Treatment Algorithms Across TNBC Populations

Tiffany Traina, MD, FASCO Memorial Sloan Kettering Cancer Center | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Early-stage triple-negative breast cancer (TNBC) is primarily treated with upfront surgery followed by adjuvant therapy, which may include chemotherapy or radiation.

• In locally-advanced TNBC, the KEYNOTE-522 regimen of neoadjuvant chemotherapy plus perioperative pembrolizumab is the current standard of care.

• For patients with residual disease after surgery, adjuvant therapy can be intensified with capecitabine or, in BRCA-mutated patients, olaparib.

• PD-L1 status affects eligibility for pembrolizumab in the advanced or metastatic TNBC population.

• Several antibody-drug conjugates (ADCs) are joining first-line treatment options for patients with metastatic TNBC.

TNBC Treatment Algorithm

On the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with breast medical oncologist, Tiffany Traina, MD, FASCO, of Memorial Sloan Kettering Cancer Center, to discuss the treatment algorithm for early-stage, locally-advanced, and advanced or metastatic TNBC.

Treatment Selection in Early-Stage TNBC

Early-stage TNBC is defined as a tumor measuring less than 2 cm in the greatest dimension (T1) with no regional lymph node involvement (N0). The standard treatment for this population is upfront surgery followed by adjuvant radiation therapy (RT) for tumors under 5 mm (T1a). For tumors between 6 mm and 1 cm (T1b) or between 1 cm and 2 cm (T1c), adjuvant chemotherapy with regimens like dose-dense doxorubicin, cyclophosphamide, and paclitaxel (ddAC-T) or docetaxel and cyclophosphamide (TC) may be added prior to RT. 

According to the National Comprehensive Cancer Network (NCCN) guidelines, neoadjuvant chemotherapy may be considered for early-stage TNBC. However, Dr. Traina prefers not to use neoadjuvant chemotherapy for most patients given the potential toxicities, instead relying on upfront surgery and adjuvant treatment. 

Management of Locally-Advanced TNBC and Residual Disease

Locally advanced TNBC is defined as tumors measuring 2-5 cm (T2) or with nodal involvement. Neoadjuvant systemic therapy is preferred for these patients per NCCN guidelines, and the KEYNOTE-522 regimen is the standard of care. When administering KEYNOTE-522, Dr. Traina starts with paclitaxel and carboplatin weekly plus pembrolizumab every third week. After 12 weeks, she switches paclitaxel and carboplatin for dose-dense AC, and gives pembrolizumab every 6 weeks. Patients typically undergo surgery by the second pembrolizumab dose, and their pathology report can inform whether adjuvant therapy should be intensified.

In patients with residual disease after surgery, Dr. Traina adds 6 months of adjuvant capecitabine alongside the remaining pembrolizumab cycles. Notably, for patients with germline BRCA mutations, 1 year of the PARP inhibitor olaparib is given instead of capecitabine, based on the overall survival data from the OlympiA trial. These regimens are usually initiated after a patient completes adjuvant RT, said Dr. Traina. 

Treatment Algorithm for Advanced or Metastatic TNBC

In advanced or metastatic TNBC, traditional first-line treatment options differ based on PD-L1 status. For PD-L1–positive disease, pembrolizumab in combination with chemotherapy is approved. For PD-L1–negative patients, approved options include chemotherapy alone or PARP inhibitors like olaparib or talazoparib in those with germline BRCA mutations. Following these regimens, two ADCs are approved for later lines of therapy: trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG). T-DXd is restricted to patients with HER2-positive tumors as determined by immunohistochemistry.

Several trials have also investigated T-DXd, SG, and datopotamab deruxtecan (Dato-DXd), another ADC, in the frontline setting. The ASCENT-03 and TROPION-Breast02 trials showed SG and Dato-DXd improved outcomes compared with traditional chemotherapy options in PD-L1–negative patients. Separately, the ASCENT-04 trial showed SG plus pembrolizumab improved outcomes for PD-L1–positive patients, and the combination was recently added as a preferred treatment option to the NCCN guidelines. 

These ADCs are promising alternative first-line treatment options, particularly in patients that experienced recurrence during or shortly after completing neoadjuvant or adjuvant treatment with a checkpoint inhibitor like pembrolizumab. Although, Dr. Traina said she may attempt to rechallenge with pembrolizumab in patients with metastatic disease who have a disease-free interval longer than 1 year. PD-L1 status affects first-line metastatic treatment options.

The optimal sequencing of treatments in later lines of TNBC therapy is unclear, particularly as more ADCs become available. Retrospective analyses have generally shown that switching to a second ADC yields poorer outcomes after a patient progressed on a first. However, some data suggest that “sandwiching” a traditional chemotherapy option in between ADCs may help the second ADC. Ongoing studies are looking to answer these sequencing questions, and the data are eagerly awaited, said Dr. Traina. 

While ADCs are expanding in use throughout the advanced or metastatic TNBC treatment algorithm, they are associated with unique side effect profiles. When using these agents, medical oncologists need to be familiar with managing toxicities to keep patients on therapy as long as possible.