Triple-negative breast cancer (TNBC), a subtype accounting for approximately 10% to 20% of all breast cancers, remains one of the most challenging breast cancer forms to treat. Unlike other subtypes, TNBC lacks estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor-2 (HER2), which limits the use of targeted hormone or HER2 therapies. However, ongoing clinical trials and emerging therapies offer promising new directions that may transform the treatment landscape for early-stage TNBC.
Understanding TNBC: A Distinct Breast Cancer Subtype
According to Alexis LeVee, MD, a principal investigator in hematology and medical oncology at City of Hope, TNBC is more commonly diagnosed in younger patients, individuals with BRCA1 mutations, and African American women. Despite its relatively lower prevalence compared to other breast cancer subtypes, TNBC is aggressive and associated with unique treatment challenges.
“One of the main challenges is that TNBC lacks classical receptors that can be targeted with hormone therapies or HER2-directed therapies,” Dr. LeVee explains. “However, the immunogenic nature of TNBC tumors presents opportunities for new treatment approaches, especially immunotherapy.”
Immunotherapy and Novel Agents: Changing the Treatment Paradigm
TNBC tumors tend to exhibit higher expression of PD-L1, increased levels of tumor-infiltrating lymphocytes (TILs), and a higher tumor mutational burden, all of which make them more responsive to immunotherapy. Immunotherapy agents, such as pembrolizumab (Keytruda), have already received FDA approval for treating early and metastatic TNBC.
Dr. LeVee highlights several exciting ongoing clinical trials aimed at further improving outcomes in early-stage TNBC:
SCARLET Trial (Phase 3; NCT05929768): Evaluates a preoperative non-anthracycline chemotherapy regimen compared with the KEYNOTE-522 regimen, which incorporates pembrolizumab. This study may help reduce chemotherapy-related toxicity while maintaining efficacy.
TROPION-Breast04 Trial (Phase 3; NCT06112379): Compares neoadjuvant therapy using datopotamab deruxtecan-dlnk (Dato-DXd) plus durvalumab to the KEYNOTE-522 regimen. This trial explores the potential of antibody-drug conjugates (ADCs) combined with immunotherapy.
BELLINI Study (Phase 3; NCT03815890): Investigates a chemotherapy-free backbone approach using nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with high TIL levels, aiming to reduce chemotherapy toxicities.
These trials are part of a broader effort to tailor treatments that enhance efficacy while minimizing side effects.
Adjuvant Therapy and Managing Residual Disease
Beyond neoadjuvant settings, adjuvant trials are exploring whether immunotherapy can be discontinued in patients achieving a pathological complete response (pCR) and how to best treat those with residual disease after surgery.
OptimICE-pCR Trial (Phase 3; NCT05812807): Evaluates the discontinuation of adjuvant pembrolizumab in patients who achieve pCR following neoadjuvant therapy.
TroFuse-011 Trial (Phase 3; NCT06841354): Tests the combination of sacituzumab tirumotecan (SKB264/MK-2870) plus pembrolizumab in patients with residual disease.
Additionally, antibody-drug conjugates such as sacituzumab govitecan-hziy (Trodelvy) and datopotamab deruxtecan (Dato-DXd) are being studied alone or with immunotherapy to improve outcomes in this difficult-to-treat population.
Real-World Evidence on Pembrolizumab Adherence and Response
Dr. LeVee was lead author on a 2024 real-world study analyzing the impact of adherence to neoadjuvant pembrolizumab treatment on pCR rates in patients with early-stage TNBC. The study revealed that younger patients responded better to the chemoimmunotherapy combination and that completing at least eight cycles of pembrolizumab correlated with higher pCR rates.
“While the study suggests completing the full pembrolizumab regimen improves outcomes, it remains unclear whether the benefit is mainly from pembrolizumab or chemotherapy, as the regimens overlap,” Dr. LeVee notes. Ongoing research aims to clarify which patients derive the greatest benefit from chemoimmunotherapy and to optimize chemotherapy regimens accordingly.
Looking Ahead: Personalized and Less Toxic Therapies
The current research momentum signals a paradigm shift in managing early-stage TNBC. By exploiting the immunogenicity of TNBC and incorporating novel agents like antibody-drug conjugates, clinicians aim to provide more personalized, effective, and less toxic treatment options.
“These trials have the potential to change the treatment paradigm for TNBC, offering hope for better survival and quality of life,” Dr. LeVee concludes.
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