Serum NSE, MMP‐9 and HER2 extracellular domain are associated with brain metastases in metastatic breast cancer patients: predictive biomarkers for brain metastases?

Abstract

Breast cancer (BC) is the second most common cause of brain metastases (BM). Predictive factors for BM have been widely studied in metastatic BC; however, there is no known serum tumor marker to accurately predict BM. Elevated serum S100ß protein and neuron-specific enolase (NSE) could reflect the brain damages induced by BM. Matrix metalloproteinase 9 (MMP-9) is involved in tumor invasion and metastatic dissemination, including BM. Also, HER2-amplified BC were shown to have a particular tropism for central nervous system (CNS). This study evaluated the correlation of these biomarkers with the presence of BM in metastatic BC patients. In this case-control study, 88 consecutive metastatic BC patients with BM (BM group) treated in our institution (2008-2015) were retrospectively selected, based on the availability of frozen serum samples for tumor marker determination. Patients were matched by age, tumor biology and number of previous metastatic chemotherapy lines to 162 metastatic BC patients without CNS involvement (control group). Serum NSE, MMP-9 and HER2 extracellular domain (ECD) levels were significantly higher in the BM group (p = 0.0051, p = 0.0062 and p = 0.0057, respectively). In multivariate analysis, serum HER2 and MMP-9 levels accurately discriminated patients with BM: odds ratios 4.4 (p < 0.001; 95%CI: 1.9-9.6) for HER2 ECD and 3.5 (p = 0.005; 95%CI: 1.5-8.4) for MMP-9. In multivariate analysis, HER2 ECD and NSE serum levels were independent prognostic factors in patients with BM. Serum HER2 ECD and MMP-9 appear to be associated with BM in metastatic BC patients. Their predictive value for BM still needs to be evaluated in further prospective studies.

Neuroendocrine Breast Carcinomas Share Prognostic Factors with Gastroenteropancreatic Neuroendocrine Tumors: A Putative Prognostic Role of Menin, p27, and SSTR-2A

“…NSE is a validated marker to identify neuronal cells and is overexpressed in small-cell carcinomas but has not previously been characterized in NEBC according to the latest WHO criteria. Serum NSE has been associated with the occurrence of breast cancer brain metastases [6]. In our patients, nuclear, cytoplasmic, and membranotic NSE expression was notably higher in NEBC than in IDC patients, but NSE was not associated with the clinicopathological prognostic factors or outcome.…”

“…The first, neuronspecific enolase (NSE) is found in neurons and other cells of neuronal origin, including neuroendocrine cells. The role of NSE has been studied in multiple cancers as well as in other diseases; increased serum NSE correlates with tuberculosis activity [4], predicts poor prognosis in smallcell lung cancer [5], and appears to be associated with brain metastases of breast cancer [6]. Because of the prognostic feature of NSE in other neuroendocrine-related cancers, the role of NSE in NEBC may be relevant.…”

Risk factors for breast cancer brain metastases: a systematic review

“…Not surprisingly, a number of proteins involved in tumor cell dissemination and BBB invasion were also found to associate with BCBM progression, including cathepsin-S [85], S100A4 [68], RANKL, RANK, Src [65], HYAL1, HAS2 [77] and prominin-1 (CD133) [37]. Darlix and colleagues also reported on serum biomarkers, originally found to reflect central nervous system damage in neurological diseases (NSE and MMP-9), to also significantly associate with BCBM progression following multivariate analysis [64].…”

“…HER2 protein expression in primary BC tumors was also found to associate with higher risk for BCBM [19,35,38,52,53,67,73,75,78] with seven studies reporting statistically significant multivariable associations (effect estimate range: 1.89 -7.039) [18,24,40,51,53,57,78]. Of note, according to the study of Darlix and colleagues, elevated serum HER2 extracellular domain was found to accurately discriminate between BC patients with and without subsequent BM (HR: 4.25, p < 0.001) [64].…”

“…Additional primary tumor markers found to associate with BCBM progression by more than one study included Ki67, EGFR, FOXC1 and CK5/6. Although different IHC staining cut-offs were used across studies, Metastatic status 4 [33,38,53,70] 3 [33,38,53] 2 Primary metastatic status M0, SHR:2.64 p = 0.007 [33]; Extracranial distant metastases, AHR=28.46, p < 0.001 [38] Number of nonbrain metastatic sites 6 [29,33,55,70,74,79] 3 [29,33,70] 5 >1 OR: 1.76, p < 0.001 [29]; ≥3, HR = 2.712, p < 0.0001 [55]; <1, sHR: 1.77 p = 0.04 [70] 1 Abnormal serum levels, HR: 3.51 p = 0.005 [64] p16 expression on metastatic lymph nodes 1 [69] 1 [69] 1 High score p = 0.01 [69] CRYAB expression 1 [63] 1 HR:1.2 p = 0.021 [63] 3q gene signature 1 [76] 1 HR: 1.61 p = 0.001 [76] GRP94 Status 2 [35,62] 1 Strong positive vs. negative [35] FN14 Status 2 [35,62] 1 Strong positive vs. negative [35] CTC status 1 [34] 1 Undetectable CTC status OR: 6.17 p = 0.001 [34] SNPs 1 [72] 1 AKT1 -RS3803304, SHR: 2.72 p = 0.008, AKT2 -RS3730050, SHR: 2.06 p = 0.041, PDK1 -RS11686903 SHR: 2.38 p = 0.001, PI3KR1 -RS706716, SHR: 2.42 p = 0.025 [72] HR -Hazard Ratio; OR -Odds Ratio; NS -Non Significant; NR -Not Reported; SHR -Subhazard ratio; IDC -Infiltrating ductal carcinoma; CTC -C...…”