Clinical Trials Are Testing Ways to Prevent Breast Cancer

January 15, 2025 by

Higher screening rates along with treatment advances have reduced breast cancer deaths by 42% in recent decades. Still, it remains the second deadliest cancer among women in the United States, with over 40,000 expected to die of the disease last year. And for the almost 4 million women living with breast cancer, the physical and mental toll of treatment and survivorship can be significant. Fittingly, researchers are exploring ways to prevent breast cancer from developing in the first place. 

During a session of the 2024 San Antonio Breast Cancer Symposium (SABCS), held December 10-13, presenters discussed potential strategies for breast cancer prevention, including vaccines, personalized doses of prophylactic tamoxifen, and targeted inhibition of the cells that give rise to breast cancer. 

Of note, all three presenters suggested applying existing therapeutic agents to cancer prevention. 

Using Vaccines to Prevent or Intercept Breast Cancer 

Vaccines have long been explored to treat cancer, with some recent headway made against pancreatic and other cancers. In the first presentation of the session, Olivera Finn, PhD, discussed how vaccines may be better suited for preventing or intercepting cancer than for treating it. 

Olivera Finn, PhD

Finn, who is a distinguished professor of immunology and surgery at the University of Pittsburgh, explained that using vaccines for treatment means having to contend with a highly immunosuppressive tumor microenvironment—a hostile setting that does not exist, or exists to a lesser extent, in precancerous or noninvasive conditions. 

“The immune system of a person at risk or a person with precancer should not be suppressed and should allow the vaccine to develop a very strong immune response,” she said. 

With this in mind, Finn and colleagues are evaluating an investigational vaccine that primes the immune system to respond to malignant cells expressing a unique form of the cell surface protein MUC1, which is found in glandular tissue. The idea is that vaccination may allow the immune system to detect and eradicate malignant cells before they are able to form a tumor or, in the case of ductal carcinoma in situ (DCIS), before a noninvasive tumor can progress to invasive cancer.  

While MUC1 is found on both normal and malignant cells, the sugar molecules bound to the protein adopt a unique pattern in the precancerous and cancerous cells that form adenocarcinomas. To spare healthy cells, the vaccine developed by Finn and colleagues trains immune cells to recognize MUC1 proteins with these cancer-associated molecular patterns. 

The approach has already shown promise for those at high risk of colorectal cancer. In 2013, Finn and colleagues reported in the AACR journal Cancer Prevention Research that the vaccine induced MUC1-targeted immune responses in individuals with precancerous colon polyps. And in 2023, they published phase II clinical trial results in the AACR journal Clinical Cancer Research showing that participants who developed vaccine-induced immune responses were 38% less likely to have their precancerous polyps return compared with those without responses. 

Now, the researchers are testing the vaccine’s potential for preventing progression of DCIS to invasive breast cancer. A phase I clinical trial is currently enrolling postmenopausal patients with newly diagnosed, hormone receptor (HR)-positive DCIS to receive neoadjuvant therapy either with or without the MUC1 vaccine. Tissue samples removed by surgery will be examined to determine if the MUC1 vaccine promoted immune changes to the tumor microenvironment. Ten patients have been enrolled since the trial opened in February 2024. 

This trial is one of many aimed at preventing or intercepting breast cancer with vaccines. In her presentation, Finn also highlighted a trial led by Susan Domchek, MD, at the University of Pennsylvania that is evaluating DNA vaccines to prevent breast cancer in BRCA mutation carriers, who have a particularly high risk of the disease. Notably, Finn added, the trial evaluates vaccines previously tested in the therapeutic setting. 

“Testing vaccines in the premalignant and in high-risk settings is feasible, and we would encourage retesting vaccines that have failed in therapeutic settings in a new setting of prevention and interception,” said Finn.  

Moreover, she suggested that “interception vaccines that prove safe and immunogenic should be very confidently given to healthy people at high risk. They don’t have the beginning of immune suppression that we see in precancers, so they may have even better responses to these vaccines.” 

Measuring Breast Density to Personalize Prevention with Tamoxifen 

In another presentation, Seema Khan, MD, a professor of surgery at Northwestern University, discussed a strategy to improve the use of prophylactic tamoxifen, an estrogen receptor-targeted drug originally developed for breast cancer treatment. The ability of low-dose tamoxifen to reduce HR-positive breast cancer risk is well established, but its uptake among high-risk individuals has been subpar, Khan explained. Part of the reason for this is the associated side effects. 

Seema Khan, MD

To limit toxicities and encourage wider use, researchers have sought to identify the minimal effective dose—that is, the lowest dose at which tamoxifen still reduces cancer risk. Khan proposes taking this a step further and personalizing the dose of tamoxifen to account for differences in baseline estrogen levels across individuals. But doing so will require biomarkers that allow tamoxifen’s efficacy to be determined in each patient in a shorter timeframe than is typically done. 

An approach Khan and colleagues are exploring is to use decreased breast density as a surrogate for tamoxifen efficacy and risk reduction; high breast density is a known risk factor for breast cancer and has been shown to decrease with tamoxifen use.  

Khan outlined a phase II clinical trial she and colleagues are conducting, the RENAISSANCE trial, in which premenopausal women at higher-than-average risk for breast cancer will receive a low dose of tamoxifen (5 mg daily) and have their breast density measured every six months. Women whose breast density has sufficiently decreased over the six-month period will continue on the same tamoxifen dose, while women whose breast density has not decreased will begin a higher dose. The trial opened in September 2024 and has enrolled 10 patients thus far. 

While Khan acknowledged that further research is needed to understand the value of breast density as a surrogate endpoint for tamoxifen efficacy, she noted that “the concept that dosing of preventive agents can be optimized using short-term surrogate endpoints will advance the field, and breast density is currently the most robust candidate with evidence that it is modifiable with an effective agent.” 

Breast Cancer Prevention in BRCA Mutation Carriers 

Despite tamoxifen’s established ability to protect against breast cancer in many individuals, it has been less effective at reducing risk for those with inherited BRCA1 or BRCA2 variants, noted Geoffrey Lindeman, MBBS, PhD, joint head of the Cancer Biology and Stem Cells Division at the Walter and Eliza Hall Institute and a medical oncologist at the Peter MacCallum Cancer Centre and at Royal Melbourne Hospital.  

Geoffrey Lindeman, MBBS, PhD

In his presentation, Lindeman proposed filling this unmet need by targeting a population of breast cells known as luminal progenitor cells—cells in which breast cancer frequently originates in carriers of BRCA1 variants.  

He shared data showing that, in ostensibly healthy BRCA1 carriers, luminal progenitor cells with mutations in the RANK and RANKL genes exhibited traits similar to those of cancer cells: they grew quickly, had faulty DNA repair, and had other molecular features of the breast cancers common among BRCA1 carriers. This suggested that RANK/RANKL-mutated luminal progenitor cells could represent the beginnings of breast cancer. 

Lindeman and colleagues therefore reasoned that targeting RANK/RANKL-mutated luminal progenitor cells could help stop the development of breast cancer in BRCA1 carriers. Consistent with their hypothesis, they observed that denosumab—a RANKL inhibitor approved for treating osteoporosis and bone metastases—reduced the proliferation of breast cells in BRCA1 mutation carriers and suppressed tumor formation in mouse models.  

Based on these preclinical observations, as well as promising findings from a pilot clinical study, Lindeman and colleagues are conducting the international phase III BRCA-P clinical trial to evaluate denosumab for breast cancer prevention in BRCA1 mutation carriers who have no evidence of breast cancer. Enrolled patients will receive either denosumab or a placebo every six months for a maximum of five years, and the time to breast cancer diagnosis will be compared between the two groups. Since the trial opened in 2023, about 340 patients across seven different countries have enrolled.  

Separately, Lindeman and colleagues have also identified the mTOR inhibitor everolimus—approved to treat breast and other cancers—as a potential preventive agent for individuals with BRCA2 mutations. This is based on studies that found increased mTOR signaling in the cells that lead to breast cancer in BRCA2 mutation carriers. 

“In closing, I’d like to point out the importance of thinking about the cells of origin that can give rise to cancer and then being selective in targeting those early perturbations as a prevention strategy,” said Lindeman. 

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