The COVID-19 pandemic has rapidly changed delivery of cancer care. Many nonurgent surgeries are delayed to preserve hospital resources, and patient visits to health care settings are limited to reduce exposure to SARS-CoV-2. Providers must carefully weigh risks and benefits of delivering immunosuppressive therapy during the pandemic. For breast cancer, a key difference is increased use of neoadjuvant systemic therapy due to deferral of many breast surgeries during the pandemic. In some cases, this necessitates increased use of genomic tumor profiling on core biopsy specimens to guide neoadjuvant therapy decisions. Breast cancer treatment during the pandemic requires multidisciplinary input and varies according to stage, tumor biology, comorbidities, age, patient preferences, and available hospital resources. We present here the Johns Hopkins Women’s Malignancies Program approach to breast cancer management during the COVID-19 pandemic. We include algorithms based on tumor biology and extent of disease that guide management decisions during the pandemic. These algorithms emphasize medical oncology treatment decisions and demonstrate how we have operationalized the general treatment recommendations during the pandemic proposed by national groups, such as the COVID-19 Pandemic Breast Cancer Consortium. Our recommendations can be adapted by other institutions and medical oncology practices in accordance with local conditions and resources. Guidelines such as these will be important as we continue to balance treatment of breast cancer against risk of SARS-CoV-2 exposure and infection until approval of a vaccine.

Breast cancer is the most commonly diagnosed cancer in women worldwide. Approximately one-tenth of all patients with advanced breast cancer develop brain metastases resulting in an overall survival rate of fewer than 2 years. The challenges lie in developing new approaches to treat, monitor, and prevent breast cancer brain metastasis (BCBM). This review will provide an overview of BCBM from the integrated perspective of clinicians, researchers, and patient advocates. We will summarize the current management of BCBM, including diagnosis, treatment, and monitoring. We will highlight ongoing translational research for BCBM, including clinical trials and improved detection methods that can become the mainstay for BCBM treatment if they demonstrate efficacy. We will discuss preclinical BCBM research that focuses on the intrinsic properties of breast cancer cells and the influence of the brain microenvironment. Finally, we will spotlight emerging studies and future research needs to improve survival outcomes and preserve the quality of life for patients with BCBM.

We present an integrated single-cell RNA-seq resource of the breast tumor microenvironment consisting of 236,363 cells from 119 biopsy samples across 8 publicly available datasets. In this computational study, we first leverage this novel resource to define cancer epithelial cell heterogeneity based on two clinically relevant markers and define six new and distinct subsets of natural killer cells. We then illustrate how cancer epithelial cell heterogeneity impacts immune cell interactions. We develop T cell InteractPrint, which considers how cancer epithelial cell heterogeneity shifts the predicted strength of T cell interactions. We use InteractPrint to predict response to immune checkpoint inhibition (ICI) in two clinical trials testing immunotherapy in patients with breast cancer. T cell InteractPrint was predictive in both trials (AUC=0.81 and 0.84), versus PD-L1 expression (AUC=0.54 and 0.72). This result provides an alternative predictive biomarker to PD-L1 to select patients who should receive ICI.

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Background: Next-generation sequencing (NGS) is becoming increasingly routine in patients with advanced cancers, and rare mutations may occasionally be identified. Evaluating the efficacy of targeting rare mutations is challenging given the low observed frequencies, which can result in slow accrual to clinical trials. The internet and social media have revolutionized the way we receive information and connect with each other, and may potentially be leveraged to identify patients with rare mutations. Spliceosome mutations, such as SF3B1, occur in approximately 4% of breast cancers. The Park Lab has demonstrated that somatic cell knock-in of an SF3B1 hotspot mutation results in new mRNA transcripts can be translated into aberrant proteins. These preliminary data suggest that spliceosome mutations could produce a high number of neoantigens, which may increase sensitivity to immune checkpoint inhibitors (ICI). Indeed, since response rates to immunotherapy in patients with metastatic breast cancer is low, identifying biomarkers predictive of response is critical. We therefore designed a remotely directed “virtual” clinical trial to determine the feasibility of evaluating Patient Response to Immunotherapy using Spliceosome Mutational Markers (PRISMM, NCT04447651). Methods: The is a prospective feasibility trial in which patients will be identified via a social media campaign that directs potential participants to a landing page where they can fill out an online form. Patients will need to self-identify as having metastatic breast cancer (any receptor status) with an SF3B1 mutation (main eligibility criteria); once this information is confirmed by the study team, outside records will be obtained and their case will be reviewed at an institutional Molecular Tumor Board; ICI may be recommended or not. Recommendations from the Board will be provided to the patient and local oncologist, who will then decide whether to proceed with the Board’s recommendation or not. Efficacy of next line therapy will be followed by physician and patient questionnaires every one to three months. During routine blood collection, we will evaluate plasma tumor DNA (ptDNA) and peripheral blood mononuclear cells (PBMCs) at baseline and three months. The primary objective of this study is to evaluate the feasibility of conducting a prospective study using online recruitment tools, and the feasibility of real-time case review by a centralized Molecular Tumor Board to assist in therapeutic decision making. Secondary objectives include evaluating the clinical effect of ICI including progression-free and overall survival, correlate SF3B1 mutations in ptDNA with tissue-based NGS, and describe immunopharmacodynamic changes by PBMC evaluation. We anticipate screening approximately 5000 patients via our social media campaign to identify 60 eligible patients. We will conduct efficacy interim analysis after 23, 35, 47, and 56 patients are enrolled. The response rate of 1% 5%, 10%, and 20% correspond to 99.8%, 74.7%, 24.9%, and 1.1% chance that the study will stop early with an average sample size of 26.2, 41.3, 53.6, and 58.7 patients enrolled and treated respectively. If the true response rate exceeds 15% the Board will continue to make recommendation for ICI in patients with SF3B1 mutations. For more information please contact us at PRISMM@jhmi.edu. Citation Format: Natasha Hunter, Jeffrey Wang, Leslie Cope, Christine Hodgdon, Vered Stearns, Elizabeth Jaffee, Ben Park, Cesar A Santa-Maria. A remote-directed “virtual” clinical trial in metastatic breast cancer to determine feasibility of evaluating patient response to immunotherapy using spliceosome mutational markers (SF3B1): The PRISMM trial (NCT04447651) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-08.