- 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 Efficiency of Drug Development through Innovative Trial Design
Theme 1: Improving the Understanding of Breast Cancer Etiology in the Context of the Microenvironment
Karla Kerlikowske, MD; Jeffrey Tice, MD; and John Shepherd, PhD, with Elad Ziv, MD, established a well-validated risk calculator that estimates five- and ten-year risk of invasive breast cancer calibrated for race/ethnicity. Together with Yiwey Shieh, MD, MAS, they also developed a breast cancer polygenic risk score that is integrated with the Breast Cancer Surveillance Consortium (BCSC) calculator.These risk calculators are the central component of the 100,000-woman personalized vs. annual screening “Women Informed to Screen Dependent On Measures of Risk” (WISDOM) trial.
Theme 2: Personalizing Screening and Diagnostics to Increase Health Care Value
Laura van ‘t Veer, PhD, lead scientist of the 6,693-patient MINDACT trial, demonstrated level 1A evidence for the 70-gene prognosis signature to identify patients at low recurrence risk by their tumor biology. The trial showed that approximately half of breast cancer patients, who would be recommended chemotherapy based on clinical-pathological high-risk assessment, can safely forego chemotherapy treatment. This clinical utility, valuable for approximately 35,000 patients per year in the US, was recently endorsed by the American Society of Clinical Oncology (ASCO). Together with Esserman, Christina Yau, PhD, and collaborators from the Karolinska Institute, Stockholm, van ‘t Veer showed that the ultralow risk 70-gene signature, indicating indolent disease over two decades, allows the possibility of reducing endocrine therapy.
Theme 3: Identifying New Therapeutic Targets for High-risk Disease
Esserman, van ‘t Veer, Nola Hylton, PhD; and Hope Rugo, MD, with collaborators and the FDA, designed the investigator-initiated, multi-arm, multi-institutional I-SPY 2 trial to rapidly increase the probability of identifying agents and combinations that effectively treat high-risk breast cancer patients. In I-SPY 2, new investigational agents are tested in combination with standard of care chemotherapy in the neo-adjuvant setting, and the trial identifies, by adaptive randomization, the optimal breast cancer subtype-drug pair with the FDA-approved endpoint of pathological complete response (pCR). The study team validated the use of pre-treatment biopsy-based molecular determinants and serial MRI imaging assessments for the adaptive randomization engine. The I-SPY network demonstrated that a precompetitive consortium can work with multiple drug companies, and that an adaptive randomization engine can efficiently evaluate many agents over a short time period (14 drugs in seven years). For example, Rugo, together with Esserman, van ‘t Veer, Hylton, Yau, and Jo Chien, MD, reported that veliparib-carboplatin added to standard therapy resulted in higher rates of pCR than standard therapy alone in triple-negative breast cancer while John Park, MD, with Esserman, van ‘t Veer, Hylton, Yau, Chien, and Michelle Melisko, MD, reported that in women with HER2-positive, hormone-receptor-negative breast cancer, the addition of neratinib added to standard therapy with chemotherapy and trastuzumab, resulted in higher rates of pCR.
Theme 4: Augmenting Efficiency of Drug Development through Innovative Trial Design
Andrei Goga, MD, PhD with Esserman discovered inhibition as potential therapeutic strategy for MYC-driven triple negative breast cancers. A CDK1/CDK2 inhibitor (dinaciclib) is now in a phase I trial (Goga and Chien) in combination with pembroluzimab. Goga worked with Zena Werb, PhD to study metastatic cells at the single-cell gene expression level. They demonstrated that early stage metastatic cells possess a distinct stem-like gene expression signature. Metastatic cells from low-burden tissues were distinct from those in high-burden tissues. Furthermore, progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with a CDK1/CDK2 inhibitor. These findings, published in Nature, support a hierarchical model for metastasis, in which metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease and suggest new routes to prevent metastasis.