Editor’s Note Triple-negative breast cancer (TNBC) has always been a challenge in clinical treatment due to its high heterogeneity, high risk of recurrence, and poor prognosis. For patients with first-line (1L) advanced TNBC who are not eligible for immune checkpoint inhibitors (PD-1/L1 inhibitors), the benefits of traditional single-agent chemotherapy are limited. The emergence of antibody-drug conjugates (ADCs) has brought new hope to this population. As the world's first approved ADC targeting Trop-2, Sacituzumab Govitecan (SG) has already demonstrated significant advantages in advanced TNBC patients who failed multiple prior lines of therapy (ASCENT study). At a recent academic conference, Professor Carlos H. Barrios from the PUCRS School of Medicine in Porto Alegre, Brazil, presented the latest biomarker subgroup analysis from the ASCENT-03 study. This analysis deeply explored the differences in efficacy between SG and chemotherapy in the first-line setting across different Trop-2 expression levels, BRCA mutation statuses, and HER2 expression statuses. This article summarizes its core academic content to provide clinical physicians with a basis for decision-making in precision therapy.

I. Research Background: Gaps and Challenges in 1L Advanced TNBC Treatment

Triple-negative breast cancer (TNBC) accounts for approximately 15%–20% of all breast cancer types. Due to the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), treatment options are relatively limited. In recent years, immunotherapy (such as the KEYNOTE-355 study) has established the first-line standard of care for PD-L1 positive patients; however, a significant proportion of patients (PD-L1 negative or those with contraindications to immunotherapy) still cannot benefit from immune checkpoint inhibitors. For these patients, traditional platinum-based chemotherapy or single-agent chemotherapy with taxanes or anthracyclines remains the current clinical routine, but the median progression-free survival (mPFS) is often only 5–6 months. Sacituzumab Govitecan (SG) is composed of a monoclonal antibody targeting Trop-2 coupled with the cytotoxic drug SN-38 via a cleavable linker, featuring a high drug-to-antibody ratio (DAR=7.6) and a unique “bystander effect.” Based on the outstanding performance of the ASCENT study, SG has become the standard of care for second-line (2L) and later-line treatment of advanced TNBC. The ASCENT-03 study further moves SG into the first-line (1L) setting, aiming to evaluate the efficacy and safety of SG in advanced TNBC patients who have not received prior systemic therapy and are ineligible for PD-1/L1 inhibitor treatment.

II. ASCENT-03 Biomarker Analysis: Study Design and Enrollment Overview

The analysis reported this time belongs to a pre-specified retrospective exploratory analysis of the ASCENT-03 trial. The study aims to verify whether the efficacy of SG is affected by specific molecular characteristics through biomarker stratification.

  1. Study Subjects: Enrolled patients were all previously untreated locally advanced or metastatic TNBC, and were assessed by physicians as ineligible for first-line PD-1 or PD-L1 inhibitor therapy.
  2. Key Biomarker Definitions and Testing: • Trop-2 Expression: Detected using immunohistochemistry (IHC), with H-score calculation (range 0-300). The population was divided into four quartile subgroups (Q1-Q4) based on the H-score. • BRCA Mutation Status: Tumor BRCA1/2 mutation status (wild-type vs. mutant) was determined through whole-exome sequencing (WES). • HER2 Expression Status: Based on IHC and in situ hybridization (ISH) techniques, classified as HER2-0 and HER2-low (IHC 1+ or IHC 2+/ISH-) according to ASCO/CAP guidelines.
  3. Analysis Population: As of the April 2025 data cutoff, approximately 89% of the intention-to-treat (ITT) population was included in the biomarker analysis set. The median follow-up time was 13.2 months.

III. Correlation Analysis of Trop-2 Expression Levels and Efficacy

Trop-2 is expressed in over 90% of TNBC cases, but whether there is a therapeutic threshold for expression density has always been a focus of clinical concern. In the subgroup analysis of ASCENT-03, researchers conducted comparative observations based on Trop-2 H-score quartiles. Data Performance: Results showed that regardless of which quartile the Trop-2 expression level fell into (from the lowest Q1 to the highest Q4), the PFS of the SG group was superior to that of the chemotherapy group. In the entire biomarker analysis population, the PFS hazard ratio (HR) for SG versus chemotherapy reached 0.62. Deep Interpretation: Professor Carlos H. Barrios emphasized that although theoretically the benefit of ADC might increase with target expression, Kaplan-Meier curves showed that in all four Trop-2 expression subgroups, the curves for the SG group and the chemotherapy group achieved early and sustained separation. This means that in clinical practice, Trop-2 testing may not be a necessary prerequisite for screening the applicable population for SG, as the drug demonstrated broad therapeutic universality.

IV. Impact of Tumor BRCA Mutation Status on First-Line Efficacy

BRCA1/2 mutations account for approximately 10%–20% of TNBC patients; these patients usually have higher genomic instability. In this analysis, approximately 18% of patients carried tumor BRCA mutations. Data Performance: • BRCA Wild-Type (WT) Population: The SG group showed significant PFS benefit over the chemotherapy group. • BRCA Mutant (Mut) Population: Clinical benefit from SG was also observed. Although interpretation requires caution due to the relatively small sample size, the data showed that the PFS benefit for mutant patients receiving SG was numerically even slightly higher than that of the wild-type population. Clinical Significance: BRCA-mutant patients are relatively sensitive to DNA damage response (DDR) related treatments. As a topoisomerase I inhibitor, SG’s payload SN-38 can induce DNA double-strand breaks. This study confirms that regardless of whether patients carry a BRCA mutation, SG can provide superior control compared to standard first-line chemotherapy, offering a new first-line treatment option for TNBC patients with genetic risks.

V. HER2-0 vs. HER2-low: Benefits Crossing Subtype Boundaries

With the rise of the “HER2-low” concept in the field of breast cancer, distinguishing between low expression and complete non-expression is crucial for the selection of treatment regimens. Data Performance: In the ASCENT-03 subgroups, researchers analyzed the HER2-0 and HER2-low populations. The data consistently showed: • In the HER2-0 subgroup, SG significantly prolonged PFS compared to chemotherapy. • In the HER2-low subgroup, SG also showed a consistent benefit trend. • For the more refined “HER2-ultra-low” population, although the sample size was limited, the preliminary observed trend remained highly consistent with the above results. Expert View: Professor Barrios pointed out that as an ADC that does not target HER2, the consistent “cross-subtype” benefit SG showed in HER2-low and HER2-0 populations further consolidates its position in 1L TNBC treatment. This also suggests that for patients with low HER2 expression who may not be suitable for HER2-ADC therapy or who progress after HER2-ADC treatment, SG can still provide a strong fallback by targeting Trop-2.

VI. Summary and Outlook

The biomarker analysis of the ASCENT-03 study provides solid evidence-based support for the application of Sacituzumab Govitecan (SG) in first-line advanced TNBC. The core conclusions are as follows:

  1. Universality: The benefit of SG in 1L advanced TNBC (PD-1/L1i ineligible population) does not depend on high levels of Trop-2 expression.
  2. Broadness: Regardless of the patient’s BRCA mutation status or HER2 expression level (HER2-0/low), SG demonstrated efficacy superior to standard single-agent chemotherapy (PFS HR=0.62).
  3. Consistency: Subgroup analysis results are highly consistent with the primary endpoint of ASCENT-03 and align with the trends observed in second-line treatment (ASCENT study). Implications for Clinical Practice: Although overall survival (OS) data are not yet fully mature (further observation is needed as of the 13.2-month follow-up), the existing PFS benefit is sufficient to prove that SG is expected to reshape the first-line advanced TNBC treatment landscape for those ineligible for immunotherapy. This “non-biomarker-dependent” benefit characteristic greatly simplifies the clinical decision-making process, allowing more patients to benefit from potent ADC therapy as early as possible. Professor Barrios concluded: “These subgroup data from ASCENT-03 not only validate the efficacy of SG, but more importantly, provide us with confidence in obtaining certain therapeutic outcomes even against a complex and ever-changing molecular subtype background. In the future, we look forward to the release of more data regarding combination regimens and mature OS data to further establish SG’s core position in the full-line treatment of breast cancer.”
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