title: Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data.
abstract: BACKGROUND
  Intermediate or surrogate endpoints for survival can shorten time lines for drug approval. We aimed to assess circulating tumour cell (CTC) count as a prognostic factor for survival in patients with progressive, metastatic, castration-resistant prostate cancer receiving first-line chemotherapy.
  
  
  METHODS
  We identified patients with progressive metastatic castration-resistant prostate cancer starting first-line chemotherapy in the IMMC38 trial. CTCs were isolated by immunomagnetic capture from blood samples at baseline and after treatment. Baseline variables, including CTC count, titre of prostate-specific antigen (PSA), and concentration of lactate dehydrogenase (LDH), and post-treatment variables (change in CTCs and PSA) were tested for association with survival with Cox proportional hazards models. Concordance probability estimates were used to gauge discriminatory strength of the informative factors in identifying patients at low-risk and high-risk of survival.
  
  
  RESULTS
  Variables associated with high risk of death were high LDH concentration (hazard ratio 6.44, 95% CI 4.24-9.79), high CTC count (1.58, 1.41-1.77), and high PSA titre (1.26, 1.10-1.45), low albumin (0.10, 0.03-0.39), and low haemoglobin (0.72, 0.64-0.81) at baseline. At 4 weeks, 8 weeks, and 12 weeks after treatment, changes in CTC number were strongly associated with risk, whereas changes in PSA titre were weakly or not associated (p>0.04). The most predictive factors for survival were LDH concentration and CTC counts (concordance probability estimate 0.72-0.75).
  
  
  CONCLUSIONS
  CTC number, analysed as a continuous variable, can be used to monitor disease status and might be useful as an intermediate endpoint of survival in clinical trials. Prospective recording of CTC number as an intermediate endpoint of survival in randomised clinical trials is warranted.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jia
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Derek
authors.initials: D
authors.lastname: Raghavan
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002986:Clinical Trials as Topic; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D009919:Orchiectomy; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000401:mortality* / Q000473:pathology*
chemical_list: D007770:L-Lactate Dehydrogenase; D017430:Prostate-Specific Antigen