adenocarcinoma Incidence in a Barrett's Esophagus Cohort
Authors: Hardikar Sheetal , Onstad Lynn , Song Xiaoling , Wilson Angela M. , Montine Thomas J. , Kratz Mario , Anderson Garnet L. , Blount Patricia L. , Reid Brian J. , White Emily , Vaughan Thomas L.
Published: August 2014

Background: Persons with Barrett's esophagus experience increased risk of esophageal adenocarcinoma. Prediagnostic inflammation markers predict several cancers, but their role in predicting esophageal adenocarcinoma is unknown.

Methods: We investigated whether biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL6), soluble tumor necrosis factor (sTNF) receptors I and II], and of oxidative stress (F2-isoprostanes) predicted progression to esophageal adenocarcinoma in a prospective cohort of 397 patients with Barrett's esophagus, 45 of whom developed esophageal adenocarcinoma. Biomarkers were measured in stored plasma samples from two time points during follow-up, the mean of which served as the primary predictor. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression.

Results: CRP level above the median was associated with an 80% increased risk of esophageal adenocarcinoma. The HR and 95% CI adjusted for age, gender, and further adjusted for waist–hip ratio and smoking were 1.98 (1.05–3.73) and 1.77 (0.93–3.37), respectively, with Ptrend for continuous CRP = 0.04. Persons with IL6 levels above the median also had almost 2-fold increased risk [HR and 95% CI adjusted for age and gender, and further adjusted for waist–hip ratio and smoking were 1.95 (1.03–3.72) and 1.79 (0.93–3.43), respectively, but no evidence of a trend was observed]. Concentrations of TNF receptors and F2-isoprostanes were not associated with esophageal adenocarcinoma risk.

Conclusions: Further research is needed to evaluate the role of inflammation and associated markers in esophageal adenocarcinoma development in persons with Barrett's esophagus.

Impact: This prospective study suggests that inflammation markers, particularly CRP and IL6, may help identify persons at higher risk of progression to esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 23(11); 2393–403. ©2014 AACR.
Plasma 25-Hydroxyvitamin D and Risk of Colorectal Cancer after Adjusting for Inflammatory Markers
Authors: Song Mingyang , Wu Kana , Chan Andrew T. , Fuchs Charles S. , Giovannucci Edward L.
Published: August 2014

Despite the substantial epidemiologic evidence on the inverse association between circulating 25-hydroxyvitamin D [25(OH)D] and colorectal cancer, it remains controversial whether this relationship is causal or due to confounding by inflammation. We reevaluated the association between plasma 25(OH)D and colorectal cancer risk by additionally accounting for inflammatory markers in a prospective case–control study nested within the Nurses' Health Study and Health Professionals Follow-up Study (615 cases and 1,209 matched controls). Conditional logistic regression was used to estimate relative risk (RR) and 95% confidence interval (CI) of colorectal cancer in relation to quartiles of plasma 25(OH)D. Results were compared before and after adjusting for inflammatory markers in the multivariable model. Plasma 25(OH)D was associated with reduced risk of colorectal cancer (multivariable RR comparing extreme quartiles = 0.71; 95% CI, 0.52–0.97; Ptrend = 0.01). Additional adjustment for C-reactive protein, IL6, soluble tumor necrosis factor receptor 2, or a composite inflammatory score did not change the results [multivariable (including inflammatory score) RR = 0.72; 95% CI, 0.53–0.98; Ptrend = 0.02). Our findings suggest that confounding by inflammation, as reflected by circulating inflammatory markers, does not appear to account for the inverse association between plasma 25(OH)D and colorectal cancer. Cancer Epidemiol Biomarkers Prev; 23(10); 2175–80. ©2014 AACR.
Molecular Pathways: Linking Tumor Microenvironment to Epithelial–Mesenchymal Transition in Metastasis
Authors: Jung Hae-Yun , Fattet Laurent , Yang Jing
Published: August 2014

During tumor development, tumor cells constantly communicate with the surrounding microenvironment through both biochemical and biophysical cues. In particular, the tumor microenvironment can instruct carcinoma cells to undergo a morphogenesis program termed epithelial-to-mesenchymal transition (EMT) to facilitate local invasion and metastatic dissemination. Growing evidence uncovered a plethora of microenvironmental factors in promoting EMT, including proinflammatory cytokines secreted by locally activated stromal cells, hypoxia conditions, extracellular matrix components, and mechanical properties. Here, we review various biochemical and biophysical factors in the tumor microenvironment that directly impinge upon the EMT program. Specifically, cytokines such as TGFβ, TNFα, and IL6 and hypoxia are capable of inducing EMT in various tumors. Several extracellular matrix (ECM) proteins, including collagen-I, fibronectin, and hyaluronan, and ECM remodeling via extracellular lysyl oxidase are also implicated in regulating EMT. In preclinical studies and ongoing clinical trials, targeting these tumor microenvironmental signals has shown promises in halting tumor progression in various human cancers. Clin Cancer Res; 21(5); 962–8. ©2014 AACR.
Phase II Study of Cetuximab in Combination with Cisplatin and Radiation in Unresectable, Locally Advanced Head and Neck Squamous Cell Carcinoma: Eastern Cooperative Oncology Group Trial E3303
Authors: Egloff Ann Marie , Lee Ju-Whei , Langer Corey J. , Quon Harry , Vaezi Alec , Grandis Jennifer R. , Seethala Raja R. , Wang Lin , Shin Dong M. , Argiris Athanassios , Yang Donghua , Mehra Ranee , Ridge John Andrew , Patel Urjeet A. , Burtness Barbara A. , Forastiere Arlene A.
Published: August 2014

Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination.

Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m2) followed by 250 mg/m2/week and cisplatin 75 mg/m2 q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival.

Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%–61%]. Two-year overall survival (OS) was 66% (95% CI, 53%–77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV+ patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively).

Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors. Clin Cancer Res; 20(19); 5041–51. ©2014 AACR.
Design of Phase I Combination Trials: Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee
Authors: Paller Channing J. , Bradbury Penelope A. , Ivy S. Percy , Seymour Lesley , LoRusso Patricia M. , Baker Laurence , Rubinstein Larry , Huang Erich , Collyar Deborah , Groshen Susan , Reeves Steven , Ellis Lee M. , Sargent Daniel J. , Rosner Gary L. , LeBlanc Michael L. , Ratain Mark J.
Published: August 2014

Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). Clin Cancer Res; 20(16); 4210–7. ©2014 AACR.
Pharmacogenomic Modeling of Circulating Tumor and Invasive Cells for Prediction of Chemotherapy Response and Resistance in Pancreatic Cancer
Authors: Yu Kenneth H. , Ricigliano Mark , Hidalgo Manuel , Abou-Alfa Ghassan K. , Lowery Maeve A. , Saltz Leonard B. , Crotty Joseph F. , Gary Kristen , Cooper Brandon , Lapidus Rena , Sadowska Mariola , O'Reilly Eileen M.
Published: August 2014

Purpose: Despite a challenging prognosis, modern cytotoxic therapy can induce tumor responses and extend life in pancreatic adenocarcinoma (PDAC). Pharmacogenomic (PGx) modeling of tumor tissue can predict the efficacy of chemotherapeutic agents in preclinical cancer models. We hypothesized that PGx profiling of circulating tumor and invasive cells (CTIC) isolated from peripheral blood could predict tumor response, progression, and resistance.

Experimental Design: A PGx model was created and validated in preclinical models. A prospective clinical trial was conducted. Fifty patients with advanced PDAC were enrolled. Before treatment, 10 mL of peripherally drawn blood was collected. CTICs isolated from this blood sample were expression profiled and the PGx model was used to predict effective and ineffective chemotherapeutic agents. The treating physicians were blinded to PGx prediction.

Results: We found that CTICs could be reliably isolated, total RNA extracted and profiled from 10 mL of peripheral blood from patients with unresectable PDAC before chemotherapy treatment and at disease progression. Using previously created PGx models to predict chemotherapy sensitivity, we found that clinical benefit was seen for study participants treated with chemotherapy regimens predicted to be effective versus chemotherapy regimens predicted to be ineffective with regard to progression-free (10.4 mo vs. 3.6 mo; P < 0.0001; HR, 0.14) and overall survival (17.2 mo vs. 8.3 mo; P < 0.0249; HR, 0.29).

Conclusions: These findings suggest that PGx profiling of CTICs can predict treatment response. Clin Cancer Res; 20(20); 5281–9. ©2014 AACR.
Phase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid Tumors
Authors: Shimizu Toshio , LoRusso Patricia M. , Papadopoulos Kyri P. , Patnaik Amita , Beeram Muralidhar , Smith Lon S. , Rasco Drew W. , Mays Theresa A. , Chambers Glenda , Ma Anna , Wang Jing , Laliberte Robert , Voi Maurizio , Tolcher Anthony W.
Published: August 2014

Purpose: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks.

Experimental Design: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75–300 mg/m2/day) following a standard 3 + 3 dose escalation design.

Results: The MTD was determined to be 275 mg/m2. Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 hours, respectively. Acetylated histone H3 induction was observed in posttreatment skin samples from 3 patients in the 275-mg/m2 dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease.

Conclusion: CUDC-101 administered by 1-hour i.v. infusion for 5 consecutive days every 2 weeks was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m2 is recommended for further clinical testing. Clin Cancer Res; 20(19); 5032–40. ©2014 AACR.
Phase II Study of Bevacizumab, Temozolomide, and Hypofractionated Stereotactic Radiotherapy for Newly Diagnosed Glioblastoma
Authors: Omuro Antonio , Beal Kathryn , Gutin Philip , Karimi Sasan , Correa Denise D. , Kaley Thomas J. , DeAngelis Lisa M. , Chan Timothy A. , Gavrilovic Igor T. , Nolan Craig , Hormigo Adilia , Lassman Andrew B. , Mellinghoff Ingo , Grommes Christian , Reiner Anne S. , Panageas Katherine S. , Baser Raymond E. , Tabar Viviane , Pentsova Elena , Sanchez Juan , Barradas-Panchal Renata , Zhang Jianan , Faivre Geraldine , Brennan Cameron W. , Abrey Lauren E. , Huse Jason T.
Published: August 2014

Purpose: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.

Experimental Design: Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.

Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.

Conclusions: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. Clin Cancer Res; 20(19); 5023–31. ©2014 AACR.
Abstract A13: Molecular profiling of low grade serous ovarian tumors
Authors: Hunter Sally M. , Gorringe Kylie L. , Anglesio Michael S. , Sharma Raghwa , Chiew Yoke-Eng , Moss Phillip , Stephens Andrew , Gilks C Blake ,   Group Australian Ovarian Cancer Study, Hunstman David , deFazio Anna , Campbell Ian
Published: August 2014

Borderline ovarian tumors fill an unusual niche between completely benign tumors and frank malignancies. These tumors tend to follow a relatively benign clinical course; however, they can recur as low grade serous carcinoma. Tumor features such as invasive implants and micropapillary growth pattern have been proposed to separate serous borderline tumors (SBTs) with invasive-like behaviour from SBTs with benign behaviour. It is currently unknown whether these features are associated with specific molecular events and whether molecular profiling of borderline tumors could offer a significant improvement of predicting likelihood of recurrence and progression.

This study aimed to perform genome-wide high-resolution molecular analysis of a large cohort of serous borderline ovarian tumors (n=57), employing copy number analysis and mutation screening, and compared these to a cohort of low grade serous carcinomas (n=19).

Clinical features such as tumor stage and laterality were found to correlate with the identity of the underlying oncogenic driver mutation, as were the presence or absence of genomic copy number aberrations and the presence of specific copy number aberrations in the SBT cohort. Comparison of genomic aberrations in SBTs to low grade serous carcinomas (LGSCs) identified loss of heterozygosity events that were very significantly enriched in carcinomas.

In conclusion, we have identified correlations between the specific oncogenic mutation a tumor carries and tumor characteristics such as level of genomic aberration and spread beyond the ovary. These findings are consistent with previous reports that specific oncogenic mutations may have a better prognosis in low grade serous tumors. Identifiable correlations between molecular events and tumor characteristics suggest it will be possible to use patient-specific tumor characteristics to better define a suitable level of treatment and follow-up. This is an important consideration as although patients have a very good short term prognosis, over an extended period recurrence and progression of SBTs to LGSCs is not insignificant and later stage LGSCs are relatively chemoresistant.

Citation Format: Sally M. Hunter, Kylie L. Gorringe, Michael S. Anglesio, Raghwa Sharma, Yoke-Eng Chiew, Phillip Moss, Andrew Stephens, C Blake Gilks, Group Australian Ovarian Cancer Study, David Hunstman, Anna deFazio, Ian Campbell. Molecular profiling of low grade serous ovarian tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A13.
Abstract A46: Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis
Authors: Vigliotti Michele , Lum Elena , Banerjee nilanjana , Cutter Noelle , Wrzeszczynski Kazimierz O. , Khan Sohail , Kamalakaran Sitharthan , Levine Douglas A. , Dimitrova Nevenka , Lucito Robert
Published: August 2014

Ovarian cancers are highly heterogeneous and while chemotherapy is the preferred treatment many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur ultimately become resistant. Recent evidence suggests that epigenetic deregulation may be a key factor in the onset and maintenance of chemoresistance. Epigenetic events are reversible and the identification of genes altered by this mechanism may lead to studies on how to reprogram the process leading up to resistance. We set out to identify epigenetically silenced genes that affect chemoresistance. The epigenomes of a total of 45 ovarian samples were analyzed to identify epigenetically altered genes that segregate with platinum response, and further filtered with expression data to identify genes that were suppressed. A tissue culture carboplatin resistance screen was utilized to functionally validate this set of candidate platinum resistance genes. Our screen identified a number of genes that when suppressed altered the chemoresistance of the cells in culture. One of the validated candidate genes identified through the pooled shRNA screen was DOK2, an adapter protein downstream of tyrosine kinase, which has been shown by others to be a lung cancer tumor suppressor. We show that suppression of DOK2 by short hairpin RNAs in ovarian cell lines conferred resistance to platinum treatment. Functional analysis of loss of DOK2 effect on chemoresistance determined that there was no change in growth or influx or efflux of carboplatin. However, we determined that loss of DOK2 increased growth in soft agar and also increased migratory capabilities. Furthermore the loss of DOK2 decreased the level of apoptosis in response to carboplatin. Furthermore, in cells with reduced DOK2, the level of anoikis was decreased. We have developed a screening methodology that analyzes the epigenome and informatically identifies candidate genes followed by in vitro culture screening of the candidate genes. To validate our screening methodology we further characterized one candidate gene, DOK2, and showed that loss of DOK2 induces chemotherapy resistance by decreasing the level of apoptosis in response to treatment.

Citation Format: Michele Vigliotti, Elena Lum, nilanjana Banerjee, Noelle Cutter, Kazimierz O. Wrzeszczynski, Sohail Khan, Sitharthan Kamalakaran, Douglas A. Levine, Nevenka Dimitrova, Robert Lucito. Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A46.
Abstract B11: Expression analysis of 2D versus 3D culture growth in HEY ovarian cancer cells
Authors: Lotito Trillitye , Powell Chase , Menzie Christopher , Aiosa Candice , Cheng Feng , Westerheide Sandy
Published: August 2014

Human tissue culture has many uses in cancer research. For example, this technique allows for a simple method of testing potential anti-cancer drugs. However, standard 2D cell culture seldom yields the same results in clinical testing. This may be due to the cell culture being exposed to a much different environment than what can be found at its site of origin, including the cellular interactions found in a 3D tumor. A cell culture spheroid model can alleviate some of these issues, creating a 3D version of the culture which more closely represents the cellular conditions experienced by a tumor. We were interested in determining which genes are most affected by 3D growth. Here, we have performed expression analysis on 2D versus 3D HEY ovarian cancer cells. Interestingly, we show that expression of many chaperone genes are increased in 3D growth conditions. This may be due to increased proteotoxic stress encountered by cells grown in spheroids. Future work will analyze the significance of chaperones and the heat shock response in 3D growth of ovarian cancer cells.

Note: This abstract was not presented at the conference.

Citation Format: Trillitye Lotito, Chase Powell, Christopher Menzie, Candice Aiosa, Feng Cheng, Sandy Westerheide. Expression analysis of 2D versus 3D culture growth in HEY ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B11.
Abstract B22: Genomic and functional analysis of gene amplification in high-grade serous and endometrioid ovarian cancer
Authors: Davis Sally J. , Simpson Kaylene J. , Campbell Ian G. , Gorringe Kylie L.
Published: August 2014

Copy number amplification is a hallmark of oncogene-associated tumor development and progression. The targeted increase in copy number of such chromosomal regions has a significant impact upon gene expression that imparts selective advantages on cancer cells. These genes are attractive therapeutic targets.

To identify amplicon targets we adopted a methodology that combines genomic copy number with RNAi to identify amplified genes that are functionally relevant in ovarian cancer. Analysis of SNP array data for a cohort of ~400 tumors identified ~300 genes amplified at a high level in 10% or more of cases. We utilized SNP array data from a panel of 39 ovarian tumor cell lines to identify 18 cell lines that recapitulate the gene amplifications observed in the clinical specimens. The set of candidate genes has been functionally assessed in these cell lines using a boutique siRNA library to interrogate phenotypic alterations in cellular viability.

Data collected from the screen identified a number of genes and pathways with potential therapeutic value including URI1, GAB2, PAK4 and DYRK1B. We have assessed the therapeutic utility of PAK4 and DYRK1B using targeted small molecule inhibitors using gene amplification as a marker for response. Our preliminary in vitro data indicates that amplification of PAK4 can lead to a marked response to PF-3758309, an ATP-competitive, pyrrolopyrazole inhibitor of PAK4.

The results from this study provide strong evidence for the value of focused functional genomic screening. It has been demonstrated that combining high-throughput technologies has the potential to rapidly identify candidate driver genes that may then be streamlined to a translational phase.

Citation Format: Sally J. Davis, Kaylene J. Simpson, Ian G. Campbell, Kylie L. Gorringe. Genomic and functional analysis of gene amplification in high-grade serous and endometrioid ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B22.
Abstract B26: Non-catalytic effects of PARP inhibitors in the context of cell cycle and homology-directed DNA damage repair
Authors: Jelinic Petar , Levine Douglas A.
Published: August 2014

Background: Poly (ADP)-ribose polymerase inhibitors (PARPis) target PARPs, the stress sensing proteins that respond to DNA single-strand breaks. PARP inhibition has been extensively explored in pre-clinical and clinical studies with successes demonstrated in homology-directed DNA damage repair (HDR) pathway-deficient ovarian cancer patients. The inhibitory potential of PARPis is well established; however non-catalytic effects that may add to their therapeutic properties are not fully understood. Our objective was to comparatively evaluate non-catalytic inhibitory properties, particularly in the context of cell cycle and HDR, of the most widely tested PARPis in pre-clinical and clinical studies, olaparib and veliparib.

Methods: To measure DNA damage repair activity upon PARPi treatment, we used a well-established DR-GFP reporter assay in two model cell lines, U2OSDR-GFP and H1299DR-GFP. Cell cycle progression was assessed by staining with propidium iodide and monitored by flow cytometry. Depletion of p53 in U2OSDR-GFP cells was performed by standard siRNA knock-down technique using electroporation for transfection. Immunoblotting was used to confirm cell cycle results and demonstrate replicative stress on the protein expression levels.

Results: We found a dramatic decrease in DNA damage repair activity in olaparib versus veliparib-treated U2OSDR-GFP cells, regardless of their inhibitory potency. This decrease in HDR activity was a result of olaparib triggering a cell cycle arrest-like state as a response to strong replicative stress. Lack of the same effect in p53-null H1299DR-GFP cells suggests that olaparib's effect is p53-dependent, which was confirmed in U2OSDR-GFP cells depleted of p53. Our data also suggest that cells treated with veliparib are more ambivalent towards p53 status, a difference in comparison to olaparib-treated cells.

Conclusion: These data demonstrate that olaparib and veliparib differ in their non-catalytic inhibitory effects, with olaparib but not veliparib mitigating DNA damage repair activity via cell cycle arrest-like effects in a p53-WT background. This new insight into olaparib's and veliparib's mechanism of action should be considered when developing inclusion criteria for treatment of ovarian cancer patients with these PARP inhibitors or others.

Citation Format: Petar Jelinic, Douglas A. Levine. Non-catalytic effects of PARP inhibitors in the context of cell cycle and homology-directed DNA damage repair. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B26.