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2-PREVENT: Secondary PREvention through SurVEillance and iNTervention
ACC Breast Cancer Translational Center of Excellence
Principal Investigators: Lewis A. Chodosh, MD, PhD and Angela DeMichele MD, MSCE
Broad Mission and Specific Objectives
Breast cancer is both common and treatable, making it by far the most prevalent cancer in the United
States. Indeed, of the estimated 12 million cancer survivors alive today in the U.S., 2.6 million are breast
cancer survivors. Despite the fact that 5-year survival rates approach 90% overall, a substantial fraction of
breast cancer patients ultimately relapse and die from their disease, and many more experience late treatment
effects or are diagnosed with a second cancer. In this regard, current prognostic factors are inadequate to
accurately identify those who will relapse, resulting in over-treatment and exposure to toxic adjuvant treatments.
As a consequence of these factors, millions of breast cancer survivors live in fear of recurrence, second
primary cancers and late treatment effects throughout the post-treatment survivorship period. At present,
however, remarkably little is done to actively monitor breast cancer survivors for these events, few approaches
are available to prevent them, and recurrent breast cancer remains a largely incurable disease. As such, the
current standard of clinical care for breast cancer patients in the post-treatment survivorship period results in
numerous missed opportunities for prevention, early detection and intervention, as well as high levels of patient
distress and dissatisfaction regarding the general lack of options for active measures to improve outcomes.
This ACC Translational Center of Excellence will focus on major unmet needs of breast cancer patients in
the post-treatment survivorship period and, in doing so, will change the paradigm of care. By focusing on
secondary PREvention through SurVEillance and iNTervention (“2-PREVENT”), the 2-PREVENT TCE will offer
a unique, innovative, personalized and integrated approach to the concerns of breast cancer patients that will
make the Abramson Cancer Center an unparalleled destination for novel clinical trials and breast cancer care.
Specifically, the Penn 2-PREVENT TCE will pursue innovative, transdisciplinary approaches to the prediction,
prevention, monitoring, detection and treatment of recurrent breast cancer, as well as provide state-of-the-art
detection of second primaries and address treatment-related adverse effects. To accomplish its goals, the
Penn 2-PREVENT Center will advance the following highly integrated and translational objectives:
1. Identify and validate novel therapeutic targets and approaches in tumor dormancy and recurrence.
This objective will focus on fundamental research to validate potential therapeutic targets for breast cancer
dormancy and recurrence, identify new targets for intervention, probe the relationship between disseminated
tumor cells (DTCs) and circulating tumor cells (CTCs), and perform proof-of-principle preclinical trials to move
candidate targets forward toward clinical trials.
2. Develop comprehensive approaches to personalized risk prediction for recurrence and late effects.
We will develop a centralized recurrence risk assessment approach that integrates existing genomic assays
and clinicopathologic markers with newly validated genomic predictors, novel imaging predictors under
development within the Breast Program, and baseline assessment of residual disease through evaluation of
DTCs and CTCs. This will be accompanied by the development of an electronic patient reported outcomes
(ePRO) system to identify predictors of late effects related to breast cancer and its treatment. In aggregate,
this centralized approach will provide an individualized risk profile that can inform decisions about subsequent
treatment, screening and clinical trial participation.
3. Develop interventions to prevent recurrence and late effects. We will develop original investigatorinitiated clinical trials to test novel therapeutic approaches aimed at reducing the burden of minimal residual
disease and preventing recurrence. These trials will be based upon innovative immune-based approaches,
targeted blockade of pathways identified and validated in preclinical studies of breast cancer dormancy and
recurrence, and behavioral interventions developed by Breast Program investigators.
4. Develop and implement innovative surveillance and detection strategies. We will develop and test the
effectiveness of surveillance and detection strategies based upon state-of-the-art functional and structural
imaging, as well as serial evaluation of CTCs and other circulating markers to monitor residual disease. These
approaches will enable therapeutic intervention prior to the development of overt metastatic disease. To this
armamentarium will be added cutting edge imaging techniques to identify second primaries, as well as in-depth
survivorship resources focused on identifying the emergence of late treatment effects.
5. Develop improved treatments for recurrence and late effects. Innovative therapeutic trials will be
developed based on preclinical studies of pathways driving breast cancer recurrence, as well as targetable
pathways identified during the detailed molecular evaluation of recurrent tumors and CTCs in patients.
Clinical Impact
Millions of breast cancer patients currently find themselves in a post-treatment survivorship period that is
largely devoid of active measures that they can take to prevent recurrence or monitor for its early detection.
The overarching objective of the 2-PREVENT TCE is to address this enormous gap. By focusing on this
window of opportunity, moving novel scientific discoveries on tumor dormancy and recurrence into the clinic,
and leveraging and integrating existing expertise and programs, the 2-PREVENT Center will deliver innovative,
personalized care tailored to the needs of breast cancer patients in the post-treatment survivorship period. In
doing so, this TCE will provide comprehensive, innovative care unlike any offered by existing breast centers in
the U.S. This will make Penn the “go-to” place for breast cancer care, while providing a new model for
comprehensive cancer survivorship care that can be broadly applied to other malignancies.
Figure 1 illustrates our vision for how the highly integrated objectives of the 2-PREVENT Center will
change the paradigm of clinical care for breast cancer patients by addressing major unmet needs through
basic discovery research, innovative clinical trials, and integration of enhanced prediction and survivorship
resources. This, in turn, will increase enrollment to clinical trials, improve outcomes and enhance patient
satisfaction, ultimately resulting in a substantial increase in the number of breast cancer patients who seek
their care through the ACC. The current standard of care for breast cancer patients (blue boxes) consists of a
modestly individualized treatment plan at diagnosis, coupled with minimal assessment during the follow-up
period. 2-PREVENT integrated model components to be developed within the context of this TCE (yellow
boxes) will include assessment and intervention research opportunities at each step of the care process aimed
at providing an unparalleled, personalized approach to improving cure rates while reducing morbidity from
breast cancer treatment. 2-PREVENT components will build upon established excellence in hereditary risk
assessment provided
Figure 1: 2-PREVENT expands standard of care in the post-treatment survivorship period
through the Cancer
Risk Evaluation
Program, as well as
follow-up care in the
Lance Armstrong
Survivorship Center of
Excellence. What
sets this model of
care apart from that
available at any other
institution will be the
integration of novel
assessment methods
with translational therapeutic interventions originating in the laboratories of ACC Breast Program investigators.
Together, the individualized approach, ability to obtain information about disease status during and after
primary treatment, and access to novel, promising therapies that are delivered prior to clinical relapse, will
result in increased patient satisfaction and the potential to improve the likelihood of cure.
Approach
The aims of the 2-PREVENT TCE encompass comprehensive risk prediction, prevention, surveillance and
interventions to reduce breast cancer recurrence and late effects, incorporated into a comprehensive model of
breast cancer care. The approach to achieving these aims requires the highly orchestrated integration of novel
investigational approaches into the clinical care environment. The laboratories of basic science investigators
involved in this effort will serve as engines for innovative interventions that can be translated to the clinic; these
interventions will then be tested in the cohort of patients receiving care within the multidisciplinary Rowan
Breast Center. The knowledge derived from these investigations will drive further improvements in care and
next-generation innovation in a recurring cycle of scientific translation between the laboratory and clinic.
1. Identify and validate novel therapeutic targets and approaches in tumor dormancy and recurrence.
The vast majority of breast cancer deaths are due to recurrence. Since dormant residual cancer cells likely
constitute the reservoir from which breast cancer recurrences arise, the lack of therapeutic approaches aimed
at these cells – as well as our lack of understanding of their biology – constitute major obstacles to the
successful treatment of this disease. The knowledge gained from these studies will drive the development of
innovative therapeutic approaches to reduce the burden of minimal residual disease and prevent recurrence,
while providing novel cellular, molecular and imaging biomarkers to enable the prediction, detection and
monitoring of recurrence. This component of the 2-PREVENT Center will leverage a broad portfolio of NIH,
DOD, and foundation-funded research aimed at identifying novel targets for intervention in breast cancer
dormancy and recurrence. For example, discovery research and preclinical studies performed under the
umbrella of the Breast Cancer program have already resulted in the identification and validation of c-MET,
mTOR, and autophagy inhibition as promising avenues for interventions to prevent and/or treat recurrent
breast cancer. Studies within this component will also address the functional validation of other candidate
pathways in tumor dormancy and recurrence, including Notch1, Ceramide kinase, and glutaminolysis, as well s
the identification of further candidates, investigation of the relationship between CTCs and DTCs in minimal
residual disease and the impact of epithelial-to-mesenchymal transition (EMT) in CTC detection, investigation
of novel imaging approaches to detect changes in tumor metabolism during recurrence, and genomic
interrogation of paired primary and recurrent breast cancers arising in clinic patients. To accomplish this latter
aim, we will use tumor and blood specimens collected through our TRACR Breast BioBank, supplemented with
bone marrow aspirates collected at surgery. Further studies will employ residual tumor cell synthetic lethality
screens focused on DNA damage repair pathways involved in breast cancer, as well as further proof-ofprinciple studies to validate the basis for immune-based therapeutic approaches.
2. Develop comprehensive approaches to personalized risk prediction for recurrence. Currently,
predicting which patients will relapse is limited to the assessment of clinicopathologic factors, OncotypeDx (in
node-negative, ER+ disease) and BRCA1 & 2 mutation testing for a subset of patients at risk. Predicting which
patients will develop a second cancer or late effect is even less developed. During the past decade, several
gene expression signatures have been shown to provide useful prognostic information, as well as predict
response to specific therapies. However, integration of these tools into risk prediction in the clinic has been
slow, decentralized, and is at times managed by those without optimal expertise in risk evaluation or
communication. To address this need, the 2-PREVENT TCE will leverage and extend the expertise of its
world-class Cancer Risk Evaluation Program (CREP) to provide newly diagnosed patients with comprehensive,
state-of-the-art personalized risk assessment for recurrence, second cancers, and late effects. This will be
accomplished by offering access to validated genomic signatures while developing approaches to clinically
integrate this information with standard clinicopathologic assessment to refine recurrence risk estimates.
These activities will be complemented by the baseline assessment of minimal residual disease (DTCs and
CTCs) at the time of diagnosis, coupled with novel image-based prediction approaches from the breast
imaging group, to provide a comprehensive assessment of recurrence risk for newly diagnosed patients.
Blood and bone marrow collected for this component will be utilized to assess the presence of micrometastatic
disease within the bone or circulation, each of which has been demonstrated to substantially affect risk of
recurrence. The genomic composition of CTCs and DTCs will be interrogated to provide further risk
stratification, as well as potential biomarkers and targets for intervention trials. In addition, the breast imaging
group will develop novel computational approaches to predict recurrence risk based upon phenotypic
characteristics of breast cancers extracted from multiple imaging modalities, including digital tomosythesis,
MRI (DCE and diffusion), and nuclear medicine studies utilizing 18F-FDG and 18F-Glutamine. The overarching
goal of this component will to integrate genomic, clinicopathologic and imaging data with the baseline
evaluation of micrometastatic disease in order to provide a novel, individualized risk assessment tool suitable
for use in the clinic and for the stratification of patients to secondary prevention trials.
3. Develop interventions to prevent recurrence. Beyond chemotherapy, estrogen pathway blockade and
trastuzumab, few therapeutic options are currently available to breast cancer patients to reduce their risk of
recurrence or late effects. The 2-PREVENT TCE will develop original investigator-initiated clinical trials to test
novel therapeutic approaches aimed at reducing the burden of minimal residual disease and preventing
recurrence. Interventions will target micrometastatic disease prior to the development of overt, incurable,
metastatic recurrence. Our approaches will focus on three areas: immunotherapy, targeted therapy, and
lifestyle/behavioral modification. Immunotherapeutic approaches will build upon work in the Czerniecki lab
developing vaccines that activate CD4, CD8 and complement fixing antibodies to eliminate micrometastatic
cells following chemotherapy. Vaccine targets will include oncogenic drivers of tumor growth, such as EGFR,
HER3 and c-MET. Specific goals of this work will be to develop MHC class I and class II peptides against
chosen targets to combine with survivin and telomerase peptides for vaccine approaches to prevent breast
cancer recurrence, to assess the feasibility and safety of vaccinating patients against HER family members in
high risk patients following completion of neoadjuvant therapy, and to develop biomarkers such as CTCs,
serum markers and immune biomarkers to identify correlates associated with successful outcomes.
Secondary prevention trials will also be pursued using targeted agents against pathways identified as
essential for the survival of dormant cancer cells in preclinical models. For example, the Chodosh laboratory
has identified c-MET, mTOR, Notch1 and autophagy as essential for the survival of dormant tumor cells, and
has identified pharmacological inhibitors agents capable of preventing tumor recurrence on this basis. We plan
to develop targeted therapy trials for patients whose primary tumors, DTCs and/or CTCs can be demonstrated
to have activated these pathways. Novel trial designs will integrate targeted therapies and biomarker
development into the potentially curable adjuvant, or post-neoadjuvant setting, based on the successful
approach used by Dr. DeMichele and colleagues in the I-SPY2 Trial. Importantly, these trials will require the
use of new surrogate markers of treatment response, such as reduction in DTCs or CTCs. One such trial
under consideration is a phase II study of Tivantinib (ARQ197) in patients with CTCs identified at baseline.
This small molecule inhibitor has completed phase I testing, is well-tolerated, and has been shown to reduce
breast cancer bone metastases in preclinical models. Another target under consideration is Notch1, which is
up-regulated in cells that survive standard adjuvant chemotherapies. We will work with Oncomed to secure
their anti-Notch1 compound at the conclusion of phase I testing to enable a trial in the minimal residual disease
setting. Additional candidate pathways will include the use of rapalogues as well as inhibitors of authophagy.
Finally, for patients who may not be interested in pharmacologic or immunologic interventions, the 2-PREVENT
TCE will develop lifestyle/behavioral intervention studies to reduce the risk of recurrence in concert with Dr.
Schmitz and the Penn TREC Center. This will capitalize on the ongoing collaboration between Drs. Schmitz,
DeMichele and Chodosh to develop diet and exercise interventions for patients at risk for lymphedema.
4. Develop and implement innovative surveillance and detection strategies. At present, astonishingly
little is done to monitor breast cancer patients for recurrence in the post-treatment survivorship period. Given
the fact that recurrent breast cancer can be treated but not cured, substantial frustration exists amongst
survivors and providers over the lack of tools to detect emergence of recurrent disease at a curable stage.
DTCs in bone marrow are currently the best biological surrogates for the population of cells that ultimately
gives rise to recurrent breast cancers. However, since serial bone marrow biopsy is a painful and challenging
clinical endpoint, attention has turned to CTCs. Biological understanding of what CTCs represent is rapidly
evolving and serial evaluation of CTCs has the potential to provide patients with real-time monitoring for
recurrence at the cellular level. In addition, CTC enumeration and characterization could enable the rational
selection of targeted adjuvant therapies, as well as measurement of their efficacy. In this component, we will
perform a cohort study of breast cancer patients to determine: 1) the frequency of DTCs and CTCs in this
patient population and their stability over time; 2) whether changes in CTCs predict or precede tumor relapse;
3) whether DTCs or CTCs isolated from patients harbor molecular abnormalities identified in preclinical
models; and 4) whether 11C-Glutamine PET tracers, alone or in combination with 18F-FDG, can be used to
detect recurrence early. An important additional component of this study will involve assessing the impact of
this intensive surveillance approach on breast cancer survivors. Currently, patients do not undergo CTC
testing or imaging and distress regarding recurrence risk is high. Given the investigational nature of the
studies proposed, we will work closely with a team of patient advocates and the Center for Bioethics to
evaluate the impact of this surveillance strategy on patient distress and quality of life.
5. Develop improved treatments for recurrence. It has become increasingly clear that recurrent breast
cancers are biologically distinct from the primary cancers from which they derive. The biological diversity
generated by tumor heterogeneity and evolution requires a new approach to the assessment and treatment of
recurrent disease. Most important is the need to obtain tissue from recurrent tumors to identify changes in ER,
PR and HER2 expression, as well as other potential targets for therapeutic intervention. To address this need,
we will pursue a comprehensive approach for evaluating recurrent disease that combines molecular tissue
profiling at the RNA and DNA level with functional imaging. Accessible metastatic tumor tissue will be sampled
for molecular interrogation. Targets of interest will include those identified in preclinical studies of pathways
driving breast cancer recurrence. For example, we have determined that c-MET inhibitors dramatically inhibit
recurrent tumor growth in preclinical models. These targets will be augmented by functional molecular imaging
approaches to evaluate the metabolic phenotype and heterogeneity of ER expression in recurrent disease.
Together, these will enable the rational assessment of targets in recurrent tumors for matching to innovative,
targeted therapy trials based upon validated targets in preclinical models.
6. Surveillance and interventions for symptoms and late effects. While reducing breast cancer recurrence
is the major focus of the 2-PREVENT Center, an important concurrent focus is on surveillance and intervention
for treatment-related symptoms and late effects. The same tenets that guide prevention, detection, and
intervention for recurrence are applicable to symptoms and late effects of treatment in breast cancer survivors,
including fatigue, sexual dysfunction, weight gain, cardiac toxicity and lymphedema. The current lack of
systematic assessment methods and underutilization of appropriate interventions contribute to persistent
distress for many survivors. Therefore, we will utilize emerging technologies to develop a flexible mobile
application and web-based platform for symptom assessment and late effects screening through patient
reported outcomes. This project will expand ongoing work in the Penn Survivorship Center of Excellence to
provide a mechanism for the surveillance of patients at risk for late effects, track the emergence of symptoms
that herald more serious problems, and identify patients eligible for intervention studies. Intervention studies to
be supported through this effort will include trials of novel herbal treatments led by Penn Integrative Medicines
investigator Jun Mao, exercise and weight reduction strategies studied within the Penn TREC Center, and
traditional pharmacologic interventions such as medications to treat and prevent neuropathy.
Organization and Leadership
This proposal represents a highly integrated, multidisciplinary translational effort to develop new prediction,
prevention, surveillance and therapeutic approaches for breast cancer recurrence. To accomplish this, we
bring together an intensely collaborative group of researchers with expertise spanning basic science,
translational research and clinical trials, to focus on a common scientific goal critical to improving outcomes in
breast cancer patients. Investigators in this TCE have extensive experience in cancer biology (Chodosh,
Greenberg, Brown, Pear, Smyth), imaging (Schnall, Conant, Mankoff, Rosen, Karp, Kontos, Rizi, Tsourkas,
Yodh), medical oncology (DeMichele, Domchek, Fox, Vonderheide), surgical oncology (Czerniecki, Tchou),
pathology (Feldman, Mies), radiation oncology (Prosnitz, Minn), genetics and risk assessment (Domchek,
Nathanson), and survivorship and outcomes research (Schmitz, Stricker, Mao). These investigators
encompass each of the areas of expertise essential to the successful comletion of its experimental aims.
Moreover, the existence of a long-standing, functional, multidisciplinary Breast Cancer Program Executive
Committee provides a robust mechanism within this TCE to facilitate the bridging of discoveries from basic to
clinical and population science, along with the movement of discoveries from the laboratory to the clinic.
The 2-PREVENT Team will be led by the co-Leaders of the ACC Breast Cancer Program, Dr. Lewis
Chodosh and Dr. Angela DeMichele. As a physician-scientist with training in endocrinology and internal
medicine, Dr. Chodosh is an internationally recognized leader in the area of genetically engineered mouse
models for breast cancer, particularly as it relates to tumor dormancy and recurrence. His laboratory’s mouse
models serve as a foundation for basic science and translational components of this application. Dr. Chodosh
currently serves as Chairman of the Department of Cancer Biology, Director of Cancer Genetics within the
Abramson Family Cancer Research Institute, as well as Associate Director for Basic Research at the ACC. Dr.
DeMichele is a breast oncologist and molecular epidemiologist whose research focuses on identifying
biomarkers of outcome and response to therapy, as well as the development of targeted therapeutics. Dr.
DeMichele currently serves as PI for multiple clinical trials. She has extensive expertise in the coordination
and conduct of biomarker studies, has been an I-SPY co-investigator since 2002, and currently chairs trial
operations on I-SPY2.
Metrics of Success
1) Identify targeted agents that reduce the burden of minimal residual disease in survivors (3-10 years)
2) Identify targeted agents and/or vaccine approaches that reduce breast cancer recurrence (10 year)
3) Identify targeted agents effective against recurrent breast cancer (3-10 years)
4) Establish a comprehensive program for personalized risk prediction for recurrence, second cancers and
late effects (3 year)
5) Develop and implement innovative surveillance and detection strategies that incorporate CTCs and
functional imaging (3 year)
6) Increase the number of investigator-initiated, translational trials in Breast Program (3 year)
Sustainability
Beyond leveraging the existing multiple R01, U01, U54, DOD and foundation-supported projects awarded
to its investigators, the 2-PREVENT Breast Cancer TCE is committed to raising extramural funds to promote
the sustainability of the TCE beyond the initial 3-year funding period. As evidence of this commitment, Drs.
Chodosh and DeMichele have recently applied for a Komen for the Cure Promise grant focused on the
evaluation of DTCs and CTCs in genetically engineered mouse models and patient samples.