Experimental Antibody-Drug Conjugate Shrinks Brain Metastasis in Rare Salivary Gland Cancer

A single patient with one of the rarest and most aggressive salivary gland malignancies has provided oncologists with an unexpected glimpse of what may become a new therapeutic avenue for tumors that have spread to the brain. In a case report published in the open-access journal Cancer Reports, clinicians at Fudan University Shanghai Cancer Center describe a 62-year-old man with HER2-negative salivary duct carcinoma whose progressive, dural-based intracranial metastasis shrank by more than half during treatment with sacituzumab tirumotecan, an experimental antibody-drug conjugate targeting the cell-surface protein TROP2. The response was achieved without corticosteroids, surgery, or any form of radiation directed at the brain, and disease control was maintained for approximately nine months of follow-up, a duration that stands out in a disease setting where effective systemic options for intracranial disease are essentially undefined.

Salivary duct carcinoma, often abbreviated SDC, is a rare but formidable malignancy that bears a striking morphologic and biologic resemblance to high-grade invasive ductal carcinoma of the breast. It carries a high risk of both local recurrence at the original site and distant metastasis, and it tends to behave aggressively even when caught early. Many of these tumors express the androgen receptor, which has allowed clinicians to borrow androgen deprivation therapy from prostate cancer management, while a subset shows amplification or overexpression of HER2, opening the door to HER2-directed drugs borrowed from breast cancer care. For patients whose tumors are HER2-negative and who have already progressed through androgen-directed treatment and chemotherapy, however, the therapeutic landscape becomes remarkably barren, and the arrival of central nervous system involvement makes an already difficult situation considerably worse.

CNS metastases are far from a marginal concern in this disease. In the largest multicenter retrospective study conducted to date, brain metastases were identified in 65 of 464 patients with salivary duct carcinoma, a prevalence of roughly 14 percent. Once the disease reaches the intracranial compartment, management rests heavily on local interventions such as surgery and radiotherapy, because the systemic evidence base consists almost entirely of retrospective series and isolated case reports. For a patient with actively progressing intracranial lesions and a HER2-negative tumor, clinicians have historically had no validated systemic therapy to offer, which is precisely the situation the Shanghai team confronted.

The patient’s clinical course illustrates how quickly this disease can outpace conventional treatment. In January 2022, he presented with a painless mass in front of his left ear and facial palsy on the same side. Imaging revealed a hypermetabolic parotid lesion with ipsilateral cervical lymph node involvement but no distant spread, and he underwent total parotidectomy with neck dissection. Pathology showed a poorly differentiated carcinoma measuring 1.7 centimeters with perineural invasion and metastases in three of nineteen lymph nodes, staging him at IVA. Immunohistochemistry demonstrated strong androgen receptor expression, a Ki-67 proliferation index near 50 percent, and complete absence of HER2. Targeted sequencing revealed a pathogenic truncating TP53 variant, and no ETV6 rearrangement was detected. He completed adjuvant radiotherapy within a few months of surgery.

Nineteen months after presentation, routine surveillance imaging incidentally revealed intracranial abnormalities, and dedicated contrast-enhanced brain MRI confirmed enhancing dural-based lesions consistent with metastatic recurrence. The patient declined a biopsy of these lesions. Androgen deprivation therapy with leuprolide and the next-generation androgen receptor antagonist rezvilutamide began at month 20 and produced only transient stabilization. By month 36, brain MRI showed progression of plaque-like dural thickening and mass-forming lesions in the left temporal and occipital regions with worsening vasogenic edema, accompanied by persistent pressure-like pain. An empiric salvage regimen combining the MAID chemotherapy protocol with the immunotherapy agent camrelizumab failed to halt the disease, as did a subsequent switch to cisplatin plus nab-paclitaxel. At this point the intracranial disease had proven refractory to hormonal therapy and two chemotherapy-containing regimens.

The turning point came from an exploratory biomarker test. Immunohistochemical analysis of the archived primary tumor revealed strong membranous expression of TROP2, or trophoblast cell surface antigen 2, with an H-score of 230 on the standard 0 to 300 scale. TROP2 is a cell-surface glycoprotein that has emerged as one of the most productive drug targets in oncology, serving as the payload anchor for approved and investigational antibody-drug conjugates across breast, bladder, and lung cancers. Prior studies had shown that TROP2 is expressed in a subset of salivary gland carcinomas including SDC, but no established treatment had been built on that observation for a patient in this position. After a candid discussion of the limited evidence, the risks, and the alternatives, the team initiated sacituzumab tirumotecan off-label at 350 milligrams every two weeks.

Sacituzumab tirumotecan belongs to a class of therapeutics often described as biological guided missiles. The drug couples a monoclonal antibody that recognizes TROP2 to a cytotoxic payload through a cleavable linker, so that the chemotherapy is released preferentially inside tumor cells bearing the target protein. This design concentrates cell-killing activity where the target is expressed while sparing normal tissue, a principle that has transformed outcomes in several refractory epithelial cancers. Before treatment began, the patient’s dominant intracranial lesion, a dural-based mass centered in the left temporal region and straddling the tentorial leaflet, measured 33.6 millimeters at its longest diameter. Critically, no steroids, stereotactic radiosurgery, whole-brain radiotherapy, or other local CNS-directed therapy was administered during the response assessment window, removing any ambiguity about what was driving the tumor’s regression.

The serial imaging results were unambiguous. Follow-up MRI at month 52 showed the target lesion reduced to 15.3 millimeters, a 54.5 percent decrease from the pretreatment baseline, with no new intracranial lesions and no unequivocal progression of non-target disease. Peritumoral edema diminished, neurologic symptoms improved, and the patient remained on treatment at last follow-up. Toxicity was manageable: grade 2 oral mucositis and leukopenia both resolved with supportive care, and neither required dose reduction or discontinuation. The authors note that adjuvant radiotherapy had been completed 39 months earlier, making a delayed radiation effect an implausible explanation, and that the response unfolded without concurrent corticosteroids, which can themselves shrink edema-associated lesions and confound radiographic interpretation.

The report’s authors are careful to frame the result as hypothesis-generating rather than practice-changing. A single case cannot establish efficacy, and because the responding intracranial lesion was never biopsied, the TROP2 status of the metastasis itself remains unknown. A small paired analysis across solid tumors found concordance in TROP2 expression between primary tumors and brain metastases in only about 79 percent of cases, and comparable cross-site data do not exist for salivary duct carcinoma, so TROP2 expression in the primary tumor cannot yet be treated as a validated predictive biomarker. The dural-based, extra-axial location of the responding lesion also complicates generalization, since drug exposure may differ substantially between dural, parenchymal, and leptomeningeal compartments of the central nervous system.

Nevertheless, the case lands in a rapidly evolving field. Early data from a 2025 master-protocol trial of the TROP2-directed antibody-drug conjugate ESG401 in salivary gland cancer reported that all three enrolled patients with brain metastases achieved intracranial partial or complete responses, though histology-specific outcomes and durability were not characterized. Sacituzumab tirumotecan is also being evaluated prospectively in triple-negative breast cancer with active brain metastases, including leptomeningeal disease. For a malignancy in which roughly one in seven patients develops brain metastases and HER2-negative disease has no established systemic option for intracranial involvement, the convergence of a druggable target, a clinically active drug class, and a documented durable response offers a concrete direction for future trials. The authors argue that such studies should incorporate standardized TROP2 assessment, paired sampling of primary tumors and metastases, and predefined CNS response criteria, and should determine whether TROP2 expression genuinely modifies treatment benefit rather than merely confirming that the target is present.

Subject of Research: TROP2-targeted antibody-drug conjugate therapy for intracranial metastases in HER2-negative salivary duct carcinoma

Article Title: Durable Intracranial Response to Sacituzumab Tirumotecan in HER2‐Negative Salivary Duct Carcinoma With High TROP2 Expression: A Case Report

Article References: Chen, G.-L., Tan, B., Cao, S., Liu, X., Guo, Y., & Ji, D. (2026). Durable Intracranial Response to Sacituzumab Tirumotecan in HER2 ‐Negative Salivary Duct Carcinoma With High TROP2 Expression: A Case Report. Cancer Reports, 9(9), Article e70676. https://doi.org/10.1002/cnr2.70676

Image Credits: AI Generated

DOI: 10.1002/cnr2.70676

Keywords: salivary duct carcinoma, sacituzumab tirumotecan, TROP2, antibody-drug conjugate, brain metastases, HER2-negative, androgen deprivation therapy, intracranial response, salivary gland cancer, precision oncology, case report, drug target