Prognostic significance of metabolic enzyme pyruvate kinase M2 in breast cancer: A meta-analysis

Abstract

Backgrounds: Numerous studies have reported that aberrant pyruvate kinase M2 isoform (PKM2) expressed in cancer, indicating that PKM2 plays a critical role in tumor initiation and progression. Nevertheless, its prognostic value in breast cancer tumor is yet contentious. Therefore, we performed this meta-analysis to evaluate the prognostic significance of PKM2 in breast cancer.

Methods: Eligible relevant literatures were retrieved by searching PubMed, the Cochrane Library, Embase through December 2016. Articles that comparing different PKM2 expression levels in human breast cancer tissues and prognostic significance were included. Software RevMan 5.3 and STATA (Review Manager (RevMan): [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Stata: StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP) were applied to analyze the outcomes. Pooled results were presented in hazardous ratios (HRs) of 5-year overall survival (OS), progression-free survival (PFS), and odds ratios (ORs) of clinicopathological features with 95% confidence intervals.

Results: Data from 6 involved studies with 895 patients were summarized. Breast cancer patients with high PKM2 had a worse OS (pooled HR = 1.65, 95% CI = 1.31-2.08, P < .001) and PFS (pooled HR = 2.49, 95% CI = 1.84-3.36, P < .00001). High PKM2 expression is related to lymph node metastasis (N1+N2+N3 vs N0, OR = 1.97, 95%CI = 1.39-2.80, P = .0001). The outcome stability was verified via sensitivity analysis. But elevated PKM2 expression was not correlated to tumor stage (T2+T3 vs T1, pooled OR = 0.80, 95% CI = 0.36-1.77, P = .58) and differential grade (G2+G3 vs G1, OR = 2.74, 95%CI = 0.76-9.84, P = .12). No publication bias was found in the included studies for OS (Begg test, P = .260; Egger test, P = .747).

Conclusions: High PKM2 expression denotes worse OS and PFS in breast cancer patients, and correlate with the lymph node metastasis. However, there is no evidence for the impact of PKM2 expression on T stage and tumor differentiation.

Figure 1

Study flow diagram for this meta-analysis.

Figure 2

PKM2 expression and the 5-year OS. Six included studies investigated the correlation between PKM2 expression and OS. High PKM2 expression was highly correlated with a worse OS (HR = 1.65, 95%CI = 1.31–2.08, P < .001, fixed effect model). A subgroup analysis for ethnicity was performed, PKM2 is not a negative prognostic factor in Caucasians (HR = 0.67, 95%CI: 0.34–1.32, P = .25), but still a negative prognostic factor in Asians (HR = 1.85, 95%CI = 1.31–2.08, P < .00001). CI = confidence interval, HR = hazardous ratio, PKM2 = pyruvate kinase M2 isoform.

Figure 3

PKM2 expression and 5-year PFS. Three included studies investigated the correlation between PKM2 expression and PFS. High PKM2 expression was highly correlated with a poor PFS (HR = 2.49, 95%CI = 1.84–3.36, P < .0001, fixed effect model). CI = confidence interval, HR = hazardous ratio, PFS = progression-free survival, PKM2 = pyruvate kinase M2 isoform.

Figure 4

PKM2 expression and T stage. Elevated PKM2 expression was not correlated to tumor stage (T2+T3 vs T1, OR = 0.80, 95%CI = 0.36–1.77, P = .58, random effect model). CI = confidence interval, OR = odds ratio, PKM2 = pyruvate kinase M2 isoform.

Figure 5

PKM2 expression and N stage. High PKM2 expression was related to lymph node metastasis (N1+N2+N3 vs N0, OR = 1.97, 95%CI = 1.39–2.80, P = .0001, fixed effect model). CI = confidence interval, OR = odds ratio, PKM2 = pyruvate kinase M2 isoform.

Figure 6

PKM2 expression and tumor differentiation. Differential grade was not correlated to PKM2 expression level (G2+G3 vs G1, OR = 2.74, 95%CI = 0.76–9.84, P = .12, random effect model). CI = confidence interval, OR = odds ratio, PKM2 = pyruvate kinase M2 isoform.

Figure 7

Funnel plots to evaluate publication bias of included studies for OS. OS = overall survival.