Stereotactic Radiosurgery Offers Better Outcomes for BRAF-Positive Patients With Melanoma Brain Metastases

Rupesh Kotecha, MD

A recent study evaluated the impact of BRAF mutation in patients with melanoma brain metastasis treated with stereotactic radiosurgery (SRS) – with surprising results. The study shows the impact of considering a patient’s molecular or mutational tumor profile.

Over 170,000 new cases of brain metastases occur each year in the United States. The selection of local treatment modalities for patients with brain metastases is often based on patient characteristics, but currently not on tumor biology. Melanoma is associated with numerous mutations, the most well-known is the BRAF mutation, which occurs in about 50 percent of patients with metastatic melanoma. The impact of this mutation on melanoma brain metastasis (MBM) is not known, according to the abstract describing the study.

Results of the study were presented by Cleveland Clinic researchers at the 2015 annual meeting of the American Society for Radiology Oncology (ASTRO).

“Approximately 20 percent of patients with metastatic melanoma have brain metastasis at first presentation, and approximately 50 percent of Stage IV patients develop brain metastasis during their disease course,” says Rupesh Kotecha, MD, the study’s lead author. “Research efforts in this patient population are clearly warranted.” Dr. Kotecha is a resident in radiation oncology at Cleveland Clinic, one of the study’s institutions.

SRS significantly improves outcomes in BRAF-positive patients

The retrospective cohort study of 256 patients with MBM found that BRAF status was available for 76 patients. Of these, 25 were treated with stereotactic radiosurgery and were included in the final analysis (13 were BRAF positive and 12 were BRAF negative). The study found that patients who were BRAF-positive and were treated with SRS had significantly reduced in-field disease recurrence and better progression-free survival and overall survival.

Dr. Kotecha says these findings build on research presented earlier this year at the American Society of Clinical Oncology (ASCO) annual meeting by Manmeet Ahluwalia, MD, Director, Brain Metastasis Research Program and Associate Director, Clinical Trials, Operations in the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center of Cleveland Clinic’s Neurological Institute. He is also Section Head of NeuroOncology Outcomes.

Dr. Ahluwalia studied all patients treated at Cleveland Clinic for brain metastases from melanoma between 2000 and 2013 and found unique factors, such as tumor biology, radiation treatment modality, and target therapies to be associated with improved survival outcomes in patients with BRAF mutations. The current study takes that work one step further by exploring the fundamental predictors of outcome in patients with brain metastasis treated only with SRS, stratified by BRAF mutation status.

“In our series, patients with BRAF mutations tended to present with fewer lesions and smaller tumor burdens,” says Dr. Kotecha. “Moreover, lesions in these patients treated with SRS were more likely to respond when compared to lesions in patients without the BRAF mutation. In fact, in our series, no lesion less than 1 centimeter recurred after stereotactic radiosurgery.”

In the series, BRAF-mutated patients had better survival outcomes. “These findings support the role of SRS not only in patients with melanoma, but even more so for patients with the BRAF mutation,” Dr. Kotecha says.

Continuing focus on molecular profiles in tumors

A variety of therapies are available for treating MBM, ranging from surgical resection to whole-brain radiation therapy, to new targeted therapies with blood-brain barrier penetration.

“It is important for us to determine the optimal treatment approach for each patient,” says Dr. Kotecha. “Currently, SRS provides excellent local control with limited morbidity. This research supports our current institutional management of patients with brain metastases. We expect in the future to also determine the added benefit of targeted agents to SRS in patients with BRAF-mutated melanoma.”

Historically, tumors were grouped by generic histology. The current study is significant for classifying them based on mutational profile and genetic analyses.

“We are already starting to use molecular profiles to differentiate outcomes,” says Dr. Kotecha. “For example, previous research has demonstrated that the ER/PR/HER2/neu molecular profile of a brain metastasis from breast cancer is important when prognosticating a patient’s survival. Our data not only show that BRAF mutational status is a similar important prognostic marker of outcome, but also suggestive that it is a predictor of favorable response to SRS.”

Future studies expected in support of biology-based, patient-centered therapies

Researchers look forward to larger studies to further evaluate and expand upon the results from the current study.

“Looking ahead, we plan to perform a larger multi-institutional analysis to examine the patterns of intracranial failure (and factors associated with outcome) in patients with brain metastases from melanoma to verify the results of our institutional series,” says Dr. Kotecha.

“These studies will also provide useful measures to determine the impact of molecular profile on radiation sensitivity and survival outcomes,” he says. “Using the results of these studies, prospective studies would then add molecular profile into their stratification schemes. We suspect that these data will provide valuable information as we embark on prospective trials investigating the use of novel agents with radiosurgery.”

“Finally, we hope that this project is the first of many which focus on delivering a biology-based radiation treatment that is patient-centered,” Dr. Kotecha says.