Clinical Summary

Validated Clinical Benefits of the Oncotype DX®
Colon Recurrence Score

Stage II

The landmark QUASAR (Quick and Simple and Reliable) clinical validation study demonstrated that the Oncotype DX Colon Recurrence Score predicts recurrence risk in Stage II colon cancer patients following surgery. The Oncotype DX test provides an individualized Colon Recurrence Score result, providing patient-specific information when deciding which of your Stage II colon cancer patients should be most appropriately considered for post-surgical chemotherapy treatment.

The Colon Recurrence Score result is based upon the quantitative expression of 7 cancer genes identified as consistently and significantly associated with recurrence free interval (RFI) in the 1,851 patients from the development studies. These 7 cancer genes include the cell cycle group (Ki-67, MYBL2, C-MYC), the stromal group (FAP, INHBA, BGN) and GADD45B. The pre-specified Colon Recurrence Score result gene panel was validated in 1,436 Stage II colon cancer patients with tissue from the QUASAR trial.

Gene Panel

QUASAR – Largest Randomized Study of Observation versus Adjuvant 5FU/LV in Stage II Colon Cancer

  • 2,146 patients with Stage II colon cancer participated in this landmark randomized study to determine the benefit of adjuvant 5FU/LV chemotherapy compared to surgery alone
  • Total QUASAR enrollment (n=3,239) included Stage III and rectal cancer patients
  • 5FU/LV produced a 20% relative risk reduction for both recurrence and survival in Stage II colon cancer, with an absolute benefit of approximately 3-4%
  • Tumor specimens were available for nearly 70% of Stage II colon cancer patients in QUASAR

QUASAR

QUASAR Validation Study: A Quantitative Multi-Gene Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) Assay for Prediction of Recurrence in Stage II Colon Cancer

The QUASAR validation study results strongly support a new paradigm for assessing risk of recurrence in Stage II colon cancer, emphasizing the critical role of three measures: Colon Recurrence Score result, Mismatch Repair/Microsatellite Instability (MMR/MSI) and T-stage.

  • QUASAR validated the Oncotype DX Colon Recurrence Score in 1,436 Stage II colon cancer patients using prospectively defined endpoints including recurrence-free interval (RFI), disease-free survival (DFS), and overall survival (OS).
  • In the primary analysis, the continuous Colon Recurrence Score value was significantly associated with recurrence risk (P=0.004), with a near linear relationship between Colon Recurrence Score value and risk of recurrence. 3 year colon cancer recurrence risk ranged from 9-11% at low Colon Recurrence Score values to 25-27% at high Colon Recurrence Score values.

 QUASAR

QUASAR Study (Stage II Validation): Beyond Existing Measures

The findings of this study also establishes that the Colon Recurrence Score result provides additional insight into the likelihood of colon cancer recurrence for individual patients which goes beyond existing measures such as T-stage, mismatch repair (MMR) status, number of nodes examined, grade and lymphovascular invasion.

In the validation study, an analysis was performed in 650 patients with available data for Colon Recurrence Score result, T stage, MMR status, tumor grade, number of nodes examined, and lymphovascular invasion. In this pre-specified multivariate analysis, Colon Recurrence Score value (P=0.008) demonstrated a significant and independent ability to predict recurrence, even after simultaneously accounting for the prognostic effects of tumor grade, lymphovascular invasion, number of nodes examined, T-stage, and MMR status. Colon Recurrence Score value, T-stage and MMR status, were the most important, independent predictors of colon cancer recurrence risk.

  1. Given the independent, significant importance of T4 stage, MMR-D, and Colon Recurrence Score value for predicting recurrence risk in Stage II colon cancer following surgery, these results support a paradigm in which individualized risk assessment can be achieved with knowledge of these three factors. Both T4 stage and MMR-D have limited applicability in terms of patient percentages for the subgroups defined by these markers. The Oncotype DX Colon Recurrence Score result provides a personalized risk analysis for each and every Stage II colon cancer patient.
  2. For Stage II patients with T3, MMR-P tumors, the Colon Recurrence Score result provides information to further delineate risk in this population, where existing markers may not be informative. The figure below illustrates the Colon Recurrence Score result by recurrence risk relationship, adjusted for 3 subgroups of patients defined by T-stage and MMR status.
    • T3, MMR-D (11% of patients): These patients are at low risk of recurrence, as conferred by MMR-D.
    • T4, MMR-P (13% of patients): These patients have a high risk of recurrence, as conferred by T4 stage
    • T3, MMR-P (74% of patients): These patients would be considered as standard risk, by current measures. The Colon Recurrence Score result will have its greatest value in this population of patients, for whom existing markers are not informative for further delineating individual recurrence risk.
    Note: The solid curves represent Stage II 3-year recurrence risk estimates from the Cox model. Dotted lines indicate 95% confidence intervals for each curve.

    QUASAR

  3. Oncotype DX Colon Recurrence Score Result Benefits:
    • For patients with Stage II disease, the Colon Recurrence Score result is independent of T-stage and MMR status and provides quantitative, individualized information regarding recurrence risk
    • The greatest value of the Colon Recurrence Score result is likely to reside in the population of patients (74%) for whom T-stage and MMR status are NOT informative (i.e. the T3, MMR-P patient) and other existing markers have limited utility

Population Distribution and Colon Cancer Recurrence Risk by Colon Recurrence Score Result in the Stage II Clinical Validation Study

  • In a secondary analysis, recurrence risk was analyzed for 3 groups of Stage II patients defined by pre-specified cutpoints in Colon Recurrence Score result. Cutpoints in Colon Recurrence Score result were defined to capture sufficiently large numbers of patients in each recurrence risk group to permit statistical analyses: the low recurrence risk group included patients with Colon Recurrence Score result <30. 

    Recurrence

CALGB 9581: Confirms the Ability to Differentiate Risk of Recurrence in Stage II Colon Cancer Patients

In the CALGB 9581 validation study, genomic and molecular markers were significantly associated with endpoints related to colon cancer and not associated with endpoints heavily influenced by deaths from other causes.

  • Both the continuous Colon Recurrence Score value and MMR were significantly associated with recurrence free interval (RFI).
  • In addition, Colon Recurrence Score value was significantly associated with colon cancer specific survival.

    Colon Cancer
  • These results from the CALGB 9581, together with previously reported studies support the paradigm for quantitative assessment of recurrence risk in Stage II colon cancer emphasizing the value of the Recurrence Score result, MMR status, and T-stage.


In Stage II Disease: The Continuous Colon Recurrence Score Value Predicts Risk of Recurrence Beyond Traditional Clinical and Pathologic Covariates

These results from CALGB 9581 build upon a large body of evidence supporting the importance of Colon Recurrence Score result and MMR in revealing the underlying tumor biology of Stage II colon cancer, providing value beyond traditional factors.

  • The Oncotype DX Colon Recurrence Score consistently shows to be highly predictive of recurrence with a statistically significant p value in this confirmatory trial just like in the QUASAR validation study.
C9581

 

Stage II and III: Validated Clinical Benefits of the Oncotype DX Colon Recurrence Score

For patients with Stage III colon cancer, current practice guidelines recommend 5FU/LV + oxaliplatin for adjuvant therapy. However, the addition of oxaliplatin to 5FU/LV benefits only a fraction of treated patients (6-7%) and comes with significant toxicity, including the prospect of long-term peripheral neuropathy. Conventional clinical and pathologic risk factors do not adequately discriminate risk and expected absolute benefit of oxaliplatin to guide decision-making.

A more accurate assessment of both recurrence risk and absolute treatment benefit as a function of risk can better inform adjuvant decision-making in resected colon cancer, particularly for Stage II patients with T3 MMR-P tumors and for Stage III A/B patients.

The 12-gene Oncotype DX Colon Recurrence Score assay is a validated predictor of recurrence risk in stage II colon cancer patients, and through a prospectively defined validation study in NSABP C-07, the Colon Recurrence Score result is validated in Stage II and Stage III colon cancer patients treated with 5FU/LV versus 5FU/LV + oxaliplatin.

A total of 892 Stage II and III colon cancer patients were randomized between 5FU/LV and 5FU/LV + oxaliplatin. Patients represented 30% Stage II, 46% Stage IIIA/B, and 24% Stage IIIC. A total of 18% of Stage II tumors were MMR-D and 9% of Stage III tumors were MMR-D.

Next: How the Colon Recurrence Score Works