Lactate dehydrogenase B: A metabolic marker of response to neoadjuvant chemotherapy in breast cancer

Jennifer B. Dennison, Jennifer R. Molina, Shreya Mitra, Ana M. González-Angulo, Justin M. Balko, María G. Kuba, Melinda E. Sanders, Joseph A. Pinto, Henry L. Gómez, Carlos L. Arteaga, Robert E. Brown, Gordon B. Mills

    Research output: Contribution to journalArticle

    58 Scopus citations

    Abstract

    Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less well-understood and may predict response to chemotherapy. This study aimed to evaluate metabolic genes as individual predictive biomarkers in breast cancer. Experimental Design: mRNA microarray data from breast cancer cell lines were used to identify bimodal genes - those with highest potential for robust high/low classification in clinical assays. Metabolic function was evaluated in vitro for the highest scoring metabolic gene, lactate dehydrogenase B (LDHB). Its expression was associated with neoadjuvant chemotherapy response and relapse within clinical and PAM50-derived subtypes. Results: LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Stable knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using patient datasets, LDHB was highly expressed in basal-like cancers and could predict basallike subtype within clinical groups [OR = 21 for hormone receptor (HR)-positive/HER2-negative; OR = 10 for triple-negative]. Furthermore, high LDHB predicted pathologic complete response (pCR) to neoadjuvant chemotherapy for both HR-positive/HER2-negative (OR = 4.1, P < 0.001) and triple-negative (OR = 3.0, P = 0.003) cancers. For triple-negative tumors without pCR, high LDHB posttreatment also identified proliferative tumors with increased risk of recurrence (HR = 2.2, P = 0.006). Conclusions: Expression of LDHB predicted response to neoadjuvant chemotherapy within clinical subtypes independently of standard prognostic markers and PAM50 subtyping. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for patients with breast cancer receiving neoadjuvant chemotherapy.

    Original languageEnglish (US)
    Pages (from-to)3703-3713
    Number of pages11
    JournalClinical Cancer Research
    Volume19
    Issue number13
    DOIs
    StatePublished - Jul 1 2013

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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    Dennison, J. B., Molina, J. R., Mitra, S., González-Angulo, A. M., Balko, J. M., Kuba, M. G., Sanders, M. E., Pinto, J. A., Gómez, H. L., Arteaga, C. L., Brown, R. E., & Mills, G. B. (2013). Lactate dehydrogenase B: A metabolic marker of response to neoadjuvant chemotherapy in breast cancer. Clinical Cancer Research, 19(13), 3703-3713. https://doi.org/10.1158/1078-0432.CCR-13-0623