Triple-negative breast cancer (TNBC) is an aggressive breast cancer. It spreads quickly and has few treatment options. It is also serious because of its rate of recurrence.

Black women are twice as likely as white women to be diagnosed with TNBC. They are also more likely to die from the devastating disease. In fact, the five-year survival rate for TNBC in Black women is only 14% compared to 36% in women from other racial backgrounds.

Multiple biological and socioeconomic factors are blamed for this higher risk. UC Davis Comprehensive Cancer Center researcher Sanchita Bhatnagar and her team have been working to get to the bottom of the genetic determinants of the racial disparity in TNBC. Results from their research were recently published in EMBO Reports.

The Bhatnagar Laboratory has been studying a protein called TRIM37 for over 10 years after Bhatnagar discovered its role as a breast cancer-causing gene.

A decade ago, Bhatnagar discovered the role of 

 gene in causing breast cancer. Since then, her lab has studied the protein encoded by that gene. The protein, called TRIM37 in reference to the gene, is present in high numbers in breast cancer tissues. It is associated with poor patient survival.

TRIM37 is a driver of TNBC spread and resistance to chemotherapy. Bhatnagar and her research team have persevered in studying TRIM37 to find out why it may hold the key to Black women getting and dying of TNBC at high rates.

The study’s findings could help develop 

 as a predictive biomarker, which eventually could improve TNBC diagnosis and prognosis in Black women.

Bhatnagar, who is an associate professor with the UC Davis Department of Medical Microbiology and Immunology, said the missing link appears to be a predictive biomarker. It may help identify patients at risk of aggressive TNBC.

“We discovered that the TRIM37 variant known as rs57141087 is predominant in Black women and modulates TRIM37 levels through enhancer-promoter interactions,” Bhatnagar said. “Specifically, TRIM37 overexpression in early stages of triple-negative breast cancer promotes neoplastic transformations (formation of tumor), accelerates tumorigenesis (tumor growth) and drives cells into malignancy (spread of cancer).”

Essentially, if a patient has tumors with high levels of TRIM37 protein, it indicates poor prognosis and overall survival and an increased likelihood of metastasis. Increased early-stage TRIM37 levels appear to give cancer cells a “head start,” impacting the disease trajectory and outcomes.

In this latest research, Bhatnagar’s lab showed that the cancer-free breast tissue from Black women expresses a relatively high level of this protein, which predisposes them to aggressive disease. The rs57141087 variant might be the reason why.

The research team used comprehensive genomic and functional analysis to uncover the genetic drivers that predispose Black women to aggressive TNBC. The analysis identified the ancestry-specific, genomic feature at a single base position in DNA called rs57141087.

Information from a total of 319 patients was included. Interestingly, the meta-analysis revealed ~1.63-fold higher 

 expression in early histological Stage I TNBC tumors from Black women than in white women, which was not the case for Stage II–IV.

The team’s analysis confirmed the association between 

 expression in the Stage I TNBC tumors with racial identity. Next, the researchers assessed to what extent the early-stage differences in 

 expression could explain the disparity in the overall survival of TNBC patients.

The findings showed Black women with TNBC tumors expressing high TRIM37 showed poor overall survival, with a median survival of ~114 months (9.5 years) as compared to white women, with a median survival of ~245 months (20.4 years). Notably, no significant differences in overall survival were observed for low 

-expressing TNBC tumors from Black women and white women.

The team has previously engineered a novel TRIM37 targeting approach. They used TRIM37-specific, synthetic RNA-based inhibitor delivered in vivo by small vesicles, called nanoparticles.

A patent for targeting TRIM37 using nanoparticle delivery mechanisms is pending.

“Our work provided pre-clinical proof-of-concept regarding 

, a clinically relevant target for TNBC treatment,” Bhatnagar said. “Our hope is that further research can be done to test TRIM37 as a therapeutic target for slowing down TNBC and develop 

 as a predictive biomarker for TNBC in Black women.”

Along with Bhatnagar, other UC Davis Comprehensive Cancer Center contributors include Laura Fejerman, Jogender Tushir-Singh, Xiaoson Huang, Hong Li, and Jie Li. The lead authors include Rachisan Djiake Tihagam, a graduate student, and Song Lou, a project scientist in the Bhatnagar Lab. Piotr Przanowski, who was a member of the Bhatnagar Lab when it was located at the University of Virginia, also contributed to the research.

This project also provided research opportunities to UC Davis undergraduate students Kammi Song-Yan Liu and Bon II Koo. Arjun Tushir Singh, a senior at Davis High School, was also involved with the study as part of a high school science program hosted by the UC Davis Department of Medical Microbiology and Immunology.

Articles

Triple-negative breast cancer (TNBC) is notably aggressive, with Black women facing a higher incidence and mortality rate compared to other racial groups. Research led by Sanchita Bhatnagar at UC Davis has identified the TRIM37 protein as a key factor in this disparity. The TRIM37 variant rs57141087, prevalent in Black women, enhances TRIM37 expression, promoting tumor growth and malignancy. This discovery could lead to TRIM37 being used as a predictive biomarker, improving diagnosis and prognosis. A novel TRIM37-targeting approach using RNA-based inhibitors is under development.

Findings point to a biomarker that may give a “head start” to triple-negative breast cancer in Black women.

UC Davis Researchers Help Decode the Cause of Aggressive Breast Cancer in Women of Color

 clinical scientist shows blood tests used to hunt for cancer DNA may help detect cancers faster and guide the use of targeted therapies. The 

, an international, peer-reviewed journal focused on targeted cancer care based on a person’s genetics.

UC Davis Professor of Medicine and the cancer center’s Chief Translational Officer 

 and his research team from several U.S. cancer centers made a potentially life-saving discovery. While monitoring a patient for prostate cancer DNA after treatment, the researchers identified genetic material coming, not from prostate cancer, but from a type of cancer that starts in or near the urinary bladder. Their analysis showed that DNA from the cancer could be detected in the blood at least 18 months prior to clinical diagnosis using conventional screening such as 

When Mitsiades’ team discovered the asymptomatic urothelial cancer, they were able to use data from the blood sample to develop a targeted treatment plan based on the newly detected cancer’s specific gene mutations.

DNA sequencing in blood provides a fast, less invasive method for cancer detection

DNA from some cancers may circulate in a patient’s blood and can be extracted from a simple blood sample. Scientists can genetically sequence the DNA—determining the order of the building blocks of genetic instructions—and characterize the cancer based on what’s found in the blood sample.

“We want to collect information about a patient’s cancer in the least invasive way possible,” Mitsiades said. “The more we can learn about a patient’s cancer, the more we can treat it with safer and hopefully more effective drugs by targeting mutations that show up in the DNA sequencing.”

Sequencing of tumor DNA circulating in the blood is a remarkable technological advancement. While a tissue biopsy is needed for a tumor’s initial diagnosis, it is painful and inconvenient to repeatedly collect samples of tumor tissue. By sequencing tumor DNA from blood samples, a patient’s tumor can be monitored with little discomfort. It can also reveal mutations that suggest a particular treatment path. “Driver mutations” that spur the growth of cancer can be found in blood samples and indicate an aggressive cancer long before it can be detected on other types of tests.

The patient in the study had already been treated for prostate cancer and was participating in a longitudinal study to track potential cancer recurrence. The research team took blood samples at regular intervals and analyzed them for cancer DNA fragments to keep an eye out for signs that his prostate cancer had returned.

Using circulating tumor DNA analysis to enhance patient treatment

“It appears that by sequencing DNA circulating in the blood, we can see evidence of cancer growth months or years before it shows up in CT scans,” Mitsiades said. “What we need now are clinical trials that will examine whether, by acting upon DNA information from a patient’s blood, we can help them live longer.”

For years, the gold standard of care for cancer treatment was to treat patients once tumors showed visible signs of growth on scans.

Now, with the development of precision oncology tools, like circulating tumor DNA sequencing, Mitsiades and his colleagues think there are opportunities to respond to cancer earlier, identify cancers that have acquired mutations driving resistance to current therapy, and quickly pivot towards alternative, targeted therapies that may be less toxic than chemotherapy.

“These new technologies are opening exciting opportunities to intervene earlier for the benefit of our patients,” Mitsiades said.

He said that DNA sequencing is becoming more widely covered by insurers and incorporated into the standard of care. At UC Davis Comprehensive Cancer Center, genetic tests are already offered regularly to patients who also have the option to participate in precision oncology research at the cancer center.

 and private insurers to cover medically necessary biomarker testing,” Mitsiades said. “This will allow more people to access individualized cancer treatments based on the genetic makeup of their cancer.”

New research led by a UC Davis Comprehensive Cancer Center clinical scientist shows blood tests used to hunt for cancer DNA may help detect cancers faster and guide the use of targeted therapies. 

Cancer Blood Tests Jumpstart Diagnoses and Targeted Therapy

Primo “Lucky” Lara Jr., MD, director, UC Davis Comprehensive Cancer Center

April is Head and Neck Cancer Awareness Month and a promising new research initiative at UC Davis Comprehensive Cancer Center could lead to a new and far more effective standard of care for this group of cancers.

The research is being funded by the cancer center’s first ever Specialized Programs of Research Excellence (SPORE) grant from the National Cancer Institute (NCI). The prestigious five-year $9.8 million federal grant is intended to translate cancer research into clinical intervention.

“We are so proud to take the lead in developing what we hope will be a clinical trial that will revolutionize treatment for head and neck cancer,” said UC Davis Comprehensive Cancer Center Director Primo “Lucky” Lara, Jr. “Along with harnessing a breakthrough therapy to treat these difficult and debilitating cancers, we are also advancing interdisciplinary team science and innovative new technologies.”

The grant comes with the recent appointment of the cancer center’s new chief science officer Xiao-Jing Wang, who came to UC Davis in 2022. Wang is building a team to investigate the potential application of immunotherapy to treat head and neck cancers. Immunotherapy uses a body’s own immune system to fight cancer.

Along with her chief science officer role, Wang is associate director of basic science at the cancer center and a professor in the Department of Pathology and Laboratory Medicine.

She began her project under the SPORE program at the University of Colorado Anschutz Medical Campus with her co-principal investigator, Antonio Jimeno.

The researchers are using mouse models to study how cancer cells evade the body’s immune system. The team wants to learn more about 

 through which immunotherapy can more effectively target head and neck cancer. The work will lead directly to a clinical trial to be initiated in the next year. It will test the efficacy of an immunotherapy drug in combination with radiation to treat patients with recurrent head and neck cancers.

“Each SPORE project requires a patient endpoint demonstrating impact to patients, in either prevention or treatment of disease, through at least one new investigator-initiated therapeutic trial,” said Wang, who holds the Robert E. Stowell Endowed Chair in Experimental Pathology at UC Davis.

“Our trial will involve UC Davis and the University of Colorado jointly recruiting participants for therapeutic intervention,” Wang said.

High incidence of head and neck cancer in Sacramento region

The trial holds particular importance for the Sacramento region where incidence of tobacco-related head and neck cancer is more prevalent than in many other areas of the nation.

“Consumption of smoking and chewing tobacco is high among farmworker populations in California’s Central Valley. Members of rural underserved populations who develop head and neck cancers typically delay seeing a doctor until their disease is in advanced stages. Those populations tend to have recurrent therapeutic resistance, the worst prognosis,” explained Wang, who works with clinical oncologists to design clinical trials.

Wang obtained her bachelor’s, M.D. and Ph.D. degrees at Beijing Medical University. After postdoctoral training at the University of Texas M.D. Anderson Cancer Center in Houston, she joined the faculty of Baylor College of Medicine, also in Houston.

“At Baylor I was fortunate to have a great mentor who guided me in gaining the expertise to develop genetically engineered mouse models for studying skin cancer. But after the head and neck department at Oregon Health and Science University in Portland recruited me as a full professor in 2003, I realized that very few scientists or physician-scientists were involved in head and neck cancer research at the time, and no genetically engineered animal model existed for head and neck cancer.”

That prompted her to seek and earn a grant in 2005 from the National Institutes of Health to create genetically engineered mouse models that could mimic head and neck cancer, enabling comparisons between mice and human cancer patients.

“That was my first grant, almost 20 years ago, and that started my head and neck cancer research career,” Wang said.

The SPORE grant will serve as an “incubator,” in Wang’s view, to spur building successful teams of investigators, which harmonizes with her philosophical spirit.

“My two biggest passions are team science and mentoring, particularly for physician-scientists,” Wang said.

Wang’s research project is important because radiation therapy — the current standard of care for head and neck cancer — not only kills tumors but also causes immune system suppression, thereby diminishing the body’s ability to fight cancer naturally.

“Immunotherapy recognizes cancer cells as foreign and then utilizes your immune system to wipe them out. But that doesn’t work for someone whose immune system isn’t functioning optimally,” Wang explained.

The major emphasis of her research is on how to make the immune system emerge from that immunosuppressive exhaustion stage and become reactivated, in combination with radiation. While she remains in the process of assembling her full team, research leading to the clinical trial is underway.

“We are determining which drug would hit the target and would be most likely to succeed,” she said. “The first direct impact of this project will be opening a new clinical trial. And the second, if that works, will be to deliver a new therapeutic intervention at UC Davis Comprehensive Cancer Center.”

April is Head and Neck Cancer Awareness Month, and a promising new research initiative at UC Davis Comprehensive Cancer Center could lead to a new and far more effective standard of care for this group of cancers.

Cancer Center Lands Prestigious NCI Grant to Advance Immunotherapy in Head and Neck Cancer

researchers have uncovered a link between a patient’s 

 that can potentially be used to improve the treatment of 

. This type of cancer is found in connective tissues like muscle, fat and nerves.

“The study’s data show new lines of research in the paradigm-shifting concept that the microbiome of a patient and their immune system can interact and shape one another, as well as be potentially engineered to improve patient outcomes,” said 

, the lead author of the study and chief of the 

The gut microbiome is made of microorganisms in the digestive tract that include bacteria, fungi and viruses. Microbial communities have also been found in other parts of the body, including the mouth, lungs and skin. And now the study shows they are also found in tumor cells.

“We found that soft tissue sarcomas harbor a quantifiable amount of microbiome within the tumor environment. Most importantly, we found that the amount of microbiome at diagnosis may be linked with the patient’s prognosis,” Canter added.

Although the levels of microbes are low, the study findings are significant because many tumors, especially sarcomas, were believed to be sterile.

Viruses within the microbiome may attract cancer-fighting cells

The UC Davis researchers also uncovered how the microbiome within a sarcoma tumor plays a role in attracting specific types of immune cells like cancer-fighting 

. Canter said that’s important because the higher the rate of natural killer cell infiltration in a tumor, the greater the chance that the sarcoma won’t spread to other parts of the body. Natural killer cells are a prime target for improving the effectiveness of immunotherapy.

The team found that viruses within the microbiome of a tumor appear to impact the amount of natural killer cells found in sarcomas and, for that reason, affect survival rates. Specifically, the study found a strong positive correlation between the presence of 

, a genre of viruses known for causing respiratory illnesses, and the presence of natural killer cells in the tumor. Canter and his colleagues are now considering ways to create viruses to attract more cancer-killing immune cells.

“It has become clear that the microbiome in the gut and other parts of the body has a major impact on human health and disease. Amazingly, it shapes the immune system throughout the body and, because of its interaction with the immune system, we now know it also has a big role in how the body responds to cancer and cancer treatments like immunotherapy,” Canter said.

The authors obtained tumor and stool samples from 15 adult patients with non-metastatic soft tissue sarcoma, which was studied for a median of 24 months. Analysis revealed that most of the tumors were advanced stage III (87%) and affected a patient’s limb (67%).

Tissue samples were sent to the university’s 

 in Davis for sequencing and to the Flow Cytometry Shared Resource Laboratory on the UC Davis medical campus in Sacramento for immune profiling. Patients were monitored for two years as part of their cancer treatment follow-up.

Canter said past research has shown the existence of microbiome inside tumors across several cancer types, including breast, lung, pancreas and melanoma. For that reason, he said further research into the connection between microbiome and the immune system in other cancer types is warranted.

Coauthors on the study are Lauren Perry, Sylvia Cruz, Kara Kleber, Sean Judge, Morgan Darrow, Louis Jones, Ugur Basmaci, Nikhil Joshi, Matthew Settles, Blythe Durbin-Johnson, Alicia Gingrich, Arta Monjazeb, Janai Carr-Ascher, Steven Thorpe, William Murphy, and Jonathan Eisen.

This work was supported by the UC Davis Comprehensive Cancer Center and the UC Davis Flow Cytometry Shared Resource Laboratory, with funding from National Cancer Institute grants P30 CA093373, S10 OD018223 and S10 RR 026825. Specimens were provided by the UC Davis Pathology Biorepository, funded by the UC Davis Comprehensive Cancer and the UC Davis Department of Pathology and Laboratory Medicine. The sequencing was carried out at the DNA Technologies and Expression Analysis Cores at the UC Davis Genome Center, supported by National Institutes of Health (NIH) Shared Instrumentation Grant 1S10OD010786-01.

New UC Davis study finds relationship between tumor microbiome and immune system in patients with soft tissue sarcoma.

Tumor Microbiome Linked to Immunotherapy Success in Sarcoma Patients

 shows that direct oral anti-coagulant (DOAC) drugs are more effective and are more cost-effective than 

 on December 27, 2022, examines the cost-effectiveness of the four most utilized anticoagulation strategies for blood clots, which include LMWH, 

. Authors of the study include oncologist and Assistant Professor of Medicine 

, a clinician scientist with UC Davis, and Professor Emeritus of Clinical Medicine 

“For reasons not completely understood, cancer can increase the risk of blood clots, and treatments such as chemotherapy can further increase the risk. Cancer patients with CAT face double the mortality rate compared to cancer patients without thrombosis. CAT also adds a significant financial burden for these patients,” said Gulati who is the corresponding author for the study.

For many years, injection of low molecular weight heparin has been the treatment of choice in patients who have cancer-associated thrombosis. The DOACs came on the scene about eight or nine years ago, and they have better safety and efficacy profiles.

“Clinical trials have shown improved efficacy and a decreased risk of major bleeding with the DOACs, but the question is whether people will be willing to pay the additional cost to get the better outcome. Many oncologists have already adopted DOACs in their clinical practice, so this is a key issue,” Gulati said.

These drugs were compared head-to-head using a computer model Eckman and Gulati constructed that simulates major health events that happen to a cohort of patients with cancer over time who have experienced a blood clot. The model simulates events including recurrent pulmonary emboli, recurring DVT without pulmonary emboli, major bleeds and clinically relevant non-major bleeds as well as mortality. Then, over the course of the lifetime of the patient cohort, the study examined the accumulating lifetime costs and lifetime effectiveness measured in a metric called quality-adjusted life years (QALYs).

“QALYs are basically years lived by the members of the cohort but adjusted for the quality of life in the different health states they experience over that time,” Gulati said. “If you were to have a recurrent blood clot or a major bleed for instance, you would have a decrease in your quality of life.”

In the base-case analysis, using the cost of drugs purchased at a federal facility such as the 

, apixaban was favored as being more effective and less costly than either LMWH or edoxaban while indicating rivaroxaban was not cost-effective. However, the study results were vastly different when analyzing average prices from 

, a free online service that provides drug coupons for discounts on medications. In this scenario, if decision makers were unwilling to spend more than $50,000 per QALY, edoxaban was favored, and using the contemporary threshold for societal willingness to pay, rivaroxaban was cost-effective, with an incremental cost-effectiveness ratio of just more than $50,000 per QALY.

Gulati said the findings demonstrate a stark difference between the real-world cost of direct oral anticoagulants and drug prices from the Veteran’s Administration and will likely have implications for value-based price benchmarks in the United States. She added that an individual’s insurance coverage plan can make a huge difference in the patient’s out-of-pocket costs for these medications.

“Most importantly, all the DOACs are more effective and have a better side-effect profile than low molecular weight heparin,” Eckman concluded. “Which of those is the most cost-effective is going to depend for any given patient on what the cost of those drugs will be for them. That decision can be one that is made in concert with the oncologist and the patient.”

Research conducted by UC Davis Comprehensive Cancer Center and the University of Cincinnati shows that direct oral anti-coagulant drugs are more effective and are more cost-effective than low molecular weight heparin for treating cancer-associated thrombosis.

UC Davis Comprehensive Cancer Center

Articles

UC Davis Researchers Help Decode the Cause of Aggressive Breast Cancer in Women of Color

Cancer Blood Tests Jumpstart Diagnoses and Targeted Therapy

Cancer Center Lands Prestigious NCI Grant to Advance Immunotherapy in Head and Neck Cancer

Tumor Microbiome Linked to Immunotherapy Success in Sarcoma Patients

Comparing the Cost-Effectiveness of Treatments for Blood Clots in Cancer Patients