Triple-negative breast cancer (TNBC), an aggressive subtype affecting approximately 15% of breast cancer patients in the United States, is seeing its treatment landscape evolve as researchers refine its definition and explore novel therapeutic approaches. Recent discussions at the 2024 San Antonio Breast Cancer Symposium highlighted the molecular diversity of TNBC and the potential for targeted therapies and innovative treatment strategies to improve outcomes.
Redefining TNBC: The Role of ER-Low Tumors
Historically, TNBC has been defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. However, the recognition of ER-low tumors, characterized by 1% to 9% ER positivity, is changing this definition. Data from large studies indicate that patients with ER-low TNBC have similar rates of recurrence and pathological complete response (pCR) to neoadjuvant chemotherapy compared to those with ER-negative TNBC. This suggests that ER-low tumors may be considered part of the TNBC spectrum, potentially influencing treatment strategies and the evaluation of therapies like immune checkpoint inhibitors (ICIs).
Advances in Targeted Therapies
Traditional treatment for TNBC has relied on cytotoxic chemotherapy due to the lack of specific targets for hormonal and HER2-targeted therapies. However, the introduction of multi-agent chemotherapy regimens and immunotherapies has significantly improved patient outcomes, increasing the 10-year disease-free survival rate to approximately 90%, according to Dr. Rebecca Dent, deputy chief executive officer of the National Cancer Center Singapore.
Novel targeted therapies, such as ICIs and antibody-drug conjugates (ADCs), are gaining prominence in TNBC treatment. Clinical trials have demonstrated that patients with TNBC and low ER expression benefit significantly from ICIs. For example, in the KEYNOTE-522 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a higher pCR rate compared to chemotherapy alone. Similarly, in the KEYNOTE-355 trial, pembrolizumab combined with chemotherapy improved progression-free survival in patients with PDL-1–positive TNBC.
The Promise of Tumor-Agnostic Therapies
Tumor-agnostic therapy, which targets the molecular features of a tumor regardless of its origin, represents a significant shift in cancer treatment. This approach is particularly relevant for TNBC due to its molecular heterogeneity. Dr. Funda Meric, chair of the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, noted that tumor-agnostic drug development could increase access to precision therapies for patients with rare tumors or molecular alterations and allow for more efficient clinical trial designs.
However, developing tumor-agnostic therapies presents challenges, including identifying actionable targets across various tumor types and understanding the distribution of molecular alterations. The FDA also requires a minimum number of patients and disease types to assess the efficacy of these therapies, adding complexity to the development process.
Shorter, Simpler Treatment Protocols
Recent clinical trials at UT Southwestern have explored shorter, less toxic treatment protocols for TNBC. These trials, published in the Journal of Clinical Oncology, found that simplified regimens produced outcomes similar to the current standard of care. Dr. Heather McArthur, professor of internal medicine and clinical director of the Breast Cancer Program at the Harold C. Simmons Comprehensive Cancer Center, suggests that biologically driven strategies could achieve the same impacts and even improve on the effectiveness of therapy with less toxicity for patients.
The Future of TNBC Treatment
The evolving understanding of TNBC heterogeneity is paving the way for identifying actionable targets and incorporating advanced treatment modalities like ICIs and ADCs. These breakthroughs hold the potential to significantly improve patient outcomes. As molecular profiles grow more complex, integrating advanced tools like generative AI and knowledge curation systems could help clinicians navigate and analyze intricate datasets, facilitating more precise and effective treatment decisions. By combining advances in molecular science with innovative technologies, the development of tumor-agnostic therapies has the capacity to transform the treatment landscape for TNBC.
