Targeted ADCs Break Through Barriers in HER2-Positive Breast Cancer

Breast cancer is the most common cancer in women, accounting for about 30% of all new cancer diagnoses. In middle and late-stage disease, some patients develop distant metastases—most frequently in the brain. HER2-positive (HER2+) breast cancer has the highest incidence of brain metastases (BMs), affecting 30% to 50% of patients.^1,2

Survival outcomes for these patients remain poor, with median survival under 6 months and only 20% to 40% living beyond 1 year. Treatment options for HER2+ metastatic breast cancer with brain involvement are limited, underscoring the urgent need for therapies that can overcome the anatomical and physiological barriers of the brain.³

At the 2025 San Antonio Breast Cancer Symposium, a panel of experts discussed the growing role of antibody drug conjugates (ADCs) in the treatment of HER2-positive (HER2+) early and metastatic breast cancer. Andrew J. Brenner, MD, PhD, from the University of Texas Health Science Center at San Antonio, shared the promising role of ADCs in treating brain metastases, emphasizing their central nervous system (CNS)-penetrant capabilities.

ADCs Show Brain-Penetrant Capabilities in HER2+ Breast Cancer

Brain tumors are difficult to treat largely because of the blood–brain barrier (BBB). The BBB is formed by endothelial cells connected by high-integrity junctions, which limit drug penetration into healthy brain tissue. These cells are reinforced by astrocytic foot processes, and even when small amounts of drug passively cross, efflux pumps like P-gp actively transport them back into the vasculature.⁴

“The brain tumor barrier is partially disrupted—astrocytic foot processes pull back, and the endothelial cells become more permeable,” explained Brenner. “As a result, larger biomolecules are thought to cross more easily through the affected tumor regions.”⁴

Emerging research shows that ADCs—large-molecule therapeutics—are demonstrating favorable intracranial responses and durable disease control in brain metastases (BMs), with documented evidence for trastuzumab deruxtecan (T-DXd; Enhertu, Daiichi Sankyo) and sacituzumab govitecan (SG; Trodelvy, Gilead Sciences).⁴

T-DXd Delivers a 50% Intracranial Response in Brain Metastases

T-DXd is a HER2-targeting ADC comprised of a humanized monoclonal anti-HER2 antibody with high membrane permeability, implying that T-DXd could cross the blood-brain barrier to target BMs.⁵ This was observed in the open-label, multicenter, international DESTINY‑Breast12 trial (NCT04739761)⁶ investigating T-DXd in patients with previously treated advanced or metastatic HER2+ breast cancer whose disease has progressed on prior anti-HER2-based regimens and who received no more than 2 prior lines of therapy in the metastatic setting. The trial included a total of 263 patients with both stable and active brain metastases who received the standard dose of T-DXd (5.4 mg per kg) every 3 weeks.^4,7

Treatment with T-DXd demonstrated statistically significant clinical benefits with favorable survival and response rates. Patients with BMs achieved a 12-month PFS of 61.6% (95% confidence interval (CI): 54.9-67.6), with a 12-month CNS PFS of 58.9% (95% CI: 51.9-65.3), and a total overall response rate of 71.7%. Response rates were slightly higher at 79% in patients with stable BMs compared with 62% in active BMs, and about 50% of those with untreated or previously treated progressing lesions achieved intracranial responses.⁷

“If you look at it across studies looking at DESTINY‑Breast12 versus other studies… the activity seems pretty significant at anywhere between 50% and 70%,” said Brenner. “And then if you look at HER2CLIMB [NCT05132582],⁸ we see significant activity there as well—47%. So, the ADCs seem to be doing this as well as the chemotherapy‑[tyrosine kinase inhibitor] combinations, if not better.”⁴

SG Targets TROP‑2 in Gliomas and Brain Metastases

SG is a TROP-2–targeting ADC that delivers the cytotoxic payload SN-38 directly to TROP-2–expressing tumor cells to induce apoptosis. Its pH-sensitive linker and CNS-penetrant SN-38 payload are thought to contribute to the intracranial activity observed in early-phase and real-world studies.

The mechanisms underlying SG’s CNS-penetrant capabilities are further clarified by a phase 0 “window of opportunity” study (NCT03995706)⁹ performed by Brenner and his colleagues. In the study, patients with BMs with planned craniotomy received a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery.^4,10

During resection, Brenner and his team collected tumor tissue, cerebrospinal fluid, and blood samples to assess intracranial concentrations of SN-38—the trial’s primary end point. They found that tumor SN-38 levels were roughly 10-fold higher than the IC50 for breast cancer cell lines, with minimal exposure in non-tumor tissue—demonstrating that SG can achieve cytotoxic concentrations within BMs.^4,10

“When we looked at TROP‑2 expression across the cohort, all of them expressed TROP‑2 to some level… [the] majority being in the intermediate‑to‑high range,” explained Brenner. “We then compared expression versus tissue SN‑38 levels and found it to be highly correlated, suggesting that the mechanism of action was really TROP‑2‑dependent and not intravascular release.”⁴

Following the phase 0 study, a larger breast cancer BM cohort treated with SG showed similar results, with an approximate 50% intracranial response rate and an overall survival between an estimated 32 and 35 months. These patients have since been moved on to a registrational phase 2 study.⁴

Together, these data highlight the expanding role of ADCs in addressing one of the most challenging complications of HER2+ breast cancer. By combining targeted delivery with CNS-penetrant payloads, agents such as T-DXd and SG are demonstrating meaningful intracranial activity in a population long underserved by existing therapies. As ongoing and future trials continue to define where ADCs fit within the treatment sequence, their potential to reshape outcomes for patients with BMs is becoming increasingly clear.

REFERENCES

1. Key Statistics for Breast Cancer. American Cancer Society. May 5, 2025. Accessed December 12, 2025. https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html

2. Xu D, Hu Z, Wang K, et al. Why does HER2-positive breast cancer metastasize to the brain and what can we do about it? Critical Reviews in Oncology/Hematology. January 23, 2024. Doi: 10.1016/j.critrevonc.2024.104269

3. Cai SL, Wang ZH, Chen XG, et al. Risk factors of brain metastasis and prognosis in HER2-positive breast cancer: A single-institution retrospective analysis from China. Front Oncol. June 27, 2022. doi: 10.3389/fonc.2022.1027199

4. 1. Waks A, Loibl S, Mahtani R, et al. Educational Session 6: ADCs in the Clinic. Presented at: SABCS 2025. December 9-12, 2025. San Antonio, TX

5. Gerlach A. Trastuzumab deruxtecan yields promising intracranial activity in patients with HER2+/HER2-low breast cancer and brain metastases. Pharmacy Times. July 24, 2025. Accessed December 12, 2025. https://www.pharmacytimes.com/view/trastuzumab-deruxtecan-yields-promising-intracranial-activity-in-patients-with-her2-her2-low-breast-cancer-and-brain-metastases

6. A study of T-DXd in participants with or without brain metastasis who have previously treated advanced or metastatic HER2 positive breast cancer (DESTINY-B12). Clinicaltrials.gov. Updated September 10, 2025. Accessed December 12, 2025. https://clinicaltrials.gov/study/NCT04739761

7. Harbeck N, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. September 13, 2024. doi: 10.1038/s41591-024-03261-7

8. A study of tucatinib or placebo with trastuzumab and pertuzumab for metastatic HER2+ breast cancer (HER2CLIMB-05). Clinicaltrials.gov. Updated December 4, 2025. Accessed December 12, 2025. https://clinicaltrials.gov/study/NCT05132582

9. Neuro/​Sacituzumab Govitecan/​Breast Brain Metastasis/​Glioblastoma/​Ph 0. Clinicaltrials.gov. September 4, 2024. Accessed December 12, 2025. https://clinicaltrials.gov/study/NCT03995706

10. Balinda HU, Kelly WJ, Kaklamani VG, et al. Sacituzumab Govitecan in patients with breast cancer brain metastases and recurrent glioblastoma: a phase 0 window-of-opportunity trial. Nat Commun. August 7, 2024. doi: 10.1038/s41467-024-50558-9