Abstract P2-10-07: Stem cell marker aldehyde dehydrogenase 1 in stromal cells strongly correlates with prognosis in breast cancer
Authors: Sjöström M , Hartman L , Holmdahl J , Grabau D , Malmström P , Fernö M , Niméus-Malmström E 
Published: August 2014

Abstract
Background: Breast cancer stem cells have the potential to provide prognostic information and be a therapeutic target. Aldehyde dehydrogenase 1 (ALDH1) is a widely used marker for cells with stem cell properties. The aim of this study was to evaluate the prognostic information of ALDH1, and its correlation with other clinical variables in early breast cancer.
Material and methods: ALDH1 expression was investigated by immunohistochemistry in tissue microarrays of breast tumors from 220 premenopausal node-negative breast cancer patients, mainly not subjected to any adjuvant systemic treatment. Cancer cells were evaluated for both staining intensity (negative, weak, moderate and strong) and percentage of stained cells. Stromal cells were evaluated for staining intensity. Spearman's rank correlation was used to investigate correlation with continuous clinical variables, the Jonckheere-Terpstra Test for ordinal variables and Mann-Whitney for binary variables. For survival analysis with 5 years of follow-up the Kaplan-Meier method and Log-rank test for trend were used with distant disease-free survival (DDFS) as endpoint. Cox regression analysis was used to obtain hazard ratios, and for multivariate modeling.
Results: ALDH1 staining intensity in stroma correlated positively with both ER and PR (p = 0.004 and p = 0.001). Stroma staining intensity was negatively correlated with Ki67 expression and high histological grade (p = 0.002 and p = 0.002). There was no significant correlation of stroma intensity with age, HER2 or tumor size. Stroma intensity showed a strong correlation with increased DDFS (Log-rank test for trend p = 0.007).
Both ALDH1 staining intensity in cancer cells as well as percentage of positively stained cancer cells correlated negatively with PR status (p = 0.08 and p = 0.03) while no correlation was found for ER (p = 0.65 and p = 0.59). Staining intensity and percentage of positively stained cancer cells correlated positively with Ki67 expression (p = 0.03 and p = 0.02). Cancer cell intensity showed a tendency of positive correlation with high histological grade (p = 0.07). There was no correlation of percentage of positively stained cancer cells with histological grade (p = 0.21), nor of staining intensity and percentage of positively stained cancer cells with HER2, tumor size, or age at diagnosis. Cancer cell intensity and percentage of positive cancer cells showed no correlation with DDFS (log rank test for trend p = 0.79 and p = 0.78).
A multivariate model of ALDH1 in stroma including ER, HER2, Ki67, age (continuous), and tumor size showed that ALDH1 was an independent prognostic marker (p = 0.036). Interestingly, ALDH1 in stroma (HR 0.58, mean per step in intensity) had stronger influence on the prognosis than ER status (HR 1.12), Ki67 (HR 1.62) and tumor size (HR 1.17).
Conclusion: Strong ALDH1 staining intensity in stromal cells, in comparison with negative or weak staining, is a strong marker for increased DDFS in breast cancer and outperforms well-known prognostic markers such as ER, Ki67 and tumor size as an independent prognostic marker. The finding that stromal cell staining is correlated to DDFS may be an indication of the importance of the tumor microenvironment.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-07.