title: Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients.
abstract: OBJECTIVE
  The initial clinical response to platinum is a major determinant of outcome for patients with ovarian cancer. This retrospective study was undertaken to correlate the response and survival of newly diagnosed advanced ovarian cancer patients who received platinum-based therapy with in vitro drug response to cisplatin or carboplatin measured as percentage cell inhibition (PCI) in the in vitro Extreme Drug Resistance (EDR) assay.
  
  
  METHODS
  Outcomes for newly diagnosed ovarian cancer patients with tumor specimens submitted in a serial fashion for the EDR assay were studied. EDR assay results for cisplatin and carboplatin were correlated with clinical outcome for 79 evaluable chemotherapy nai;ve cases who presented with advanced (stages IIC, III, and IV) ovarian cancer. Stage IV and suboptimally debulked stage IIIc accounted for 16 cases, while 63 cases were optimally debulked Stage III/IIc. All patients were treated with platinum-based combination chemotherapy at a single institution. In vitro results for patient tumors were classified as low drug resistance (PCI > median), intermediate drug resistance [PCI between the median and 1 standard deviation (SD) below the median], or extreme drug resistance (PCI more than 1 SD below the median). For the purpose of this analysis, in vitro EDR to either cisplatin or carboplatin was considered to represent extreme resistance to platinum (EDRP), while the absence of EDR to either cisplatin or carboplatin was considered to represent low resistance to platinum (LDRP). Patients demonstrating relative in vitro resistance to paclitaxel and non-cross-resistance to cyclophosphamide and/or doxorubicin received cyclophosphamide plus platinum (CP); cyclophosphamide, doxorubicin, and platinum (CAP); or platinum alone in place of paclitaxel plus platinum (TP). Progression-free survival (PFS) and overall survival (OS) were correlated with EDR assay results.
  
  
  RESULTS
  Median PFS was 6 months for the 17 cases exhibiting EDRP, compared to 24 months for the 62 cases exhibiting LDRP in vitro [relative risk (RR) 3.78, confidence intervals (CI) 1.82-7.83], adjusted for stage, debulking status, in vitro response to 3-OH-cyclophosphamide, and histological grade. Estimated overall 5-year survival was 19% for patients with tumors showing EDRP, compared to 68% for patients with tumors showing LDRP (RR 2.32, CI 1.06-5.07). Patients treated with CP (n = 20) showed no significant difference in OS compared to patients treated with TP (n = 54), CAP (n = 4), or cisplatin (n = 1) alone. In vitro platinum response remained an independent predictor of PFS and OS in multivariate analyses adjusted for CP versus TP, CAP, or platinum administration, and adjusted for debulking status. Median PFS for all 79 patients was 22 months, with an estimated 5-year survival of 57%.
  
  
  CONCLUSIONS
  Patients with tumors demonstrating in vitro EDR to platinum were at significantly increased risk for progression and death when treated with standard platinum-based regimens. Such patients may therefore benefit from entry onto trials with novel agents or combinations.
authors.affiliation: Walt Disney Memorial Cancer Institute at Florida Hospital, Orlando, FL 32804, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Holloway
authors.forename: Rita S
authors.initials: RS
authors.lastname: Mehta
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Finkler
authors.forename: Kuo-Tung
authors.initials: KT
authors.lastname: Li
authors.forename: Christine E
authors.initials: CE
authors.lastname: McLaren
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Parker
authors.forename: John P
authors.initials: JP
authors.lastname: Fruehauf
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin