Researchers are actively exploring innovative strategies to prevent breast cancer, addressing a critical need for individuals at high risk of developing the disease. These approaches, presented at the 2024 San Antonio Breast Cancer Symposium (SABCS), include vaccines, personalized tamoxifen dosing, and targeted inhibition of specific cell populations.
Vaccines for Prevention and Interception
Olivera Finn, PhD, from the University of Pittsburgh, discussed the potential of vaccines in preventing or intercepting breast cancer. Unlike therapeutic vaccines that face an immunosuppressive tumor microenvironment, preventive vaccines can leverage a more responsive immune system in individuals at risk or with precancerous conditions. Finn's team is evaluating a vaccine that targets a unique form of the MUC1 protein found on malignant cells in glandular tissue. This vaccine aims to prime the immune system to detect and eradicate malignant cells before they form a tumor, or before ductal carcinoma in situ (DCIS) progresses to invasive cancer.
A phase I clinical trial is currently enrolling postmenopausal patients with newly diagnosed, hormone receptor (HR)-positive DCIS to receive neoadjuvant therapy with or without the MUC1 vaccine. Tissue samples will be analyzed to assess immune changes in the tumor microenvironment. Finn also highlighted a trial led by Susan Domchek, MD, at the University of Pennsylvania, evaluating DNA vaccines in BRCA mutation carriers.
Personalizing Tamoxifen with Breast Density Measurements
Seema Khan, MD, from Northwestern University, presented a strategy to personalize prophylactic tamoxifen dosing. While low-dose tamoxifen is effective in reducing HR-positive breast cancer risk, its use is limited by side effects. Khan proposes personalizing the dose based on individual estrogen levels, using breast density as a biomarker for tamoxifen efficacy. High breast density is a known risk factor for breast cancer and decreases with tamoxifen use.
The RENAISSANCE trial, a phase II clinical trial, is enrolling premenopausal women at higher-than-average risk for breast cancer. Participants receive a low dose of tamoxifen (5 mg daily), and breast density is measured every six months. Women with sufficient breast density reduction continue on the same dose, while others receive a higher dose. Khan noted that "the concept that dosing of preventive agents can be optimized using short-term surrogate endpoints will advance the field."
Targeting Luminal Progenitor Cells in BRCA1 Carriers
Geoffrey Lindeman, MBBS, PhD, from the Walter and Eliza Hall Institute, addressed the limited effectiveness of tamoxifen in BRCA1/2 mutation carriers. He proposed targeting luminal progenitor cells, where breast cancer frequently originates in BRCA1 carriers. Lindeman's data showed that RANK/RANKL-mutated luminal progenitor cells in healthy BRCA1 carriers exhibit cancer-like traits.
Based on these findings, Lindeman and colleagues are conducting the phase III BRCA-P clinical trial to evaluate denosumab, a RANKL inhibitor, for breast cancer prevention in BRCA1 mutation carriers without evidence of breast cancer. Participants receive denosumab or a placebo every six months for up to five years, with the primary endpoint being time to breast cancer diagnosis. Lindeman's team has also identified everolimus, an mTOR inhibitor, as a potential preventive agent for individuals with BRCA2 mutations, based on increased mTOR signaling in cells leading to breast cancer in these carriers.
