The overarching goal of the Breast Oncology Program is to develop innovative approaches to describe the molecular and cellular networks underlying breast cancer susceptibility, heterogeneity, diversity, and disparities with the aim of improving outcomes for healthy women and women with breast cancer.
The Breast Oncology Program aims to stimulate a transformative, transdisciplinary, integrated, inter-institutional environment inclusive of appropriate private partnerships to study the biological basis of the diseases that comprise breast cancer; to develop methods for early detection; to define the risk of developing or progressing with specific types of breast cancer; to develop novel interventions that work locally and globally to reduce morbidity and mortality from breast cancer and its treatment; and to promote and foster the Breast Oncology Program framework for integrated clinical care and research.
All of the work of the Breast Oncology Program is critically informed by a committed group of patient advocates, who participate in regular research meetings, help to establish program priorities, and undertake efforts to educate their peers about participation in clinical research studies.
- Theme 1: Improving the understanding of breast cancer etiology in the context of the microenvironment
- Theme 2: Personalizing screening and diagnostics to increase health care value
- Theme 3: Identifying new therapeutic targets for high-risk disease
- Theme 4: Augmenting the efficiency of drug development through innovative trial design
Theme 1: Improving the understanding of breast cancer etiology in the context of the microenvironment
Understanding breast cancer etiology requires studying the biological complexity of breast epithelium, breast cancer cells of origin, the influence of host immune cell signaling, and mechanisms that drive transformation. New BR member Gartner is at the forefront of this research and has built impressive knowledge around organoids as a dynamic model, including live imaging focusing on invasion and morphogenesis (U01CA244109). Tlsty is PI of a Cancer UK Challenge grant (C19767/A27145) to study the role of inflammation. Tlsty, with Weaver (CII) and other experts, published a consensus statement on cancer-associated fibroblasts (CAFs): their definition, origin, antitumorigenic role, context of matrix deposition and remodeling, crosstalk with other microenvironment cell types, and potential target for intervention. Shieh, Yau, Ziv (MO), and Sayaman have made many contributions to the field of germline status, in particular single nucleotide polymorphisms (SNPs) to predict risk of developing breast cancer. Most recently, their contribution to a consortium revealed in an analysis across 33 cancer types of TCGA germline ancestry-associated differences in cancer specific molecular features, including relevant finding for breast cancer.
Theme 2: Personalizing screening and diagnostics to increase health care value
BR Program members use risk models integrating personal, genetic, and in case of diagnosis, tumor information to increase intervention efficacy and reduce morbidity (Esserman, Belkora, James, Hylton, Shieh, Tice, van ‘t Veer, Yau). The nationwide WISDOM personalized screening study of 100,000 healthy women (NCT02620852; PCS-1402-10749; R01CA237533), the San Francisco Bay Area Mammography Registry (SFMR) (2P01CA154292), and predominantly Californian Athena Breast Health Network of 150,000 women, are central to the theme. BR investigators addressed in these large cohorts the evaluation of additional risk factors, including BMI and menopausal status and co-morbidities (with Walter (CC)). Also, modality of screening (tomosynthesis), definition of staging endpoints, and risk of interval cancers were studied to increase screening and prediction accuracy (with Ziv (MO)). Knowledge on who is at risk for what type of cancer is an emerging theme, specifically aimed to guide efficient prevention based on the anticipated type of breast cancer for which someone is at risk, (with Cooperberg (PR)). A main emphasis is on ethnic differences in risk (Latina women, with Ziv (MO)), and improved risk communication to ethnically diverse women across multiple healthcare systems.
Theme 3: Identifying new therapeutic targets for high-risk disease
Therapy resistance is a recurring phenomenon often hampering effective cancer treatment. Basic biology efforts are aimed to unravel the underlying biology, and a phase 1-3 trial program tests new promising drugs.
Goga and Rugo identified that MYC-driven breast cancer have dysregulated mitoses and revealed targetable cancer vulnerabilities, important for this often hard to treat subtype. Yau, Esserman, and van ’t Veer revealed mechanism of action of AKT-inhibition in patients enrolled in the I-SPY 2 trial relevant to alleviate resistance.
Dhawan, Chien, Moasser, Melisko, Munster (MO), and Daud (CII) found that an ‘exhausted T-cell signature’ predicts response in ER-positive breast cancer. The molecular information of the MINDACT trial of 6,693 breast cancer patients has been made publicly available for others to interrogate biological pathways in a representative early-stage breast cancer trial (van ‘t Veer). BR Program members are involved in a broad portfolio of phase 1-3 trials, highlighted in recent publications on updated follow-up Atezolizumab trial (Impassion130; Rugo), as well as the highly anticipated results of pembrolizumab (KEYNOTE-355; Rugo).
Theme 4: Augmenting the efficiency of drug development through innovative trial design
The neo-adjuvant adaptive randomization I-SPY 2 trial (NCT01042379; P01CA210961) is central to screen new drugs efficiently, use intermediate endpoints, minimize toxicity, and maximize efficacy, with over 2,300 patients across 22 treatment arms enrolled to-date, and 17 drugs successfully evaluated (Esserman, Ewing, Chien, Goga, Hylton, Melisko, Mukhtar, J Park, Rugo, Balassanian, Campbell, Shieh, van ‘t Veer, Yau).
Two investigational drugs, MK2206 (AKT inhibitor) and Pembrolizumab (Pembro, PD1-inhibitor), showed substantial efficacy at pathological complete response (pCR) compared to standard chemotherapy. Pembro improved results in HER2-negative patients (both HR-negative and HR-positive). MK2206 improves outcomes in HR-negative patients and may have the ability to impact unique subsets that do not respond well to other drug combinations. Most importantly, three-year follow-up after surgery across investigational and standard of care treatment arms showed that pCR leads to over 95% survival, in this high-risk patient population. To improve our intermediate endpoint assessments of therapy response in I-SPY 2, van ‘t Veer with young investigators Magbanua and Lin were awarded R01CA255442 to study the combination of MRI-volume and circulating tumor DNA changes.
Roster of Breast Oncology Program
For details on membership criteria, please see our membership page.