Brain metastases can develop in any patient with metastatic breast cancer; however, it is more common in HER2-positive and triple-negative subtypes, according to Sheheryar Kabraji, BM, BCh, a physician at Dana-Farber Cancer Institute, who presented research at the 2021 San Antonio Breast Cancer Symposium.
"To validate observations of efficacy in our preclinical models of breast cancer brain metastese (BCBM), we undertook a retrospective cohort study of patients with BCBM who were being treated with T-DXd [trastuzumab deruxtecan] for metastatic breast cancer," he said. "At the time, there was no data on whether T-DXd was active against BCBMs, especially untreated or progressive BCBMs."
The primary objective was to determine whether T-DXd could treat HER2-positive BCBMs. "This was a tandem study of T-DXd using BCBM PDX models developed in the Zhao Lab at Dana-Farber, as well as a retrospective study of patients treated during routine care at three U.S. institutions: Dana-Farber Cancer Institute, Duke Cancer Institute, and MD Anderson Cancer Center," he noted.
Genetic Alterations: Higher Risk of BCBM
Although the risk of being diagnosed with brain metastasis at early-stage breast cancer is less than 3 percent, Kabraji said the risk increases in the setting of metastatic breast cancer to 10-16 percent. "In metastatic HER2-positive breast cancer, the risk can be as high as 50 percent."
He said there are genetic alterations associated with a higher risk of brain metastases, including the HER2 amplification, alterations in the BRCA1/2 genes, mutations in the PIK3CA gene, and emerging data that loss of the tumor suppressor PTEN may also increase risk of brain metastases.
"One of the challenges is distinguishing between genetic alterations that accumulate with increasing metastatic burden versus those that work to help metastatic breast cancer cells reach and survive in the brain," he said.
BCBMs can affect patients at any age if they have advanced breast cancer; however, studies have suggested that younger patients (<40) are at higher risk of BCBMs and this may be a function of the breast cancer subtypes identified in this subset of patients, Kabraji explained.
"While hormone replacement therapy (HRT)-that includes both estrogen and progesterone-can slightly increase the lifetime risk of breast cancer, HRT has not been clearly identified as a risk factor for developing BCBMs," he added.
Improved Progression-Free Survival
"While the intracranial activity of antibody-drug conjugates like T-DXd had not been demonstrated when we undertook this study, we found that T-DXd could reduce tumor growth and extend survival in patient-derived orthotopic mouse models of HER2-positive BCBMs," said Kabraji. "This is when BCBM tissue is removed by surgery from a patient and used to grow a tumor within a mouse brain, providing a high-fidelity model of BCBMs for translational research. In addition, we found that a BCBM model that was resistant to TDM1 was sensitive to T-DXd."
T-DXd also appeared to be active in a BCBM model of HER2-low breast cancer (not HER2-amplified or in situ hybridization) by immunohistochemistry or in situ hybridization, he added. In the retrospective cohort of 17 patients, the study showed that T-DXd had activity in patients with untreated and treated BCBMs.
"We measured time on treatment, and intracranial and extracranial response by radiology review," Kabraji noted. "Our data is consistent with results presented at SABCS21 from a randomized trial of T-DXd versus TDM1 (DESTINY-BREAST03), where in the cohort with stable BCBMs, T-DXd was also associated with improved progression-free survival versus TDM1."
In both models and patients, he said the results show that T-DXd is active against BCBMs and may improve patient outcomes. In addition, the efficacy of T-DXd in patients with active BCBM is being formally tested in the DESTINY-BREAST12 study.
Future Testing of Similar Agents
"We integrated data from models and patients to show that a new and widely tested class of drugs, antibody-drug conjugates, appears to be active against HER2-positive BCBMs," Kabraji noted, further stating that the study will be submitted for publication and he hopes to test similar agents against BCBMs using this framework.
"Importantly, we hope that researchers and our industry partners will be encouraged by these data and include more patients with BCBMs in trials of different therapies, including antibody-drug conjugates," he concluded.
Amy Gallagher is a contributing writer.