Translational breast cancer researcher Dr. Cyrus Ghajar, epidemiologist Dr. Christopher Li, and immunotherapy expert Dr. Stanley Riddell of Fred Hutchinson Cancer Center have received a four-year, $25 million grant from the U.S. Department of Defense to learn how to kill metastatic cancer’s deadly seeds before they can sprout.
The new Transformative Breast Cancer Consortium Award, specifically designed to fund high-risk/high-reward research, will bring together a dream team of Hutch researchers, breast cancer patient advocates and collaborators at Huntsman Cancer Institute of Salt Lake City and the University of California at San Francisco.
The scientific teams will focus their efforts on devising ways to squelch disseminated breast cancer tumor cells that have traveled to distant tissues like bone marrow and become dormant, a vulnerable precursor state before tumor spread. The researchers will initially focus on bone metastasis and expand from there to research other areas in the body where breast cancer can metastasize or spread.
“We have to move the needle on metastasis,” Ghajar said. “But we’re not going to be able to do that until we understand the biology of dormancy and you’re not going to do that until you start looking closely at these cells and how they’re regulated. Not in animal models. In humans. This grant and our team finally provide a vehicle to do that.”
According to the Department of Defense, a longtime funder of breast cancer research, the new grant mechanism is designed to “support collaborations and ideas that will transform the lives of individuals with, and/or at risk for, breast cancer and will significantly accelerate progress toward ending breast cancer.”
And this transformation must be in people's lives, “not in the health care or research system,” the DOD said.
Ghajar, who joined the Hutch in 2013 and runs the Laboratory for the Study of Metastatic Microenvironments, will serve as the scientific director of the newly formed consortium; Li will serve as its administrative director.
The principal objective is to develop therapies to either kill or silence dormant disseminated tumor cells, or DTCs. The collaboration, which uses the acronym TRANCE, will attempt to do this by “TaRgeting ANd reprogramming DTCs to prEvent lethal metastasis.”
“Targeting and eradicating the root of distant breast cancer recurrence — breast tumor cells that have disseminated and lie dormant in distant organs like the lung, bone marrow and brain — may be the paradigm-shifting therapeutic strategy that prevents lethal metastatic disease,” the team wrote in the proposal.
Unlike early-stage disease, metastatic breast cancer is treatable, but not yet curable.
Median survival for newly diagnosed metastatic patients is three years and metastatic breast cancer kills more than 41,000 people each year. According to Hutch research, around 20% of early-stage patients go on to develop metastasis within 20 years. These diagnoses are often the result of DTCs that have spread and survived systemic, or system-wide, treatments like chemotherapy. Metastatic tumors most often appear in the bones, liver, lungs and, eventually, brains, of metastatic breast cancer patients.
“Patients with DTCs in their marrow are more likely to recur than those who do not,” said Ghajar, who’s researched metastatic breast cancer and the metastatic process for over a decade. “We’ve known this for 17 years but we have not yet gone beyond that. There are currently no drugs to selectively target these cells.”
Ghajar believes that targeting disseminated breast tumor cells — by either keeping them sound asleep or killing them while they slumber — will shut down the metastatic cascade.
And that could mean peace of mind for many.
“What we want is to prevent patients from looking over their shoulder in five or 10 years, wondering if the cancer’s going to come back," he said.
Lynda Weatherby of Seattle was first diagnosed and treated for stage 0 breast cancer, also known as ductal carcinoma in situ or DCIS, in 2001. Twelve years later, she learned her cancer had spread to her bones and brain.
“The thing about Cyrus’ work on disseminated tumor cells and dormant cells is that’s exactly what happened to me,” she said. “As soon as I heard about his work, I said, ‘I want to know what caused it. Take my blood, take whatever you need.’”
A metastatic breast cancer, or MBC, patient advocate, Weatherby recently worked with the MBC Alliance and the women’s cancer nonprofit SHARE to create MBCBrainmets.org, a new website for patients.
“There was really not a good resource out there for MBC brain mets patients,” she said. “So a great team of patient advocates built one from the ground up, with information and resources and clinical trial matching. All completely vetted by a medical advisory board.”
Thanks to research and new therapies, MBC patients like Weatherby are living much longer than the median three years. She uses much of that time to advocate for more research into metastatic breast cancer, particularly brain mets.
“I’m thrilled to see Cyrus and his team acknowledged and funded in this way,” she said. “When I was first diagnosed, the amount of research that went to metastatic breast cancer as opposed to prevention, screening and early detection was like 5% to 7%. We seem to be seeing a sea change. People like Cyrus are starting with metastasis now.”
And for Weatherby and thousands of other metastatic cancer patients in the U.S., that’s the holy grail.
“If you can solve for the metastatic problem, that benefits every single early-stage patient and every single metastatic patient,” she said. “And sometimes, it benefits across tumor types.”
But targeting dormant DTCs means first fully understanding the mechanisms that drive metastasis. And not all dormant cancer cells go on to become distant tumors.
“Two-thirds of breast cancer patients with detectable bone marrow DTCs will not recur,” Ghajar said. “But we’re currently unable to distinguish between the DTCs capable of initiating metastasis — clinically relevant mets — from those that are not. And without this knowledge, indiscriminate use of DTC-targeted therapies would result in an unacceptable level of overtreatment,” meaning people who would never benefit would be put through unnecessary treatment side effects.
The TRANCE consortium aims to learn the mechanics, overcome the barriers and discover actionable strategies to target and/or reprogram disseminated tumor cells and mitigate their lethal potential. They’re doing this through a comprehensive assessment of the genome of DTCs, the way genes are activated and regulated in these cells, how the immune system responds to them and the cellular environment they live in within the body.
Five separate research teams will work on five distinctive but related projects for the consortium’s deep and definitive dive into DTCs. A team of MBC patient advocates will provide input, advice and help disseminate the information to the cancer community and public.
Epidemiologist Li, holder of the Helen G. Edson Endowed Chair for Breast Cancer Research, will lead one project designed to predict the risk of recurrence among early-stage breast cancer patients with disseminated tumor cells.
Li and colleagues will enroll newly diagnosed early-stage breast cancer patients (stages 1 to 3) at three sites: the Fred Hutch/University of Washington/Seattle Children's Cancer Consortium, Huntsman in Salt Lake City and Washington University in St. Louis. These patients will allow their surgeons to harvest solid and fluid bone marrow samples during either a port-placement surgery before their chemotherapy starts or during a lumpectomy or mastectomy.
“This study is designed to identify DTCs in patients that have not been impacted by breast cancer treatments so that we can study them before they have been influenced by chemotherapy or radiation,” Li said.
After that, researchers will study the patients for several years.
“An important part of this study is our annual follow-up of patients we recruit for the next 10 years,” he said. “Each year patients will complete a questionnaire and donate a blood sample, and then throughout follow-up we will also be collecting rich clinical data from patient medical records. We recognize that we are asking a lot of participants.”
But they’ll be getting back a lot in return.
Li and his team will use the molecular sequencing data from the patient tissue samples to create risk prediction models that distinguish between DTC-positive patients likely to develop metastasis versus DTC-positive patients unlikely to develop it.
This information will help the researchers determine which patients should be included in future clinical trials that target DTCs. It will also reduce the likelihood of unnecessary overtreatment of patients.
Fred Hutch translational researcher Dr. Cyrus Ghajar
What exactly can be used to treat DTCs? That’s what the rest of the consortium will discover.
Ghajar and immunology expert Riddell, who holds the Burke O’Reilly Family Endowed Chair in Immunotherapy, will co-lead another project that aims to use both natural and engineered immunity to neutralize disseminated tumor cells.
This team will use deep precision profiling of primary tumors, disseminated tumor cells and the immune microenvironments — the immune cells in and around tumor cells — to identify candidate antigens (markers on tumor cells that immune cells could be programmed to target) for engineered T-cell immunity. They’ll also look at the mechanisms used by the tumor and its microenvironment to suppress immune response as future drugs could potentially target these mechanisms to neutralize DTCs.
Ghajar and Riddell’s team will use patient data and specimens from the sister projects to drive their project’s discovery pipeline which in turn, will inform additional projects.
Metastatic breast cancer patient Teri Pollastro of Seattle, one of the advocates on this project, said she and fellow advocates were involved in every step of the proposal.
“We read it, we edited it, we did a patient advocate piece for it and talked about what the project would look like,” she said. “We were all very involved and the scientists were very accepting and appreciative. They took everything we said very seriously. To me that was exceptional. We definitely were a team.”
Like Weatherby, Pollastro also progressed from DCIS to metastatic breast cancer (stage 4) after several years. She is still in treatment and advocates for MBC research through the Hutch and other organizations, such as the MBC Alliance.
Pollastro, who has participated in clinical trials herself, said inviting patients to the research table is both necessary and beneficial to science.
“I can’t tell the researchers about science but I can tell them what it’s like to be a patient,” she said.
Li said the yearlong contribution of time and insights from patient advocates was immense.
“They have been critical in every aspect of this proposal,” he said.
UCSF researchers Dr. Jayanta Debnath, a cell biologist and expert on autophagy (how the body devours damaged cells) and Dr. Arun Wiita, a physician-scientist who has developed cutting-edge strategies to define the sets of proteins that are on cell surfaces, will lead an effort to define and re-engineer the DTC and metastatic cell surface to prevent metastasis. Their goal is to either re-engineer and uncloak these cancer cells for elimination by host immune cells or render them incapable of metastatic progression.
Dr. Alana Welm of Huntsman Cancer Institute, a cancer biologist with expertise in modeling and the tumor microenvironment, will expand her rapid autopsy program, which collects tissue from patients immediately after death, to reveal tissue-specific features of DTCs and the microenvironments that keep them alive even through cancer therapy. She and her team will look for ways to make the environment less supportive, then will trial these therapies in humanized mouse models (that is, laboratory mice engineered to have some human biological features).
The final project is on epigenetics, the changes on top of our genes that are influenced by environmental factors such as stress and nutrition and passed down from parent to child. The team will define epigenetic variants in “clinically relevant DTCs” – the ones that go on to drive metastasis – in hopes they can potentially be targeted with treatment. Led by Dr. Katherine “K-T” Varley at Huntsman, a computational biologist who has pioneered methods to profile cancer epigenomes (all the epigenetic modifications on a cancer cell that tell it what to do), this project is intended to define epigenetic changes associated with DTC emergence that enable early detection of subclinical (or undetected) recurrence and devise therapies to keep DTCs dormant or target them for immune detection (and destruction).
Along with Pollastro, patient advocates include Sharon Folland, working with researchers at Huntsman; Vivian Lee, partnering with the UCSF team; and Debbie Laxague and Tracy Solak, both from the National Breast Cancer Coalition.
“Our goal is to prevent lethal metastasis,” Li said of TRANCE’s objective. “That could happen different ways: by identifying patients up front who are at high risk for metastasis, through different forms of treatment that prevent metastasis, and by more frequent follow-ups of patients who are high risk. We want to prevent lethal metastasis through a combination of potential strategies.”
And the TRANCE consortium, he added, is a unique opportunity to do what “none of us could have done by ourselves.”
“We’re basically taking all these unknowns about disseminated tumor cells and throwing every available technology at them,” Ghajar said. “The goal is to learn everything we can about DTCs and use all of this information to finally do something about them.”
Is this work relevant to those currently living with metastatic disease?
“Our hope is that some of the approaches we develop could have relevance to the metastatic setting,” Li said. “We have to evaluate and test but there is certainly potential for the work to be relevant to current metastatic patients.”
In April 2022, Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance became Fred Hutchinson Cancer Center, an independent, nonprofit organization that also serves as UW Medicine’s cancer program.
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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