Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin.
OBJECTIVE
Accurate assessments of recurrence risk and absolute treatment benefit are needed to inform colon cancer adjuvant therapy. The 12-gene Recurrence Score assay has been validated in patients with stage II colon cancer from the Cancer and Leukemia Group B 9581 and Quick and Simple and Reliable (QUASAR) trials. We conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07.


METHODS
Recurrence Score was assessed in 892 fixed, paraffin-embedded tumor specimens (randomly selected 50% of patients with tissue). Data were analyzed by Cox regression adjusting for stage and treatment.


RESULTS
Continuous Recurrence Score predicted recurrence (hazard ratio for a 25-unit increase in score, 1.96; 95% CI, 1.50 to 2.55; P < .001), as well as disease-free and overall survival (both P < .001). Recurrence Score predicted recurrence risk (P = .001) after adjustment for stage, mismatch repair, nodes examined, grade, and treatment. Recurrence Score did not have significant interaction with stage (P = .90) or age (P = .76). Relative benefit of oxaliplatin was similar across the range of Recurrence Score (interaction P = .48); accordingly, absolute benefit of oxaliplatin increased with higher scores, most notably in patients with stage II and IIIA/B disease.


CONCLUSIONS
The 12-gene Recurrence Score predicts recurrence risk in stage II and stage III colon cancer and provides additional information beyond conventional clinical and pathologic factors. Incorporating Recurrence Score into the clinical context may better inform adjuvant therapy decisions in stage III as well as stage II colon cancer.
Greg Yothers, Michael J. O'Connell, Soonmyung Paik, Saima Sharif, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project (NSABP) Operations and Biostatistical Centers; Greg Yothers, University of Pittsburgh Graduate School of Public Health; Saima Sharif and Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA; Mark Lee, Margarita Lopatin, Kim M. Clark-Langone, and Steven Shak, Genomic Health, Redwood City, CA.
Greg
G
Yothers
Michael J
MJ
O'Connell
Mark
M
Lee
Margarita
M
Lopatin
Kim M
KM
Clark-Langone
Carl
C
Millward
Soonmyung
S
Paik
Saima
S
Sharif
Steven
S
Shak
Norman
N
Wolmark
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D015203:Reproducibility of Results; D016019:Survival Analysis
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil