Editor’s Note: Triple-negative breast cancer (TNBC) is a heterogeneous disease that historically had limited treatment options. Driven by rapid advances in antibody–drug conjugate (ADC) technology, the therapeutic landscape has seen major breakthroughs that offer patients new hope. The Shanghai International Breast Cancer Symposium (SIBCS) opened on November 14, 2025. On the first day, Professor Sibylle Loibl, Chair of the German Breast Group (GBG) and a professor at Goethe University Frankfurt, delivered a plenary lecture entitled “Precision Treatment of Triple-Negative Breast Cancer in the ADC Era.” Her talk reviewed the definition and clinical challenges of TNBC, analyzed the latest developments in the ADC field, interpreted the pivotal advances and application strategies of Trop-2-targeting ADCs such as sacituzumab govitecan (SG), and looked ahead to ADCs directed at HER2, HER3, LIV-1, Nectin-4, CEACAM5 and other targets. The key points are summarized below for readers.
Content summary
- Disease nature: TNBC is a highly heterogeneous breast cancer subtype.
- Biomarkers: gBRCA status, PD-L1 and HER2 can be referenced; routine Trop-2 expression testing is currently unnecessary for patient selection.
- ADC drugs: SG, datopotamab deruxtecan (Dato-Dx d), and trastuzumab deruxtecan (T-DXd) are used in metastatic TNBC (mTNBC); ADCs have demonstrated meaningful improvements in clinical outcomes.
- Future directions: Next-generation antibody formats and novel payloads are in development and promise to expand therapeutic options.
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Definition of TNBC and clinical challenges
According to ESMO and ASCO/CAP guidelines, TNBC is defined as breast cancer with estrogen receptor (ER) and progesterone receptor (PR) expression below 1% and negative HER2 status. Recently, HER2 classification has evolved beyond a binary positive/negative scheme to a more granular spectrum—zero, ultra-low, low, and high (positive). HER2 low expression is closely associated with ER status; roughly 40% of TNBC cases fall into HER2 low, while among tumors with >95% ER expression the proportion rises to about 62%.
TNBC is highly heterogeneous across histologic features, gene expression profiles, epigenetic regulation, and metabolic patterns. This multidimensional heterogeneity drives diverse biological behaviors and complicates therapeutic decision making. Multiple TNBC molecular subtyping schemes are under investigation, and research is actively identifying and validating biomarkers. In immunotherapy, PD-L1 expression, tumor mutational burden (TMB), and immune cell infiltration correlate with checkpoint inhibitor responses. Circulating tumor DNA (ctDNA) shows potential as an early prognostic marker in TNBC. Nonetheless, heterogeneity and a complex biomarker network create clinical challenges. Conventional chemotherapy remains the backbone of treatment but delivers limited durable benefit and high relapse risk, underscoring the urgent need for innovative strategies. ADCs have emerged as a promising modality to improve TNBC outcomes.
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Trop-2 ADCs keep breaking ground and are reshaping TNBC treatment
ADCs combine an antibody, a linker, and a cytotoxic payload to achieve targeted delivery and potent cell killing, and they have become an important therapeutic innovation in breast cancer. Regulatory authorities such as the EMA and FDA have approved multiple ADCs for breast cancer, including HER2-directed agents (e.g., T-DM1, T-DXd) and Trop-2-targeting agents such as sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-Dx d). Trop-2 ADCs were among the first to show broad clinical benefit in TNBC, and they are actively reshaping the field by offering new options for patients.
Trop-2 is a cell-surface glycoprotein widely expressed in TNBC that contributes to tumor proliferation and metastasis, making it an attractive ADC target. Trop-2 ADCs are being deployed across the disease continuum, from advanced to earlier stages.
In the second-line setting, the ASCENT trial was the first global phase III study to validate Trop-2 as a therapeutic target in mTNBC. ASCENT established SG’s role in advanced TNBC and formed the clinical basis for Trop-2 ADC adoption. Compared with physician’s choice chemotherapy (TPC), SG significantly improved median progression-free survival (mPFS: 4.8 vs. 1.7 months; HR = 0.43, 95% CI 0.35–0.54, P < 0.0001) and median overall survival (mOS: 11.8 vs. 6.9 months; HR = 0.51, 95% CI 0.41–0.62, P < 0.0001). Importantly, benefit was observed across subgroups with differing Trop-2 expression, reinforcing SG’s standard position in second-line mTNBC.
At the 2025 ASCO and ESMO meetings, ASCENT-04 and ASCENT-03 results further advanced SG into first-line scenarios. ASCENT-04 showed that in PD-L1-positive (CPS ≥ 10) TNBC patients, SG combined with pembrolizumab improved mPFS versus chemotherapy plus pembrolizumab (11.2 vs. 7.8 months; HR = 0.65, 95% CI 0.51–0.84, P < 0.001). ASCENT-03 complemented these data by demonstrating that for PD-L1-negative (CPS < 10) patients or those unsuitable for immunotherapy, single-agent SG also produced significant mPFS gains over chemotherapy (9.7 vs. 6.9 months; HR = 0.62, 95% CI 0.50–0.77, P < 0.001). Together, these trials validate SG across different immune-status cohorts and support Trop-2 ADCs as potential first-line options.
Dato-Dx d was evaluated in TROPION-Breast02 and also demonstrated statistically significant first-line benefit. In that study, median PFS for Dato-Dx d was 10.8 months versus 5.6 months for investigator-choice chemotherapy (HR = 0.57, 95% CI 0.47–0.69, P < 0.0001).
In clinical practice, selecting SG or Dato-Dx d for PD-L1-negative or immunotherapy–ineligible mTNBC patients requires weighing efficacy and safety. Both agents show clear PFS improvement relative to chemotherapy, but adverse event profiles differ: SG is associated with neutropenia—prophylactic G-CSF may be warranted in high-risk patients—whereas Dato-Dx d requires vigilance for ocular toxicity, mucositis, and interstitial lung disease (ILD). Treatment decisions should be individualized based on patient characteristics.
Concurrently, SG is expanding into early-stage TNBC. The GBG-led SASCIA trial is evaluating SG as adjuvant escalation therapy versus chemotherapy in HER2-negative patients with residual invasive disease after neoadjuvant therapy. ASCENT-05 is testing SG plus pembrolizumab for non-pCR TNBC after neoadjuvant treatment. In summary, SG and other Trop-2 ADCs are accelerating toward full-spectrum TNBC development—from early to advanced disease—bringing new hope to patients across stages.
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From Trop-2 to many more targets: ADCs continue to broaden TNBC treatment options
Beyond Trop-2 ADCs, HER2-targeted ADCs and novel agents directed at HER3, LIV-1, Nectin-4, CEACAM5 and other antigens are under exploration and development. These programs promise an expanding therapeutic armamentarium for TNBC.
The evolution of TNBC care—from chemotherapy dominance to immune combinations, and now to ADC-driven strategies—reflects continuous advances in precision oncology and drug development technologies. Trop-2 ADCs have achieved breakthrough results in mTNBC and are moving into earlier settings, while ADCs against other targets are rising in parallel. Together, these developments map a new era in which TNBC increasingly enters the ADC age, offering diversified and more effective treatment possibilities.
