2609 - Divergent Intracranial and Meningeal Failure Phenotypes after Brain Metastases Resection: Genomic Associations In 1006 Patients
Presenter(s)
A. Skakodub1,2, R. R. Patel1, H. Walch3, R. Homsi3, E. Miao1, J. E. Lee1, C. Gui4, M. I. Parker1, Z. Yazdani1, J. A. Wilcox5, N. S. Moss6, R. Bou-Nassif6, J. N. Stember7, A. T. Ilica8, G. Cederquist1, H. Yu9, P. Razavi10, W. Chatila3, K. Yu6, N. Schultz3, and L. R. G. Pike1; 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 4Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 5Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, 6Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, 7Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 8Department of Neuroradiology, The University of Miami Miller School of Medicine, Miami, FL, 9Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, 10Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Purpose/Objective(s):
Brain metastases (BM) contribute significantly to cancer morbidity and mortality. We sought to characterize distinct patterns of intracranial and meningeal failure following craniotomy and identify genomic alterations associated with these progression phenotypes.Materials/Methods:
Patients with solid malignancies undergoing craniotomy and MSK-IMPACT sequencing of BM specimens were identified. Outcomes included post-resection intracranial progression-free survival (iPFS; recurrent intracranial disease or death), classical leptomeningeal disease (LMD; diffuse leptomeningeal involvement and/or positive CSF cytology), and pachymeningeal disease (PMD; nodular meningeal disease with negative CSF cytology). Cumulative incidence (CI) functions accounted for death as a competing risk. Cause-specific and subdistribution hazard models were used to evaluate genomic associations. Gene frequencies were compared using Fisher’s exact test.Results:
Among 1006 patients (median age 60; 57% female), common histologies were NSCLC (359, 36%), breast cancer (BrC; 181, 18%), melanoma (128, 13%), and gastrointestinal (GI) cancers (GI; 109, 11%). At surgery, 53% of patients had a single BM; 79% of lesions were supratentorial. Most (88%) received adjuvant radiation to the surgical cavity and 30% received SRS to intact lesions. Median follow-up and overall survival were 24.8 and 25.1 months, respectively; median iPFS was 7.3 months. Intracranial progression occurred in 595 patients (59%). Stratified by histology, median iPFS was longest for BrC (9.4 months) and NSCLC (9.2 months), and shorter for melanoma (4.6 months) and GI (5.3 months) (HR 1.5, p<0.001). The CI of LMD at 2 years was 13.8%, whereas the CI at 2 years of PMD was 16.2%. By histologies, incidence of LMD at 2 years was highest among BrC (17.7%) and NSCLC (16.4%), followed by melanoma (13.6%), while GI had lower rates (9.5%). GI demonstrated the highest incidence of PMD at 2 years (20.6%), followed by BrC (19.4%), NSCLC (17.0%), and melanoma (13.8%). PTEN alterations were significantly associated with a shorter iPFS (HR 1.37; p=0.002). Additionally, alterations in the PI3K pathway were also associated with a worse iPFS (HR 1.21; p=0.007). Alterations in EGFR (HR 2.36; p=0.0001), RB1 (HR 1.78; p=0.004), and the cell cycle pathway (HR 1.36; p=0.048) were associated with a shorter time to LMD. Similarly, alterations in APC (HR 1.73; p=0.0201), PTEN (HR 2.04; p=0.0002), SMARCA4 (HR 1.81; p=0.0442), in the MYC pathway (HR 1.53; p=0.0219) and PI3K pathway (HR 1.56; p=0.0027) were associated with a shorter time to PMD.Conclusion:
In this large cohort of cancer patients, intracranial and meningeal progression remained prevalent despite multimodality treatment. Histology-specific patterns of progression were observed, with higher rates of LMD in BrC and NSCLC, and higher PMD rates in GI. Genomic alterations were found to correlate with worse outcomes, suggesting that molecular drivers may influence intracranial disease control.