## The University of Chicago Breast Cancer SPORE

**Director: Olufunmilayo Olopade, MD**

**Co-Director: Maryellen Giger, PhD**

**Overall Abstract**

The University of Chicago Breast Cancer SPORE brings together a
multidisciplinary team of basic, clinical, and population science
investigators to design innovative research that will reduce the
worldwide suffering from breast cancer using a uniquely global strategy.
This integrated effort aims at developing genetic and imaging-based
approaches to the prevention, detection, and treatment of breast cancer
in women who are at increased risk of developing an aggressive form of
malignancy at a young age. This is a grave clinical issue because
currently there is no defined screening strategy for reducing breast
cancer mortality in women less than 40 years of age. This is a
particular problem for young women of African ancestry, because this
type of breast cancer disproportionately affects them. Thus, a portion
of the study tackles the global issue of health disparities between
different ethnic and racial groups. The goal of the SPORE is to get to
the root of the problem by identifying genetic mutations and altered
protein pathways that promote aggressive behavior in breast cancer and
limit the effectiveness of treatment for some patients. Understanding
these cellular dynamics will help us create more effective and less
harmful ways to prevent, screen, diagnose, and treat breast cancer in
all women. The Breast Cancer SPORE is composed of four primary research
projects, which will be supported by three core resources that will
serve the purposes of administration, biospecimen management, and
informatics. In addition, a Developmental Research Program and Career
Development program will promote new research endeavors and enhance the
quality of breast cancer research and investigators at University of
Chicago for years to come. The SPORE investigators, core facilities, and
development programs are joining and expanding upon the current efforts
of the University of Chicago Cancer Research Center with the expectation
that together our work will translate into dramatic improvements in
breast cancer outcomes. The four main projects of the SPORE are as
follows:

**Project 1**

**"Estimation of Breast Cancer Risk from Mammography and Breast MRI"**

*Project Leader: Maryellen Giger, PhD*

*Co-Project Leader: Gillian Newstead, MD*

*Co-Investigators: Robert Nishikawa, PhD; Charlene Sennett, MD*

This project focuses on developing multi-modality, image-based markers
for assessing breast density and parenchymal structure that may be used
alone or together with clinical information and biomarkers to quantify
breast cancer risk and monitor response to chemopreventive agents. The
general hypothesis is that inclusion of automated analyses of the
parenchyma will improve the assessment of breast cancer risk. In the
future, it is expected that the proposed image-based markers will be
useful for improved assessment of patients at high risk for breast
cancer and for monitoring the response to preventive treatments.

[Specific Aims]{.underline}

1)  Perform image-based categorization of patient databases based on
    breast density, parenchyma morphology, and automatically extracted
    parenchyma kinetics.

2)  Yield new image-based markers of risk by correlating and modeling
    various characteristics of breast density and parenchymal patterns
    with known surrogate markers of risk, such as BRCA1 and BRCA2
    genetic mutations and the presence of cancer in the contralateral
    breast.

3)  Develop a better understanding of breast cancer risk by correlating
    various image-markers with developing biomarkers and candidate
    genes.

4)  Use these new models to perform preclinical assessment and
    translation of the density and parenchymal characteristics of women
    at high risk.

The clinical translational component of this project will involve
quantitative comparison of the current method of risk assessment using
the Gail model and a case control study of databases from other
institutions relating the image-based markers to onset of cancer. In the
future, it is expected that such image-based markers will be useful for
improved assessment of patients at high risk for breast cancer and for
monitoring the response of preventive treatments. The proposed research
is novel in that other correlative image-based research of breast cancer
risk involves only breast density. However, here we incorporate two
additional, potentially complementary, analyses of the breast parenchyma
into the correlative and modeling research. The University of Chicago is
extremely well-positioned to perform this correlative research on
multi-modality image-based analyses for breast cancer risk because of
its 20-year history of developing multi-modality computer-aided
diagnostic methods for mammography, sonography, and MRI, and its
integration with the University of Chicago Cancer Risk Clinic.

**Project 2**

**"Specificity of MRI with Optimal Temporal, Spatial, and Spectral
Sampling in Early Breast Cancer"**

*Project Leader: Greg Karczmar, PhD*

*Co-Project Leaders: Gillian Newstead, MD; Nora Jaskowiak, MD*

*Co-Investigators: Dezheng Huo, PhD; Wendy Recant, MD; Olufunmilayo
Olopade, MD*

This project studies new ways to use magnetic resonance imaging (MRI) to
detect pre-cancerous lesions in their earliest stages of development.
MRI is excellent in detecting potential malignancies before they become
serious; however, this sensitivity leads to many false positives, and
physicians hesitate to act for fear of performing unnecessary biopsies,
surgery, and other treatments. Researchers are developing and testing
MRI techniques that enable them to better determine whether very small
lesions are cancerous. They hope that eventually they will be able to
destroy the ones identified as cancerous with MRI-directed, minimally
invasive procedures, such as ultrasound. The research will have a
significant impact on clinical management of breast cancer. If the
results demonstrate that these new techniques will be more effective in
identifying early breast cancer, this will support increased clinical
use of MRI for screening high risk women and integration of improved
sampling techniques into clinical MRI. In addition, the research
provides an unusual opportunity to correlate MRI parameters with
biological markers for malignancy in early breast cancers. This could
lead to improved design of MRI protocols and interpretation of MR
images.

[Specific Aims]{.underline}

1)  Use MRI with improved spectral, spatial, and temporal sampling
    (MRITSS) to acquire images of suspicious incidental lesions found in
    high risk women. Determine whether MRITSS increases specificity
    while maintaining adequate sensitivity. MRITSS will be compared to
    conventional MRI, and pathology will be used as the gold standard.

2)  Determine whether conventional and/or MRITSS MRI can distinguish
    between invasive and non-invasive (in situ) cancers.

3)  Determine whether breast lesions in African American women who are
    at risk for high grade, estrogen receptor negative breast cancer are
    significantly different from those of the other women in the study.

4)  Test whether there are specific biological markers that are strongly
    correlated with MRI parameters, and explain the appearance of
    functional and anatomic MR images of early breast cancers.

**Project 3**

**"Variation in Hormone and Xenobiotic Metabolizing Enzyme Genes and
Breast Cancer Risk"**

*Project Leader: Olufunmilayo Olopade, MD*

*Co-Project Leader: Anna Di Rienzo, PhD*

*Co-Investigators: Nancy Cox, PhD; James Fackenthal, PhD; Dezheng Huo,
PhD*

Breast cancer is a very complex disease, which varies dramatically from
person to person in the age of the individual at diagnosis, its effects,
and its genetic composition. This variability suggests the presence of
multiple genetic and/or environmental factors that alter how the disease
affects each individual. This project will enhance our understanding of
the interacting role of genes in causing breast cancer. This information
will help us move toward the goal of tailoring risk assessment and
treatment in terms of the unique genetic make-up of each person. This
project aims to test whether sequence variation in genes involved in the
metabolism of sex hormones (such as estrogen and androgens) and
xenobiotics (such as environmental toxins) increases the risk of breast
cancer. To accomplish this, we will extend our existing studies and
determine whether sequence variation in specific clusters of genes and
enzymes influence breast cancer risk. Constructing genetic profiles for
use in risk assessment may increase understanding of the role of gene
environment interactions in breast cancer etiology and treatment.
Moreover, by researching the role of these genes and enzymes in the
metabolism of anticancer agents, the information obtained through these
studies may help in dissecting the genetic basis of individual
variability in response to cancer treatment and, ultimately, lead to
individualized therapy. This would lead to reduced breast cancer
morbidity and mortality and improved clinical outcomes for all women
with breast cancer.

[Specific Aims]{.underline}

1)  Re-sequence the UGT2B gene cluster based on comparative genomics
    analyses in ethnically diverse population samples to select specific
    pieces of DNA for association study.

2)  Examine whether variations in the UGT2B genes are associated with
    breast cancer risk in women of African descent.

3)  Examine whether UGT2B genes and environmental factors are associated
    with age at diagnosis, tumor grade, and estrogen
    receptor/progesterone receptor staining.

**Project 4**

**"Identifying Population Specific Variants Important in Toxicity to
Breast Cancer Chemotherapy"**

*Project Leader: M. Eileen Dolan, PhD*

*Co-Project Leader: Mark Ratain, MD*

*Co-Investigators: Nancy Cox, PhD; Olufunmilayo Olopade, MD*

This project also focuses on genetic variation and its impact on breast
cancer treatment by identifying genetic influences of breast cancer
chemotherapy-associated toxicity and response. We will develop and
validate a genome-wide, comprehensive approach to test the hypothesis
that genetic variation significantly influences susceptibility to
toxicities and response associated with breast cancer chemotherapeutic
agents*.* A cancer therapy that is perfectly safe for one person may be
highly toxic to another. Similarly, some therapies are very effective
for some people and ineffective for others. Since chemotherapy is one of
the mainstays for treatment of breast cancer, this project has great
potential for enhancing treatment of the disease. This concerted
translational research effort devoted to understanding individual
variability in chemosensitivity and toxicity is long overdue within the
SPORE program. Although this approach will eventually be applied to a
variety of breast cancer agents, we will focus on fluoropyrimidines
(capecitabine) and platinating agents (carboplatin).

The project is highly translational, employing two clinical trials and
the use of state of the art, complementary approaches including
heritability analysis, linkage analysis, expression studies, and
association studies. This global approach opens up the possibility of
identifying genes that were previously unknown or unrecognized and
offers an advantage over studies that focus on a single gene or pathway.
An important outcome of this research is the identification of genetic
variations in individuals of European and African descent. Functional
studies will follow concomitant with two clinical trials of breast
cancer patients treated with capecitabine. The first study we will
utilize is a phase II study of capecitabine as neoadjuvant therapy in
newly diagnosed locally advanced breast cancer in Nigeria. The second
study we will utilize is the CALGB pharmacogenetic study of capecitabine
as second line therapy of metastatic breast cancer progressing on
initial chemotherapy.

[Specific Aims]{.underline}

1)  Determine the heritability of variation in the susceptibility to the
    cytotoxic and apoptotic effects of capecitabine and carboplatin.

2)  Perform association studies on CEPH and Yoruban HapMap trios.

3)  Examine the relationship between global gene expression patterns and
    capecitabine and carboplatin-induced cytotoxicity and perform
    functional studies on candidate genes.

4)  To determine whether polymorphisms in candidate genes identified
    using our global approach are associated with survival or toxicity
    in breast cancer patients treated with capecitabine.

**Core 1**

**Administrative Core**

*Director: Olufunmilayo Olopade, MD*

*Co-Director: Gini Fleming, MD*

The purpose of the Administrative Core is to facilitate translational
research in breast cancer by harnessing intellectual capacity and
providing a mechanism for cost effective utilization of resources. The
Core will provide necessary administrative support structure to
components of the SPORE program such that communication, integration,
and oversight activities are optimized. The Administrative Core will
facilitate communication and effectiveness in the activities among SPORE
participants, involvement of other researchers and clinical providers at
the University, collaborations with investigators and SPOREs outside of
the University, interaction with government agencies, and relations with
the outside patient and advocate community.

[Specific Aims]{.underline}

1)  Provide necessary administrative assistance to SPORE leaders and
    investigators.

2)  Manage all SPORE finances.

3)  Convene all meetings of the SPORE including monthly research
    meetings, Internal Advisory Board, External Advisory Board, and
    Executive Committee meetings.

4)  Provide day-to-day logistical coordination for the SPORE.

5)  Maintain responsibility for administration of the Developmental
    Research Program and the Career Development Program.

6)  Ensure compliance with all institutional, governmental, and
    NCI-specific regulations and requirements, including timely
    communication and consultation with NCI staff.

**Core 2**

**Biospecimen, Pathology, and Genotyping Core**

*Director: Thomas Krausz, MD*

*Co-Director: Soma Daz, PhD*

*Co-Investigator: Shelly Cummings, MS; James Fackenthal, PhD; Maria
Tretiakova, MD, PhD*

Effective procurement of tissue and other biospecimen, and their optimal
utilization is vital for meaningful translational research activities.
Thus, the function of the Biospecimen, Pathology, and Genotyping Core is
to facilitate acquisition, preservation, analysis, and dispersal of
well-annotated clinical samples and to provide histopathologic
characterization of tumor tissues for all project investigators. The
Core will obtain and maintain a repository of biospecimen including
tumor tissue, pre-malignant tissue, adjacent non-malignant tissue,
serum, plasma, peripheral blood lymphocytes, and lymphoblastoid cell
lines, along with their derivates such as DNA and RNA samples for
laboratory use. An effective coding system for all laboratory specimens
will ensure patient confidentiality and prevent experimental bias.
Continuous communication between the surgeons, research nurses,
biostatisticians, and pathologists, as well as standardized operating
procedures will provide for optimal biospecimen collection and accurate
processing, analysis, and storage of each sample. Samples will be
prepared for genotyping in an efficient manner in a CLIA certified
laboratory that assures quality control while ensuring that these
precious materials are not wasted.

The Biospecimen, Pathology, and Genotyping Core of the Breast Cancer
SPORE will be integrated with two existing resources of the University
of Chicago Cancer Research Center -- the Human Tissue Research Core
Facility and the DNA Sequencing and Genotyping Core Facility. Currently,
these facilities provide tissue and pathology services for cancer
research, including microdissection, tissue microarray,
immunohistochemistry, and genomics analysis. By collaborating with these
facilities in the Cancer Research Center, the Biospecimen Core can
provide investigators with a coordinated, efficient service for managing
the procurement and analysis of biospecimen and clinical data from
breast cancer patients.

**Core 3**

**Analytic and Informatics Core**

*Director: Nancy Cox, PhD*

*Co-Director: Jonathan Silverstein, MD*

*Co-Investigator: Dezheng Huo, PhD; Xiaoming Wang, PhD; Charlene
Sennett, MD; Yves Lussier, MD*

# The goal of the Analytic and Informatics Core (AIC) is to work with each SPORE research project and the Biospecimen, Pathology, and Genotyping Core to provide an integrated data management system to facilitate integration among all projects and cores and to serve as a resource for the design of basic science experiments and clinical trials, development of innovative statistical methodology, statistical analysis, and publishing translational research generated through the Breast SPORE program. The AIC will merge all demographic, epidemiology, and specimen data into a single database to meet statistical needs and ensure research quality of all translational projects supported by this SPORE. This effort will be integrated with the Cancer Center Biostatistics Core Facility and the Bioinformatics Core of the University of Chicago for ease of administration, avoiding duplication of existing infrastructure and taking advantage of existing expertise. The Analytic and Informatics Core will incorporate sound experimental design principles within each project to enhance interpretability of study results, will carry out data analyses using appropriate statistical methodology, and will contribute to interpretation of results through written reports and frequent interaction with project investigators. {#the-goal-of-the-analytic-and-informatics-core-aic-is-to-work-with-each-spore-research-project-and-the-biospecimen-pathology-and-genotyping-core-to-provide-an-integrated-data-management-system-to-facilitate-integration-among-all-projects-and-cores-and-to-serve-as-a-resource-for-the-design-of-basic-science-experiments-and-clinical-trials-development-of-innovative-statistical-methodology-statistical-analysis-and-publishing-translational-research-generated-through-the-breast-spore-program.-the-aic-will-merge-all-demographic-epidemiology-and-specimen-data-into-a-single-database-to-meet-statistical-needs-and-ensure-research-quality-of-all-translational-projects-supported-by-this-spore.-this-effort-will-be-integrated-with-the-cancer-center-biostatistics-core-facility-and-the-bioinformatics-core-of-the-university-of-chicago-for-ease-of-administration-avoiding-duplication-of-existing-infrastructure-and-taking-advantage-of-existing-expertise.-the-analytic-and-informatics-core-will-incorporate-sound-experimental-design-principles-within-each-project-to-enhance-interpretability-of-study-results-will-carry-out-data-analyses-using-appropriate-statistical-methodology-and-will-contribute-to-interpretation-of-results-through-written-reports-and-frequent-interaction-with-project-investigators. .n}

#  {#section .n}

# [Specific Aims]{.underline} {#specific-aims .n}

#  {#section-1 .n}

# Complete the development of SPORE databases, including development of systems to enhance the accuracy and completeness of project data and facilitate the sharing of data and results among SPORE investigators. The systems will link clinical, tissue, and laboratory data in a relational schema and include a web application interface to allow researchers to access databases, perform queries and edit checks, and export the data for statistical analysis.  {#complete-the-development-of-spore-databases-including-development-of-systems-to-enhance-the-accuracy-and-completeness-of-project-data-and-facilitate-the-sharing-of-data-and-results-among-spore-investigators.-the-systems-will-link-clinical-tissue-and-laboratory-data-in-a-relational-schema-and-include-a-web-application-interface-to-allow-researchers-to-access-databases-perform-queries-and-edit-checks-and-export-the-data-for-statistical-analysis. .n}

# Provide statistical and statistical genetic expertise in designing and conducting laboratory experiments, clinical trials, and genetic and epidemiologic studies arising from the primary research projects included in the SPORE. {#provide-statistical-and-statistical-genetic-expertise-in-designing-and-conducting-laboratory-experiments-clinical-trials-and-genetic-and-epidemiologic-studies-arising-from-the-primary-research-projects-included-in-the-spore. .n}

# Perform statistical and statistical genetic analyses and assist in the interpretation of study findings, summarization of results, and preparation of manuscripts for publication. {#perform-statistical-and-statistical-genetic-analyses-and-assist-in-the-interpretation-of-study-findings-summarization-of-results-and-preparation-of-manuscripts-for-publication. .n}

# Conduct methodological research to provide research infrastructure for SPORE projects. Among the first of the research projects on which the AIC will collaborate is the extension of HapMap information to members of CEPH pedigrees not included in the HapMap through use of linkage mapping information on all pedigree members. This research project will substantially improve the power and resolution of Project 4, as well as provide a public resource with phenotype information on CEPH cell lines for use by other investigators.  {#conduct-methodological-research-to-provide-research-infrastructure-for-spore-projects.-among-the-first-of-the-research-projects-on-which-the-aic-will-collaborate-is-the-extension-of-hapmap-information-to-members-of-ceph-pedigrees-not-included-in-the-hapmap-through-use-of-linkage-mapping-information-on-all-pedigree-members.-this-research-project-will-substantially-improve-the-power-and-resolution-of-project-4-as-well-as-provide-a-public-resource-with-phenotype-information-on-ceph-cell-lines-for-use-by-other-investigators. .n}

# Collaborate and assist all project investigators with the publication of scientific results. {#collaborate-and-assist-all-project-investigators-with-the-publication-of-scientific-results. .n}

**Developmental Research Program**

*Director: Geoffrey Greene, MD*

*Co-Director: Suzanne Conzen, MD*

The objective of the University of Chicago Breast Cancer SPORE
Developmental Research Program (DRP) is to create a streamlined and
transparent mechanism for soliciting and selecting exciting and novel
research projects that have significant potential for translational
success. Such projects may be collaborative among scientists within our
SPORE or outside the SPORE environment. Most importantly, they should be
innovative, have the potential for high impact results, and preferably
be multi-disciplinary.

[Criteria for Selection]{.underline}:

1)  Scientific merit and potential relevance to clinical breast cancer

2)  Originality

3)  Expertise of key personnel

4)  Perceived likelihood of generating peer-reviewed external grant
    support to establish further work in preclinical and clinical work
    in breast cancer

The University of Chicago Breast Cancer SPORE DRP will provide
\$50,000/year (\$25,000 of SPORE funds matched with \$25,000 of
institution support) to each of four projects per year. There will be a
possibility of a second year of support based on progress. The
University of Chicago SPORE Executive Committee will work with the
Internal Advisory Committee to encourage successful investigators to
pursue independent funding so that even investigators who may be new to
breast cancer research will have a high likelihood of successful
application of their ideas to breast cancer prevention, diagnosis, and
treatment.

[Specific Aims]{.underline}:

1)  Establish a mechanism for soliciting DRP applications that reaches
    beyond cancer center members and the local SPORE community to all
    biological, physical, computer and social science faculty members at
    the University of Chicago and Argonne National Laboratory, as well
    as to investigators at other SPOREs nationwide.

2)  Encourage, support, and nurture interdisciplinary collaboration
    using the expertise of our interdisciplinary Internal Scientific
    Advisory Committee.

3)  Select and assess projects that help generate new hypotheses for
    development as full-fledged SPORE projects.

**Career Development Program**

*Director: Olufunmilayo Olopade, MD*

*Co-Directors: M. Eileen Dolan, PhD; Maryellen L. Giger, PhD*

This program will be used to support early careers of the most promising
junior investigators and to recruit new senior investigators into breast
cancer translational research. The University of Chicago has long
recognized the importance of clinician scientists capable of using
clinical observations to inform and shape basic investigations, and in
turn, evolving novel therapeutic approaches through laboratory
discoveries. The Career Development Program of the Chicago Breast Cancer
SPORE is committed to identifying and mentoring investigators interested
in translational breast cancer research. The program will primarily
provide tightly-structured, multidisciplinary mentoring for junior
faculty with the greatest potential of developing independent programs
in translational breast cancer research; however, exceptional senior
faculty who demonstrate strong interest in developing such programs may
also be eligible. Investigators may come from clinical or basic science
backgrounds, provided that their research aims are translational in
nature. We will use a rigorous review process, working with department
Chairs to identify and recruit the most talented and promising
candidates to participate in our comprehensive mentoring program.
Programmatic leadership and individual mentoring will be provided by a
multidisciplinary mentoring committee, which must include the necessary
representation from the basic/population sciences, clinical sciences,
and biostatistics so that all disciplines are represented for optimal
mentoring of the awardees. These mentors are established cancer
researchers, and as members of the UCCRC, have access to all the Cancer
Center sponsored Cores.