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Validation study of MARCKSL1 as a prognostic factor in lymph node-negative breast cancer patients.

ABSTRACT: Protein expression of Myristoylated alanine-rich C kinase substrate like-1 (MARCKSL1) has been identified as a prognostic factor in lymph-node negative (LN-) breast cancer patients. We aim to validate MARCKSL1 protein expression as a prognostic marker for distant metastasis-free survival (DMFS) in a new cohort of LN- breast cancer patients. MARCKSL1 expression was evaluated in 151 operable T1,2N0M0 LN- breast cancer patients by immunohistochemistry. Median follow-up time was 152 months, range 11-189 months. Results were compared with classical prognosticators (age, tumor diameter, grade, estrogen receptor, and proliferation) using single (Kaplan-Meier) and multivariate (Cox model) survival analysis. Thirteen patients (9%) developed distant metastases. With both single and multiple analysis of all features, MARCKSL1 did not show a significant prognostic value for DMFS (p = 0.498). Of the assessed classical prognosticators, only tumor diameter showed prognostic value (hazard ratio 9.3, 95% confidence interval 2.8-31.0, p <0.001). MARCKSL1 expression could not be confirmed as a prognostic factor in this cohort. Possible reasons include changes in diagnostic and treatment guidelines between the discovery and validation cohorts. Further studies are needed to reveal the potential biological role of this protein in breast cancer.

SUBMITTER: Egeland NG

PROVIDER: S-EPMC6411117 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Validation study of MARCKSL1 as a prognostic factor in lymph node-negative breast cancer patients.

Egeland Nina Gran NG Austdal Marie M van Diermen-Hidle Bianca B Rewcastle Emma E Gudlaugsson Einar G EG Baak Jan P A JPA Skaland Ivar I Janssen Emiel A M EAM Jonsdottir Kristin K

PloS one 20190311 3

Protein expression of Myristoylated alanine-rich C kinase substrate like-1 (MARCKSL1) has been identified as a prognostic factor in lymph-node negative (LN-) breast cancer patients. We aim to validate MARCKSL1 protein expression as a prognostic marker for distant metastasis-free survival (DMFS) in a new cohort of LN- breast cancer patients. MARCKSL1 expression was evaluated in 151 operable T1,2N0M0 LN- breast cancer patients by immunohistochemistry. Median follow-up time was 152 months, range 11 ...[more]

PMID: 30856208

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Project description:BackgroundDual-targeted therapy is currently the standard adjuvant treatment for human epidermal growth factor receptor 2-positive (HER2+) and lymph node-positive (LN+) breast cancer. However, the optimal therapeutic strategy for patients with HER2+ and lymph node-negative (LN-) breast cancer remains unclear. This population-based study aimed to explore the factors associated with survival in patients with HER2+ and LN- breast cancer, and develop a survival-predicting nomogram in the era of trastuzumab-based single-targeted therapy.MethodsWe collected the clinicopathological information of HER2+ and LN- breast cancer patients who underwent chemotherapy and surgery from The Surveillance, Epidemiology, and End Results (SEER) database (2010-2016, the Trastuzumab-based single-targeted therapy era). We subsequently explored the risk factors for breast cancer-specific survival (BCSS) and overall survival (OS) using a Cox proportional hazards regression model, aiming to identify subgroups with worse prognosis, which would indicate potential demand for dual-targeted therapy. Three- and 5-year survival probability-predictive nomograms were established and subjected to bootstrap internal validation. The concordance index (C-index) and calibration curve were applied to evaluate the performance of the model.ResultsAfter data cleansing, a total of 13,755 patients were included in the current analysis. Using univariate and multivariate Cox proportional hazards regression, higher clinical T stage, hormone receptors-negative (HR-), and partial mastectomy without radiotherapy were identified as independent risk factors for BCSS and OS in patients with HER2+ and LN- breast cancer. Nomograms for 3- and 5-year BCSS and OS incorporating the selected prognostic factors were established. Calibration curves verified good consistency between the actual and nomogram-predicted survival probability. The C-index values of the BCSS and OS predictions and 95% confidence interval (CI) were 0.773 (0.740-0.806) and 0.764 (0.737-0.791), respectively.ConclusionsHigher clinical T stage, HR-, and partial mastectomy without radiotherapy predicted worse prognosis in patients with HER2+ and LN- breast cancer. In clinical practice, patients can be recommended for single-targeted or dual-targeted therapy according to the individualized factors.

Project description:IntroductionThe overall survival rate is good for lymph-node-negative breast cancer patients, but they still suffer from serious over- and some undertreatments. Prognostic and predictive gene signatures for node-negative breast cancer have a high number of genes related to proliferation. The prognostic value of gene sets from commercial gene-expression assays were compared with proliferation markers.MethodsIllumina WG6 mRNA microarray analysis was used to examine 94 fresh-frozen tumour samples from node-negative breast cancer patients. The patients were divided into low- and high-risk groups for distant metastasis based on the MammaPrint-related genes, and into low-, intermediate- and high-risk groups based on the recurrence score algorithm with genes included in Oncotype DX. These data were then compared to proliferation status, as measured by the mitotic activity index, the expressions of phosphohistone H3 (PPH3), and Ki67.ResultsKaplan-Meier survival analysis for distant-metastasis-free survival revealed that patients with weak and strong PPH3 expressions had 14-year survival rates of 87% (n=45), and 65% (n=49, p=0.014), respectively. Analysis of the MammaPrint classification resulted in 14-year survival rates of 80% (n=45) and 71% (n=49, p=0.287) for patients with low and high risks of recurrence, respectively. The Oncotype DX categorization yielded 14-year survival rates of 83% (n=18), 79% (n=42) and 68% (n=34) for those in the low-, intermediate- and high-risk groups, respectively (p=0.52). Supervised hierarchical cluster analysis for distant-metastasis-free survival in the subgroup of patients with strong PPH3 expression revealed that the genes involved in Notch signalling and cell adhesion were expressed at higher levels in those patients with distant metastasis.ConclusionThis pilot study indicates that proliferation has greater prognostic value than the expressions of either MammaPrint- or Oncotype-DX-related genes. Furthermore, in the subgroup of patients with high proliferation, Notch signalling pathway genes appear to be expressed at higher levels in patients who develop distant metastasis.

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Validation study of MARCKSL1 as a prognostic factor in lymph node-negative breast cancer patients.

Publications

Validation study of MARCKSL1 as a prognostic factor in lymph node-negative breast cancer patients.

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