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Exploring the Role of Tumor Biology in Redefining Triple-Negative Breast Cancer Treatment
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Emerging research in triple-negative breast cancer highlights the promise of molecular-based approaches to improve treatment outcomes.
Approximately 15% of all breast cancer cases in the United States are triple-negative breast cancer (TNBC), an aggressive subtype with limited therapeutic options. At the 2024 San Antonio Breast Cancer Symposium in San Antonio, Texas, a panel discussed the evolving definition of TNBC, sharing novel findings regarding the disease’s heterogeneity that may lead to the development of advanced targeted therapies and innovative treatment approaches.1,2
Accumulating malignant tumor cells | Image Credit: © Kiran - stock.adobe.com
TNBC has been a largely misunderstood subtype of breast cancer, often overshadowed by the early discoveries of estrogen receptor positivity (ER+) and HER2 positivity (HER2+). These discoveries led to the development of therapies such as tamoxifen (Soltamox; Mayne Pharma Group Limited) for ER+ breast cancer, and trastuzumab deruxtecan (Enhertu; AstraZeneca) and other HER2-targeted agents for HER2+ breast cancer, as well as targeted therapies like PARP inhibitors for specific subgroups of breast cancer.
“[TNBC] really has been a diagnosis of exclusion,” explained Rebecca Dent, MD, deputy chief executive officer of the National Cancer Center Singapore, Singapore. “So, it was really in the ’60s that we finally realized we have [ER+] breast cancer. And then it took into the ’90s to come up with some criteria as to how to define [ER+] breast cancer with the sole purpose, really, to develop therapies that target this ER+ subtype. Then we have [HER2+] breast cancers, but again, IEC [information, education, and communication] defined. So, triple-negative was really defined by what it wasn't, rather than what it was.”
TNBC is molecularly diverse, consisting of different subtypes based on their gene expression. This heterogeneity can interfere with the response to therapy, making it challenging to develop effective treatments for patients who have more aggressive disease, poorer prognoses, and a higher risk of cancer recurrence and metastasis. The definition of TNBC has been refined over time as clinical understanding of the disease’s characteristics and biologic features expands, leading to the recognition of ER-low tumors.
ER-low tumors are characterized as breast cancers with 1% to 9% ER positivity, distinguishing them from being ER negative. According to data from large studies, patients with ER-low and ER-negative TNBC had comparable rates of local recurrence, lymph node recurrence, and distant recurrence. Additionally, they had similar pathological complete response (pCR) rates to neoadjuvant chemotherapy between ER-low and ER-negative TNBC. These findings may provide a rationale for considering ER-low tumors as part of the TNBC spectrum, helping to better evaluate the efficacy of immune checkpoint inhibitors (ICIs) and other therapies.
Therapy options for TNBC are limited and reliant on cytotoxic chemotherapy, which remains the standard of care for early-stage TNBC. This is due to the lack of targets for hormonal and HER2-targeted therapies. However, the introduction of multi-agent chemotherapy regimens and immunotherapies has greatly improved patient outcomes, increasing the 10-year disease-free survival rate to approximately 90%.
Chemotherapy drug molecules interacting with cancer cells, causing cell death | Image Credit: © Ummeya - stock.adobe.com
“Over the last 30 years, we've had a lot of progress in triple-negative [BC],” said Dent. “So, from 2007, there’s a 70% to 75% recurrence-free survival, but when we give multi-agent chemotherapy and potentially immunotherapy, this increases to up to almost 90%.”
Novel targeted therapies, such as ICIs and antibody-drug conjugates (ADCs), have become of particular interest in the TNBC treatment landscape. Several clinical trials have shown that patients with TNBC and low ER expression seem to achieve the greatest benefit from ICIs. In the KEYNOTE-522 trial (NCT03036488), adding pembrolizumab to neoadjuvant chemotherapy resulted in a higher pCR rate compared to chemotherapy alone. This held true in the metastatic setting, where the addition of pembrolizumab to chemotherapy improved progression-free survival in patients with PDL-1–positive TNBC in the KEYNOTE-355 trial (NCT02819518).
Another treatment area of interest is tumor-agnostic therapy, which focuses on the molecular features of a tumor rather than the organ of origin. The concept is that if a molecular target is actionable, it may be so regardless of the type of tumor. Tumor-agnostic drug development is associated with multiple advantages, including increased access to precision therapies for patients with rare tumors or molecular alterations, as well as allowing for more efficient clinical trial designs capable of evaluating a therapy across tumor types. There are several notable FDA-approved tumor-agnostic therapies, such as pembrolizumab for MSI-high or mismatch repair-deficient tumors and encorafenib (Braftovi; Array BioPharma Inc) for BRAF-mutant tumors.
"Tumor-agnostic drug development can increase access to precision therapies for patients with rare tumors or rare molecular alterations,” explained Funda Meric, MD, chair of the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center in Houston. “It allows for more efficient clinical trial designs, such as basket trials, that can evaluate a therapy across multiple tumor types.”
Developing tumor-agnostic therapies presents several challenges for researchers. For instance, identifying actionable targets across a wide range of tumor types and understanding the distribution of these molecular alterations is crucial to determine the feasibility of success. Additionally, FDA guidance underscores the importance of establishing a minimum number of patients and disease types required to assess the efficacy of these therapies—a process that becomes particularly complex when rare molecular alterations or tumor types are involved. The need for rigorous and inclusive study designs underscores the importance of understanding these challenges, highlighting the complex nature of developing effective tumor-agnostic therapies.
“There are complications with this kind of study design as well,” said Meric. “From a preliminary data standpoint, if you're going to go down a tumor-agnostic drug development path, how many different disease types do you need precompiled data for? How much safety data do you need to have to launch a cooperative group study?”
Cancer detection | Image Credit: © Corona Borealis - stock.adobe.com
This challenge reflects a broader shift in cancer classification, moving away from traditional organ-based methods toward a molecular-driven approach. Molecular alterations and biological characteristics are increasingly recognized as the primary determinants of drug sensitivity and treatment response, particularly in metastatic disease. However, as molecular profiles grow more complex, interpreting this data becomes equally demanding. Integrating advanced tools, such as generative AI and knowledge curation systems, could provide clinicians with the frameworks needed to navigate and analyze these intricate datasets, facilitating more precise and effective treatment decisions.
The evolving landscape of TNBC research underscores the importance of refining classifications and developing innovative therapies. Progress in understanding TNBC heterogeneity has paved the way for identifying actionable targets, such as ER-low tumors, the incorporation of advanced treatment modalities like ICIs and ADCs. These breakthroughs highlight the potential of novel approaches to significantly improve patient outcomes, yet challenges remain in translating these discoveries into broader clinical practice.
Tumor-agnostic therapies represent an exciting evolution in precision oncology, shifting the focus from a tumor's organ of origin to its molecular characteristics. However, significant challenges remain, including the complexities of designing inclusive clinical trials and meeting regulatory standards to demonstrate efficacy across diverse tumor types. By combining advances in molecular science with innovative technologies, the development of these therapies has the capacity to transform the treatment landscape for TNBC.
