Breast Cancer Research(4)

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					                                 Breast Cancer Research
Lori J. Goldstein, M.D., Member, Director, Breast Evaluation Center, Leader, Breast Cancer Research
V. Craig Jordan, O.B.E., Ph.D., D.Sc., Senior Member, Vice President and Scientific Director for Medical
   Science, Alfred G. Knudson Jr. Chair in Cancer Research
Monica Morrow, M.D., F.A.C.S., Senior Member, Chairman, Surgical Oncology, G. Willing “Wing” Pepper
   Chair in Cancer Research
Mary B. Daly, M.D., Ph.D., Senior Member, Senior Vice President, Population Science, Timothy R. Talbot Jr.
   Chair for Cancer Research
Elin R. Sigurdson, M.D., Ph.D., Senior Member, Chief, Surgical Oncology Clinical Research
Sharon L. Manne, Ph.D., Senior Member
Suzanne M. Miller, Ph.D., Senior Member
Kathryn Evers, M.D., Member, Director of Mammography
Roger B. Cohen, M.D., Member
Joanne F. Dorgan, Ph.D., Member
Andrew K. Godwin, Ph.D., Member
Natalie E. Joseph, M.D., Member
Margaret von Mehren, M.D., Member
Penny R. Anderson, M.D., Associate Member
Gary M. Freedman, M.D., Associate Member
Nancy L. Lewis, M.D., Associate Member
Ramona F. Swaby, M.D., Associate Member
Marilyn Tseng, A.M., Ph.D., Associate Member
Patricia Ann Robinson,*a M.D., Assistant Member
Linda Sesa, A.O.P.N., Breast Cancer Coordinator
Joseph Hayburn, Clinical Research Coordinator
Wahiba Gherraby, Clinical Research Associate
Deena Dell, R.N., B.S.N., A.O.C.N., B.C., Clinical Nurse Specialist
Carolyn Weaver, R.N., B.S.N., A.O.C.N., Clinical Nurse Specialist
Donna Juhas, R.N., Staff R.N./Outpatient Department
Coleen Boyd, M.S.S., L.S.W., Oncology Social Worker
Pat Dessin, Administrative Assistant

It is estimated that 180,000 women will be diagnosed with
breast cancer and about 40,000 women will succumb to their
disease in the United States in 2007. Breast cancer remains
second to lung cancer as the leading cause for cancer related mortality in women. Over the last decade,
mortality due to breast cancer has decreased likely due to improved adherence to screening and
advances in therapy for both early and late stage breast cancer. We have embarked upon a new era
where translation between laboratory-based and clinical research in prevention, epidemiology, and
treatment have had true impacts on the lives of women at risk for and with breast cancer. Through
genetics we can now classify specific subgroups of women at risk for the disease. In addition, with
genetic profiling we can predict which patients benefit from specific hormonal, chemotherapeutic, and
biologic treatments in the adjuvant setting. Furthermore, we have seen the impact of targeted therapies,
such as trastuzumab targeting HER-2/neu, result in improvement of breast cancer survival both in
early and late stage disease. The investigators of the Breast Cancer Research Program are organized
into four scientific groups that interact with one another. It is through translational research among
the genetic, behavioral, basic and clinical investigators that we will continue to better understand
the etiology and biology of breast cancer to reduce its incidence and morbidity.

Genetics, epidemiology, prevention and con-            tions that are at an increased risk of developing
trol of breast cancer. Daly,§ Godwin,§ Dorgan,§        breast cancer using epidemiologic, genetic, and
Tseng§                                                 molecular studies. Under the direction of
The focus of the research by this group is the         M. Daly, the Fox Chase Breast Cancer Risk
identification and characterization of popula-          Registry has been developed to allow for the
                             Fox Chase Cancer Center 2006 Scientific Report                 1
transfer of cancer control expertise and tech-      which is less than originally estimated. In spite
nology to the community. The registry will          of the large number of sequence variants identi-
increase the scientific database for future          fied in BRCA1 and BRCA2 mutation analyses,
genetic and epidemiologic research. Daly has        many of these genetic alterations are still classi-
demonstrated the efficacy of a computerized          fied as variants of unknown significance (VUS).
interactive program to educate women about          Godwin and colleagues recently evaluated
the genetics of breast cancer. In addition, she     BRCA1/2 intronic variants in order to differen-
has piloted a psycho-educa t ional support          tiate their pathogenic or polymorphic effects on
group for women who have received BRCA1/2           the mRNA splicing process. They demonstrated
genetic test results. She and colleagues, includ-   that several of these intronic VUSs effect mRNA
ing A. Godwin and members of the Breast             splicing fidelity and expression. What is also
Cooperative Family Registry (Breast-CFR), have      clear from their studies and those of others is
identified modification of BRCA1/2-associated         that multiple genes remain to be identified
breast cancer risk by the A1B1 phenotype.           among BRCA1 and BRCA2 mutation-negative
Godwin and Daly have participated in a num-         breast cancer-prone families. Mounting evi-
ber of Breast-CFR studies. For example, the         dence suggests that there may be additional,
Breast-CFR has examined the effects of alcohol      but less prevalent, breast cancer susceptibility
intake on breast cancer risk in woman with          genes; however, the identification of these
BRCA1 or BRCA1 mutations and reported no            genes remains elusive. Godwin and colleagues
significant increase in risk of disease as a func-   are attempting to identify these novel breast
tion of alcohol consumption and carrier status      cancer risk factors by evaluate genes coding for
under 50 years of age. This same group evalu-       proteins that interact with BRCA1 in a multiple
ated a large series of BRCA2-associated breast      protein complex. These BRCA1-associated pro-
cancers and found that significant pathologic        teins are potentially functional “modifiers” of
differences exist between BRCA2-associated          BRCA1 and are, therefore, likely to contribute
breast cancer and tumors from non-carriers.         to breast cancer susceptibility. Godwin and col-
The Breast-CFR investigators also studied 497       leagues have recently reported that a novel
BRCA1 and 307 BRCA2 mutation carriers, of           multiprotein complex, termed BRCC (BRCA1/2
whom 195 and 128, respectively, had been            Containing Complex), contains seven polypep-
diagnosed with breast cancer to evaluate the        tides, including BRCA1, BRCA2, BARD1,
risk of breast cancer with use of oral contracep-   RAD51, and three novel subunits (BRCC36,
tives (OCs). They found no evidence overall         BRCC45, BRCC120) with E3 ligase activity.
that use of OCs for at least one year was associ-   One of the novel BRCA1-associated proteins,
ated with breast cancer risk for BRCA1 and          BRCC36, has been found to physically interact
BRCA2 mutation carriers before age 50. How-         with BRCA1. They have demonstrated that can-
ever, the study did suggest that for BRCA2 muta-    cer-associated mutations in BRCA 1abrogates
tion carriers, use of OCs may be associated with    the association of BRCC36 with BRCC complex
an increased risk of breast cancer among women      and BRCA1. Godwin and colleagues have
who use them for at least five years.                reported that BRCC36 is aberrantly expressed
   In collaboration with I. Russo, § Daly has       in the majority of invasive ductal carcinomas.
been conducting a pilot study to identify novel     In addition, they have recently demonstrated
molecular biomarkers of premalignant change         that the knock-down of BRCCC36 sensitizes
from ductal lavage specimens. These markers         breast cancer cells to ionizing radiation (IR)
are being correlated with cytologic findings and     and disrupts IR-induced phosphorylation of
with level of genetic risk ( see Daly’s and         BRCA1. However, the mechanisms and conse-
I. Russo’s reports and publications).               quences of abnormal expression of BRCCs in
   Godwin’s breast research group focuses on        breast cancer are presently unknown, and the
the identification of novel genetic factors that     role of BRCC36 and other BRCC proteins in
contribute to breast cancer susceptibility. Muta-   BRCA1 mediated DNA repair and ubiquitina-
tions (e.g., frameshifts, nonsense, splice site,    tion is actively being investigated (see Godwin’s
large deletions/insertions) in the coding regions   report and publications).
of BRCA1 and BRCA2 are associated with 30 to           J. Dorgan is a molecular epidemiologist
40% of hereditary breast cancer, a proportion,      whose interests include the interrelationships
                            Fox Chase Cancer Center 2006 Scientific Report              2
of diet, physical activity, and hormones with           tion processes among women with early stage
the risk of breast cancer. She has initiated two        breast cancer and their spouses using paper-
projects in these areas. The first is a feasibility      and-pencil surveys. The second project is a ran-
study for a case-control study of adrenal andro-        domized clinical trial evaluating the efficacy of
gen production in post-menopausal women                 two different communication and intimacy-
with breast cancer. The second is in premeno-           enhancing psychological interventions for
pausal women with breast cancer, to determine           women and their spouses. The third project
the feasibility of a case-control study of pitu-        evaluates the efficacy of two couple-focused
itary-ovarian function (see Dorgan’s report and         group interventions for women with early stage
publications).                                          breast cancer and their partners. The fourth
   The importance of dietary intake in the etiol-       project evaluates the efficacy of a communica-
ogy and prevention of common cancers such as            tion skills-enhancing versus supportive coun-
breast or prostate cancer remains unclear, and          seling intervention for women with metastatic
this is the focus of the work conducted in              breast cancer.
M. Tseng’s research program. The experience of             The comprehensive research program of
migrant populations is of particular interest           S. Miller studies the processes of and methods
because they experience substantial changes in          for facilitating successful adaptation across the
lifestyle and in disease risk, often in adulthood.      breast cancer spectrum, including breast cancer
Evidence of changes in risk occurring in the            risk, treatment, and survivorship. These dis-
migrating generation would suggest that factors         tinct, yet interrelated topics are addressed
occurring in adulthood can affect risk. From a          through a number of studies derived from and
recently completed study conducted among                integrated by, a unifying theoretical frame-
foreign-born Chinese women in the Philadel-             work—the Cognitive-Social Health Informa-
phia region, the first evidence of substantial dif-      tion Processing (C-SHIP) model. This model
ferences in mammographic density, and hence             specifies the principles for developing and eval-
possibly breast cancer risk, by level of accultur-      uating tailored breast cancer communication
ation was found. Currently, Tseng is conducting         strategies to enhance decision making, improve
a larger, prospective study in a similar popula-        quality of life, and promote adherence to
tion of women to examine how changes in                 screening, treatment, and behavior change regi-
acculturation and dietary westernization over           mens. In these studies, these investigators are
time relate to changes in breast density. Another       focusing particularly on the role of information
area of investigation is the use of dietary pat-        seeking, since they have identified distinctive
terns as an alternative method for characteriz-         individual differences among women in coping
ing dietary intake in nutritional epidemiologic         with breast cancer risk and disease feedback. In
studies. Work conducted in this area includes           prior and ongoing work, it has been found that
analyses of dietary patterns in relation to breast      patients benefit from different types of counsel-
density, breast cancer risk, and prostate cancer        ing interventions, tailored to their own psycho-
risk, and with active collaborations with inves-        logical profile and behavioral signature.
tigators interested in applying a dietary pattern          The research program examines three main
approach to other disease outcomes. The pri-            behavioral aspects of breast cancer: risk assess-
mary objective of Tseng’s research program is to        ment and decision making, reaction to and pro-
examine the association of effectiveness of             cessing of cancer diagnoses, and the transition
dietary modification as a strategy for the preven-       to survivorship. Many of these projects are
tion of cancer (see Tseng’s report and publications).   linked together by a Department of Defense
                                                        Behavioral Center of Excellence Award and the
Psychosocial and behavioral medicine of                 remaining projects extend and complement the
breast cancer. Manne, Miller, in collaboration          work of this award. First, the population of
with Barsevick,§ Buzaglo,§ Fleisher§
                                                        high-risk underserved African-American
S. Manne, in collaboration with L. Goldstein,           women is being assessed to explore barriers to
G. Grana,b T. Frazier,c J. Kendall,d and L. Patrick-    the uptake of risk counseling programs and
Miller,e has four ongoing studies focusing on           breast cancer screening adherence. A related
women with breast cancer. The first project              pilot study is exploring the barriers to and facili-
investigates marital support and communica-             tators of participation in high-risk breast cancer
                              Fox Chase Cancer Center 2006 Scientific Report                 3
risk assessment program among an ethnically         as other associated fears. To address these
diverse population of women, with a particular      needs, an intervention has been developed to
focus on their attitudes about genetic screen-      identify and modify maladaptive thoughts and
ing. Both of these studies address the lack of      behaviors that interfere with consistent, long-
evidence-based research on interest in, aware-      term health-protective behaviors, quality of life,
ness of, and the psychological and behavioral       and coping efficacy. We are also conducting an
implications of familial cancer risk among          in-depth assessment of the psychosocial factors
underserved populations.                            involved in lymphedema symptom minimiza-
   In a second context, various aspects of the      tion management among women recovering
response to a diagnosis of breast cancer are        from surgery for primary breast cancer.
being investigated. This includes an examina-          The department also has become involved in
tion of the impact of a web-based program to        a multi-site, randomized trial to assess the
promote informed decision making around             impact, utility, and feasibility of newly devel-
treatment for early stage breast cancer. An         oped NCI print materials focused on facilitating
intervention for promoting utilization of family    survivorship issues for patients completing
risk assessment programs and increasing adher-      medical treatment for breast cancer, as well as
ence to breast cancer screening guidelines,         to provide an evaluation of the mechanisms
among daughters of breast cancer patients, is       underlying the effect of the materials. Finally,
also being assessed. With the collaboration of      the investigators currently are developing a
nine community hospitals, this study is explor-     study to comprehensively assess how women,
ing an individually-tailored approach, for high     with DCIS, cognitively and emotionally process
and low monitors, to using a breast cancer          and respond to decision aids. The study hopes
diagnosis in the family as a teachable moment       to gain insight into patient-centered factors that
to address the needs and concerns of at-risk        contribute to DCIS decision-making and to
family members. A new direction is the devel-       understand how to tailor decision support pro-
opment of a pilot navigator program, funded         grams to individual differences in patient deci-
by the Pennsylvania Department of Health.           sion-making styles. Taken together, these
This program is designed to develop a model         studies will enable the development of a profile
lay navigator program in both urban and rural       of patient needs across the breast cancer spec-
contexts that is theoretically-guided by the        trum, with a view to designing tailored health
C-SHIP model. The goal is to reduce the time        communication messages (see Miller’s report and
from diagnosis to treatment initiation through      publications).
the use of a lay patient navigator. Additionally,      The focus of the Quality of Life research pro-
we are applying techniques from cognitive           gram is the assessment and modification of
science through the use of an attentional search    risk. A. Barsevick is conducting a randomized
task to the study of individual differences in      clinical trial, in collaboration with the Univer-
attentional styles on the processing of cancer      sity of Utah (S. Beck), of a symptom manage-
risk-related information among high-risk            ment intervention focused on energy and sleep
women.                                              enhancement to reduce fatigue and insomnia
   Improvements in breast cancer treatments         during cancer treatment. Barsevick’s current
have greatly reduced mortality rates; conse-        intervention study for the management of two
quently, more attention needs to be given to        symptoms builds on the findings of the com-
survivorship issues. To address this issue, the     pleted study of an energy conservation activity
team is evaluating a population of early stage      management (ECAM) intervention to manage
breast cancer survivors at the re-entry stage to    fatigue. The results demonstrated a small but
facilitate the transition between active treat-     significant effect of the ECAM intervention on
ment and the resumption of every-day life. This     fatigue during cancer treatment (A.M. Barsevick
individually tailored intervention is designed to   et al., Cancer 100:1302, 2004).
prepare women for the challenges that emerge           Barsevick is collaborating with P. Engstrom§ in
during the re-entry phase. For example, the         the conduct of a longitudinal descriptive study
need to initiate and maintain cancer-screening      of symptom patterns during cancer chemo-
regimens can reactivate deep anxieties about        therapy. The objective of this study is to con-
the cancer reoccurring or progressing, as well      duct a systematic assessment of a group of
                            Fox Chase Cancer Center 2006 Scientific Report              4
physical symptoms (fatigue, insomnia, pain,             for Breast Cancer Exploiting Low-Dose Estro-
and nausea/vomiting) in order to examine the            gen-Induced Apoptosis.” The research program
pattern of relationships between and among              is centered at Fox Chase where laboratory mod-
them and the impact of symptoms on quality of           els of antihormonal resistance are being used to
life. This study will provide information relevant      determine the molecular events involved with
to the assessment and management of cancer              estrogen-induced breast cancer cell survival and
treatment-related symptoms. Barsevick is collab-        apoptosis. Tissue from the Jordan laboratory is
orating with Daly in the conduct of a random-           being processed for genomic analysis at Transla-
ized clinical trial of a counseling/decision            tional Genomics (TGen) in Phoenix, Arizona
making intervention to teach women undergo-             and proteomics will be completed at George-
ing genetic testing how to communicate their            town University (GU). Clinical Protocols devel-
test results to their relatives. Barsevick is collab-   oped by Swaby and Daly will be coordinated by
orating with Miller on two projects, “Under-            Goldstein with the goal of determining the
standing Breast Cancer Risk Assessment and              response rate of tumors to pharmacological
Screening Behavior of the Underserved.”                 estrogen in patients who have responded and
Barsevick has conducted focus groups with               failed two consecutive antihormonal therapies.
minority first-degree relatives of breast cancer         Serum and tissue samples are being taken to
patients to understand barriers to screening            determine early markers of apoptosis. Clinical
and risk assessment. She has also conducted             and laboratory results will be analyzed through a
focus groups facilitating re-entry following            secure web system controlled by E. Ross.§ The
adjuvant treatment for primary breast cancer.           overall aim of the 5-year project is to introduce a
The information gained from the focus groups            new therapeutic step in the treatment of antihor-
is being used in the development of interven-           monal resistant breast cancer so that tumors can
tions to assist women in making responsible             again be controlled with aromatase inhibitors.
decisions about screening and risk assessment              I. Russo is a Primary Member of the Program.
and improving quality of life after completion          Russo’s laboratory has demonstrated that the
of cancer therapy (see Barsevick’s report and pub-      susceptibility of rats to develop mammary
lications).                                             cancer induced by an environmental polycyclic
                                                        hydrocarbon is maximal during a specific
Molecular biology of breast cancer. Jordan,             period of the animal’s sexual development. That
J. Russo,§ I. Russo,§ Seeholzer,§ Murphy,§
                                                        period is encompassed between the initiation of
Golemis,§ Chernoff,§ Cukierman§
                                                        ovarian function and the first pregnancy. It rep-
Investigators in the Molecular Biology Group            resents a “high risk window” that is progres-
are basic scientists who are also members of the        sively diminished by the first and subsequent
Molecular Oncology, Tumor Cell Biology pro-             pregnancies. These findings have been essential
grams and the Division of Medical Science. The          for unraveling the mechanisms that determine
common theme of the scientific interests of these        the greater breast cancer incidence associated
members is the generation and transduction of           with nulliparity and the influence of exposure
signals that regulate cellular proliferation and        to environmental factors during critical phases
differentiation using breast cancer as a model          of breast development for increasing breast
system to better understand breast cancer               cancer risk. A large body of evidence has con-
carcinogenesis and progression. The goal is to          firmed that nulliparity increases breast cancer
identify new targets for prevention and therapy.        risk, whereas early pregnancy exerts a protec-
  C. Jordan’s current research focus includes           tive effect that is further increased by additional
investigation of the mechanisms of anti-hormone         pregnancies and breast feeding. Both the sus-
resistance, the molecular mechanism and clini-          ceptibility of the breast to undergo neoplastic
cal application of estrogen-induced apoptosis           transformation and the prevention of cancer are
in collaboration with R. Swaby and L. Goldstein         regulated by endocrinological conditions that
and anti-androgen action in breast cancer.              in turn are under the control of a fully func-
  Jordan is the Principal Investigator and              tional hypothalamic-pituitary-gonadal axis.
Goldstein the co-Principal Investigator of a            The main goal of Russo’s research is the preven-
Department of Defense Center of Excellence              tion of breast cancer through the utilization of
Grant, entitled “A New Therapeutic Paradigm             physiological mechanisms of differentiation
                              Fox Chase Cancer Center 2006 Scientific Report                5
that are triggered by early pregnancy, but               This specific signature is composed of genes
whose basis are set by the interaction of endog-         that are controlling cell proliferation, differenti-
enous and environmental influences on the                 ation, apoptosis and DNA repair.
development of the hypothalamic-pituitary-                  Russo directs the Environment Research
gonadal axis (see I. Russo’s report and publications).   Center at Fox Chase Cancer Center (FCCC),
   J. Russo is a Primary Member of the Program           which collaborates with centers at the Univer-
with a long-standing research interest in mam-           sity of Cincinnati, University of California at
mary carcinogenesis. In addition to his collabo-         San Francisco, and Michigan State University.
rative work with I. Russo on the biological              The main goal of these centers is to test the
functions of hCG and the downregulation of               hypothesis that exposure to estrogenically
the estrogen receptor alpha gene expression              active environmental compounds during early
occurring during differentiation of the mam-             critical periods of development might act as
mary gland there are three additional main               endocrine disruptors, altering the proteomic
areas of research interest in Russo’s laboratory:        and genomic signatures of rat mammary
The role of estrogen receptor beta (ERb) in              glands, affecting the predisposition of the
mammary carcinogenesis, influence of environ-             breast to develop cancer later in life. These
mental xeno-estrogenic substances in mam-                studies are being carried out by analyzing the
mary gland development and differentiation,              development and genomic profile of mammary
and study of the genomic signature induced by            glands of female rats exposed to xenobiotics
pregnancy in the human breast. Russo’s labora-           such as Bisphenol A (BPA), butyl benzyl phtha-
tory has conducted pioneering work in devel-             late (BBP) and TCDD from the prenatal period
oping an in vitro system of cell transformation          only, and from birth to 21 days of age. These
using estrogens and its metabolites as carcino-          studies provide a blueprint for a collaborative
genic agents in human breast epithelial cells.           project with M. Wolff (MSSM), that includes
He has demonstrated that the main endoge-                the investigation of breast cancer risk factors
nous estrogen 170-beta estradiol and its metabo-         for pubertal milestones in young African-Amer-
lite 4 hydroxy-estradiol are carcinogenic agents         ican and Hispanic girls, specifically for age at
in human breast epithelial cells, in which they          first breast development, age at menarche, and
induce specific genotoxic effects in chromo-              tempo (duration of puberty, or time from breast
some 17 (p53) and chromosome 13. Russo has               development to menarche) (see J. Russo’s report
also identified a new tumor suppressor gene in            and publications).
Ch 17p13.2 that is controlling the Fas-associ-
ated apoptotic process in breast epithelial cells        Studies of the pro-metastatic protein HEF1.
(DAMD17-02-1-0249 and DAMD17-02-1-0247).                 Golemis,§ in collaboration with Henske,§ Chernoff,§
                                                         Roegiers,§ Wu,§ Cukierman,§ Godwin§
In addition, his group has been able to demon-
strate the mutation of the hMPS2 mismatch                The major source of cancer morbidity and mor-
repair gene plays an important role in the early         tality is uncontrolled metastasis. E. Golemis’s
stages of neoplastic transformation of human             laboratory seeks insight into the molecular
breast epithelial cells and has further deter-           basis for metastasis, focusing primarily on anal-
mined that this mutation results in a truncated          ysis of the protein HEF1 (Human Enhancer of
protein that is expressed in “ in vitro ” trans-         Filamentation 1, also known as NEDD9 and
formed cells as well as in primary breast can-           Cas-L). In the past year, three independent
cers. Furthermore, he has also identified a               studies have indicated that elevated HEF1
specific genomic signature in the differentiated          expression is a driving force for breast adeno-
breast epithelial cells of postmenopausal parous         carcinoma and melanoma metastasis to lung, and
women (R01CA93599) that will serve as a sur-             for the invasive behavior of glioblastomas. Since
rogate marker for evaluating hormone preven-             Golemis first described HEF1 in 1996, work by
tive agents. He has also established that both           her group and others has revealed a complex
pregnancy and treatment of virgin rats with the          action for this scaffolding protein. HEF1 is well-
placental hormone human chorionic gonado-                established as an important component of the
tropin (hCG) induce in the mammary gland a               cell polarization, attachment, and invasion
genomic signature that is an indicator of the            signaling pathways including FAK and Src active
refractoriness of the gland to carcinogenesis.           at focal adhesions. In 2005, her laboratory
                               Fox Chase Cancer Center 2006 Scientific Report                 6
defined an important new function for HEF1 in          and stroma permissiveness, and use this assay
regulation of mitosis through activation of the       to score the effectiveness of targeted cancer
Aurora A kinase at the centrosome. In the past        drugs in inhibiting different stages of breast
year, she has built from this finding to deter-        cancer cell metastasis (see Cukierman’s report
mine that HEF1 and Aurora A collaborate to            and publications).
control the stability of cell cilia. Cilia protrude
like antennas from the apical surface of cells,       Breast cancer diagnosis and treatment.
                                                      Goldstein, Morrow, Freedman, Swaby, Robinson,
and act as sensory organs that respond to exter-
                                                      Lewis, Joseph, in collaboration with von Mehren,§
nal cues to influence cell proliferation, polarity     Weiner,§ Patchefsky,§ Adams§
and differentiation. Her ongoing work seeks to
understand which of these HEF1 functions are          The Breast Cancer Research Group has been
most critical for breast cancer metastasis (see       involved in overcoming obstacles to effective
Golemis’s report and publications).                   therapy in breast cancer. The areas of investiga-
   E. Cukierman, § in collaboration with              tion include novel biologically targeted agents,
E. Golemis,§ is involved in a project in which        and targeted immunotherapy. New breast cancer
the goal is to improve the preclinical cancer         patients are seen by the Breast Evaluation Center
drug development process. Currently, many             (BEC), a multidisciplinary program in which
drugs developed against rational protein targets      patients are seen by medical oncologists, radia-
are effective in in vitro biochemical and cell cul-   tion oncologists and surgical oncologists.
tures based experiments, but fail throughout          Through the BEC, patients are offered state-of-
later stage development, during assay in ani-         the-art treatment recommendations and oppor-
mals and phase I trials. Recent advances in the       tunities to participate in clinical, translational,
study of cellular microenvironment have estab-        laboratory and behavioral studies aimed at
lished that the protein content and fibrillar          improving not only the outcome for patients
organization of extracellular architecture can        but also expanding our understanding of breast
profoundly affect many properties of cellular         cancer biology.
growth including proliferation, sensitivity to        Novel Therapeutic Agents. L. Goldstein is the
apoptosis, differentiation, migration, and the        principal investigator of the current Intergroup
specific function of individual signaling cas-         adjuvant trial, E2197, investigating adriamycin
cades. Cukierman’s project hypothesis predicts        and cyclophosphamide versus adriamycin and
that these differences induced by microenviron-       docetaxel and reported the first efficacy analy-
ment can significantly alter the efficacy of drugs      sis. Sub-group analysis did support that hor-
for breast cancer. In her research, Cukierman         mone receptor negative tumors might benefit
has developed a unique approach to simulating         from taxanes. Tumor samples from E2197 are
the cellular microenvironment in vitro . This         currently being evaluated with genomic profil-
approach uses pre-growth of normal, pre-              ing to determine both prognostic and predic-
cancerous (primed) or tumor-associated stro-          tive genomic signatures. She is also studying a
mal fibroblasts to synthesize physiological            novel inhibitor of urokinase plasminogenic acti-
matrices on tissue culture plastic, followed by       vator (μPA) in combination with capecitabine.
removal of the fibroblasts and seeding a plethora      Goldstein is collaborating with Chernoff§ and
of breast cancer cells that vary in their meta-       Cukierman§ to investigate the functional stud-
static potential (MCF-10A, MCF7 and MDA               ies of the plasminogen system as a target for
MB231) into the residual matrix. In extensive         breast cancer carcinogenesis, treatment and
preliminary work, there are numerous striking         prevention. She has completed a phase I study
differences between cells grown on these matri-       combining a novel dual kinase inhibitor with
ces and cells grown under normal culture con-         Letrozole, which is now in a phase III study.
ditions. She will compare the effectiveness of           R. Swaby is a clinical investigator with a
targeted chemotherapeutic drugs in inducing           focus in breast cancer research. She is the Study
cytostasis and apoptosis in cancer cells grown        Chair for, a Phase I/II Study of Suberoylanilide
under different matrix conditions for better          Hydroxamic Acid (SAHA) in Combination with
drug selection prior to animal tests, and she is      Trastuzumab (Herceptin) in Patients with
in the process of developing a novel matrix-          Advanced Metastatic and/or Local Chest Wall
based assay to score tumor cell invasiveness          Recurrent Her-2 Amplified Breast Cancer.
                             Fox Chase Cancer Center 2006 Scientific Report               7
Swaby is the Principal Investigator of a multi-       Her-2/neu expressing cancers had greater stimu-
institutional trial, Reversal of Anti-Estrogen        lus to grow in vitro when stimulated by steel
Resistance by Pharmacologic Dose Estrogen in          factor, the ligand of KIT. KIT is a growth factor
a Single Arm Phase II Study of Post-Meno-             receptor that functions as a tyrosine kinase and
pausal Women with Hormone Receptor-Positive           whose function is inhibited by imatinib mesy-
Metastatic Breast Cancer After Failure of             late. In addition, platelet derived growth factor
Sequential Endocrine Therapies. She is evaluat-       receptor is present in stroma surrounding
ing immunohistochemistry correlative transla-         breast cancer and has a role in angiogenesis.
tional pathology endpoints in conjunction with        Lastly, imatinib mesylate has been shown to
this clinical trial. Swaby also serves as Chair of    decrease interstitial pressure within tumor tis-
the intergroup trial, a Phase II Study of Goserelin   sues and may allow for improved penetration
Plus Anastrozole for the treatment of Male            of trastuzumab. The regimen was found to be
patients with Hormone-Receptor Positive Meta-         safe without unanticipated toxicity. Correlative
static or Recurrent Breast Cancer. She serves as      studies will be conducted in conjunction with
study co-chair for: A Double Blind Phase III          J. Testa§ and D. Altomare§ (see Testa’s report).
Trial of Doxorubicin and Cyclophosphamide                The past year G. Adams§ and M. Robinson§
followed by Paclitaxel with Bevacizumab or            have continued their efforts to develop bispe-
Placebo in Patients with Lymph Node Positive          cific single-chain Fv molecules (bs-scFv) that
and High Risk Lymph Node Negative Breast              are capable of simultaneously binding to HER2
Cancer. She is the local site Principal Investiga-    and HER3. Their lead molecule, ALM, selec-
tor of the clinical trial, a Phase I/II Study of      tively localizes on human breast tumor cells
HKI-272 in Combination with Trastuzumab               that express both targets in vitro and in vivo, and
(Herceptin) in Advanced Breast Cancer.                triggers cell cycle arrest in in vitro assays.
   Swaby is the FCCC site Principal Investigator      Adams, § Robinson § and L. Weiner § are also
of a New York Cancer Consortium clinical trial,       finalizing plans to initiate an ImmunoPET
a Phase I/II study of a Combination of Suberoyl-      imaging trial using anti-HER2 diabodies (engi-
anilide Hydroxamic Acid (vorinostat) plus             neered divalent antibody fragments) in patients
Paclitaxel and Bevacizumab in Patients with           with metastatic breast cancer.
Advanced Metastatic and/or Local Chest Wall           Surgical Oncology. (M. Morrow) The Breast
Recurrent Breast Cancer. She is also laboratory       Service is actively exploring the role of mag-
co-chair for: A Randomized Phase III Double-          netic resonance imaging (MRI) in the selec-
Blind Placebo Controlled Trial of First-Line          tion of patients for the local therapy of breast
Chemotherapy and Trastuzumab with or with-            cancer. Morrow reviewed this topic with
out Bevacizumab for Patients with Her-2/neu           G. Freedman (Radiation Oncology) for the
Over-Expressing Metastatic Breast Cancer.             Magnetic Resonance Imaging Clinics of North
   N. Lewis is the breast cancer liaison to the       America. R. Bleicher§ is leading a study to doc-
Phase I program for novel agent development           ument the consequences to patients of both
including two studies of oral tyrosine kinase         true and false positive MRI findings. Collabora-
inhibitors. One agent targets the PDGF tyrosine       tors include: E. Sigurdson, N. Joseph, L. Sesa,
kinase. Another agent is a dual erb B kinase          M. Morrow, and K. Evers.
inhibitor. These targets are particularly interest-      Morrow continues her collaboration with
ing in breast cancer signal transduction and          S. Katz (University of Michigan) on decision
hold great therapeutic potential.                     making for the local therapy of breast cancer. In
Targeted Immunotherapy. The Breast Cancer             a population based sample of women treated in
Research Group has completed a study investi-         the Detroit and Los Angeles SEER areas in
gating the activity of trastuzumab, a mono-           2002, pathology reports were used to identify
clonal antibody that targets HER2 /neu , in           at least one treating surgeon for 98.5% of the
combination with docetaxel. The response rate         patient sample. Surveys of both surgeons and
for this combination was 55%. M. von Mehren           patients were performed to assess each group’s
has completed a trial evaluating the combina-         perception of the decision making process. The
tion of trastuzumab with imatinib mesylate.           surgeon response rate was 80%, the mean sur-
This combination of targeted therapies has pre-       geon age was 49 years and 14% were women.
clinical data to support their combined use.          Data reported in 2005 indicating that surgeons
                             Fox Chase Cancer Center 2006 Scientific Report               8
were most likely to recommend breast conserv-      Monte Carlo dose calculations and multileaf
ing therapy (BCT) for breast cancer manage-        collimation. IMRT improves the dose homoge-
ment while patients actively involved in           neity across the different areas of the skin and
decision making were most likely to chose mas-     breast tissue to reduce the dose of radiation
tectomy prompted a study of conflict in deci-       given to the heart. Hypofractionation is the
sion making. Surgeons reported that regardless     delivery of larger daily doses of radiation than
of the treatment recommendation made (mas-         standard to complete treatment sooner. Lastly,
tectomy or breast conserving therapy) they         the trial delivers a higher daily dose to the
experienced conflict with patients 50% of the       tumor bed, or a boost, rather than extending
time and with other physicians approximately       treatment an extra 1.5 to 2 weeks for the boost,
one-third of the time. Conflicts with patients      as is usually done. G. Freedman§ reported the
and other providers were more common when          side effects during treatment for the first
high volume surgeons recommended breast            40 women enrolled on the study. The 4-week
conserving therapy. No relationship between        course of postoperative radiation using IMRT
volume and conflict was observed when the           was feasible and associated with low acute skin
surgeon recommended mastectomy. Surgeons           toxicity. The rate of grade 2 skin toxicity was
practicing in cancer centers were more likely to   only 16% with no grade 3 or higher acute
experience conflict than those in other practice    toxicity. Data is also being collected on tumor
settings. In follow-up work examining patient      recurrence, cosmesis and quality of life.
satisfaction in involvement with decision mak-        P. Anderson published a study of complica-
ing, 68% of patients reported that the actual      tions in women with breast reconstruction
amount of involvement in the decision making       treated with post mastectomy radiation
process was appropriate, 21% noted that their      (P.R. Anderson et al., Int. J. Radiat. Oncol. Biol.
level of involvement was greater than what they    Phys. 59:1080, 2004). The study included
wanted, and 13% had less involvement than          85 women reconstructed with either trans-
they desired. Patients who perceived too little    verse rectus abdominis myocutaneous (TRAM)
involvement in decision making were younger,       flap or saline tissue expander implants. Many
felt that only one treatment option was dis-       were treated at Fox Chase with specialized
cussed, and were more likely to have been seen     techniques designed to improve upon prob-
by a high volume surgeon. In another study         lems with conventional radiation, such as high-
examining variation in the use of mastectomy       energy beams modified by beam spoiler or cus-
between surgeons, only 23% of the variation        tom fashioned tissue bolus. The overall compli-
could be explained by tumor characteristics        cation rate was 26%. There were no major
and 1% by patient demographics. Surgeon vol-       complications in TRAM patients. Thirty-nine
ume, demographics, and treatment recommen-         percent of TRAM patients at 5 years had minor
dations accounted for 12%, 5%, and 5% of           complications, such as fat necrosis, but non
variation respectively. As a follow up to these    required major corrective surgery and all of
studies Morrow is working with S. Miller §         these remained associated with a good/excel-
(Behavioral Research) to examine the role of       lent cosmetic result. Of the implant patients,
baseline personality traits in determining how     5% have serious complications, including
cancer treatment information should be deliv-      2 patients requiring implant removal. Overall,
ered and in what quantity (see Morrow’s report     these results are significantly better than other
and publications).                                 experiences with reconstruction and radiation
Radiation Oncology. The department has             previously reported in the literature. Her con-
implemented intensity modulated radiation          clusions were that postmastectomy radiation
therapy ( IMRT ), hypofractionation and an         should be given to women with indications
incorporated breast boost to shorten treatment     regardless of the presence of a reconstruction.
time for postlumpectomy radiation from the            A. Konski§ reviewed the cost-effectiveness of
traditional 6–7 weeks to 4 weeks. IMRT is a        whole breast radiation compared with differ-
further advance in the way radiation is deliv-     ent techniques of partial breast irradiation
ered for an individual patient—it uses 3-D         (A. Konski, Comm. Oncol. 1:93, 2004). Partial
determination of the lumpectomy site and           breast irradiation, or treatment only of the area
breast target volumes, dose planning with          of the breast around the tumor bed, is highly
                           Fox Chase Cancer Center 2006 Scientific Report              9
topical and the subject of intense controversy                  concluded that partial breast irradiation could
in the U.S. Konski’s article addresses the high                 be cost-effective compared to current forms of
initial costs of partial breast irradiation, particu-           whole-breast radiation if associated with much
larly with a method of brachytherapy that                       higher patient utilities due to lower recurrence
involves 10 high-dose-rate treatments given in                  rates of greater quality of life with long-term
one week that was recently FDA approved. He                     follow-up.

Berry, D.A., Cirrincione, C., Henderson, I.C., Citron, M.L., Budman, D.R., Goldstein, L.J., Martino, S., Perez, E.A.,
Muss, H.B., Norton, L., Hudis, C., Winer, E.P. Estrogen-receptor status and outcomes of modern chemotherapy for
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Carlson, R.W., Moench, S.J., Hammond, M.E., Perez, E.A., Burstein, H.J., Allred, D.C., Vogel, C.L., Goldstein, L.J.,
Somlo, G., Gradishar, W.J., Hudis, C.A., Jahanzeb, M., Stark, A., Wolff, A.C., Press, M.F Winer, E.P., Paik, S.,
Ljung, B.M. HER-2 testing in breast cancer: NCCN task force report and recommendations. J. Natl. Compr. Canc. Netw. 3:
S1-S22, 2006.
Goldstein, L.J. Controversies in adjuvant endocrine treatment of premenopausal women. Clin. Breast Cancer 2:S36-S40,
Goldstein, L.J., O’Neill, A., Sparano, J., Perez, E., Shulman, L., Martino, S., Davidson, N. Presented at ASCO Annual
Meeting, June 2006. E2197: Phase III ATC doxorubicin (docetaxel) vs. AC (doxorubicin) Cyclophosphamide in the adju-
vant treatment of node positive and high risk node negative breast cancer. Part 1 of II, June Supplement 23(16S):512, 2006.
Gradishar, W.G. Adjuvant therapy for hormone receptor-negative, HER-2-overexpressing. Oncology Consultations 3(5):1-12,
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Manne, S.L., Ostroff, J.S., Norton, T.R., Fox, K., Goldstein, L., Grana, G. Cancer-related relationship communication
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Morrow, M., Goldstein, L. Surgery of primary tumor in metastatic breast cancer: closing the barn door after the horse has
bolted. J. Clin. Oncol. 24(18):1-2, 2006.

§ Fox Chase researcher
* Personnel left Fox Chase
a P.A. Robinson: Present address—Loyola University Medical Center, Maywood, IL 60153
b G. Grana: Cooper Medical Center, Camden, NJ 08103
c T. Frazier: Bryn Mawr Hospital, Bryn Mawr, PA 19010
d J. Kendall: Christiana Hospital, Newark, Delaware 19718
e L. Patrick-Miller: Cancer Institute of New Jersey, New Brunswick, NJ 08903

                                   Fox Chase Cancer Center 2006 Scientific Report                        10