Brain metastases are a devastating complication of cancer, and occur in up to 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer. Management of brain metastases requires individualized coordination between the traditional treatment modalities for intracranial sites of disease, which include surgery, radiosurgery, and/or whole-brain radiation therapy, and the need for ongoing systemic therapy in a patient with metastatic disease.
With the increase in screening brain magnetic resonance imaging scans and the prolongation of survival from improved treatment of systemic disease, there is an increasing prevalence of brain metastases in HER2-positive breast cancer patients. Often, these lesions are small and asymptomatic. Importantly, due to the potential for neurologic morbidity associated with unrestrained growth of a metastatic focus in the brain, control of brain metastases can become a rate-limiting step in both quality of life and overall survival, and represents a leading edge in the ongoing efforts to improve outcomes for these patients.
To establish the current best practices, the American Society of Clinical Oncology recently provided clinical guidelines for the management of brain metastases from HER2-positive breast cancer, as reported by Ramakrishna and colleagues in the Journal of Clinical Oncology1 and reviewed in this issue of The ASCO Post. Although general guidelines for the management of brain metastases exist,2 including guidelines from the National Comprehensive Cancer Network, there is a paucity of disease-specific guidelines.
Nevertheless, it is becoming increasingly clear that the management of brain metastases must account for the histology of the primary malignancy, since clinical decision-making takes place against the baseline expectation of overall survival and anticipates the administration of differing treatments for systemic metastatic disease. The ASCO recommendations, formulated by expert consensus, provide us with a general framework for managing brain metastases from HER2-positive breast cancer.
Prolonging Survival
In the Breast Cancer Graded Prognostic Assessment, a prognostic scoring metric derived from a multi-institutional database of 400 breast cancer patients, the median overall survival was 17 months (95% confidence interval [CI] = 13–23) in HER2-positive patients with brain metastases3; significant prognostic factors were Karnofsky performance status, age, HER2 status, and the interaction between estrogen receptor and progesterone receptor status and HER2. Other large retrospective series have reported median survival as high as 23 months in these patients.4
Given the potential for prolonged survival in many patients, it is critical to individualize treatment in this population. For example, controversy exists around the optimal timing for whole-brain radiation therapy, which is highly effective for securing local and distal/regional control of often-radiosensitive breast cancer brain metastases, but interrupts systemic treatment cycles and can be associated with transient neurocognitive effects. The new recommendations frame the key considerations for appropriately guiding management decisions in this patient population, including assessing performance status, the number of symptomatic lesions, the status of systemic disease, and the potential short- and long-term toxicities of therapies.
Evolving Recommendations
These recommendations also highlight the areas of need for randomized trials of systemic agents in both newly diagnosed and recurrent brain metastases. Indeed, interpreting results from clinical trials and their applicability to patients has been a challenge, given the heterogeneous patient populations and variable endpoints across trials. Traditional cytotoxic agents have some activity in the brain,5 but have often required coordination with radiation and/or surgical interventions to obtain durable control. As systemic therapies improve and begin to include combinations of agents with penetration across the blood-brain barrier, the guidelines will also likely evolve to include more frequent use of chemotherapeutic regimens as a primary treatment modality for HER2-positive breast cancer brain metastases.
As the prototypic example, the small-molecule tyrosine kinase inhibitor lapatinib (Tykerb) as a single agent has modest activity in recurrent brain metastases, with more recent data indicating that the combination of lapatinib and capecitabine shows promise both upfront6 and in the progressive setting.7 A recent study presented at the ASCO Annual Meeting investigated the use of carboplatin and bevacizumab (Avastin) in progressive brain metastases (including HER2-positive and HER2-negative patients), demonstrating a very promising response rate of 63% in the central nervous system.8
Heterogeneity in Trial Designs
As mentioned above, one of the key challenges in assessing data from clinical trials in brain metastases is the significant variability in response criteria across trials. To improve this situation, the Response Assessment in Neuro-Oncology (RANO) Working Group recently published guidelines for assessing response to therapy in high-grade gliomas,9 and this group is now working on compiling similar criteria for brain metastases,10,11 with the goal of standardizing endpoint and response criteria.
Such guidelines are urgently needed, given the heterogeneity in trial designs. More comprehensive guidelines for the management of leptomeningeal metastases are also needed. One limitation to developing such guidelines is the lack of high-quality studies in this often very disabled patient population.
Conclusions
In summary, the ASCO clinical practice guideline for brain metastases in HER2-positive breast cancer presents an important working framework for the practicing oncologist in the management of this common complication of breast cancer, using currently available evidence. In addition, it highlights the key areas where additional well-conducted clinical trials in well-defined patient populations (with standardized response criteria) are needed for further improvement in the care of these patients. ■
Disclosure: Drs. Brastianos and Cahill reported no potential conflicts of interest.
References
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