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Breast Cancer

CareyPerouscan.JPGThe UNC Breast Cancer Research Program has enjoyed exceptional growth with a broad range of studies starting with population-based studies into etiology and breast cancer behavior, molecular biology and genetics, biologically-driven clinical trials, health disparities research, and innovative approaches to bioinformatics, novel therapeutics and imaging. This growth, permitted by a philosophy of interdisciplinary collaboration, bidirectional translational research, emphasis upon developmental programs, and inter-SPORE and inter-Center partnerships, prompted the Breast Cancer Research Program to be turned into a free-standing Program in 2008. Prior to that time, Breast Cancer Research was under the auspices of the Clinical Research Program, however the highly integrated nature of the Breast Program’s clinical, basic, and epidemiologic research fit more naturally into a tumor-specific program model. Importantly, Breast Research remains integrated with the Clinical Research Program, particularly in the setting of early drug development. Our ongoing success depends upon strategic recruitment of faculty in emerging fields, research that uses cutting-edge technology, and enhanced relationships with other centers and SPORE programs.

Our vision is of integrating basic science into clinical research and clinical questions into basic investigations. This approach has become increasingly important as the heterogeneity of breast cancer, first noted in Chuck Perou’s seminal molecular portraits Nature paper naturally means that breast cancer investigations, from etiologic to therapeutic, are appropriately segregated into investigations based upon each of the distinct subtypes. These subtypes, which include the Luminal A and B subtypes making up the majority of hormone receptor-positive breast cancer and the Basal-like, HER2-enriched, and Claudin-low comprising the majority of hormone receptor-negative breast cancers, are biologically and behaviorally distinct. This holds great promise for the future of targeted and combinatorial approaches to poor prognosis subtypes, but also means that breast cancer research has become increasingly complex. Rationally designed clinical trials targeting specific lesions within a subtype and tissue-based biomarker studies are seldom feasible within a single institution, and thus inter-institutional collaborations have become key to success. We have a long track record of inter-SPORE and inter-Center collaborations, among these include the development and validation of a qRT-PCR-based assay permitting intrinsic subtyping on fixed clinical specimens and successful completion within 18 months of a randomized phase II study of EGFR inhibition in basal-like breast cancer that included over 100 patients from 12 institutions Multiple highlights and high impact publications will be noted, but with pride we note that co-Leader Chuck Perou was awarded the AACR Outstanding Investigator in Breast Cancer Research Award in 2009.

Critical to the Cancer Center's mission are member collaborations that permit translation of exciting basic science leads into clinical and laboratory based investigations. These efforts are directed toward advancing the state of clinical cancer care in our region, the state of North Carolina to which we have a unique relationship and responsibility, and the nation. This iterative process depends upon a well-organized clinical care system interacting with the university’s rich blend of basic and clinical investigators engaged in basic and population-based research. The Breast Cancer Research Program has this infrastructure and a uniquely integrated clinician/scientist network that facilitates delivery of novel findings.

The conceptual framework for the Breast Program is that the distinct biology of the intrinsic subtypes of breast cancer mandate that investigations into etiology, biology, and treatment must not focus upon breast cancer as a disease entity but on subtype-specific lesions or on pathways and molecules mindful that biologic approaches effective in one subset of tumors may be irrelevant in others. We believe that the “low hanging fruit” of single agent biologic therapy has been picked with ER and HER2 targeting; further advances in endocrine resistance, HER2 resistance, and other subtypes will likely require combinatorial approaches and a systems philosophy.  Based on this framework, Program faculty have outlined several strategic areas for research emphasis:

  • Integrating molecular subtypes into epidemiology and microenvironment. Once one recognizes that breast cancer is not one disease but a family of diseases, it no longer makes sense to ask “what causes breast cancer?” It is likely that gene:gene and gene:environment causes of breast cancer vary by subtype. Our population-based studies, which are among the largest ever performed and systematically oversample young and African-American women, are predicated on the hypotheses that there will be specific predisposition to individual breast cancer subtypes including potential subtype specific associations with defined allelic variants in DNA repair genes, oxidative and hormonal metabolism, and proliferation genes. In addition, we also believe that there will be subtype-specific microenvironmental influences.
  • Technological advances in imaging and analysis. Building upon the UNC Nanotechnology Center of Excellence, Biomedical Research Imaging Facility, and our Bioinformatics Core, we are able to provide the translational and clinical mechanisms for testing improved breast imaging and irradiation techniques such as the carbon nanotube-based designs, imaging advances for dynamic MRI and digital tomosynthesis, analysis of microscopic images and of high dimensional datasets as are generated by imaging studies.
  • Genomic Analyses of Tumors and Normal Breast Tissues. Building upon our history to DNA microarray finding, new and additional genomic profiling studies will be performed focused primarily upon identifying biomarkers predictive of chemotherapy responsiveness, and markers predictive of new biological agents like angiogenesis inhibitors and PARP inhibitors. These studies will also transition to newer genomic technologies include NexGen sequencing approaches that will quantitate gene expression and simultaneously sequence the entire transcriptome, thus providing a level of detail never achieved before when using DNA microarrays.
  • Mouse models. We have genetically engineered, or obtained, mouse models representing many of the intrinsic subtypes of breast cancer. These defined models are being used to test combinations and novel agents in the Mouse Phase I Unit (see Molecular Therapeutics). The mouse studies are designed to either mirror or inform human clinical trials.
  • Tissue-based discovery, translation, and clinical research program. Our Program begins with strong integration of laboratory and clinical scientists fostered by an interdisciplinary structure and collaborative environment. We believe that translational research must be bidirectional, meaning embedded correlative studies in clinical trials and tumor/tissue resources being used for basic research questions. Our clinical trials uniformly include correlative endpoints and are either subtype-specific or stratified in analysis. In addition, based upon strong Inter-SPORE and Inter-Center relationships, and the roles several Program members have in national cooperative groups, we are examining tissues from a variety of prospective clinical trials to answer questions about subtype-specificity in response to defined cytotoxic and biologic therapies.  We are proud of a track record of taking bench findings and testing them in clinical trials with predefined correlative studies and effective multicenter coordination of both tissue and clinical data.

Given an increasing emphasis upon breast cancer-specific basic, translational, and epidemiologic studies, Breast Cancer Research was created as an independent Program in 2008 with Chuck Perou as the basic science co-Leader and Lisa Carey as the clinical research co-Leader.