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Reducing Risk: MUC1 Vaccines, Tamoxifen, and Denosumab in Breast Cancer Prevention
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Advancements in prevention address cancer risk in high-risk patients and BRCA mutation carriers.
Alongside the advent of novel therapies and innovative treatment approaches, prevention remains an essential component of cancer research. With the approval of notable interventions such as the human papillomavirus (HPV) vaccine, which contributed to a 62% drop in cervical cancer deaths over the last decade, clinicians have been able to prevent and treat a broad range of cancers, marking a pivotal shift in oncology care.1
Needle and cancer cell | Image Credit: © radekcho - stock.adobe.com
At the 2024 San Antonio Breast Cancer Symposium (SABCS) in Texas, experts presented recent advancements in breast cancer (BC) prevention, calling attention to the evolution of vaccines, refinements in dose optimization of tamoxifen (Soltamox; Mayne Pharma Group Limited), and RANK ligand (RANKL) pathways as therapeutic targets to prevent BC in BRCA1 and BRCA2 carriers. Their insights emphasize the crucial role of continued advancements in prevention strategies as a cornerstone of comprehensive BC care and management.2
Vaccines as preventative therapies have been clinically proven to be safe and effective, driving down cancer rates significantly since their initial development. In the 1980s and 1990s, cancer immunologists tested the efficacy of therapeutic cancer vaccines in patients with advanced disease and limited treatment options. By the 2000s and 2010s, researchers shifted their focus to testing vaccines for minimal residual disease after primary tumor removal, aiming to prevent recurrence by generating a strong immune response. However, this approach showed limited efficacy.1
“In the 1980s the whole goal of cancer immunologists was to identify molecules on cancer that would be of interest to the immune system so that we can use them to generate vaccines to boost that immune response against those molecules and hopefully change the clinical outcome for cancer patients, prolonged survival, disease-free survival, and perhaps overall survival,” said Olivera Finn, PhD, professor of Immunology and Surgery and chair of the Department of Immunology at the University of Pittsburgh in Pennsylvania.1
Vaccines as a monotherapy have shown no efficacy in changing clinical outcomes for patients, with no significant improvements in survival or disease-free survival. The highly immunosuppressive nature of the tumor microenvironment (TME) is a driving factor behind the lack of success in these therapies. Even if a vaccine could generate an immune response, the cells were unable to overcome the suppressive TME, resulting in little clinical benefit for patients.1
“That also led to a renaissance of therapeutic cancer vaccines that are now under development based on either shared antigens or unique antigens, unique tumor mutations or personalized antigens; not as monotherapy, but in combination with other agents that will beat immunotherapy or other agents that change the tumor microenvironment,” said Finn. “So, if you're looking here, in terms of therapy, we are still developing therapeutic vaccines, but now in combination with immune checkpoint inhibitors or other immunoregulatory molecules that will allow these vaccines to work.”1
According to Finn, the field has shifted its interest in cancer vaccines again, instead focusing on prevention and interception of disease through vaccination of pre-cancerous or high-risk individuals. She highlighted several ongoing trials investigating the efficacy and safety of antigen-based vaccines for the prevention and treatment of colon cancers and BCs.1
In the randomized, double-blind, placebo-controlled Colon Cancer Prevention Trial (NCT02134925), patients with newly diagnosed advanced adenomas were vaccinated with MUC1 antigen, a glycosylated protein found on epithelial cells. During cancer and pre-cancerous transformation, MUC1 becomes aberrantly processed and presented on the cell surface, making it a promising target antigen for cancer vaccines.3
“So, this is a molecule that's always present, but never presented until there is a malignant transformation,” explained Finn. “Even though it is not a mutated molecule, it is a very good tumor antigen.”1
The data showed that 47% of patients with newly diagnosed advanced adenomas vaccinated with the MUC1 antigen experienced a 38% reduction in new polyps at 3 years, exceeding the trial’s predefined primary end point of a 25% reduction in new polyps at 3 years. Additionally, the vaccine was well-tolerated with no reported toxicities.1
The MUC1 vaccine is also being investigated in a BC trial being carried out at Finn’s institution, where they aim to evaluate mechanisms of immune activation and suppression in post-menopausal women with ductal carcinoma in situ. In the trial, the patients will receive the MUC1 vaccine prior to undergoing surgery, with the goal of generating an immune response to eliminate the lesion.1
Concept of the tumor microenvironment | Image Credit: © Justlight - stock.adobe.com
In another BC trial, investigators at the University of Pennsylvania are assessing the safety and efficacy of the experimental vaccine INO-5401 alone or in combination with INO-9012 followed by electroporation in adult patients carrying BRCA1 or BRCA2 mutations, with or without prior cancer. They aim to identify whether the vaccine can prevent BC development in high-risk patients.1
While innovative vaccines like INO-5401 are exploring new preventive approaches, established treatments such as tamoxifen continue to play a critical role in BC prevention, as demonstrated in major clinical trials. Tamoxifen is a hormone therapy shown to reduce the incidence of BC in high-risk women in the 1992 landmark NSABP P-1 trial. According to the data, tamoxifen reduced BC incidence by approximately 50% at a dose of 20 mg a day for 5 years.5
Even more favorable results were seen in the TAM-01 trial (NCT01357772) when the treatment was reduced to 5 mg daily for 3 years. According to data from the 10-year follow-up, the reduced dose significantly prevented recurrence of noninvasive BC for 7 years after treatment cessation, without long-term adverse events. Despite its proven effectiveness, real-world implementation remains limited.6
“So, there was a lot of excitement, obviously, about that; but the downer came over the next couple of decades, where we saw that implementation was poor,” said Seema A. Khan, MD, professor of surgery in the Surgical Oncology Division at Feinberg School of Medicine. “Women, in general, even though they were at increased risk and knew they were at increased risk, were informed by their clinicians, they didn't want to take this drug.”1
Although tamoxifen has shown promise in breast cancer prevention, particularly for estrogen receptor-positive patients, there remains a significant unmet need for more effective interventions targeting aggressive disease in carriers of BRCA1 and BRCA2 mutations. Geoff Lindeman, PhD, clinician-scientist, joint head of the Cancer Biology and Stem Cells Division at the Walter and Eliza Hall Institute, presented his team’s hypothesis that inhibiting the RANK ligand (RANKL) pathway could be an effective preventative therapy based on findings that aberrations in the RANK-positive luminal progenitor cells in normal breast tissue from BRCA1 carriers were highly proliferative, exhibited DNA repair defects, and were hyper-responsive to progesterone signaling, suggesting that targeting this pathway could reduce cancer risk.1
"Many groups have shown the importance of the RANK signaling pathway as an enabler of progesterone signaling in the normal mammary gland,” explained Lindeman. “Cathrin Brisken’s, MD, PhD, [associate professor of Life Sciences at the Swiss Federal Institute of Technology Lausanne] group, for example, showed the tremendous importance of paracrine signaling through a progesterone receptor-positive cell, which can produce [RANKL] and switch on an adjacent hormone receptor-negative cell through [RANKL]."1
Using mouse models, Lindeman’s team discovered that RANKL inhibition, either through genetic deletion or pharmacologic inhibition, could delay or prevent tumor onset, leading to the initiation of the randomized, double-blind, placebo-controlled, multi-center, international, phase 3 BRCA-PREVENT study (NCT04711109). The trial is evaluating BC risk reduction (invasive or ductal carcinoma in situ [DCIS]) in women with germline BRCA1 mutation who are treated with the RANKL-inhibiting, monoclonal antibody denosumab (Prolia; Amgen), compared with placebo.7
As prevention strategies continue to evolve, the integration of vaccines, hormonal therapies, and targeted approaches offer renewed hope for reducing cancer incidence and improving patient outcomes. These advancements underscore the need for further study in prevention research to address gaps in care, particularly for high-risk populations.1
