Advances in Managing CNS Metastases in Breast Cancer: SABCS 2024 Insights
May 23, 2025
With the 2025 ASCO Annual Meeting just around the corner, including over 20 sessions centered on breast cancer, it’s a good time to review recently reported updates in this space. At the latest San Antonio Breast Cancer Conference (SABCS), held in December 2024, several presentations focused on breast cancer brain metastasis (BCBM) and treatment of neurotoxicity. In a Poster Spotlight session on brain metastases, a panel of experts including William Gradishar, MD, of Feinberg School of Medicine; Carey Anders, MD, of Duke Health; and Andrew Brenner, MD, of The University of Texas Health Science Center at San Antonio covered the latest trial data and translational work on neurological complications of breast cancer.
Across all three BCBM subtypes, use of hypofractionated stereotactic radiotherapy was presented as an alternative method of treatment, with the goal of avoiding toxicities such as radiation necrosis. Jin Meng and Zhaozhi Yang reported on outcomes in a phase 2 trial of this intervention for patients with 1 to 10 brain metastases, most of which were at least 3 cm, who received 8 Gy per fraction in 3 to 5 fractions to their tumor. The results showed a notable level of local disease control of 89% at 1 year and 77% at 2 years. Intracranial distant control was 52% and 27% at 1 and 2 years, respectively. Also examining BCBM across tumor types, Gaia Griguolo and colleagues assessed genomic alterations in BCBM using whole exome sequencing to identify clinically actionable alterations. They found that DNA-repair alterations were particularly enriched in triple-negative breast cancer (TNBC), as well as in PIK3CA and PTEN pathway alterations distributed across all breast cancer subtypes.
In the hormone-positive space, two phase 1 studies showed promising activity with brain-penetrant oral selective estrogen receptor degraders (SIM0270 alone and SIM0270 plus everolimus), reported by Qingyuan Zhang, Jiong Wu, and colleagues (NCT05293964). In the analysis of SIM0270 combined with everolimus, 2 of 4 patients experienced complete remission. A phase 3 randomized trial of SIM0270 versus physician’s choice following first-line CDK4/6 inhibitor treatment is planned.
Focusing on HER2-positive BCBM, Nadia Harbeck and colleagues presented DESTINY-Breast-12 endpoints that characterized the important outcomes of health-related quality of life and neurological function in patients with HER2-positive advanced or metastatic breast cancer. This analysis compared neurological outcomes in patients with active versus stable BCBM treated with trastuzumab deruxtecan (T-DXd). For context, this single-arm trial has shown a 61.5% 12-month progression-free survival (PFS) and a 72% central nervous system (CNS) overall response rate. Cognitive function was well preserved in patients who had baseline brain metastases. During treatment with T-DXd, just over half (55.1%) of these patients maintained neurological stability across cognitive, emotional, psychosocial, social, and pain symptom domains, based on the Neurologic Assessment in Neuro-Oncology (NANO) scale.
Intriguing work regarding CNS as the first site of relapse in TNBC patients who achieved pathological complete response (pCR) after neoadjuvant therapy was also presented. Both Davide Massa and Thomas Grinda and their colleagues showed that among patients with and without pCR, most recurrences occur in the CNS. Isolated brain relapse and leptomeningeal disease were also more common. There was no statistical difference between incidence of CNS recurrence in patients with pCR versus those without. As Dr. Brenner noted, this highlights the importance of investigating CNS-penetrant drugs in patients with early TNBC, with the goal of preventing brain and leptomeningeal metastasis.
In the field of BCBM prevention, Jerzak and colleagues reported an update on a multicenter, phase 2 study of magnetic resonance imaging screening for BCBM versus symptom-directed imaging in patients with HER2-positive breast cancer and TNBC. So far, 50 patients have been enrolled, though the researchers noted a high rate of brain imaging in the control arm (69%, with almost a third not having neurological symptoms). Additional data are needed to determine the feasibility and practicality of screening interventions.
Finally, two ongoing trials led by Ting Bao and colleagues are investigating acupuncture and yoga for treatment-related complications of peripheral neuropathy.
Overall, SABCS offered highlights from a range of studies on CNS complications from breast cancer, which remain a challenge given the difficulty of finding brain-penetrant therapeutics to ease the neurological symptom burden. Community oncologists hope that future updates at premier oncology events such as SABCS and ASCO will point to promising treatment options.
References
Bao T et al. A randomized phase III clinical trial of acupuncture for chemotherapy-induced peripheral neuropathy treatment (ACT). Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 1396.
Bao T et al. A randomized phase III clinical trial of yoga for chemotherapy-induced peripheral neuropathy treatment (YCT). Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 1398.
Griguolo G et al. Clinically actionable genomic alterations in breast cancer brain metastases. Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 1602.
Grinda T et al. Incidence and pattern of central nervous system recurrence in TNBC according to response after neoadjuvant treatments. Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 2461.
Harbeck N et al. Effects of trastuzumab deruxtecan (T-DXd) on health-related quality of life (HRQOL) & neurological function in patients (pts) w/ HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINY-Breast12(DB-12) results. Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 3641.
Jerzak KJ et al. MRI screening for brain metastases versus SYMptom-directed brain imaging for patients with triple neg or HER2+ metastatic breast cancer: updated primary outcome analysis and preliminary quality of life data from a randomized phase II pilot study. Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 1469.
Massa D et al. Central nervous system as the primary site of first relapse in patients with triple-negative breast cancer achieving pathological complete response after neoadjuvant treatment. Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 1330.
Meng J et al. A prospective phase II trial of hypofractionated stereotactic radiotherapy (FSRT) for patients with 1-10 brain metastases from breast cancer. Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 1167.
Zhang J et al. SIM0270, a brain-penetrant oral SERD, in combination with everolimus in patients with ER+/HER2- advanced breast cancer: the phase Ib study. Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 1214.
Zhang Q et al. Updated analyses from a phase I study of the brain-penetrant oral SERD- SIM0270 in patients with ER-positive, HER2-negative advanced breast cancer. Poster presented at SABCS; December 10-13, 2024; San Antonio, TX. Session 1590.