Up to 45 percent of patients with metastatic breast cancer develop brain metastases, and those who do have an average survival of three to 23 months. Researchers are addressing clinical challenges and exploring the biology of brain metastases to develop novel treatment strategies and combat this devastating occurrence.
At this year’s San Antonio Breast Cancer Symposium (SABCS), researchers gave an overview of the treatment landscape for patients with breast cancer brain metastases (BCBM) and highlighted some promising new areas for future research.
Updates from the pivotal HER2CLIMB trial
Clinical trials have almost universally excluded patients with a history of brain metastases, making testing novel therapies particularly challenging. For HER2-positive breast cancer patients, the pivotal HER2CLIMB trial led by BCRF investigator Dr. Nancy Lin was the first to enroll patients with a history of brain metastases. This study showed that adding tucatinib, a small molecule HER2 inhibitor, resulted in clinically meaningful outcomes. Earlier this year, the FDA approved tucatinib in combination with standard HER2 therapies.
A follow-up analysis of patients from the HER2CLIMB trial was presented at this year’s SABCS meeting. Investigators examined the health-related quality of life (HRQoL) in these patients and showed that, in addition to its clinical benefit, tucatinib positively influenced HRQoL by significantly decreasing the progression of several adverse effects including mobility issues, pain and discomfort, and anxiety and depression.
Investigating novel therapies that cross the blood–brain barrier
Current treatment options for BCBM are limited, with surgery (if possible), radiation therapy (such as whole brain radiation and targeted/stereotactic radiation), and chemotherapy as the standard of care. Developing more effective treatments is challenging because systemic therapies are unable to cross the blood–brain barrier, a border of cells that filters blood and controls what molecules can pass into the brain to keep out any harmful toxins or pathogens. Several studies presented at SABCS examined the efficacy of novel agents that can cross the blood–brain barrier.
One of these agents is the potent anti-cancer drug SN38, which is part of an antibody-drug conjugate called sacituzumab govitecan (SG). SG has three components: an antibody that targets and binds to tumor cells; the drug SN38; and a pH-sensitive linker that connects SN38 and the antibody component. Recently, SG obtained accelerated FDA approval to treat metastatic triple-negative breast cancer. Researchers including BCRF investigators Drs. Hope Rugo, Tiffany Traina, and Lisa Carey compared SG to chemotherapy in BCBM patients. They showed SG to be better than chemotherapy for progression-free survival but not overall survival. Because of the small number of patients in the sample, further investigation is underway.
In preliminary experiments, other investigators showed that SN38 was efficiently delivered to brain metastases by the SG antibody-drug conjugate; compared to a control group, SN38 levels were 150 times greater in BCBM and 40 times greater in other brain tumors. Since SN38 is attached to a pH-sensitive linker, this increase is thought to be due to the release of SN38 as SG encounters the reduced pH of the tumor microenvironment allowing SN38 to traverse the blood-brain barrier and affect tumor cells.
The Lupus antibody 3E10 has also been shown to cross the blood-brain barrier by binding to the ENT2-protein expressed on brain cells. Researchers are exploring its utility as an effective vehicle for delivering anti-cancer drugs to brain metastases and presented their findings at SABCS. The investigators tested the ability of a fragment of 3E10 called DX1 to cross the blood–brain barrier and penetrate brain metastases. In laboratory models of BCBM, they showed that not only does DX1 cross the blood–brain barrier, but it also suppresses the growth of tumors. DX1 provides a novel way to target brain metastases and has exciting potential applications in BCBM treatment.
Improving our biological understanding of brain metastases
Other presentations at SABCS focused on uncovering new insights into the biology of brain metastases that could provide insight into potential therapeutic targets.
BCRF investigator Dr. Priscilla Brastianos discussed her previous studies examining the gene expression profiles of primary tumors compared to BCBM. Her team showed clinically relevant gene alterations in BCBM samples that were not present in the primary tumors. BCRF investigators Drs. Steffi Oesterreich, Adrian Lee, and Fergus Couch also presented findings focused on gene expression differences. They showed an enrichment in the gene mutation signatures associated with DNA repair (including homologous recombination deficiency and mismatch repair deficiency) in BCBM, compared to primary breast cancers. They also demonstrated that inhibiting DNA repair with the PARP inhibitor niraparib (previously shown to cross the blood-brain barrier) demonstrated significant anti-tumor activity in patient-derived BCBM samples. This may provide a rationale for targeting defects in the DNA repair mechanism as an effective therapeutic strategy for brain metastases.
Other studies showed that breast cancer leptomeningeal metastases—where the disease spreads to the meninges surrounding the brain and spinal cord—are genomically distinct from other metastases. The investigators have developed laboratory models to determine if the genomic differences may provide actionable targets for treatment of this rarer BCBM subtype affecting five percent of breast cancer patients.
What’s to come in the study of BCBM
Thanks to recent progress, clinical trials are now being designed specifically for patients with stable and/or progressive brain metastases, as well as treatment-naïve brain metastases (those that have not undergone any treatment). In fact, both the American Society of Clinical Oncology and the National Cancer Institute have endorsed the inclusion of patients with brain metastases in clinical trials.
The studies presented at SABCS this year support the utility of molecular profiling in the discovery of therapeutic targets and provide evidence for novel drug delivery vehicles for the treatment of BCBM. While delineation of predictive biomarkers is still needed and further preclinical and clinical studies with PARP inhibitors are warranted, current advances in treatment strategies present exciting areas of investigation that could lead to significant improvements in the care of BCBM patients.
Read more of BCRF’s SABCS 2020 coverage here.
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