Five Fred Hutchinson/University of Washington/Seattle Children’s Cancer Consortium researchers have received additional funding from the Breast Cancer Research Foundation, or BCRF, to continue ongoing studies.
Fred Hutch physician-scientists funded for another year include Executive Vice President for Clinical Affairs Nancy E. Davidson, MD, holder of the Raisbeck Endowed Chair for Collaborative Research; epidemiologist Chris Li, MD, PhD, associate director of Diversity, Equity and Inclusion of the Cancer Consortium and epidemiologist and internist Anne McTiernan, MD, PhD, of Fred Hutch’s Public Health Sciences Division.
BCRF also awarded another year of funding to University of Washington School of Medicine physician-researcher 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, long supported by BCRF.
The ongoing projects drill down into everything from the benefits of exercise for breast cancer survivors to a new vaccine to prevent breast cancer in obese women. Read on for more details.
Davidson, a medical oncologist and Fred Hutch's Executive Vice President for Clinical Affairs, received another year of funding to research the expanded use of the targeted treatment known as PARP inhibitors. Currently, this type of therapy is highly effective in about 60% of BRCA mutation-driven breast cancers.
PARP inhibitors could potentially help other patients, though, if they can be identified.
The BCRF funding will be used to launch a clinical trial of a novel molecular imaging radiotracer known as fluorthanatrace, or (18F) FTT PET, a PARP-targeted tracer, to measure PARP1 tumor expression without the need for biopsy. Led by medical oncologist Shaveta Vinayak, MD, and Director of Molecular Imaging Delphine Chen, MD, the trial is scheduled to start recruiting in early 2024.
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.
“With targeted therapies such as PARP inhibitors, giving the ‘right treatment’ to the ‘right patient’ at the ‘right time’ can significantly impact cancer control and patient survival,” Davidson wrote in her proposal. “This will allow us to validate the utility of a non-invasive imaging tool to predict PARP inhibitor therapy response.”
Li, holder of the Helen G. Edson Endowed Chair for Breast Cancer Research, received another year’s worth of funding — $225,000 — to continue his work to uncover predictors of cancer recurrence within different types of breast cancer.
Previous work by Li and Fred Hutch computational biologist Gavin Ha, PhD, focused on the development and validation of a risk prediction model for luminal B breast cancer recurrence using integrated genomic, transcriptomic and clinical/epidemiologic data.
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.
This new funding will be used to create better recurrence prediction for each of the most common breast cancer subtypes, including both basal-like (often referred to as triple negative) and luminal A using spatial transcriptomic analyses.
“Several studies underscore the biological importance and prognostic and predictive value of detailed spatially resolved single-cell phenotyping of immune cells,” Li wrote in his proposal.
Li and team will use patient data and samples from a large, population-based cohort known as BRAVO (Breast Cancer Risk Factors And Various Outcomes), which contains 1,216 luminal A, 607 luminal B, 487 HER2-overexpressing and 1,267 triple-negative breast cancer patients.
In particular, they will focus on matched sets of breast cancer patients who did versus did not experience a recurrence of their cancer. They plan to conduct spatial transcriptomic analyses on all these patients (approximately 280 women) to identify and spatially map the many different cell types and states at single-cell resolution.
Aims for this phase of the study are twofold. First, they plan to perform deep immune cellular profiling of tumor tissue biospecimens from the matched sets of breast cancer patients at single-cell resolution in hopes of discovering new spatially resolved biomarkers of recurrence for basal-like, luminal B and luminal A breast cancers.
Second, they plan to develop and validate multi-omic predictors of cancer recurrence of each subtype using machine learning.
“We aim to identify patients who will rapidly fail standard first-line therapy,” Li wrote. “Currently, there are no recurrence risk prediction models specific for luminal B or basal-like breast cancer patients that have sufficient performance to be clinically useful.”
The bottom line?
“We hope to improve the delivery of tailored treatments for patients at a high risk of recurrence while at the same time being able to identify low risk patients who may be able to avoid more toxic/invasive breast cancer treatments,” Li said.
McTiernan’s ACE exercise study received an additional $225,000 to fund another year of her investigation into the mechanisms of how physical exercise improves breast cancer outcomes.
Previously, the ACute Effects of Exercise in Women (ACE) randomized controlled trial examined changes in biomarkers related to inflammation and blood vessel growth in blood and muscle tissue samples from 102 women without breast cancer before and after 45 minutes of either exercise or rest (the control arm).
After analysis, McTiernan and team found intriguing evidence that exercise changes muscle cell proteins involved in the regulation of genes that are important in breast cancer.
The next phase — in collaboration with Fred Hutch co-investigators Catherine Duggan, PhD, Ching-Yun Wang, PhD, Jean de Dieu Tapsoba, PhD and Taran Gujral, PhD — will continue to test the effects of acute exercise on muscle, fat and blood biomarkers in women with breast cancer.
Last year, McTiernan began enrolling for a second phase of ACE, open to women ages 36 to 75 who’ve been diagnosed with stage 0 to stage 3 breast cancer within the last five years and who have finished all treatment at least six months ago (anti-hormone treatments are okay).
Funds from BCRF will be used to continue the study’s implementation.
McTiernan and colleagues will measure the effect of acute exercise on the levels of proteins in participants’ 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.
The researchers will also compare tissue samples before and after exercise to see how exercise effects differ in women with and without breast cancer.
“This trial will provide answers to questions on how exercise affects biology related to breast cancer, so that precise prescriptions can be provided to women to change lifestyle to reduce their risk and improve prognosis,” McTiernan said.
Nora Disis, MD, director of the UW Medicine Cancer Vaccine Institute, associate dean of the UW School of Medicine and a Fred Hutch clinical researcher, will continue work on a vaccine to address obesity. Inflammation of adipose tissue has been shown to be a risk factor for breast cancer in individuals with obesity.
Obesity promotes the infiltration of CD8+ T-cells early on, altering the microenvironment from anti-inflammatory to pro-inflammatory. Type I CD4+ T-cells maintain that inflammation, which results in metabolic dysfunction in the fat tissue and in the T-cells themselves.
“Losing weight will not solve this problem; these inflammatory T-cells persist even after weight loss,” Disis said. “To combat adipose inflammation and its associated health risks, we have developed an anti-inflammatory vaccine that elicits a response from Type II anti-inflammatory T-cells.”
Disis and her team identified six non-mutated proteins expressed at high levels in inflamed adipose tissue, then used those proteins to design their ADVac (adipose directed vaccine).
The funding from BCRF will be used to conduct a year-long pre-clinical study of ADVac in mice to determine to what extent the vaccine reverses metabolic dysfunction at the tumor site and prevent development of breast cancer and to learn about the systemic effects of the ADVac vaccine.
Using mass spectrometry to glean a better understanding of the metabolic changes in adipose tissues after vaccination, Disis found levels of 50 metabolites were lower in the adipose tissue of ADVac-vaccinated mice when compared to control mice.
“The top four metabolic pathways modified by ADVac vaccination are associated with glycolysis, an important mechanism for cancer cell metabolism and growth,” Disis said, adding research has shown that an increase in glycolysis can promote metastasis in breast cancer cells.
Their results also showed some of the metabolites in ADVac-vaccinated mice were decreased to levels similar to lean (non-obese) mice.
“Our data suggest that the ADVac vaccine led to a metabolic reprogramming in adipose tissue of obese mice to resemble the metabolic profile seen in lean mice,” Disis said. “This shift in adipose tissue metabolism may discourage breast cancer growth.”
Moving forward, the researchers plan to look at ADVac-associated systemic effects by comparing ADVac-immunized mice and control non-vaccinated mice and validate whether the T-cells are recognizing ADVac antigens. They also plan to examine the livers of ADVac vaccinated mice to see the extent to which vaccination limits non-alcoholic fatty liver disease and to evaluate vaccine-associated effects on the aorta, as adipose inflammation may be responsible for the increased risk of atherosclerosis.
Additionally, since obesity can lead to low-grade inflammation in the colon, they plan to evaluate the severity and extent of inflammation and the infiltration of ADVac-specific T cells and assess if vaccination can restore microbiome diversity in the gut.
“To our knowledge, ADVac is the first vaccine that targets a risk-factor for cancer-obesity,” Disis said. “If the vaccine is shown to be safe, we believe it can eliminate the risk of chronic inflammation and the development of metabolic dysfunction that leads to a variety of cancers including breast cancer.”
The vaccine may also be able to benefit individuals suffering from metabolic syndrome, Type II diabetes, fatty liver disease and other disorders associated with adipose inflammation, she said.
Mary-Claire King, PhD, professor of medical genetics at the University of Washington School of Medicine and the first person to determine breast cancer could be inherited, will continue her research projects focused on inherited breast cancer.
“For many families severely affected with breast cancer, no genetic reason for their illness has been discovered,” King said. “Our goal is to understand inherited breast cancer in these families.”
The new BCRF funding will support two ongoing projects, one of which involves a new technology platform that enables the researchers 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, adding that this year, she and her team will be applying long-read genomic sequencing to the discovery of previously cryptic alleles and genes that predispose people to breast cancer.
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 the estrogen receptor,” King said. “These subtle effects are not mutations, but simply changes in level of expression of the gene, all within a normal range. We have very preliminary evidence that these effects may influence breast cancer risk.”
Breast cancer oncologist and researcher Hannah Linden, MD, associate program director of the Medical Oncology and Hematology Fellowship Program at Fred Hutch and UW Medicine, will continue to investigate whether 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. Linden holds the Athena Distinguished Professorship of Breast Cancer Research at UW Medicine.
The upcoming clinical trial, funded by BCRF, marks the first multi-center study to test the accuracy of FFNP-PET for predicting response to endocrine therapy.
In 2022, BCRF established the Leigh Pate Living Biorepository of Invasive Lobular Breast Cancer. Pate was a longtime Seattle resident and a Fred Hutch patient advocate.
Founded in 1993 by Evelyn H. Lauder, the Breast Cancer Research Foundation is the largest private funder of breast cancer research in the world. By investing in the best minds in science to examine every aspect of the disease from prevention to metastasis—and fostering cross-disciplinary collaboration — BCRF is accelerating the entire field and moving us closer to the answers we urgently need to end breast cancer. Learn more and get involved at BCRF.org.
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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