Primary Mutational Landscape Linked with Pre-Docetaxel Lactate Dehydrogenase Levels Predicts Docetaxel Response in Metastatic Castrate-Resistant Prostate Cancer

Abstract

Background: Docetaxel chemotherapy is a standard of care for metastatic castrate-resistant prostate cancer (mCRPC): 40–50% of patients achieve a biochemical response. However, there is a lack of response predictive biomarkers. Objective: To assess lactate dehydrogenase (LDH) as a docetaxel response biomarker in mCRPC and to examine the association of LDH with genomic alterations in primary diagnostic biopsies. Design, setting, and participants: Clinical and associated primary tumour-targeted next-generation sequencing data from matched training (n = 150) and test (n = 120) cohorts of progressive mCRPC patients receiving docetaxel therapy were analysed. Data were correlated with large-scale prostate cancer genomic datasets. Outcome measurements and statistical analysis: Prostate-specific antigen (PSA) response, radiographic response, biochemical progression-free survival (PFS), overall survival (OS), genomic analysis of primary biopsies, and genomic datasets (Memorial Sloan Kettering Cancer Center [MSKCC] and SU2C/PCF). Results and limitations: Serum LDH ≥450 U/l is a reliable prognostic biomarker (area under the curve: 0.757 [standard deviation 0.054, 95% confidence interval [CI] 0.650–0.864, p < 0.001]) in progressive mCRPC, predicting PFS at 3 mo. Patients with LDH ≥450 U/l were poorer PSA responders, with shorter PFS (213 vs 372 d, hazard ratio [HR] 1.876, 95% CI 1.289–2.7300) and OS (362 vs 563 d, HR 1.630, 95% CI 1.127–2.357). High LDH is an independent surrogate marker for survival following docetaxel and predicts a poor radiological response (p = 0.043). Of the 14 patients with LDH ≥450 U/l available for next-generation sequencing, nine (64.3%) were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2, Fanconi anaemia gene) in their primary biopsy. Cross correlation with MSKCC and SU2C/PCF databases revealed a positive correlation between LDHA, PARP1 (r = 0.667, p < 0.01), and other DNA repair genes. Conclusions: Genomic abnormalities of LDHA and DNA repair in primary biopsies link to high pretreatment LDH and poor response to docetaxel in mCRPC. Patient summary: The presence of mutations of the lactate dehydrogenase and DNA repair pathways are associated with aggressive prostate cancer and poor response to chemotherapy later in the disease.