The evolution of breast cancer diagnosis and treatment is an epic journey spanning past and present, marked by transformative breakthroughs that have profoundly reshaped patient outcomes. From January 9 to 11, 2026, the Northern China Breast Cancer Salon · Annual Progress Review was held in Beijing. One of the most highly anticipated sessions was the Annual Review of Advances in Breast Cancer Therapy, which brought together leading experts to examine and synthesize the most significant international and domestic developments of 2025. Topics ranged from surgery, pathology, and radiotherapy to molecular classification and precision treatment, highlighting studies that have reshaped clinical practice.To document the academic milestones of the past year, Oncology Frontier launched the “Breast Cancer Chronicle · Year 2025” series. During the Northern China Breast Cancer Salon · Annual Progress Review, we invited participating experts to jointly review the year’s landmark events in breast cancer research, drawing lessons from history while recording progress for the future. In this installment, we invited Professor Jin Yang of the First Affiliated Hospital of Xi’an Jiaotong University to review recent advances in the treatment of advanced triple-negative breast cancer (TNBC).
Advances in the Treatment of Advanced Triple-Negative Breast Cancer
Among all breast cancer subtypes, advanced triple-negative breast cancer is associated with the poorest prognosis and is often referred to as the “most aggressive” form of breast cancer. In recent years, with increasingly refined molecular characterization and subtype classification of TNBC, immunotherapy and targeted therapy have gradually entered routine clinical practice, giving rise to a new treatment paradigm that integrates chemotherapy, targeted therapy, and immunotherapy.
Particularly noteworthy is the emergence of novel membrane antigen–targeting therapies, represented by TROP2-directed antibody–drug conjugates (ADCs). In later-line treatment settings for advanced TNBC, these agents have demonstrated consistent benefits in objective response rate, median progression-free survival (PFS), and overall survival (OS), establishing a new therapeutic benchmark.
Looking back at 2025, the most impactful advances in the treatment of advanced TNBC unquestionably stemmed from TROP2-targeted ADCs. Across both PD-L1–positive and PD-L1–negative TNBC populations, results from three large randomized controlled trials—ASCENT-04, ASCENT-03, and TROPION-Breast02—demonstrated that TROP2 ADCs combined with immunotherapy can deliver meaningful clinical benefit. These findings collectively define a new treatment landscape for TROP2-targeted ADCs in advanced TNBC.
ASCENT-04: Redefining First-Line Therapy in PD-L1–Positive TNBC
At the 2025 ASCO Annual Meeting, results from the ASCENT-04 trial were presented. This study showed that in previously untreated, PD-L1–positive, locally advanced unresectable or metastatic TNBC, sacituzumab govitecan (SG) plus pembrolizumab significantly improved median PFS compared with chemotherapy plus pembrolizumab (11.2 months vs 7.8 months). This corresponded to a 35% reduction in the risk of disease progression or death (HR 0.65, 95% CI 0.51–0.84; P < 0.001).
Importantly, the control arm of ASCENT-04—chemotherapy plus pembrolizumab—was essentially identical to the experimental arm of the KEYNOTE-355 trial. The patient populations in both studies were highly comparable in terms of age, disease-free interval, and other baseline characteristics. Against this benchmark, achieving a hazard ratio of 0.65 with SG plus pembrolizumab represents a particularly compelling and clinically meaningful improvement.
Breakthroughs in PD-L1–Negative TNBC: The “Twin Stars” of TROP2 ADCs
Even greater attention has been directed toward PD-L1–negative TNBC, which accounts for a larger proportion of advanced TNBC cases and is characterized by short therapeutic windows and rapid disease progression. In many of these patients, median PFS is less than six months, making this subgroup one of the most challenging areas in clinical practice.
At the 2025 ESMO Congress, results from two pivotal phase III randomized trials—ASCENT-03 and TROPION-Breast02 (TB-02)—were announced. These studies evaluated two major TROP2-targeted ADCs, sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd), respectively, often referred to as the “twin stars” of TROP2 ADC therapy.
Both trials enrolled PD-L1–negative TNBC patients and compared SG or Dato-DXd with physician’s choice of chemotherapy. However, there were important design differences. ASCENT-03 used PFS as the primary endpoint and mandated crossover to SG in the control arm upon progression, reflecting ethical considerations given SG’s established OS benefit in the second-line setting. In contrast, TB-02 adopted dual primary endpoints of PFS and OS and did not allow crossover.
Despite these differences, both trials met their primary endpoints, yielding positive results.
Comparative Insights and Clinical Implications
When the results of these two “twin star” studies are examined side by side, both demonstrated remarkably consistent PFS benefits, with hazard ratios of approximately 0.6 (ASCENT-03: HR 0.62; TB-02: HR 0.57).
In the first-line TNBC setting, differences in OS outcomes were largely driven by study design. In ASCENT-03, mandatory crossover has thus far precluded a statistically significant OS difference. In contrast, TB-02 did not permit crossover, and all control-arm patients received single-agent chemotherapy. In this study, Dato-DXd monotherapy achieved a median OS of 23.7 months, a result comparable to outcomes historically observed in PD-L1–positive patients treated with chemotherapy plus immunotherapy in the pre-ADC era—representing a major therapeutic advance.
Looking ahead, these two trials have the potential to reshape first-line treatment paradigms for PD-L1–negative advanced TNBC. Final analyses suggest that first-line therapy with TROP2 ADCs not only improves PFS1, but also confers benefits in PFS2, a finding particularly pronounced in ASCENT-03.
From a safety perspective, although both ADCs were administered over relatively long durations, no significant increase in grade ≥3 treatment-related toxicities was observed. Taken together, these studies represent clinically pivotal trials that combine substantial efficacy with favorable safety profiles, paving the way for a new era of precision therapy in advanced TNBC.
Professor Jin Yang First Affiliated Hospital of Xi’an Jiaotong University
