Profiles of brain metastases: Prioritization of therapeutic targets

Abstract

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

Effects of single-nucleotide polymorphisms in the mTORC1 pathway on the risk of brain metastasis in patients with non-small cell lung cancer

“…Furthermore, while NSCLC patients with EGFR mutations had a higher risk of brain metastases, they had better prognosis than those with EGFR wild-type mutations (Hsu et al 2016). In our study, the frequency of EGFR mutation was 36.9% in 130 BM patients, which is consistent with previous finding (Ferguson et al 2018). Moreover, the frequency of EGFR mutation was significantly higher in patients with AA genotype of mLST8:rs26865 than those with AG/GG.…”

“…Recently, one study profiled the characteristics of brain metastases from NSCLC and showed that the EGFR mutation rate in BM was 36.3% (Ferguson et al 2018). Furthermore, while NSCLC patients with EGFR mutations had a higher risk of brain metastases, they had better prognosis than those with EGFR wild-type mutations (Hsu et al 2016).…”

Patterns of recurrence and metastasis in BRCA1/BRCA2‐associated breast cancers

“…24 Ferguson et al reported overexpression of multiple proteins involved in DNA repair in brain metastases across several solid tumor histologies. 25 Balendran et al reported a high rate of BRCA1 or BRCA2 mutations detected in the brain metastases of patients with ovarian cancer. 26 Of interest, platinum agents have demonstrated efficacy against brain metastases across many tumor types, including breast cancer, suggesting vulnerability of brain metastases to DNAdamaging agents.…”

PLEKHA5 regulates tumor growth in metastatic melanoma

“…Our understanding of the brain‐homing process has been rather limited because research focused on brain dissemination has been restricted by the paucity of available preclinical models and human specimens annotated for development of cerebral lesions. The emergence of newer studies of key molecules involved in brain metastasis has added some new insights to our current understanding of the pathogenesis of disease while providing new opportunities for developing brain metastasis–specific therapies …”

“…The emergence of newer studies of key molecules involved in brain metastasis has added some new insights to our current understanding of the pathogenesis of disease while providing new opportunities for developing brain metastasis-specific therapies. [8][9][10][11][12][13][14][15][16] Using an integrated clinical and bench-based approach, we previously showed that melanomas that tend to spread, survive, and proliferate in the central nervous system (brain-tropic) display distinct molecular features. 13 Our study identified PLEKHA5, a gene involved in normal brain development, as a likely mediator of melanoma brain dissemination.…”