A number of newly identified genetic drivers behind brain metastases in patients with breast cancer were presented at the San Antonio Breast Cancer Symposium (Abstract PD13-01).
Led by Nicola S. Cosgrove, MD, of the Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, researchers reported that the data reflect the results of RNA sequencing performed on a cohort of patient-matched primary and resected brain metastatic tumors, including 90 samples from 45 patients.
Brain metastatic disease occurs in 10-30 percent of metastatic breast cancer cases, according to Cosgrove. The incidence of brain metastases is increasing, yet overall survival remains < 2 years. Furthermore, treatment is limited, with current clinical practice centered on radiation, chemotherapy, and surgery.
"Homologous recombination deficiency represents a new therapeutic strategy," said Cosgrove. "Although these treatments may prolong survival in the short term, targeting oncogenic alterations in brain metastases may deliver a more sustained clinical benefit," he said.
In a multicenter study, researchers comprehensively characterized DNA and RNA alterations that aberrantly drive specific oncogenic pathway activity pertinent to breast cancer brain metastases (BCBM). The investigators performed whole exome DNA sequencing for 18-45 patients, including 54 trios consisting of primary tumor, brain metastasis, and matched normal issue. An independent brain metastatic whole exome DNA sequencing cohort of 21 patients was also analyzed, resulting in a total of 39 patient samples.
The researchers discovered recurrent somatic copy number alterations (SCNA), somatic single nucleotide variants (SNVs), and mutational signatures were identified from WXS data, while expressed gene fusions were detected computationally from RNA sequencing in 45 cases.
Of the 45 BCBM patients, median age at diagnosis was 51 years, median overall survival at 57 months, and ranged from 18 to 255 months, with median brain metastases-free survival at 34 months, ranging from 5 to 216 months.
Clinical molecular subtype of the primary tumor included 13 ER+/HER2 in 29 percent of patients, 16 HER2+ (35.5%), and 16 TNBC (35.5%). Regions of significant recurrent amplifications and deletions in metastases were identified in 4q12, 10q11.21, 8p11.23, 8q23.3, and 17q12 (FDR < 0.10).
Recurrent expressed gene fusions identified in known cancer driver genes were associated with chromatin modification, MAPK and HER signaling pathways. Mutational signature analysis of SNVs identified signatures associated with aging, mismatch repair, and homologous recombination deficiency (HRD) mutational processes.
"The relative contribution of the HRD signature was significantly increased in brain metastases compared to matched primary tumor type, while concordantly increased HRD in the brain metastatic transcriptome was confirmed by gene set variation analysis (GSVA) of homologous recombination pathway genes."
Moreover, in the extended BCBM RNA-Seq (N=45 patients) GSVA pathway scores were elevated in brain metastases relative to primary tumors, validating the functional significance of altered DNA repair defects in brain metastases.
"We are reporting recurrent genetic drivers, supported by altered functional transcriptome, unique to brain metastasis that may have clinical implications for prognosis and treatment choice," said Cosgrove.
"Specifically, targeting defects in the homologous recombination repair mechanism may represent new therapeutic strategies and management opportunities for breast cancer brain metastases patients."
Kurt Samson is a contributing writer.