bluuebunny/crossref_metadata_2025 huggingface dataset:
P5-23-03: Breast Cancer in Elderly Treatment Algorithm – A New Approach To Optimize the Management of Breast Cancer in Older Patients.
Authors: Tahir M , Pretorius R , Robinson T , Walker R , Stotter A
Published: June 2012

Background: Elderly patients have been receiving a sub-standard treatment for early breast cancer when compared to younger age group patients. A higher percentage of them are being treated with primary endocrine therapy (PET) based on the premise that they may not survive surgery or live long enough to benefit from it. In clinical practice, however, there is no validated assessment in place to assess their surgical risk or estimate their life expectancy. This study aimed to optimize the treatment of early breast cancer in older patients using comprehensive geriatric assessment (CGA). It tested the hypothesis that CGA could be used to predict 2-year survival in older breast cancer patients. Based on that a treatment algorithm was devised which could be used to recommend whether PET or surgery plus endocrine treatment would be best indicated in individual patients. Methods: The study included women >70 years of age with early breast cancer, seen in a dedicated Leicester clinic between 04/2005 and 04/2007. All patients had comprehensive assessment including documentation of co-morbidities, Mini-mental state examination (MMSe), Geriatric depression score (GDS), Activities of daily living (ADL), Instrumental activities of daily living (IADL) and American society of anesthesiologist score (ASA). Analysis was performed to find components of the CGA that were helpful in predicting 2-year survival in these patients.

Results: 123 patients were included; age range was 70–94 (median-82). Twenty-two patients died within 2-years. Logistic regression analysis found MMSe, ADL, and ASA score to have an independent association with 2-year survival. A statistically significant correlation (p-value 0.000) was found between the dichotomized combined-score of these components and 2-year survival. Breast Cancer in Elderly Treatment Algorithm (BCETA) was devised using the scores of these three components. Patients who scored one or higher (high-risk group), were found to have <48% two-year survival; those, who scored zero (low-risk group), have >86% chance of two-year survival. The overall accuracy for the algorithm was 81%.

Conclusion: Breast Cancer in Elderly Treatment Algorithm is a new and systematic approach to optimize the management of breast cancer in elderly patients. It is helpful in identifying high-risk patients with expected short-survival who may benefit from PET, if their cancer is hormone receptor positive. Patients with predicted longer life expectancy (low-risk) may be recommended standard treatment. A prospective study is ongoing at Leicester research clinic to validate the results.

BREAST CANCER IN ELDERLY TREATMENT ALGORITHM

Name:

Hospital No: DOB:

Address: Diagnosis:

COMPREHENSIVE GERIATRIC ASSESSMENT

TOTAL BCETA SCORE

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-23-03.
PD02-03: The Effect of Breast Conservation Therapy vs Mastectomy on Symptoms, Physical Impairments, and Function.
Authors: Kesarwala AH , Pfalzer LA , O'Meara WP , Stout NL
Published: June 2012

Background: Early-stage breast cancer (BC) patients choose between breast conservation therapy (BCT) and mastectomy based on comparable recurrence rates and overall survival. In the absence of mortality benefit, consideration of anticipated functional impairments could guide decision making. Although BCT offers less extensive surgery, the administration of radiation therapy (RT) may adversely impact upper extremity (UE) function. The purpose of this analysis is to investigate the effect of BCT vs modified radical mastectomy (MRM) without RT on functional impairments among BC survivors.

Materials and Methods: 196 women diagnosed with BC between 200105 were enrolled and treated in a prospective surveillance physical therapy program. 115 received either BCT, including lumpectomy and whole breast RT, or MRM without RT and were analyzed for this report. Participants’ UE range of motion (ROM), strength, and limb volume were assessed pre-operatively and at 1, 3, 6, 9, and 12+ months post-operatively by a physical therapist. Limb volume was assessed using infrared optoelectronic perometry. At 12+ months, overall health status, UE symptoms and function, and physical activity levels were reported using standardized questionnaires. Analysis of variance estimated differences in impairments and self-reported symptoms and function. One-way ANOVA analysis was used to determine significance between groups (p ≤ 0.05).

Results: 65 women (57.5%) received BCT and 50 women (42.5%) received MRM. No significant differences in age, BMI, stage, ER/PR status, and number of dissected lymph nodes were found between groups. At 1 month post-operatively, shoulder internal rotation (p=0.03), abduction (p=0.01), and flexion (p=0.004) were worse in post-MRM patients, with a trend towards worse external rotation (p=0.06). A higher rate of axillary cording was seen in patients post-MRM (p=0.02). By 12+ months post-operatively, there were no differences in any of the shoulder ROM variables. BCT patients reported, however, greater weakness (p=0.03) and diminished ability to perform heavy household tasks (p=0.03). There was no significant difference between BCT vs. MRM in rates of early lymphedema (40% vs 38%) or seroma (14% vs 22%).

Conclusion: Functional impairments represent an important category of morbidity for BC survivors and should be considered in pre-treatment decision making. Post-operative RT as part of BCT may not contribute significantly to impairment over the first year of treatment. The presence of self-reported weakness and difficulty performing heavy household tasks at 12+ months suggest possible future functional deficits, especially considering the potentially progressive nature of RT-associated tissue changes. Additional research is needed to assess longer-term changes and the impact of RT in the context of aggregate effects of other BC treatment modalities.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD02-03.
PD02-07: Models Predicting Non-Sentinel Node Involvement in Breast Cancer Also Predict for Regional Recurrence If the Axilla Is Not Treated.
Authors: Pepels M , Vestjens H , de Boer M , Bult P , van Dijck J , Mencke M , van Diest P , Borm G , Tjan V
Published: June 2012

Background

Series on breast cancer patients with sentinel node (SN) isolated tumor cells or micrometastases show low recurrence rates in the presence of SN isolated tumor cells, and varying recurrence rates in the presence of SN micrometastases. Non-SN prediction models are frequently used as a decision aid to identify patients that may not need axillary treatment, but this still needs to be validated in respect to regional recurrence.

Patients and Methods

We followed a cohort of 486 patients in the MIRROR-study of whom none received axillary treatment with favorable primary tumor characteristics and pN0(i+)(sn) or pN1(mi)(sn) for a median of 5 years. The patients were categorized into low or high-risk subgroups based on several published non-SN prediction models (cut-off levels between models varied from 3 to 10%), i.e. the Tenon Scoring system, MSKCC nomogram, Stanford nomogram and a Dutch model (Bolster et al.). The primary endpoint was 5-year regional recurrence-free survival.

Results

The overall 5-year regional recurrence rate was 3.0% (+/− 0.1%). Using the Tenon scoring system, we identified 438 patients with a low risk score of 3.5 or lower with a 5-year regional recurrence rate of 2.3% (+/− 0.8%), compared to a recurrence rate of 10.1% (+/− 0.4%) in 48 patients with a score above 3.5. For the MSKCC nomogram a low risk score of 0.10 or lower identified 300 patients with a 5-year recurrence rate of 2.8% (+/− 1.1%), and a score above 0.10 identified 166 patients with a recurrence rate of 3.4% (+/− 1.5%) (20 patients not assessable). By the Stanford nomogram a low risk cutoff level of 10% identified 21 patients without recurrence, whereas 465 patients had a 3.2% (+/−0.9%) recurrence rate. Using a Dutch model, a low risk cutoff score of 20 discriminated between 384 patients with a 5-year recurrence rate of 2.2% (+/− 0.8%) and 102 patients with a recurrence rate of 6.3% (+/− 2.9%). Further analyses with different cut-off values and subgroups will be presented at the conference.

Conclusion

Using several published non-SN prediction models for predicting regional recurrence, the Tenon scoring system outperformed the other models in that it identified the largest subgroup of patients with a low recurrence rate. We would recommend axillary treatment in patients classified as high risk according to the Tenon score.

Funding: Netherlands Organization for Health Research and Development (ZonMw 945-06-509).

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD02-07.
PD03-08: BRCA1-Like Triple Negative Tumors: Clinicopathological Variables and Chemosensitivity to Alkylating Agents.
Authors: Wesseling J , Lips EH , Oonk AMM , Smits RM , van Rijn CCM , Mulder L , Laddach N , Savola SS , Wessels LFA , Nederlof PM , Rodenhuis S , Imholz ALT
Published: June 2012

Background

Our group has previously employed array Comparative Genomic Hybridization (aCGH) to assess the genomic patterns of BRCA1-mutated breast cancers. It is reasonable to assume that this pattern indicates ‘BRCAness’ and thus serves as a marker for homologous recombination deficiency. This BRCA1-like aCGH profile is also present in about half of all triple negative sporadic breast cancers and has been shown to be predictive for benefit from intensive chemotherapy with DNA crosslinking agents. To study BRCA1-like tumors and conventional dose chemotherapy sensitivity in more detail, we compared clinical factors and survival rates in a uniform cohort of triple negative breast tumors treated with alkylating agents.

Patients and methods

103 patients with triple negative tumors received conventional dose adjuvant chemotherapy with doxorubicin/cyclophosphamide. DNA was extracted from tumor samples and BRCA1-like profiles were assessed. Tumors were classified as BRCA1 -like or non-BRCA1-like. Standard clinical and histopathological factors were determined and compared between both groups. Relapse free survival (RFS), disease specific survival (DSS) and overall survival (OS) after diagnosis were compared between BRCA1-like and non-BRCA1-like tumors.

Results

66 tumors (65%) had a BRCA1-like profile, while 35 tumors (35%) did not show such a profile. Patients with BRCA1-like tumors tended to be younger and had more often node-negative disease compared to the patients with non-BRCA1-like tumors (p=0.058 and p=0.034, respectively). There was no significant difference in survival between BRCA1-like and non BRCA1-like patients after treatment with alkylating agents: the median RFS was 121 vs. 109 months, median DSS was 129 vs. 114 months and OS was 127 vs. 110 months, for BRCA1-like versus non-BRCA1-like tumors. T-stage was the only variable significantly associated with survival.

Conclusion

BRCA1-like tumors occurred in younger patients and were more often node negative, which are features shared with tumors in BRCA1-mutation carriers. We did not observe a difference in survival between BRCA1-like and non-BRCA1-like triple negative breast cancers after treatment with conventional dose chemotherapy with alkylating agents. These results confirm our previous findings that BRCA1-like tumors have similar sensitivity to anthracycline-based adjuvant chemotherapy as other triple-negative tumors. It will be important to establish whether BRCA1-like tumors also share the exquisite sensitivity of BRCA-mutated tumors to PARP-inhibitors.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD03-08.
PD04-06: A Randomised Controlled Trial of Quality of Life and Fatigue after Support Group Intervention in Primary Breast Cancer Patients.
Authors: Granstam Björneklett H , Lindemalm C , Ojutkangas M-L , Berglund A , Letocha H , Strang P , Bergkvist L
Published: June 2012

Background: When diagnosed with breast cancer, most women's lives change as well as their perspectives on and appreciation of life. The aim of the present study was to evaluate whether psychosocial support intervention could influence health- related quality of life and fatigue during the first year after diagnosis.

Material and Methods: Of 382 patients with newly diagnosed breast cancer, 191 + 191 patients were randomized to an intervention group or to a routine control group respectively.

The intervention group received support intervention that lasted one week on a residential basis, followed by four days of follow-up two months later. The support intervention included informative-educational parts, relaxation training, mental visualisation and nonverbal communication. Health-related quality of life was measured using the EORTC-QLQ 30 and QLQ-BR23 questionnaires and fatigue with the Norwegian version of the Fatigue scale at baseline, 2, 6 and 12 months after intervention.

Result: There were a time-dependant improvement in both functional and symptom scales between baseline and 12 months as measured by the EORTC QLQ 30 and BR 23 questionnaires and there was a decrease in fatigue between baseline and after 2 months with further improvement up to 12 months in both groups but there were no differences between the intervention and control groups at any point in time.

Conclusion: Health related Quality of Life improves and symptoms of fatigue decreases over time, but we could not see any additional effect from the rehabilitation program in this setting.

Key words: Support intervention, breast cancer, health- related quality of life, fatigue, EORTC-QLQ 30 and BR 23, the Norwegian version of the fatigue scale.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-06.
PD08-11: Targeting Porcupine, a Critical Node for Wnt Signalling in Cancer.
Authors: Liu J , Pan S , Sun F , Kasibhatla S , Schuller A , Li A , Li C , Cui X , Wang T , Villarroel M , Mclaughlin M , Sellers W , Boral A , Harris J
Published: June 2012

Wnt ligands were first discovered based upon their transforming activity in the setting of mouse mammary tumor virus (MMTV) induced mammary carcinogenesis. Wnt signalling is required for normal development of the mammary gland and dysregulated Wnt signalling is implicated in cancers of the breast and colon among others. Furthermore, lobular breast cancer commonly shows reduced expression of E-cadherin that can lead to release of membrane-bound b-catenin into the cytoplasm and potentially increase Wnt signalling in the presence of Wnt ligand. To date, however, low-molecular weight therapeutic inhibitors of the Wnt pathway have not been developed. We set out to discover key points of intervention in the Wnt pathway and to develop low molecular weight inhibitors against such nodes. To this end, a cellular high-throughput screen for small molecule inhibitors of the Wnt pathway was performed. In this assay, cells secreting Wnt3a were co-cultured with cells harboring a luciferase reporter driven by the Wnt/beta-catenin responsive elements. Potent and specific Wnt pathway inhibitors were identified from this screen. To discern the mechanism of action of these compounds, a lead inhibitor was radiolabeled and used to probe protein targets in a radioligand binding assay. From these assays a candidate target of the inhibitor was identified as Porcupine. Porcupine is a membrane bound O-acyltransferase enzyme that is required for and dedicated to palmitoylating Wnt ligands, a necessary step in the process of Wnt ligand secretion. Inhibition of Porcupine blocks Wnt dependent activities, including LRP6 phosphorylation and the expression of Wnt target genes, such as Axin2, which in turn reduces the growth of cancer cells dependent on autocrine or paracrine Wnt signaling. A selective and orally bioavailable Porcupine inhibitor (NVP-LGK974) that inhibits the Wnt pathway in vitro and in vivo was developed through medicinal chemistry optimization. In preclinical evaluation, the compound robustly suppressed Wnt pathway signaling in vivo resulting in tumor regression in a murine breast cancer model driven by MMTV-Wnt1. In addition, this inhibitor attenuated tumor growth as a single agent and induced tumor regression in combination with Taxol in a human primary breast tumor model.

Wnt signalling is also important for the maintenance and homeostasis of normal tissues including gastrointestinal tissue. However, preclinical rodent efficacy models of cancer demonstrate that intermittent pharmacological inhibition of Porcupine can be effective against the tumor and mostly spare the normal gastrointestinal tissue, with an acceptable therapeutic window.

A Phase I dose escalation study of NVP-LGK974 in patients with melanoma and lobular breast cancer to evaluate the safety, tolerability, PK, and PD properties is expected to begin this year.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD08-11.
PD09-05: SU2C Phase Ib Study of pan-PI3K Inhibitor BKM120 Plus Aromatase Inhibitor Letrozole in ER+/HER2− Metastatic Breast Cancer (MBC).
Authors: Mayer IA , Balko JM , Kuba MG , Sanders ME , Yap J , Li Y , Winer E , Arteaga CL
Published: June 2012

Background: Experimental evidence and clinical data suggest that PIK3CA mutations (present in approximately 35% of ER+ cancers) are associated with de novo or acquired resistance to antiestrogen therapy. Considering that most breast cancers resistant to antiestrogen therapy retain ER and estrogen sensitivity, treatment of ER+ breast cancers with single-agent PI3K-targeted therapy may be insufficient to inhibit tumor growth.

Materials and Methods: To evaluate safety/tolerability, we initiated a phase Ib clinical trial of letrozole with the pan-PI3K inhibitor BKM120 (Novartis) in post-menopausal patients with ER+/HER2−MBC. Letrozole (2.5 mg/d) and BKM120 (100 mg/d) were given on a 28-day cycle. When necessary, BKM120 was reduced to 80 and 60 mg/day. Treatment was continued until unacceptable toxicity or progression of disease. Disease was assessed every 2 months. FDG-PET imaging was performed at 2 weeks to identify changes indicative of pharmacodynamic modulation of PI3K/AKT.

Results: Twenty patients have been accrued; all but 2 patients had previously progressed on an aromatase inhibitor (AI) in the metastatic setting. Median age was 56 years; 85% of patients had metastatic bone disease, 70%, visceral metastases. Twelve patients are still on treatment, 2 of these are currently on BKM120 80 mg/day. Three patients discontinued treatment within 2 months of initiation due to grade 3 transaminitis, grade 2 irritability, and grade 2 hyperglycemia, despite dose reductions and/or optimal treatment. Most common toxicities are summarized in the table below. Transaminase elevation was the only DLT at 100 mg/d BKM120. Of the 12 evaluable patients that completed at least 8 weeks of treatment, 1 had a partial response, 7 had stable disease, and 4 had disease progression (RECIST). So far 3 patients have been on treatment for >4 months. Over 50% of patients had >25% reduction in their peak SUV at the 2-week FDG-PET scan.

Discussion: The letrozole + BKM120 combination is active in patients with ER+/HER2− MBC refractory to previous therapy with an AI. At this time, all patients’ primary diagnostic tumor biopsies and/or metastatic biopsies are being analyzed for the presence of PIK3CA, AKT1, or PTEN mutations and PTEN loss (immunohistochemistry). FDG-PET imaging at 2 weeks appears to be a useful pharmacodynamic biomarker of PI3K pathway inhibition. Correlation of mutational analysis with clinical benefit will be presented at the meeting. Despite an overall safe side effect profile, an alternative administration schedule of BKM120 with letrozole is planned to enhance tolerability of the combination.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-05.
PD09-06: Phase II Trial of RAD001 (Everolimus), an mTOR Inhibitor, with Weekly Cisplatin and Paclitaxel in Patients with HER2−Negative Metastatic Breast Cancer (MBC).
Authors: Mayer IA , Means-Powell J , Abramson VG , Shyr Y , Balko JM , Kuba MG , Gharavi HM , Schlabach L , Arteaga CL , Pietenpol JA
Published: June 2012

Background: In basal-like breast cancers, drugs that either negatively modulate p63 and/or activate p73, such as cisplatin and paclitaxel, promote p73-dependent apoptosis. Further, the serine threonine kinase mTOR negatively regulates p73. Inhibition of mTOR with RAD001 upregulates p73, and results in p73-mediated apoptosis. Therefore, we conducted a phase II trial in patients with HER2−negative MBC to explore safety, tolerability and anti-tumor activity of the combination of paclitaxel, cisplatin and RAD001.

Materials and Methods: We initiated an open-label, phase II multi-institutional study of weekly cisplatin (25 mg/m2), paclitaxel (80 mg/m2) and daily RAD001 (5 mg), given on a 28-day cycle. Treatment was continued until unacceptable toxicity or progression of disease. All toxicities were documented using the NCICTCv.4. Disease was assessed every 2 months.

Results: A total of 55 patients were enrolled. Median age was 55 years; 62% of patients had prior chemotherapy with a median of 3 previous regimens in the metastatic setting. Sixty-three percent of patients had triple-negative disease, 81% patients had visceral disease, and 35% had bone metastases. Twenty-one patients are still on study. The most common toxicities are summarized in the table below. Neutropenia was the main cause for dose reductions, mainly after cycle 3. Only 1 patient developed febrile neutropenia. Of the 44 patients assessed for best response (RECIST) thus far, 11 had partial response, 21 stable disease, 9 disease progression, and 3 were not evaluable. Thirty eight patients have discontinued treatment so far; 30 due to disease progression, 5 due to toxicity, and 3 withdrew consent. Current median time to progression on the evaluable patients is 6 months.

Discussion: The combination of RAD001, cisplatin and paclitaxel was overall very well tolerated despite cumulative pancytopenia. Significant antitumor activity in this heavily pre-treated patient population was seen. All patients’ primary diagnostic and/or metastatic tumor biopsies are currently being analyzed for the presence of PIK3CA and AKT1 mutations, and immunohistochemical expression of p53, p63, p73, and PTEN. Microarrays are being generated to determine whether time to progression is superior in patients with basal-like breast cancers. Microarrays will be mined to identify a pretreatment profile that mirrors a low p63/high p73 gene expression signature. Correlation of mutational analysis and gene signatures with clinical benefit will be presented at the meeting

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-06.
PD10-01: Prevalence of Dysfunctional Fanconi Anemia (FA) DNA Repair Pathway in Breast Cancer.
Authors: Ramaswamy B , Srividya V , Mullins DA , Carothers S , Young G , Wenrui D , Zhao W , Lustberg M , Leon M , Weslowski R , Layman R , Mrozek E , Shapiro CL , Villalona-Calero M
Published: June 2012

Purpose: BRCA1/2 deficient breast tumors are highly sensitive to poly- ADP-ribose polymerase inhibitors (PARPi). The Fanconi Anemia (FA) associated gene products along with BRCA 1/2 function in a common pathway that regulates the cellular response to DNA damage, suggesting that tumors with dysfunction of any of the components of FA network would be susceptible to PARPi. Understanding the prevalence of such defects in breast tumors using reproducible methodology will help us target these tumors with novel agents and potentially improve outcomes. Hence we sought to assess the prevalence of FA pathway defect in breast tumors by the absence of nuclear FANCD2 (a pivotal protein in the FA/BRCA pathway which is monoubiquitylated in the nucleus in response to DNA damage) repair foci using a novel immunofluorescence method and correlate this with known molecular markers of breast cancer.

Methods: Using primary tumors obtained from the ongoing PARPi clinical trials (NCT01017640 and NCT01251874) and tumor bank, we evaluated 102 breast tumors for the somatic functionality of the FA pathway (FANCD2 foci formation) by the FA Triple Stain Immuno-Fluorescence (FATSI) test performed in a CLIA-certified laboratory using paraffin embedded tissues. The tissue sections are incubated with a primary antibody cocktail of rabbit polyclonal FANCD2 antibody and a monoclonal anti-Ki67 mouse antibody, followed by co-incubation with a secondary antibody (FITC conjugated to anti-rabbit IgG and Alexafluor 594 donkey anti-mouse), mounted on glass slides in a DAPI containing embedding medium and evaluated by a fluorescence microscope. Absence of nuclear FANCD2 formation in 100 proliferating tumor cells was considered positive for FA defect. Hormone receptor (HR) and Her2 status was compared between the groups using Fisher's exact test.

Results: A total of 102 primary breast tumors were analyzed for FANCD2 by FATSI test of which 62 were triple negative (TN), 37 were HR positive and 3 were Her2 positive. Of these, 29 tumors (28%) were positive for FA defect with no significant differences among the molecular subtypes (26% in TN vs 32% in HR + vs 33% in Her2+).

Conclusions: We report a novel methodology to efficiently screen archival FFPE tumors for somatic functional defect of FA DNA repair pathway and demonstrated a high prevalence (one-third) in breast tumors irrespective of molecular subtype. We are currently conducting clinical trials with PARPi including patients with tumors that test positive for FA defect to demonstrate if such tumors are sensitive to PARPi.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD10-01.
SR2-6: Genome Data for the Masses: Presentation of TCGA and IGC Breast Tumor Data.
Authors: Haussler D
Published: June 2012

Large-scale cancer genomics projects will sequence tens of thousands of tumors in the next few years, along with matched normal tissue samples. Among these are The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and the International Cancer Genomics Consortium (ICGC). TCGA alone plans to analyze 500 clinically characterized samples from each of 20 different cancer types, detecting frequently mutated genes, common copy number variants, rearrangements, altered gene expression, and methylation changes. These data will provide an exceptional resource for identifying new diagnostic targets and predictors of response.

As a data analysis center and the primary sequence database for TCGA, we have built on technology developed for the UCSC Genome Browser to develop a cancer genome analysis pipeline and a cancer genomics browser (genome-cancer.ucsc.edu). These interpret cancer genomics data to aid in the identification of new targets. We reconstruct changes in tumor genomes and their expressed transcripts from tumor sequencing data (DNA, RNA, methylation) and use an approach based on factor graphs, called PARADIGM, to map multiple data types into a single coherent pathway model that includes thousands of genes and interactions for higher-level interpretation. By transforming raw genomic data to pathway activity levels, PARADIGM provides a comprehensible window into the data that can be coupled to predictors of response to improve accuracy. This paves the way to form hypotheses that clinical investigators can test in cell-line models and later explore in clinical trials.

Today's concurrent cancer genomic projects provide an exceptional opportunity to study the molecular nature of cancer on an enormous scale never before possible. A cancer genomics data repository that hosts multiple large projects and makes them accessible through a general cancer genomics browser (with effective data access control) will leverage each study and enable cross-tumor cancer research.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr SR2-6.
Abstract A6: A global sensitivity test for evaluating hypotheses with non- and weakly identifiable statistical models: An application to breast cancer outcomes
Authors: Todem David , Cao Guanqun , Yang Lijian , Fine Jason P.
Published: June 2012

Background and objectives: Motivated from a study on breast cancer, we consider the problem of evaluating a statistical hypothesis when some model characteristics are potentially non or weakly identifiable from observed data. Such scenarios are common in longitudinal studies for evaluating a covariate effect when dropouts may be informative. The hypothesis related to treatment effects may not be testable nonparametrically, with untestable model restrictions necessary for inference. A popular approach is to assume a finite dimensional model and to fix a minimal set of parameters, called sensitivity parameters, conditional upon which hypothesized parameters are assumed identifiable. These profile models, viewed as a functional of the secondary or sensitivity parameters, form the basis of sensitivity analysis. In the current literature, however, inference regarding significance of the covariates is ad hoc, ignoring that multiple tests are conducted and that the working model may be misspecified.

Methods and results: In this paper, we propose conservatively testing the null hypothesis of interest across the support of the sensitivity parameters using an infimum test statistic. The test must account for the facts that inferences are carried out simultaneously across the entire range of the sensitivity parameters and that the model may be misspecified under certain values of the sensitivity parameters, as might occur if a nonignorable model is fit, when, in reality, missingness is ignorable. We characterize the limiting distribution of the statistic as a functional of processes in the sensitivity parameters, which involves a careful theoretical analysis of its behavior under model misspecification. In practice, we suggest a simple yet flexible resampling procedure to implement the infimum test as well as to construct confidence bands for simultaneous pointwise tests across all values of the sensitivity parameters. The methodology's practical utility is illustrated in simulations and an analysis of quality-of-life outcomes from a longitudinal study on breast cancer. Interestingly in this example, a covariate effect on cancer outcomes is detected over a wide range of the sensitivity parameter when a Wald test that assumes identifiability fails.

Implications and next steps: The key implication of this work is that the hypothesis of interest can be conservatively evaluated across the support of the sensitivity parameters using an infimum test statistic over the space of these parameters. A key assumption of this paper is that the working model is finite dimensional although the full specification of distribution of the data is not required. The methodology should be broadly applicable to infinite dimensional models, such as survival models for censored data. This extension is the focus of current research work.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A6.
Abstract A60: Second primary breast cancer incidence rates among black and white female breast cancer survivors
Authors: Nsouli-Maktabi Hala , Henson Donald E. , Younes Naji , Young Heather A. , Cleary Sean D.
Published: June 2012

Background: Breast cancer incidence increases with age and exhibits a Black-to-White incidence crossover around age 45. Breast cancer survivors are at a significantly elevated risk of developing a second primary breast compared with the general population. The purpose of this study was to determine whether a similar crossover occurs in second primary breast cancer incidence in Black and White women.

Methods: The Surveillance, Epidemiology, and End Results’ Registry 9 was used to follow 415,664 White and 39,887 Black female breast cancer survivors, diagnosed at age 19 or older, for a second primary breast cancer between 1973 and 2007. Cumulative incidence curves, which account for the competing risk of death and the occurrence of second primary non-breast cancers, were generated; Pepe and Mori's test was used to test for significance.

Results: A total of 22,290 (40.7%) second primary breast cancers were observed among 450,936 women who had survived 2 months or more after an in situ or invasive breast cancer. The majority, 18,227 (81.7%) cases, occurred in women diagnosed with a first primary breast cancer at age 45 or older. Second primary breast cancer followed the incidence pattern of the first primary breast cancer in Black and White women diagnosed before age 45. It was opposite of the pattern of first primary breast cancer in Black and White women diagnosed at age 45 or later.

Despite the Black-to-White crossover of first primary breast cancer around age 45, the incidence of second primary breast cancer was higher in Blacks than in Whites.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A60.
Abstract A61: Modulation of proteasome expression in dendritic cells and melanoma cells
Authors: Robinson John L. , Mackay Amy , Pilon-Thomas Shari
Published: June 2012

The proteasome is a cellular subunit that degrades intracellular proteins into small pieces called peptides. Degradation of proteins into peptides occurs through one of two types of proteasomes: constitutive proteasome (cPr) and immunoproteasome (iPr), each giving rise to a unique repertoire of peptides. Most cells, including tumor cells, express the cPr, while dendritic cells (DCs), the master T cell educators of the immune system, constitutively express the iPr. Presentation of peptides processed through the iPr in DCs may activate T cells that cannot recognize peptides processed through the cPr in tumor cells, leading to a non-functional antitumor immune response. To eliminate this problem, we have investigated the use of two drugs discovered by Onyx Pharmaceuticals that selectively inhibit either the c20S of the cPr or the i20S of the iPr in tumor cells and DCs respectively. The drug ONX 0914 inhibits iPr activity. We have determined that the ONX 0914 concentration of 250nM is optimal to block iPr function and maximize DC viability. Using ONX 0914 we have demonstrated that the major histocompatibility complex I (MHC I) Kb-restricted epitope, gp-10025-33, is processed through the iPr. The drug PR-825 inhibits cPr activity. Using PR-825, we have determined that the peptide OVA257-264 is processed through the cPr. We are using these drugs to optimize DC-based vaccines in a murine model of melanoma.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A61.
Abstract A68: Familial colorectal cancer registry in Hispanics: A feasibility study
Authors: Lozada María Eugenia , Bernabe-Dones Raúl , López-Enriquez Reynold , Haile Robert , Mosquera-Fernández Rafael , Cruz-Correa Marcia R. , Díaz-Algorri Yaritza , Acosta Delma , Nuñez Cristina , Rosado Edwin , Torres-Cintrón Mariela , Figueroa-Vallés Nayda , Cardona Alberto , Lacourt-Ventura Mercedes
Published: June 2012

Background: In Puerto Rico (PR), colorectal cancer (CRC) represents the second most common cause of cancer in men and women. Incidence and mortality of CRC are increasing in Puerto Rican Hispanics, especially among young individuals. Screening rates for CRC are lower in Hispanic-American individuals compared to non-Hispanic patients. However, there is limited data on genetic epidemiological CRC disparities in Hispanic patients.

Objectives: (1) To prospectively identify and recruit 30 probands with a family history of CRC and 15 family-history negative. (2) To prospectively identify and recruit selected relatives from the 45 probands.

Methods: Eligible cases are Hispanic patients with incident diagnosis of CRC, ≥ 21 years old. We identified the probands and their selected family members using the Puerto Rico Central Cancer Registry from July 1, 2007 to the present. Preliminary data and recruitment: Seven hundred and fifty-one communications were sent to the physicians, three hundred and seventy-four communications were responded (374/751=49.8%). Three hundred and forty-one communications were sent to the patients, one hundred and forty-seven letters were responded (147/341=43.1%) and 16 refused. One hundred and fifty-nine participants (probands and relatives) were enrolled. One-hundred and two probands (mean age 56.9 ± 13.3 yrs., 54.9% male); 30 with and 72 without family history of CRC. At present, we collected 153 (96.2%) risk factors questionnaires, 135 (84.9%) blood samples and 60 (52.6%) blocks of tissue.

Successful implementation of logistics for identification of incident CRC through the PR Central Cancer Registry during a three-year period. We established the first Familial CRC island-wide registry in Puerto Rico through the implementation of a network of community physicians, laboratories and professional societies. We are developing a tissue and blood bank with epidemiological, nutritional, and demographic data that will assist us to understand the genetic epidemiology of CRC in Puerto Ricans.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A68.
Abstract A69: Identification of prostate cancer genes in the African American Hereditary Prostate Cancer (AAHPC) study
Authors: Ricks-Santi Luisel J. , Mason Tshela , Abbas Muneer , Dunston Georgia M. , Kolluri Supraja , Gold Bert , Im Kate , Lautenberger James , Dean Michael , Bailey-Wilson Joan , Carpten John , Ahaghotu Chiledum
Published: June 2012

Background: Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among African American men. The hereditary prostate cancer 1 gene (HPC1-1q24-25) was initially implicated as a PCa susceptibility locus in 1996, but was not replicated in the African American Hereditary Prostate Cancer (AAHPC) study, which recruited African American families with four or more affected family members (n=95 families). The objective of our study is to identify and confirm PCa genetic susceptibility loci in African Americans.

Methods: Short tandem repeat polymorphism (STR) scans implicated several loci, but no specific family had a logarithm of odds score higher than 1.8. We sought to refine implicated loci through single nucleotide polymorphism microarray. Therefore, we devised a prioritization scoring system where families with multiple affected and unaffected brothers within a likely onset age bracket scored the highest. After Illumina 660K microarray run, Bayesian prior likelihoods will be coupled with family based statistics to analyze the data in 6 families (n=32).

Results: Scoring criteria was effective at identifying families (n=31, 14 cases, 17 controls) most informative at identifying genes and SNPs associated PCa. A total of 51 SNPs in 13 genes were found to be associated with PCa Risk at the p<0.05 level including CTBP2 (4p16), HNF1B (17cen-q21.3), and PKHD1 (6p12.2).

Conclusions: This study is a first step in identifying PCa genes that warrant further follow-up in the rest of the AAHPC families.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A69.
Abstract B10: Utilizing community-based participatory research and emerging technology to design a theory-based health education intervention on prostate cancer for African American men
Authors: August Euna M. , Dickerson Sean , Sultan Dawood , Green B. Lee , Roetzheim Richard , Rivers Brian M.
Published: June 2012

Introduction: Despite overall declines in incidence and mortality in prostate cancer, African American men continue to experience disproportionate rates. Multiple socio-cultural factors have been associated with this disparity, including attitudes and perceptions regarding the healthcare system, prostate cancer knowledge, and lifestyle and environmental factors. As community-based participatory research (CBPR) involves community members and recognizes multiple levels of influence on health, it has been shown to be effective in identifying the contextual influences of health issues and determining culturally relevant and linguistically appropriate, multi-level health strategies.

Methods: To facilitate the development of a theory-based prostate cancer intervention for African American men, lay health advisors (LHA) were recruited, trained, and equipped with iPads to serve as a conduit between researchers and the community. LHAs were involved in all study phases and were instrumental in engaging community members. Additionally, a community advisory board was utilized for quarterly review of the study protocol and implementation.

Results: The results were two-fold. First, community members were actively engaged in the study, which helped build trust with the host institution, while also enabling the LHAs with health-related knowledge, communication skills, and leadership experience. Secondly, a culturally and linguistically appropriate theory-based prostate cancer intervention using iPads was developed to provide accurate, relevant information to African American men in the community.

Conclusions: CBPR, in tandem with LHAs, is a valuable approach for engaging African American men at risk for prostate cancer. The involvement of community members aided in acceptance and sustainability of the intervention. Additionally, the utilization of emerging technology, iPads, supports the timely dissemination of standardized health messages within the community setting.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B10.
Abstract B108: Combining Notch immunostimulation and bortezomib with adoptive immunotherapy in breast cancer
Authors: Malhotra Anshu , Pellom Samuel Troy , Carbone David P. , Dikov Mikhail M. , Shanker Anil
Published: June 2012

Breast cancer mortality occurs primarily due to invasive metastasis and takes a disproportionately heavy toll in African American women. Clinical immunotherapy efforts prove largely ineffective, partly due to the numerous immune-regulatory circuits influenced by cancers, which alter the differentiation and function of immune cells, including T cells. The long-term objective of this study is to enhance immune mechanisms of cancer rejection to provide durable clinical benefits against breast cancer. Our recent work using mouse models has revealed the therapeutic potential of combinatorial adoptive cell transfer regimens along with immunostimulatory and tumor cell-death-sensitizing treatments. We found that the proteasome inhibitor bortezomib selectively sensitized mammary tumor cells to apoptosis by amplifying caspase-8 activation in the death-inducing signaling complex. This resulted in reduced lung metastases in mice. In addition, bortezomib could be combined with adoptive T cell transfer with no adverse effects on the antigen-specific T cell proliferative or cytolytic functions in vivo. However, no long-term survival benefits could be observed, likely due to immunosuppressive effects of tumor. More recently, we observed that Delta-like ligand (DLL1)-specific immune Notch activation could enhance antitumor T cell immunity by overcoming tumor-associated immunosuppression. These data predict the potential of combining immunostimulatory Notch activation by soluble clustered DLL1 ligand treatment and bortezomib-induced sensitization of breast tumor cells to apoptosis with T cell adoptive transfers. This could prevent tumor metastasis and significantly improve breast cancer therapy.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B108.
Abstract B3: A novel participatory approach to increasing colon cancer screening in community health centers
Authors: James Aimee , Wang Jean , Massey Kristen , Colditz Graham
Published: June 2012

Although colorectal cancer (CRC) screening rates have been increasing, they are rising at a far slower pace in underserved populations such as the under- and un-insured. CRC remains the second leading cause of cancer death among US men and women. Under- and un-insured adults are the least likely to get screened, more likely to be diagnosed at later stages, and have poorer survival rates. While several evidence-based strategies for increasing screening exit, most interventions have moderate, if any, success and there is not strong evidence that these strategies can effectively translate to underserved settings. Our study uses community-based participatory approaches and draws from the dissemination and implementation literature to implement and evaluate system-level evidence-based strategies for increasing CRC screening in “safety-net” health centers. We present this cluster -randomized delayed-start trial as a novel design for cancer disparity research.

We are working with health centers to track uptake into the study (response rates) and including conducting assessments to evaluate organizational characteristics. In September 2011, we will hold workshops with intervention and control health centers to conduct participatory exercises in order to have health center representatives play an active role in selecting – and defining – the intervention strategies. These workshops will create the “Menu” of intervention strategies that will be tested in the trial. In the cluster randomized trial, set to begin in Winter 2012, intervention health centers will have access to the “Menu” and we will track not only effectiveness of change, but also which strategies were implemented and which will be sustained after the end of the trial.

We will present strategies for engaging health centers at multiple levels, strategies for working with communities and providers for developing interventions, and lessons learned during recruitment efforts. This study balances the need to engage communities and stakeholders in the development and implementation of disparity-reducing interventions and the need to conduct rigorous randomized research to obtain strong evidence. The measures in place to engage health centers at the start of the trial takes more time but helps us gauge the representativeness of the health center population and, we hope, increases external generalizability and potential for dissemination to other settings.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B3.