Brain metastases rare but deadly as first sign of breast cancer return

When early-stage breast cancer returns after adjuvant therapy, the first sign of relapse is far more likely to appear elsewhere in the body than in the brain. Yet a new analysis of thousands of Greek patients shows that when the brain is the first site of recurrence, the outlook is markedly worse than when the disease reappears in other organs. The findings, drawn from a large prospectively annotated database, also identify which patients face the highest risk of brain metastases as the first evidence of their cancer coming back.

The analysis, known as the BRACE study, included 5,318 patients with early breast cancer who had received adjuvant therapy. After a median follow-up of 137.0 months, ranging from 0 to 334.1 months, the invasive breast cancer-free survival at 120 months stood at 73.2 percent, with a 95 percent confidence interval of 72.0 to 74.4 percent. Overall survival at the same time point was 78.3 percent, with a confidence interval of 77.2 to 79.4 percent.

Among the entire cohort, 106 patients, or 2 percent, developed brain metastases at first recurrence. Of those, 68 patients, representing 64.2 percent, had brain metastases only, without simultaneous disease elsewhere. The rarity of this pattern is striking given the size of the database, but the clinical consequences for those affected proved severe. Patients whose first recurrence was in the brain had a median survival from that point of 8.0 months, compared with 31.2 months for those whose cancer first returned outside the central nervous system. In statistical terms, brain-first recurrence carried a hazard ratio of 2.66 for death, with a 95 percent confidence interval of 2.15 to 3.29.

To pinpoint which patient characteristics predicted brain-first relapse, the investigators fitted cause-specific Cox models across the whole cohort. Two factors emerged as independently associated with brain metastases at first recurrence: triple-negative subtype, with a hazard ratio of 3.43 and a confidence interval of 2.05 to 5.75, and involvement of four or more axillary lymph nodes, with a hazard ratio of 2.52 and a confidence interval of 1.47 to 4.33. In alternative model parameterizations, AJCC stage III disease, with a hazard ratio of 3.41 and a confidence interval of 1.56 to 7.44, and hormone receptor negativity, with a hazard ratio of 2.08 and a confidence interval of 1.37 to 3.15, also remained independently associated.

The cumulative incidence of brain metastases differed sharply by molecular subtype. Patients with triple-negative breast cancer had a cumulative incidence of 3.86 percent at 120 months, with a confidence interval of 2.74 to 5.42 percent, compared with 1.27 percent, with a confidence interval of 0.90 to 1.79 percent, in those with luminal A or B disease. The difference was highly significant by Gray’s test, with a p value below 0.0001. Notably, the cumulative incidence curve for triple-negative patients showed a steep rise in the early years after adjuvant therapy.

Survival after brain metastases also varied by subtype. Patients with HER2-positive disease whose cancer spread to the brain lived significantly longer than those with other subtypes, with a median brain metastasis-specific survival of 13.0 months versus 5.4 months. The corresponding hazard ratio was 0.56, with a 95 percent confidence interval of 0.36 to 0.86 and a p value of 0.007. The study’s authors caution, however, that these estimates describe an era in which adjuvant trastuzumab was reimbursed in Greece only from 2006 onward and contemporary central nervous system-active regimens were not yet available, so the figures should be read with that context in mind.

The rationale for the analysis rests on a gap in current knowledge. Data on the risk factors that increase the likelihood of brain metastases in breast cancer remain scarce, and the authors argue that mining prospectively collected data from adjuvant trials for brain metastases at first recurrence may identify a population for whom prevention strategies could be developed.

The overall picture that emerges is one of rarity combined with gravity. Brain metastases as the first sign of relapse occurred in only 2 percent of more than five thousand patients, yet those patients faced a median survival measured in single-digit months, far shorter than the roughly two and a half years seen in patients whose disease first returned elsewhere. In this cohort, triple-negative subtype and four or more positive axillary nodes were independently associated with brain metastases at first recurrence, and AJCC stage III and hormone receptor negativity remained independently associated in alternative parameterizations.

For clinicians and researchers, the study provides quantified benchmarks drawn from a single national cooperative group’s experience across seven consecutive adjuvant trials. The authors state that mining prospectively collected data from adjuvant studies for brain metastases at first recurrence may identify a population for prevention strategies. The authors emphasize that these estimates describe an era in which adjuvant trastuzumab was reimbursed only from 2006 and contemporary CNS-active regimens were not available, and that they should be read accordingly.

Subject of Research: Risk factors and outcomes for brain metastases as the first site of recurrence after adjuvant therapy in early breast cancer

Article Title: Brain as a site of first recurrence after adjuvant therapy for early breast cancer: mining the hellenic cooperative oncology group database-The BRACE study

Article References: Razis, E., Papadopoulou, K., Korfiatis, N., Christodoulou, C., Kourea, H. P., Goussia, A., Tzaida, O., Batistatou, A., Mamilos, A., Markopoulos, C., Venizelos, V., Xepapadakis, G., Skarlos, P., Pentheroudakis, G., Pectasides, D., Koutras, A., Christopoulou, A., Psyrri, A., Gogas, H., … Fountzilas, G. (2026). Brain as a site of first recurrence after adjuvant therapy for early breast cancer: mining the hellenic cooperative oncology group database-The BRACE study. Breast Cancer Research and Treatment, 220(1), Article 24. https://doi.org/10.1007/s10549-026-08085-2

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08085-2

Keywords: brain metastases, breast cancer, adjuvant therapy, triple-negative, HER2-positive, recurrence, Hellenic Cooperative Oncology Group, survival, risk factors, early breast cancer, central nervous system, prognosis