On the trail of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a disease with an often aggressive course and a poor prognosis compared to other subtypes of breast cancer. It accounts for around 10-15% of all diagnosed breast cancer cases. Until a few years ago, chemotherapy was the only systemic treatment option for this subtype. Several new strategies for the treatment of TNBC patients have been investigated in recent years. These include immunotherapy, antibody-drug conjugates, new chemotherapeutic agents and targeted therapies.

Breast cancer is the most common malignant disease in women worldwide and is associated with the highest mortality rates of the disease. Triple-negative breast cancer is an entity in which the expression of the estrogen receptor (ER), the progesterone receptor (PR) and the human epidermal growth factor receptor 2 (Her-2) is negative. It is characterized by poor differentiation, high invasiveness, a tendency to local and distant metastases, a poor prognosis and high recurrence rates. Gene expression analyses show that immune markers, mesenchymal phenotypes, androgen receptors, stem cell markers and baseline markers are associated with TNBC.

One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases. The classification into six subtypes has been proposed: two basal-like (BL1 and BL2) subtypes, a mesenchymal (M) subtype, a mesenchymal stem-like (MSL) subtype, an immunomodulatory (IM) subtype and a luminal androgen receptor (LAR) subtype. Subsequent studies have shown that the IM and MSL subtypes do not correlate with independent subtypes, but reflect background expression by dense infiltration of tumor infiltrating lymphocytes (TILs) or stromal cells. Based on this finding, the classification of TNBC was revised into the following four subtypes: Basal 1, Basal 2, LAR and mesenchymal subtypes.

New treatment strategies for better prognoses

Breast cancer was long considered a “cold” tumor, as it has only limited T-cell infiltration and a low tumor mutation burden. However, TNBC has a larger number of infiltrating lymphocytes, creating a favorable immune microenvironment for the potential use of immune checkpoint inhibitors (ICI). TNBC also has a relatively high tumor mutation load and thus provides an antigenic basis for recognition by immune cells. The expression of PD-L1 is significantly increased in TNBC and therefore represents a promising target for the use of ICIs.

In recent years, other drugs have also been developed that are more effective and more specific than conventional drugs against tumor surface proteins. These new drugs are antibody-drug conjugates (ADCs), in which a monoclonal antibody against the target protein of the cancer cell is conjugated with a cytotoxic agent. The first ADCs to be approved for clinical use were ado-trastuzumab emtansine and brentuximab vedotin. Many more followed, aimed at identifying better target proteins, more effective cytotoxic agents and more sophisticated linker technology.

Sacizutumab-Govitecan (SG) is an antibody-drug conjugate consisting of a humanized monoclonal antibody targeting trophoblastic cell surface antigen 2 (TROP2). TROP2 is a transmembrane calcium signal transducer involved in multiple pro-oncogenic signaling pathways and is expressed in a variety of epithelial tumors, including TNBC. The Phase III ASCENT trial compared SG with investigator’s choice of monotherapy (capecitabine, vinorelbine, eribulin or gemcitabine) in 468 patients with TNBC who had previously been treated with at least two lines of chemotherapy for advanced disease or at least one line for metastatic disease if a relapse occurred within one year of (neo)adjuvant chemotherapy. The primary endpoint was progression-free survival (PFS) without brain metastases in the initial stage. The median PFS in the SG group was 5.6 months compared to 1.7 months in the control group. Overall survival (OS), the most important secondary endpoint of the study, was also longer in the SG group (12.1 vs. 6.7 months). In addition, the ORR for SG patients was 35% compared to 5% for control patients.

Therapy regimen for mTNBC

In the treatment of mTNBC, chemotherapy is the first-line treatment for all patients. In about 40% of patients with PD-L1-positive tumors, the combination of CPI and chemotherapy leads to a prolongation of survival. In Europe, both atezolizumab in combination with nab-paclitaxel and pembrolizumab in combination with paclitaxel, nab-paclitaxel or gemcitabine/carboplatin are approved for the treatment of mTNBC. From second-line treatment onwards, sacituzumab govitecan is the preferred systemic treatment option as it prolongs OS compared to chemotherapy. Chemotherapy or PARP inhibitors in BRCA1/2-mutated patients and T-DXd in HER-low patients can also be considered as second and subsequent lines of treatment for TNBC.