Six researchers within the Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium have received grants from the Breast Cancer Research Foundation, or BCRF, a longtime funder of the Consortium’s Breast and Ovary Cancer Research Program.
The proposed projects will further clarify the benefits of exercise for breast cancer survivors; validate a new imaging tracer to help expand the use of PARP inhibitors; test the effectiveness of an anti-inflammatory vaccine to prevent breast cancer in obese women and much more.
Funded Fred Hutchinson Cancer Center scientists include Senior Vice President and Clinical Research Division Director Nancy E. Davidson, MD, PhD, holder of the Raisbeck Endowed Chair for Collaborative Research; epidemiologist Chris Li, MD, PhD, associate director of Diversity, Equity and Inclusion of the Fred Hutch/University of Washington Cancer Consortium; epidemiologist and internist Anne McTiernan, MD, PhD and Hannah Linden, MD, associate program director of the Medical Oncology and Hematology Fellowship Program at Fred Hutch and UW Medicine.
BCRF also awarded funds to University of Washington physician-scientist Nora Disis, MD, and breast cancer geneticist Mary-Claire King, PhD. Disis and King are faculty members in the Hutch’s Clinical Research Division. All are part of the Cancer Consortium’s Breast and Ovary Cancer Research Program.
Li, holder of the Helen G. Edson Endowed Chair for Breast Cancer Research, received a one-year, $225,000 grant to analyze an existing breast cancer tissue database in order to find and validate novel predictors of cancer recurrence among patients with luminal B breast cancer.
Luminal B breast cancers tend to have a poorer prognosis than luminal A breast cancers (those that are positive for estrogen and progesterone and negative for HER2 expression), which grow more slowly.
Currently, Oncotype DX and other risk prediction tools help guide clinical decision making for newly diagnosed breast cancer patients, helping differentiate who needs more aggressive treatment such as chemotherapy. But these tests were created using data from patients with luminal A breast cancers, not luminal B.
Li and Fred Hutch computational biologist Gavin Ha, PhD, will partner on a project focusing on luminal B cancers, including triple negative (also known as basal-like breast cancer or BLBC) and other luminal B subtypes.
The team will use data from a large breast cancer database from a 2009 study known as BRAVO that includes baseline demographic, clinical and epidemiologic risk factor information and tumor tissue from a diverse group of breast cancer patients. The BRAVO cohort also includes germline, or inherited, DNA information for most of its patients along with outcomes.
“We have prospectively followed these patients for various clinical outcomes including recurrence and mortality,” Li said.
Li and his team will focus on a subset within BRAVO of 66 luminal B patients who developed a recurrence and 66 carefully matched luminal B patients who have not developed a recurrence. They will use patient data to develop a risk prediction model that integrates genomic, transcriptomic, clinical and epidemiologic data to help stratify luminal B patients based on their risk of developing a recurrence.
The researchers will validate the model using various publicly available data sources including The Cancer Genome Atlas program (or TCGA), and METABRIC, the Molecular Taxonomy of Breast Cancer International Consortium.
“If successful, we’re hoping this risk prediction model, which we’re calling BRAVO-DX, can be used to guide clinical decision making for patients with luminal B breast cancer, including identifying high-risk patients who won’t respond to standard treatment regimens and could benefit from more aggressive first-line treatments and more frequent clinical follow-up,” Li said. “We hope it will also help low-risk patients avoid more toxic/invasive breast cancer treatments.”
Davidson, an award-winning breast cancer researcher and medical oncologist as well as Fred Hutch's Executive Vice President for Clinical Affairs, received funding to pursue a new research project involving PARP inhibitors which will be led by medical oncologist Shaveta Vinayak, MD, and Director of Molecular Imaging Delphine Chen, MD. Currently, this type of targeted treatment is highly effective in about 60% of BRCA mutation-driven breast cancers. But PARP inhibitors could potentially help additional solid tumor patients.
Davidson and her team will explore the use of a novel molecular imaging radiotracer known as fluorthanatrace, or (18F) FTT PET, the first PARP-targeted tracer to be used in humans, as a noninvasive way to measure PARP1 tumor expression.
The FTT PET will evaluate patients’ tumor heterogeneity as well as the extent of its PARP1 expression; the researchers hope this will help determine whether it can predict PARP inhibitor response in germline BRCA or other DNA repair mutation-associated metastatic breast cancer.
“Our intent is to test it as an imaging biomarker for predicting PARP inhibitor therapy benefit, and to assess in real time which patients would benefit the most from this therapy,” Davidson wrote in her proposal. “We also aim to evaluate tissue-based immune markers in relationship to PARP inhibitor therapy response. A combination of biomarkers, including FTT PET imaging and tissue-based immune markers, may be more successful than either strategy alone in identifying patients who are likely to respond to PARP inhibitors.”
If successful, Davidson said the technology could potentially be applicable to other tumor types, including ovarian and prostate cancers where PARP inhibitors are approved, as well as to other DNA repair mutation associated cancers, for PARP inhibitor combination therapies.
McTiernan will continue to investigate the mechanisms by which physical exercise improves breast cancer outcomes with her one-year $225,000 grant.
Her new study will build on findings from the ACute Effects of Exercise in Women (ACE) randomized controlled trial, which examined changes in biomarkers related to inflammation and blood vessel growth in blood and muscle tissue samples from 102 healthy women (i.e., women without breast cancer) before and after 45 minutes of either exercise or rest (the control arm).
Results from the study suggested a specific mechanism that links exercise with proteins involved in preventing tumor growth.
With the new BCRF funding, she and Fred Hutch co-investigators Catherine Duggan, PhD, Ching-Yun Wang, PhD, Jean de Dieu Tapsoba, PhD and Taran Gujral, PhD, will test the same protocol in 20 women who have been diagnosed with breast cancer (10 randomly assigned to exercise, 10 to resting control).
The investigators will measure the effect of acute exercise on levels of proteins in the blood, in samples of fat from the abdomen, and in muscle tissue, and will examine how the proteins are activated in response to exercise.
Protein levels will be measured in Gujral’s lab, which has created technologies capable of analyzing different signaling networks in cell lines and human tissue samples.
McTiernan and her collaborators will also compare these biological data in tissue samples before and after exercise, to see how exercise effects differ in women with and without breast cancer.
“The ACE randomized controlled trial is designed to provide answers to questions on how exercise affects biology related to breast cancer,” McTiernan wrote in her proposal. “In time, precise prescriptions can be provided to women to change lifestyle to reduce their risk and improve prognosis.”
Breast cancer oncologist Linden, the Athena Distinguished Professor of Breast Cancer Research at the UW School of Medicine, along with nuclear medicine physician Delphine Chen, have received funding from BCRF, along with the Translational Breast Cancer Research Consortium and drug maker Eli Lilly, to lead a multi-center collaborative study with partner institutions Washington University in St. Louis, Missouri, the University of Illinois at Urbana-Champaign and the University of North Carolina.
“This study will build on our experience with FES PET — a PET scan that uses an estrogen-based tracer — and our national collaboration with the outstanding group at Washington University,” Linden said. “We are working now on FFNP, a radiotracer that images the progesterone receptor.”
For the last several years, Linden has been researching the clinical utility of FES-PET, which illuminates estrogen receptors and can be used to predict whether endocrine therapy will be effective in patients. Now, she is leading a study to determine if a progesterone tracer known as FFNP-PET (short for 21 [18F] fluorofuranylnorprogesterone) can be used as a better predictive marker of endocrine therapy’s efficacy.
“While FES-PET is able to quantify the presence of estrogen receptors and evaluate for tumor heterogeneity, it does not appear to be as accurate as FFNP-PET in predicting patients that will or will not respond to endocrine therapy,” Linden wrote in the proposal.
This will be the first multi-center study to test the accuracy of FFNP-PET for predicting response to endocrine therapy.
“If we’re successful,” she wrote, “it will enable the future studies of FFNP-PET as an integral and predictive imaging biomarker to inform physicians when it is reasonable to use endocrine therapy with or without novel targeted therapy that relies on an active estrogen pathway.”
The Phase 2 multi-site study will enroll 60 patients with hormone receptor-positive, HER2-negative metastatic breast cancer to assess the accuracy of FFNP-PET imaging to predict response to abemaciclib (also known as Verzenio) plus endocrine therapy.
“The trial is not open yet, but we are hoping we can enroll a patient before the end of the year,” Linden said.
Disis, director of the UW Cancer Vaccine Institute and a Fred Hutch clinical researcher, will continue her work on a vaccine designed to address obesity, an important risk factor for breast cancer, particularly when it comes to women with metabolic syndrome and metabolic dysfunction.
Previous research has shown that obesity triggers the infiltration of CD8 T cells into fat, which in turn secretes Type I (inflammatory) cytokines. This change in the fat results in an immune response which leads to metabolic dysfunction in both the adipose (fat) tissue and the T cells themselves. Once this happens, T cells are no longer able to maintain tumor immune surveillance. Additionally, the secretion of adipokines promotes malignant, or harmful, cell transformation.
“Losing weight will not solve this problem,” Disis wrote in her proposal. “Immunologic memory prevents T-cell associated inflammation from resolving even if an individual becomes normal weight.”
So the team has focused on strategies to increase Type II (anti-inflammatory) T cells in inflammatory adipose tissue, with a particular focus on creating an inflammatory adipocyte-directed (AD) vaccine.
In a preliminary experiment, ten-week-old mice were fed a high fat, high sucrose diet, then once they were obese, randomized into two cohorts. One received the ADVac, the other received an adjuvant only. Significantly, fewer CD8+ cells were observed in the breast adipose tissue of ADVac immunized mice as compared to the control obese mice. There was also significantly less leptin detected in the serum of ADVac vaccinated mice as compared to controls. Additionally, 60% of the vaccinated mice were tumor free at study termination, whereas 100% of the control mice had developed tumors.
With the new one-year, $225,000 grant, Disis and her team aim to determine the extent to which ADVac immunization can restore metabolic function at the tumor site and prevent mammary cancer development and identify the systemic effects of ADVac immunization.
“We do not mean for ADVac to replace the need for weight loss, but immunization with ADVac, if the vaccine were shown to be safe, could eliminate the risk of chronic inflammation and the development of metabolic dysfunction that leads to breast cancer,” Disis wrote in her proposal. “The systemic effects of the vaccine could bring additional significant health benefits to men and women who struggle with obesity such as restoring insulin sensitivity.”
Finally, Lasker Award winner King, the first person to determine breast cancer could be inherited, will continue to work to understand inherited breast cancer in families where genetic mutations have not yet been found. Her BCRF funding will go toward two projects.
The first involves new technology. King and her team have adapted rapidly evolving genomic technology to sequence large swaths of DNA in single very long strands, rather than thousands of short bits.
“This approach enables us to discover complex mutations in DNA that could not otherwise be detected,” King said.
With the funding, they’ll use this long-read sequencing approach to evaluate families from the New York Breast Cancer Study. The NYBCS aims to identify all the genes responsible for inherited breast cancer among women of Ashkenazi Jewish ancestry.
The second project will be an exploration of dysregulation of gene expression as a basis for inherited breast cancer.
“We are focusing particularly on inherited genetic variation that subtly alters expression of genes important to breast cancer,” King said. “These subtle effects are not mutations, but simply changes in level of expression of the gene, all within a normal range.”
King will study this variation in more detail and explore its effects on age at diagnosis of breast cancer.
The Breast Cancer Research Foundation, founded in 1993 by Evelyn H. Lauder, is dedicated to “being the end of breast cancer” by advancing the world’s most promising research.
Diane Mapes is a staff writer at Fred Hutchinson Cancer Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at dmapes@fredhutch.org. Just diagnosed and need information and resources? Visit our Patient Care page.
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