TNBC defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is recognized as the most aggressive molecular subtype of breast cancer (BC), accounting for 10–15% of all BC cases. Compared with hormone receptor (HR)-positive or HER2-positive tumors, TNBC is associated with significantly shorter disease-free survival (DFS) and overall survival (OS) (1). Population-based studies indicate that more than 50% of patients with localized TNBC who receive standard multimodal therapy experience disease recurrence within 5 years of initial diagnosis (2, 3). The liver is a common site of distant metastasis in BC, and hepatic involvement is associated with accelerated therapeutic resistance and increased mortality risk. Historical studies report a median survival of 3–15 months after the detection of liver-only or liver-dominant metastases, with a 5-year survival rate as low as 8.5% (3, 4).

Trophoblast cell-surface antigen 2 (Trop-2), a transmembrane epithelial glycoprotein overexpressed in 80–90% of TNBC, is associated with accelerated tumor growth, shortened survival and poor prognosis, thus serving as a validated therapeutic target (5–7). SG is an antibody–drug conjugate(ADC) consisting of a humanized anti-Trop-2 monoclonal antibody, a cleavable hydrolysable linker and SN-38, the active metabolite of irinotecan that inhibits topoisomerase I. In the randomized phase III ASCENT trial (NCT02574455), SG was compared with physician’s choice of standard chemotherapy (TPC) in patients with metastatic TNBC who had progressed after ≥ two prior systemic regimens SG significantly prolonged both PFS and OS. The median PFS was 5.6 months versus 1.7 months with TPC (hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.32–0.52; p < 0.001), and the median OS was 12.1 months versus 6.7 months (HR 0.48; 95% CI 0.38–0.59; p < 0.001). These data have established SG as the standard second-line treatment for metastatic TNBC (8).

When metastatic tumor burden leads to rapid deterioration of organ function, the condition is termed “ VC “, which occurs in approximately 10%–15% of patients diagnosed with advanced breast cancer (9). HVC in breast cancer specifically refers to a critical clinical state characterized by rapid multi-organ dysfunction induced by tumor burden; its definition remains imprecise and largely depends on individual clinical judgment.Liver-specific VC is defined as a rapid elevation of bilirubin to >1.5 times the upper limit of normal, with the exclusion of Gilbert’s syndrome or biliary tract obstruction (9). This condition is associated with an extremely poor prognosis, with a mortality rate of 90% even after standard treatment (10). Notably, VC is a common exclusion criterion in clinical trials, leaving the optimal treatment strategy in a gray area. Furthermore, the administration of anticancer therapy presents particular challenges in patients with extensive liver metastases. Currently, data on systemic treatment for TNBC complicated by VC remain limited.

In this report, we present the clinical course and outcomes of a patient with metastatic, early-recurrent TNBC and HVC who achieved a remarkable response to SG as third-line treatment.

SG is a novel ADC consisting of a humanized anti-Trop-2 antibody (RS7) conjugated to SN38 (11, 12). SN38 selectively binds to topoisomerase I and abrogates the religation of topoisomerase I-mediated single-strand DNA breaks, ultimately culminating in DNA damage, subsequent apoptosis, and eventual cell death. Beyond the direct cytotoxic effects exerted by SN38, SG further elicits antibody-dependent cellular cytotoxicity (ADCC) (13).

The phase III ASCENT trial led to the approval of SG (10 mg/kg, d1, 8 q3w) in patients with advanced or metastatic TNBC who have received ≥2 prior systemic therapies (14). In the subgroup analysis of this trial, patients with liver metastases constituted 43% of the total study population (42% in the SG group vs. 44% in the treatment of physician’s choice [TPC] group). The final results demonstrated that, in patients with liver metastases, SG achieved a statistically significant improvement in both PFS (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.31–0.57) and OS (HR, 0.53; 95% CI, 0.40 to 0.70) compared with TPC. The magnitude of clinical benefit was analogous to that observed in the overall study population, indicating that the presence of liver metastases did not significantly alter the therapeutic effect of SG (15). However, it is noteworthy that this trial excluded patients with severe visceral involvement or HVC. The efficacy of SG observed in this patient with HVC is consistent with and extends the findings of the phase III ASCENT trial. Specifically, our case addresses a critical gap in the literature by providing real-world evidence of SG’s antitumor activity in TNBC patients with HVC. This patient experienced a significant reduction in intrahepatic metastatic lesions after only two cycles of SG combined with pembrolizumab, with sustained lesion shrinkage noted during subsequent SG monotherapy. Ultimately, HVC was reversed, and the PFS was prolonged to 16.3 months; throughout the entire treatment period, the patient maintained a favorable quality of life.

Regrettably, owing to the high cost of the drugs, the patient opted to extend the medication interval and reduce the administration frequency, which ultimately resulted in disease progression. This observation aligns with preclinical and clinical evidence highlighting that optimal dosing of ADCs is critical for sustaining therapeutic efficacy; deviations from the recommended regimen may compromise drug exposure and thereby diminish antitumor activity.

Notably, financial barriers to cancer treatment represent a prominent global challenge. A cost-effectiveness analysis conducted from the perspective of a third-party US payer revealed that SG was not a cost-effective treatment option relative to single-agent chemotherapy in patients with pretreated, unresectable or metastatic HR+/HER2− breast cancer. Specifically, SG treatment increased the quality-adjusted life years (QALYs) by 0.217 years compared with chemotherapy, yielding an incremental cost-effectiveness ratio of US$612, 772 per QALY—exceeding the widely accepted willingness-to-pay (WTP) threshold of US$150, 000 per QALY (16). Additionally, a study conducted in China indicated that the price of SG was substantially higher than that of chemotherapy, which emerged as a key determinant of cost-effectiveness. Therefore, targeted measures—including substantial price reductions, robust patient assistance programs, and optimized dosing strategies—are warranted to render SG a cost-effective therapeutic option for TNBC treatment (17, 18).

Building on the aforementioned context and the charitable drug donation program for pembrolizumab, the patient in this case initially received two cycles of pembrolizumab in combination with SG, which yielded robust therapeutic efficacy. Unfortunately, prolonged administration of pembrolizumab induced immune-related cystitis, prompting the discontinuation of this agent, the patient continued to exhibit favorable therapeutic responses during subsequent SG monotherapy. However, several challenges remain in the use of SG. As reported in a study by Kumari et al. (19), the efficacy of SG may be different in patients treated with different types of drugs owing to their different mechanisms of action. The genetic profiling of patients specifically for cell cycle or DNA repair genes will also be helpful in evaluating the effect of SG in TNBC patients.

Mechanistically, pembrolizumab competitively binds to programmed cell death protein 1 (PD-1), blocks the PD-1/programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) signaling pathway, alleviates tumor-mediated T-cell suppression, restores and enhances the antitumor functionalities of CD8⁺ cytotoxic T lymphocytes and CD4⁺ helper T cells, and concurrently facilitates the generation of memory T cells—ultimately culminating in a sustained antitumor immune response (20).

The effectiveness and safety of pembrolizumab in combined with SG remain under active investigation. As a global, multicenter, randomized Phase III trial, the AsK-04/KEYKEYNOTE -D19 study enrolled 443 patients with PD-L1 positive (CPS≥10) locally advanced or metastatic TNBC to compare the efficacy of SG plus pembrolizumab versus standard chemotherapy plus pembrolizumab. Preliminary findings demonstrated that the median progression-free survival (mPFS) in the SG plus pembrolizumab group reached 11.2 months, which was significantly superior to the 7.8 months observed in the chemotherapy plus pembrolizumab group (HR = 0.65, P<0.001), representing a 35% reduction in the risk of disease progression or death. The objective response rate (ORR) was 59% vs 53%, and the median duration of response was prolonged to 16.8 months (8.6 months in the chemotherapy combination group). While OS data remain immature, a trend toward clinical benefit has been observed, and the safety profile was consistent with the known characteristics of each monotherapy. Notably, this study is the first to confirm that SG combined with immune checkpoint inhibitors (ICIs) is superior to chemotherapy combined with ICIs, and is anticipated to become a new standard of care for first-line treatment of PD-L1-positive mTNBC (21). Results from another phase II trial (LBA1004) in patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer showed that the combination of SG plus pembrolizumab did not yield a statistically significant difference in PFS compared with gemcitabine plus capecitabine (22). Therefore, the efficacy and safety of pembrolizumab combination with SG still require further in-depth research and exploration.

Patients with HVC represent an urgent and unmet clinical need, as they are frequently excluded from clinical trials, —primarily due to their rapid disease progression and poor prognosis. To the best of our knowledge, this is the first case report documenting the efficacy of SG in HVC. A significant and sustained clinical response was observed after the first cycle of treatment, with a remarkable PFS of 16.3 months, during this period, the patient achieved complete clinical recovery and maintained an active quality of life. This case underscores the critical need for further dedicated research focusing on the management of HVC.