Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin.
OBJECTIVE
These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients.


METHODS
We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06.


RESULTS
A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV.


CONCLUSIONS
RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study.
O'Connell
Michael J
MJ
National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh, Pittsburgh, PA 15212, USA. michael.oconnell@nsabp.org
Lavery
Ian
I
Yothers
Greg
G
Paik
Soonmyung
S
Clark-Langone
Kim M
KM
Lopatin
Margarita
M
Watson
Drew
D
Baehner
Frederick L
FL
Shak
Steven
S
Baker
Joffre
J
Cowens
J Wayne
JW
Wolmark
Norman
N
D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002955:Leucovorin; D005472:Fluorouracil