In the present study, we describe the outcomes of 153 breast cancer patients newly diagnosed with HER2 + BCBrM who received radiation at a single institution. For the first time to our knowledge, we describe ECD status in a large cohort at the time of first HER2 + BCBrM. In this patient cohort, most patients had ECD that was absent or controlled, indicating that therapeutic efficacy between intracranial and extracranial disease diverges in modern times. Trastuzumab remains the most commonly used HER2-targeting agent in neoadjuvant, adjuvant, and first-line metastatic HER2 + breast cancer. Trastuzumab has very limited intracranial activity in an intact blood brain barrier allowing metastatic escape into the CNS. Antibody drug conjugate, trastuzumab emtansine is now used in the adjuvant early stage setting when residual disease is present after neoadjuvant trastuzumab and taxane based therapy [1]. In the Katherine clinical trial, 6% of patient still presented with isolated intracranial relapse as their first metastatic event [18, 19]. These findings highlight the need for agents in the curative and early metastatic setting with robust intracranial efficacy to prevent brain relapse.
Our findings demonstrate that patients with isolated brain relapse as their first metastatic event have inferior OS from metastatic diagnosis to death compared to those that develop BCBrM later in their metastatic disease course with concurrent ECD (Fig. 4). The current first-line systemic therapy for advanced HER2 + BC remains a taxane, pertuzumab and trastuzumab regardless of BCBrM status [20]. The intracranial activity of trastuzumab and pertuzumab is minimal compared to newer generation HER2-targeted therapies [21]. Tucatinib is a highly HER2-selective small-molecule oral tyrosine kinase inhibitor. When used in combination with trastuzumab and capecitabine in the HER2CLIMB clinical trial, patients with baseline active, stable or progressive BCBrM had improved CNS-PFS and OS with the addition of tucatinib [9]. Given the poor OS in patients with isolated brain relapse, we believe clinical trials utilizing brain penetrable HER2-targeted therapies such as tucatinib combinations in the first-line setting are warranted. Clinical trials utilizing tucatinib added to T-DM1 or trastuzumab/pertuzumab after isolated brain relapse for secondary BCBrM prevention are underway (NCT05323955).
OS from BCBrM to death also differed significantly depending on ECD status (Fig. 5). Patients with concurrent progressive ECD had the worst OS from first BCBrM to death. Current ASCO guidelines recommend a change in systemic therapy when there is concurrent intracranial and extracranial disease progression. Finding robust agents in this setting with both intracranial and extracranial activity are imperative.
Lastly, in this patient cohort, there was no statistically significant difference in intracranial progression free survival based on the status of ECD. However, median iPFS for patients with progressive ECD was 7.7 (95% CI: 6.0-13.3) months versus 11.2 (95% CI: 9.2–16.3) months for stable/responding and 8.3 (5.7–12.0) months for patients without ECD. This data suggests that patients with concurrently progressive intracranial and extracranial disease may have shorter iPFS than those with controlled or absent extracranial disease, though further studies are needed. For clinical trials utilizing intracranial progression-free survival as a primary endpoint, stratifying by extracranial disease status may be necessary.
This study has several limitations. This study was only performed at one institution, Duke University, which inherently limits our population of patients. However, with over 150 HER2 + patients, this study constitutes one of the largest retrospective analyses of HER2 + intracranial metastases. Another limitation is the retrospective nature of this study. All patients with HER2 + BCBrM treated with any radiation at Duke between 2008 and 2021 were included, but there may still be confounding factors uncontrollable in retrospective series. Furthermore, only clinically significant brain metastases leading to MRI diagnosis were included as is standard practice and implications of asymptomatic brain metastases are unknown. Also, few patients in this cohort were treated with newer HER2 targeted agents such as trastuzumab deruxtecan or tucatinib-containing regimens which both prolong survival in HER2 + BCBrM patients. Finally, it is unknown when these patients may have developed asymptomatic BCBrM as MRI screening is not standard of care for breast cancer treatment, which could have an impact on the demonstrated survival in this study.
In conclusion, patients with isolated HER2 + brain relapse had shorter OS compared to those developing BCBrM later in their treatment course with either controlled or progressive ECD. Clinical trials exploring highly brain penetrable HER2 targeting agents after initial first brain relapse are warranted in this population.