Abstract P5-08-38: Low lactate dehydrogenase B expression correlates with decreased distant-metastasis free- and recurrence-free survival post-chemotherapy in basal-like breast cancer

Abstract

Abstract Background: Metabolism is an important differentiating feature of cancer cells. Lactate dehydrogenases (LDH A/B) are metabolically important proteins involved in the critical inter-conversion of pyruvate to lactate and vice versa. Several reports suggest that LDHB levels are elevated in TNBC, compared to other breast cancer subtypes. However, we recently published that LDHB levels are low in TNBC cell lines and restoring LDHB results in decreased cell proliferation, oxidative phosphorylation, and reversal of EMT. Furthermore, in a small patient cohort, we have shown that although LDHB levels are higher in TNBC patients compared to non-TNBC patients, LDHB levels where consistently lower when compared to LDHA levels. Thus, we set out to determine if either "Hi" or "Low" LDHA and LDHB levels effect patient survival. Methods: Utilizing the publically available datasets contained within kmplot,which contains gene expression data and relapse free and overall survivall, we determined mean levels of LDHA and LDHB in breast cancer patients. To analyze the prognostic value, patient samples were split into two groups based upon expression above the mean (considered high expressors, "Hi") or below the mean (considered low expressors, "Low"). The two patient cohorts were compared by a Kaplan-Meier survival plot, and the hazard ratio with 95% confidence intervals and logrank P value calculated. Groups were further stratified based upon LDH levels prior to- and post-chemotherapy. Results: We found that in patients with luminal A and luminal B breast cancer, there were no significant changes in either LDHA (p=0.1) or LDHB (p=0.21) on distant metastasis-free (DMFS) or recurrence–free (RFS) survival. However, in the basal subtype (i.e. patients with ER negative and PR negative breast cancer), low levels of LDHB was significantly associated with poorer DMFS (p=0.025) (n=240) prior to chemotherapy and both DMSF (p=0.048) (n=176) and RFS (p=0.0082) (n=388) post-chemotherapy. Examining the mean expression values for each of these patient populations, we did not observe any significant changes in DMSF or RFS pre or post-chemotherapy, suggesting an intrinsic feature of basal-like patients with low LDHB expression to have a more aggressive phenotype. Interestingly, we did observe significance in RFS (n=581, p=0.0043) in patient with "Hi" LDHA expression pre-chemotherapy, however there was no significant associations of LDHA with RFS (p=0.19) (n=388) or DMSF (n=176, p=0.75) post-chemotherapy. Conclusion: These findings, coupled with our cell line data, showing overexpressing LDHB in TNBC cell lines results in decreased proliferation with increased mitochondrial damage and apoptosis, suggests that lower levels of LDHB expression is indeed associated with an aggressive breast cancer phenotype that undergoes EMT and the Warburg effect. This could contribute to the lack of pathological response after chemotherapy and thus increased risk for later metastasis. Additionally, given the very large number of patients examined within these independent datasets, these findings further suggest that low LDHB expression is a robust prognostic biomarker of clinical outcome in patients with a basal-like phenotype. Citation Format: Dean-Colomb W, Tan M, Tang W, Ambs S, Yates C. Low lactate dehydrogenase B expression correlates with decreased distant-metastasis free- and recurrence-free survival post-chemotherapy in basal-like breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-38.