Triple-negative breast cancer (TNBC) is an aggressive subtype accounting for about 10% to 15% of all breast cancer diagnoses. This classification means the cancer cells test negative for three common targets: the estrogen receptor (ER), the progesterone receptor (PR), and the HER2 protein. Because these cells lack the receptors that fuel most other breast cancers, traditional hormone therapy and HER2-targeted drugs are ineffective. The absence of these targets historically made treatment challenging, often relying solely on standard chemotherapy, but recent breakthroughs have introduced new systemic therapies, offering more effective and personalized strategies for patients with both early-stage and advanced disease.
Foundational Local and Systemic Treatments
Initial management of TNBC relies on local control measures and systemic chemotherapy. For localized disease, surgery is a primary step, typically involving either a lumpectomy to conserve the breast or a full mastectomy to remove the entire breast. Radiation therapy is often administered after a lumpectomy or after a mastectomy if lymph nodes were involved or the tumor was large, aiming to eliminate any residual cancer cells and reduce the risk of local recurrence.
Standard systemic treatment involves chemotherapy, which is effective because TNBC cells tend to grow and divide rapidly. Regimens often utilize a combination of drugs, such as anthracyclines and taxanes, to attack the fast-growing cancer cells. This treatment is commonly given before surgery, known as neoadjuvant therapy, which can shrink the tumor and increase the likelihood of a successful surgical outcome.
Neoadjuvant chemotherapy is especially beneficial in TNBC. Achieving a pathological complete response (pCR)—meaning no detectable cancer remains in the breast and lymph nodes at the time of surgery—is strongly associated with a better long-term prognosis. If cancer cells are still present after neoadjuvant treatment, oncologists may recommend additional chemotherapy, such as capecitabine, or other new therapies after surgery, known as adjuvant therapy.
Immunotherapy: Changing the Treatment Landscape
Immunotherapy utilizes the body’s own immune system to fight cancer cells by targeting specific mechanisms cancer uses to hide. Immune checkpoint inhibitors are a major class of these drugs. They block the interaction between the PD-1 protein on immune T-cells and the PD-L1 protein on tumor cells. This blockade essentially takes the “brakes” off the immune system, allowing T-cells to recognize and destroy the cancer.
The PD-1 inhibitor pembrolizumab is now a standard part of treatment for many patients with TNBC. In the early-stage setting, it is combined with chemotherapy as a neoadjuvant regimen, which has been shown to increase the rate of pathological complete response. This combination of chemotherapy and immunotherapy continues after surgery to reduce the chance of recurrence.
For patients with advanced or metastatic TNBC, the decision to use immunotherapy depends on PD-L1 testing results. If the tumor expresses high levels of PD-L1, drugs like pembrolizumab or atezolizumab may be combined with chemotherapy as a first-line treatment. This strategy has demonstrated improved progression-free and overall survival rates in patients with PD-L1-positive advanced disease. The integration of these inhibitors into both the early and advanced disease settings marks a substantial shift in the therapeutic approach for TNBC.
TNBC tumors often have a higher number of genetic mutations and tumor-infiltrating lymphocytes (TILs) compared to other breast cancer types. These features make the tumor more visible to the immune system once the checkpoint pathway is blocked, contributing to immunotherapy’s success.
Antibody-Drug Conjugates: Precision Delivery
Antibody-Drug Conjugates (ADCs) represent a major development in TNBC treatment. An ADC consists of three parts: a monoclonal antibody targeting a specific protein on the cancer cell surface, a potent chemotherapy drug payload, and a linker connecting the two. This design allows for the precise delivery of a high dose of chemotherapy directly to tumor cells while minimizing exposure to healthy tissues.
Sacituzumab govitecan is the first-in-class ADC approved for TNBC. It targets the Trophoblast Cell-Surface Antigen 2 (Trop-2) protein, which is highly expressed on most TNBC cells. Once the antibody binds to Trop-2, the complex is internalized, and the linker releases the chemotherapy payload (SN-38, a potent metabolite of irinotecan). This mechanism ensures the chemotherapy is concentrated where it is needed most.
This Trop-2-directed ADC has demonstrated significant efficacy in patients with metastatic TNBC who have already received prior lines of therapy. By selectively targeting Trop-2-expressing cells, sacituzumab govitecan offers a new avenue for systemic treatment that is more potent than traditional chemotherapy alone in this heavily pretreated population. The drug is now an established option for those with locally advanced or metastatic TNBC, improving outcomes compared to standard chemotherapy options in this setting.
ADCs also benefit from the “bystander effect,” where the released chemotherapy payload can diffuse out and kill neighboring cancer cells. This characteristic is beneficial in heterogeneous tumors like TNBC, ensuring a broader anti-tumor action.
Targeted Therapies and Emerging Research
For a specific subset of TNBC patients, targeted therapies that exploit genetic vulnerabilities offer a highly personalized approach to treatment. Approximately 15% to 20% of TNBC patients have a germline mutation in the \(BRCA1\) or \(BRCA2\) genes, which are involved in repairing damaged DNA. This defect makes their cancer cells particularly susceptible to Poly(ADP-ribose) Polymerase (PARP) inhibitors.
PARP inhibitors, such as olaparib and talazoparib, block a second DNA repair pathway, leading to a synthetic lethality where the cancer cells cannot repair their DNA damage and die. These oral medications are approved for patients with advanced TNBC who harbor a germline \(BRCA\) mutation, providing an effective alternative to traditional chemotherapy. They may also be used in the adjuvant setting for patients with a \(BRCA\) mutation who still have residual disease after neoadjuvant chemotherapy.
Novel Targets and Combination Strategies
Beyond currently approved treatments, research is actively exploring other novel targets and combination strategies. Clinical trials are investigating the use of PARP inhibitors in patients without a \(BRCA\) mutation but with other defects in the DNA damage repair pathway. There is also ongoing research into combining PARP inhibitors with immunotherapy, given the potential for synergistic effects in preclinical models.
Immunotherapy Enhancements
Other emerging areas include the development of personalized vaccines designed to train the immune system to recognize specific tumor antigens. Scientists are also studying Tumor-Infiltrating Lymphocytes (TILs) therapy, where a patient’s own immune cells are extracted from the tumor, multiplied in a lab, and then infused back into the body. These efforts aim to further refine treatment, moving closer to truly individualized medicine for all patients with triple-negative breast cancer.