As reported by Alan P. Venook, MD, Professor of Medicine (Hematology/Oncology) at the University of California, San Francisco, and colleagues in Journal of Clinical Oncology, a 12-gene recurrence score (Oncotype DX Colon Cancer Assay) was shown to predict recurrence in stage II colon cancer in a validation study performed in the population of the Cancer and Leukemia Group B (CALGB) 9581 trial.1 These findings are consistent with those in a validation study of the assay performed in patients with stage II disease in the QUASAR study.2
The recurrence score appears to have greatest discerning power in patients with stage T3 mismatch repair gene–intact tumors. Given the lower recurrence risk observed in patients with mismatch repair–deficient vs mismatch repair–intact tumors, the ability to discriminate risk in patients with T3 mismatch repair–intact tumors may have implications for use of adjuvant therapy in such patients.
The 12-gene recurrence score is calculated from a validated and standardized quantitative reverse transcriptase polymerase chain reaction assay that measures the expression of seven “recurrence” genes and five reference genes in formalin-fixed paraffin-embedded primary colon tumor tissue. Six of the recurrence genes are in the key biologic pathways of cell cycle control (MKI67, MYC, MYBL2) and stromal response (FAP, BGN, INHBA); the seventh (GADD45B) is a marker of genotoxic stress and may regulate activity of stromal response genes.
In CALGB 9581, 1,713 patients with stage II colon cancer were randomly assigned to treatment with the investigational monoclonal antibody edrecolomab or observation, with no survival difference found between groups. The current analysis included all 162 patients in the trial with recurrence of disease and available tissue and 528 randomly selected patients (approximately 1:3) without recurrence.
Predictors of Recurrence
Recurrence score values ranged from 2 to 78, with a median of 31.4 and a mean of 33. Continuous recurrence score was significantly associated with risk of recurrence on the primary Cox proportional hazards analysis, with a hazard ratio (HR) of 1.52 for each 25-unit increase in score (P = .013).
Estimates of 5-year recurrence risk according to predefined percentile thresholds for low risk (below 40th percentile, which corresponded to a recurrence score of 29), medium risk (40th to 75th percentile, which corresponded to a recurrence score of 39), and high risk (above 75th percentile) were 12%, 15%, and 18%, respectively. On univariate analysis, the only other factor significantly associated with risk was mismatch repair–deficiency (HR = 0.62, P = .044, vs mismatch repair–intact status). Presence of lymphovascular invasion was associated with borderline significantly increased risk (HR = 1.56, P = .062).
On multivariate analysis including mismatch repair status (deficient vs intact), T stage (T4 vs T3), number of lymph nodes examined (< 12 vs ≥ 12), tumor grade (high vs low), lymphovascular invasion (present vs absent), and continuous recurrence score, only recurrence score was a significant predictor of recurrence (HR = 1.62 per 25 units, P = .004).
In a model examining the contribution of the recurrence score to prediction of recurrence in the context of mismatch repair status and T stage (which are consistent prognostic covariates in stage II colon cancer), recurrence score (P = .007) and mismatch repair status (P = .02) were significant predictors. Among patients with T3 mismatch repair–intact tumors (75% of those with mismatch repair results, the largest subgroup in the study), 44% were in the low recurrence score group and 22% were in the high recurrence score group. Estimated 5-year recurrence risks for the prespecified low-, intermediate-, and high-risk subgroups among these patients were 13%, 16%, and 21%, respectively.
Potential Drug Targets?
The authors noted that the results of the CALGB 9851 and QUASAR analyses are consistent with the involvement of cell-cycle control and stromal response as determinants of recurrence in colon cancer, and that it is plausible that directing inhibitors toward elements of the pathways identified in the recurrence score could lead to the development of new adjuvant therapies for colon cancer.
The authors concluded:
Following on the results of QUASAR, the results presented here confirm the accuracy of the standardized, validated recurrence score and its relevance for patients with T3 [mismatch repair–gene] intact tumors, in which further risk discrimination may be factored into the decision of whether or not to offer adjuvant chemotherapy. In addition, the genes comprising the recurrence score highlight biologic pathways that may be most responsible for cancer recurrence and represent genes that should be interrogated further to identify promising [drug] targets…. Hopefully, the results presented here will lead to both immediate and future improvements in treatment for patients with colorectal cancer. ■
Disclosure: Among the study authors, Margarita Lopatin, Mark Lee, Kim Clark-Langone, Carl Millward, and Steven Shak reported employment or leadership positions with and stock ownership of Genomic Health, Richard L. Schilsky reported a consultant or advisory role with Foundation Medicine and stock ownership of Foundation Medicine and Universal Oncology, and Alan P. Venook reported research funding from Genomic Health. All other authors reported no potential conflicts of interest.
1. Venook AP, Niedzwiecki D, Lopatin M, et al: Biologic determinants of tumor recurrence in stage II colon cancer: Validation study of the 12-gene recurrence score in Cancer and Leukemia Group B (CALGB) 9581. J Clin Oncol. March 25, 2013 (early release online).
2. Gray RG, Quirke P, Handley K, et al: Validation study of a quantitative multigene reverse transcriptase polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol 29:4611-4619, 2011.
Patients with stage II colon cancer generally have a favorable prognosis, with about 80% of patients surviving 5 years after surgery and the majority of these long-term survivors presumed to be cured. Clearly though, some patients are destined to recur after surgery, and there is an urgent need to...
Mismatch repair genes are involved in numerous cellular functions, including the recognition and correction of errors in DNA replication. Germline mutations of mismatch repair genes have been shown to be involved in various types of cancer. ■