Abstract
Objective: Cancer stem cell marker CD44 and its variant isoforms (CD44v) may be correlated with tumor growth, metastasis, and chemo-radiotherapy resistance. However, the prognostic power of CD44 and CD44v in advanced cancer remains controversial. Therefore, the purpose of our study was to generalize the prognostic significance of these cancer stem cell markers in advanced cancer patients.Methods: Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated from multivariable analysis to assess the associations among CD44, CD44v6, and CD44v9 positivity and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), and recurrence-free survival (RFS). Trial sequential analysis (TSA) was also conducted.Results: We included 15 articles that reported on 1,201 patients with advanced cancer (CD44: nine studies with 796 cases, CD44v6: three studies with 143 cases, and CD44v9: three studies with 262 cases). CD44 expression was slightly linked to worse OS (HR = 2.03, P = 0.027), but there was no correlation between CD44 expression and DFS, RFS, or PFS. Stratified analysis showed that CD44 expression was not correlated with OS at ≥5 years or OS in patients receiving adjuvant therapy. CD44v6 expression was not associated with OS. CD44v9 expression was closely associated with poor 5-years CSS in patients treated with chemo/radiotherapy (HR = 3.62, P < 0.001). However, TSA suggested that additional trials were needed to confirm these conclusions.Conclusions: CD44 or CD44v9 might be novel therapeutic targets for improving the treatment of advanced cancer patients. Additional prospective clinical trials are strongly needed across different cancer types.
Highlights
Cancer remains a pressing worldwide health issue [1], surgery, chemotherapy, radiotherapy therapy, and targeted molecular therapy have greatly changed clinical outcomes for cancer patients in recent years
CD44 standard (CD44s) or CD44v6 expression has been shown to be correlated with poor overall survival (OS) in gastric cancer [19], but CD44 or CD44v6 expression has been found to not be correlated with OS in ovarian cancer [20]; these findings suggest that some prognostic information regarding CD44 is still conflicting
Eligible publications were included when the given eligibility criteria were satisfied: [1] studies reporting patients with advanced/metastatic cancer or stage III cancer or stage IV cancer; [2] studies investigating the prognostic value of the expression of CD44 and its isoforms using immunohistochemical (IHC) assays; [3] studies reporting multivariable survival analysis with hazard ratio (HR) with 95% confidence interval (CI) for overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), relapse/recurrence-free survival (RFS), metastasis-free survival (MFS) or cancer-specific survival (CSS); [4] In the case of insufficient data, such as only P-value with HR or only the 95% CI, HR and 95% CI were calculated using the previously described method [22, 23], or the corresponding author with an available email was contacted to request the relevant information
Summary
Cancer remains a pressing worldwide health issue [1], surgery, chemotherapy, radiotherapy therapy, and targeted molecular therapy have greatly changed clinical outcomes for cancer patients in recent years. Advanced cancer patients (advanced-stage or metastatic disease) are resistant to chemotherapy, radiotherapy and targeted therapies (due to secondary mutations). The prognosis of patients with advanced cancer remains very poor such as a low 5-years survival rate [2,3,4,5,6]. It varies; for example, the 5-years survival rate is 14% for advanced colorectal cancer and 29% for advanced ovarian cancer [7]. Novel molecular therapeutic targets to prolong survival in advanced cancer are warranted and could help physicians to stratify cancer patients
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