Mayo Clinic Breast Cancer SPORE
Mayo Clinic
Principal Investigator:
Matthew Goetz, MD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: The influence of variants in ER-positive BC predisposition genes on BC risk and response to therapy
- Project 2: Improving the endocrine management of premenopausal ER+/HER- BC
- Project 3: Development of a novel multi-antigen BC prevention vaccine for women with premalignant disease
- Administrative Core
- Biospecimen and Pathology Core
- Biostatistics, Bioinformatics and Patient Registry Core
- Developmental Research Program
- Career Enhancement Program
Principal Investigator(s) Contact Information
Matthew P. Goetz, MD
Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, MD
Professor of Oncology and Pharmacology
Mayo Clinic
200 First St. S.W.
Rochester, MN 55905
(507) 266-9160
Overview
It is the vision of the Mayo Clinic Breast Cancer SPORE that the burden of breast cancer (BC) can be reduced through the performance of innovative translational research accomplished by addressing research questions of high significance for women. The mission of the SPORE is to accomplish this vision. The Mayo Clinic Breast Cancer SPORE addresses significant problems relating to breast cancer with the goal of reducing morbidity and mortality from the disease. This will be accomplished through projects focusing on breast cancer risk, prevention, and development of a novel approach to treat premenopausal ER+/HER2- breast cancer. The research addresses vitally important issues to an enormous number of women both with, and at risk of, developing breast cancer.
Project 1: The influence of variants in ER-positive BC predisposition genes on BC risk and response to therapy
Project 2: Improving the endocrine management of premenopausal ER+/HER- BC
Project 3: Development of a novel multi-antigen BC prevention vaccine for women with premalignant disease
These research projects are supported by three highly interactive cores: Administrative Core, Biospecimen and Pathology Core, Biostatistics, Bioinformatics and Patient Registry Core
The Developmental Research Program (DRP) supports innovative and scientifically meritorious research projects that have the greatest potential to be translated into clinically important applications for the prevention, diagnosis and treatment of women with breast cancer. The Career Enhancement Program (CEP) is focused on identifying, supporting and mentoring the most highly qualified investigators in basic science, population science and clinical research who have the greatest potential to conduct meaningful translational research in breast cancer and develop independent research programs directed at reducing the burden and mortality from breast cancer. Qualified minority individuals, women and persons with disabilities are encouraged to apply to the Breast SPORE DRP and CEP.
Project 1: The influence of variants in ER-positive BC predisposition genes on BC risk and response to therapy
Project Co-Leaders:
Fergus J. Couch, PhD (Basic Co-Leader)
Susan M. Domchek, MD, PhD (Clinical Co-Leader)
Germline pathogenic variants (PV) in the BRCA1, BRCA2 and PALB2 cancer predisposition genes are associated with high risks of breast cancer (BC) whereas PVs in ATM and CHEK2 are associated with moderate lifetime risks.Of these, PVs in ATM, BRCA2, CHEK2 and PALB2 are predominantly associated with estrogen receptor positive (ER+) BC. While much is known about ER+ BC, little is known about the contribution of PVs in these predisposition genes to ER+ BC risks and to the influence of these PVs on prognosis. Here we aim to address some of the important clinical questions that remain unanswered for these ER+ BC predisposition genes. In Aim #1 we propose to assess age-related risks of cancers associated with ER+ BC predisposition gene PVs. While overall risks of BC are well established, age-related risks of BC in 5-10 year categories and risks of contralateral BC are not known for the ATM, CHEK2 and PALB2 genes. In the absence of this information the overall risks of cancer associated with PVs are of limited clinical value. We will use information from large population-based studies, including targeted studies of African Americans and West Africans to estimate these cancer risks. In Aim #2 we propose to establish the influence of PVs in ER+ BC predisposition genes on prognosis. It is not currently known whether breast cancers driven by ER+ predisposition genes, other than BRCA2, display specific responses to standard therapy (such as chemotherapy or endocrine therapy). We propose to screen germline DNA from participants in large BC adjuvant clinical trials for PVs in the ER+ BC predisposition genes and to assess the influence of PVs on DFS and OS in response to adjuvant therapy. In addition, we will determine whether the PVs are correlated with the Oncotype Dx Breast Recurrence Score, which is aprognostic and predictive biomarker for ER+ BC patients. In Aim #3 we propose to determine the clinical relevance of Variants of Uncertain Significance (VUS) in ER-positive BC predisposition genes. Individuals carrying germline VUS, which are predominantly missense variants, cannot benefit from enhanced risk assessment and cancer screening or make informed decisions about surgical prevention or screening. We will conduct individual and high-throughput functional assay studies and apply rules-based FDA-approved ClinGen methods for determination of the clinical relevance of many VUS in these genes.
Project 2: Improving the endocrine management of premenopausal ER+/HER- BC
Project Co-Leaders:
Matthew P. Goetz, MD (Clinical Leader)
John R. Hawse, PhD (Basic Leader)
Matthew J. Schellenberg, PhD (Basic Leader)
Breast cancer (BC) remains the most commonly diagnosed cancer in premenopausal women (pre-MW) worldwide and its incidence is increasing in developed countries. BCs in pre-MW are more likely to be of an aggressive intrinsic subtype, higher grade, and advanced stage compared to BCs in post-MW. Pre-MW with ER+/HER2- BCs are commonly treated with chemotherapy (CT), endocrine therapy (ET) and ovarian function suppression (OFS). Long-term data from the SOFT and TEXT adjuvant trials demonstrated that aromatase inhibitors (AI)+OFS improved DFS but have yet to improve OS, compared to tamoxifen (TAM) or TAM+OFS. Premature menopause (PM is known to be associated with higher rates of cardiac disease, hypertension, diabetes, hyperlipidemia, osteoporosis and death. Therefore, alternative endocrine strategies for pre-MW with ER+/HER2- BC are critically needed, especially for pre-MW who cannot tolerate OFS. Endoxifen (ENDX) is an active TAM metabolite, and the PI’s have led the development of ENDX as a novel ET for BC. Through completion of phase I and II trials, we have demonstrated that ENDX is safe, well-tolerated, has substantial oral bioavailability and is superior to TAM in endocrine therapy (ET) resistant BC. Furthermore, the PI’s have identified a novel mechanistic basis for the superior anti-cancer effects of ENDX; namely, the novel ENDX target, PKCβI. Based on these data, the central hypothesis of this proposal is that ENDX is a superior ET in part due to its ability to dually target both ER and PKCβI. We further hypothesize that the optimal treatment of pre-MW with ER+/HER2- BC can be achieved using ENDX monotherapy without the need for OFS. To test our hypotheses, we will 1) develop ENDX for pre-MW with ER+/HER2- BC; 2) elucidate the mechanisms by which PKCβI contributes to ENDX responsiveness in endocrine sensitive disease; and 3) determine the predictive and prognostic value of PKCβI in ER+/HER2- BC patients treated with TAM and ENDX. Given the increasing incidence of BC in pre-MW, along with the known morbidity associated with OFS, the proposed studies are of critical importance towards improving the endocrine management of ER+/HER2- BC in pre-MW.
Project 3: Development of a novel multi-antigen BC prevention vaccine for women with premalignant disease
Project Co-Leaders:
Amy Degnim, MD (Clinical Lead)
Keith Knutson, PhD (Basic Lead)
Derek Radisky, PhD (Basic Lead)
Vaccine-based prevention of breast cancer (BC) is a promising strategy for substantially reducing the impact of disease incidence, treatment, and mortality. Vaccines can induce highly specific immune responses that self-regulate in the absence of disease. Ongoing clinical trials of vaccines targeting antigens expressed by BC cells, have shown that vaccines can induce T-cell-based immunity that can last for years. Effective implementation of a prevention vaccine will require identification of which antigens are associated with BC risk and progression and definition of tissue and blood-based metrics of vaccine response. The experiments in this project will pair with our new Phase Ib trial of a novel multi-antigen prevention vaccine to advance it toward a clinical prevention trial. In Aim 1, we will draw upon an extensive tissue resource of women diagnosed with benign breast disease at the Mayo Clinic and at the Karmanos Cancer Center to assess which of the antigens in the prevention vaccine are expressed in premalignant breast tissue and which are most associated with subsequent BC development. This information will be critical for identifying which antigens should be included in the future prevention trial and which patients are most likely to benefit from it. In Aim 2, we will evaluate blood-based antibody and cellular immune responses to the multiantigen vaccine in our current Phase1b clinical trial. We will use high dimensional cellular analysis and targeted sequencing approaches, information that will provide minimally invasive endpoints of immune response for a larger scale future prevention trial. In Aim 3, we will assess pre- and post-vaccine background normal breast tissues from patients in the clinical trial to identify how changes in antigen expression are associated with activation of specific immune cell subtypes and changes in the T- and B-cell repertoire. This information will inform the future prevention trial by defining how the vaccine and its specific components impact antigen expression and immune response in nonmalignant breast tissue. Successful completion of this project will define which vaccine components should be advanced to a larger vaccine-based BC prevention clinical trial, which has the potential to drive significant reductions in overall disease incidence, burden and mortality.
Administrative Core
Core Director:
Matthew P. Goetz, MD
The overall goals of the Mayo Clinic Breast SPORE are to identify significant and innovative SPORE Research Projects; identify Developmental Research Projects with the greatest potential for advancing to full SPORE Research Projects; through the Career Development Program, identify scientists with the greatest potential for developing independent translational research programs and advancing to future leadership positions in the SPORE; and finally, to maximize collaborations with other SPOREs (breast and other organ-based) and other NIH-funded instruments both intra- and extra-murally. The Administrative Core has served as the organizational hub of the Mayo Breast SPORE during Years 1-15 of funding. During the next funding period (Years 16-20), it will continue to provide organizational and communications support for the SPORE leadership, Research Projects, scientific Cores, the Developmental Research Program (DRP) and Career Enhancement Program (CEP). Specifically, the Administrative Core will: (1) Maximize breast cancer translational research through provision of leadership and oversight of the SPORE Research Projects and Cores; 2) Facilitate the activities of the SPORE Executive Committee through organization of meetings and development of materials related to oversight and programmatic development; 3) Organize meetings of the SPORE Advocacy Advisory Committee facilitate collaborations between the Mayo Breast SPORE advocacy committee and advocates involved in other SPOREs; 4) Organize meetings of the SPORE Internal Scientific Advisory Committee; 5) Organize meetings of the SPORE External Advisory Committee, 6) Provide administrative support to the Director of the DRP 7) Provide administrative support to the Director of the CEP; 8) Organize monthly SPORE scientific meetings, 9) Organize monthly SPORE Key Personnel Meetings, 10) Organize twice-monthly SPORE Operations Committee meetings; 11) Coordinate and facilitate investigator participation in NCI Translational Science Meetings as well as the Translational Breast Cancer Research Consortium; 12) Monitor, manage and coordinate fiscal activities of the SPORE program, 13) Serve as a liaison between the Breast SPORE, the National Cancer Institute, the Mayo Clinic Comprehensive Cancer Center (MCCCC) and Mayo Clinic; 14) Identify and facilitate development of inter-breast SPORE collaborations, 15) Prepare reports relating to Breast SPORE activities, including annual Progress Reports and the competitive renewal application, and finally, 16) Coordination of visiting scientists.
Biospecimen and Pathology Core
Core Director:
Mark E. Sherman, MD
The Biospecimen and Pathology Core of the Mayo Clinic Breast Cancer SPORE provides an expert centralized pathology consultative service and a comprehensive resource of breast tissues, blood and “living samples” for preparation of organoids and patient-derived xenografts, linked to epidemiological and clinical data. The Core also curates clinically derived benign and neoplastic breast tissue samples with detailed clinicopathological evaluation (e.g., stage, histologic features, clinical and emerging biomarker assessments) to establish registries and cohorts for research. Samples collected include fresh, fresh-frozen, cryopreserved and formalin-fixed paraffin embedded specimens from 1) treated or untreated breast cancers with mapped background “benign-adjacent” tissues, 2) lymph node metastases and distant metastases, 3) benign breast disease tissues across the spectrum of pre-neoplasia and 4) “normal” breast tissue harvested from mammoplasty/risk reduction specimens from patients with or without clinical or genetic “high-risk” factors (e.g. known germline BC predisposition gene mutations), as well as blood. The Core performs expert pathological evaluation of research- related histopathological parameters (e.g., atypia in benign breast disease, involution status of breast lobules, histologic subclassification of TNBC, evaluation of tumor response to neoadjuvant therapy, stromal and intratumoral TIL scoring). In addition, the Core performs antibody optimizations as required by the SPORE projects (e.g., PKCBeta1), followed by interpretation and scoring of these immunohistochemical stains, and application of digital image-based approaches (e.g., optimization and interpretation of digital image analysis algorithms with Aperio (Leica) (or HALO (Indica Labs) software systems, high-plex quantitative digital spatial profiling (e.g., Nanostring GeoMX™ platform) for SPORE projects. The Core coordinates with the Mayo Biospecimen Accessioning and Processing (BAP) Shared Resource to store fresh-frozen and cryopreserved specimens and to process blood samples to provide genomic DNA and serum and plasma aliquots; it collaborates with the Mayo Pathology Research Core (PRC) Shared Resource to obtain essential technical tissue-based services including conventional and cryostat tissue sectioning, immunohistochemistry, tissue microarray construction, slide scanning and cytotechnologist assistance for optimizing digital imaging algorithms. Partnering with these institutional shared resources minimizes redundancy of services and capitalizes both on technical experience and state-of-the-art technologies.
Biostatistics, Bioinformatics and Patient Registry Core
Core Directors:
Vera J. Suman, PhD
Krishna Rani Kalari, PhD
The Biostatistics, Bioinformatics and Patient Registry Core provides statistical and bioinformatics collaboration and data management support for each of the SPORE Projects and the research projects initiated through the Breast Cancer SPORE Developmental Research Program and the Career Enhancement Program. Each project has a biostatistician and/or bioinformatician embedded into its research team with the breast cancer content knowledge to understand the central hypothesis being tested and the analytic expertise to ensure the development of a study design which can generate data to address the questions posed as well as ensure the application of or development of statistical and bioinformatics analysis techniques that are appropriate to assess the central hypothesis.
Developmental Research Program
Program Director:
John R. Hawse, PhD
The goal of the DRP is to support innovative and scientifically meritorious research projects that can be translated into clinically important applications impacting diagnosis and management of breast cancer to decrease the burden and mortality from this disease. The DRP will: 1) encourage and solicit innovative translational laboratory, population, and clinical study proposals; 2) encourage and support interdisciplinary collaboration in translational research in breast cancer; and 3) generate new hypotheses that can be tested in larger-scale research projects. This support will expand the research portfolio of the SPORE. A process has been established involving a call for applications and a formal peer review utilizing the expertise of the Internal Scientific Advisory Committee and other experienced investigators. Criteria for selection of projects for funding are based upon scientific merit, originality, qualifications of the applicant, and translational potential. It is expected that support of developmental research projects will result in generation of data that will serve as the basis for additional SPORE-sponsored projects or support through peer-reviewed external grant support. The three main metrics for productivity of the DRP are advancement of DRP projects to a full Project in the SPORE, acquisition of extramural funding, and publications by the project awardees. The DRP has been highly successful in identifying a cadre of investigators that has expanded and enriched the scientific portfolio of the SPORE and provided a mechanism for development of Co-Leaders in full Projects.
Career Enhancement Program
Program Director:
Matthew P. Goetz, MD
The Career Enhancement Program (CEP) of the Mayo Clinic Breast Cancer SPORE is committed to identifying and mentoring junior faculty with the greatest potential of developing independent programs in translational breast cancer research. This is accomplished through a rigorous review process aimed at identifying the most talented and promising candidates followed by an intensive, rigorous, and effective mentoring program. The mentoring program is based on the establishment and optimal functioning of a Multidisciplinary Mentoring Committee led by a senior investigator with the scientific expertise and commitment to developing the next generation of translational breast cancer researchers. The Committee will be composed of the primary mentor and the complementary clinical and/or basic investigator necessary for a comprehensive mentoring program plus a statistician. It is viewed as crucial to the success of the awardee that the mentoring be ongoing and robust. This will be accomplished by close oversight by the Director of the CEP of the mentoring process and progress of the awardee. Dr. Goetz, the Director of the CEP and SPORE Director, will report to the SPORE Executive Committee. This intensive oversight process was established because of the firm conviction of the SPORE Director that the development of independent investigators and translational breast cancer research is central to the SPORE mission. The explicit expectation is that the awardees will utilize the resources made available to them for the development of independent research programs and acquisition of independent funding in breast cancer research.