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    • Globally the total number of patients included in

    2023-01-21

    Globally, the total number of patients included in the meta-analysis was 1885, ranging from 40 to 442 patients per study. All eligible studies reported the association between ALDH1 expression and patients' OS [24-26, 3241], whereas nine studies evaluated the relationship between ALDH1 expression and patients' PFS [24,25,33,[35], [36], [37], [38], [39], [40], [41]]. Seven [[24], [25], [26],32,33,35,41], nine [[24], [25], [26],32,33,35,37,40,41], five [25,26,32,33,38] and five [26,32,35,38,41] studies reported data regarding the association between ALDH1 expression and tumor histology, FIGO stage, tumor grading, and patients' lymph nodal status, respectively. Data regarding the relationship with patients' age could be pooled from 4 studies [25,32,37,40]. ALDH1 expression was evaluated by WS IHC in 8 studies [25,26,32,[35], [36], [37], [38],41] and by TMA IHC in 5 studies [24,33,34,39,40]. The main characteristics of the selected studies were listed in Table 1.
    Discussion With the Era of Precision Medicine and Personalized Care advent, the identification of cancer molecular biomarkers and their impact on the natural course of patients' disease has become the basic challenge for researchers worldwide searching for new oncologic targets. In the last 20 years, as a result of NGS technology progress and novel bioinformatic tools, a big panel of new cancer biomarkers has been identified with the final aim of targeting the poor prognostic biomolecular factors in individual patients based on specific characteristics of their disease. In this context, cancer stem sta 90 biomarkers appear to be particularly attractive, since this special cancer cell subpopulation have shown to trigger and sustain oncogenesis, tumor progression and chemoresistance [7,8,19,42]. Several experimental studies showed that ALDH1-expressing cancer cells exhibit stem-like properties, due to their self-renewal, high proliferative and high coloning capabilities, as well as cancer initiating properties, in different solid tumor setting [[14], [15], [16], [17], [18]]. In ovarian cancer setting, the role of ALDH1 in predicting patients' survival outcome and clinico-pathological characteristics remains debated. With the present meta-analysis, we observed that ALDH1 hyper-expression within the tumor tissue was significantly correlated with poor patients' 5-year OS and 5-year PFS, although ALDH1 status did not influence FIGO Stage, tumor grading, lymph nodal status and patients' age at diagnosis. Furthermore, although not significant, there was a strong tendency towards significance (p = 0.06) for ALDH1-positive tumors to have a non-serous histology. This is in line with 3 out of 7 included studies [24,25,33], reporting a higher percentage of mucinous and/or endometrioid cases among ALDH1-positive tumors. The first data about ALDH1 expression in cancer tissue traced back to 1996, when its expression profile was analyzed in a lung cancer mouse model [43]. Approximately 10 years later, a study carried out on human retinoblastoma firstly highlighted the role of ALDH1 as potential cancer stem cell biomarker [44]. In the last decade, many studies have been carried out to identify the cancer stem-like cells expression profile in solid tumors and, to date, different cell surface molecules such as CD133, CD44, CD24, CD117 and ABCG2 have been indicated as putative cancer stem cell markers in ovarian cancer [42]. Future analysis on the expression profiles of different ovarian cancer stem-like cells biomarkers within primary tumor and their relationship with patients' survival, may clarify the future potentials of translating the cancer stem-like cells concept into the clinical practice of ovarian cancer management. To our knowledge, the present meta-analysis is the first study, which systematically investigates the role of the cancer stem-like cell biomarker ALDH1 expression in ovarian cancer patients' prognosis and clinico-pathological characteristics. Involving 1885 patients, our results may be more reliable than single studies. Nevertheless, our findings may be accompanied by some limitations. First, the cut off value for determining a “high” ALDH1 expression was heterogeneous among studies. In some cases only the percentage of ALDH1-expressing cancer cells was considered for the definition of ALDH1-high group of patients [24,26,33,35,37]; in other cases, an immunoreactive score (IRS), taking into account the cell percentage together with the intensity of the staining (negative, weak, moderate, strong) has been applied [25,32,34,36,40]. In order to limit the heterogeneity among studies, only studies adopting IHC on whole slides or TMA as ALDH1 expression-detecting method were included. Furthermore, in order to fully understand the role of ALDH1 in the regulation of stemness within ovarian cancer tissue and its significance for disease progression, studies adopting other methodological readouts in large prospective series, such as detection of live ALDH1-positive cells in xenograft models, alone or in combination with other candidate markers, will have a clarifying role.