Addressing the unmet need: Oncotype DX® assay
What is the Oncotype DX assay?
The Oncotype DX assay is a validated genomic test that predicts the likelihood of breast cancer recurrence, the likelihood of patient survival within 10 years of diagnosis and the likelihood of chemotherapy benefit in early-stage, node-negative, ER-positive breast cancer. The Oncotype DX assay uses a reverse-transcriptase (RT) polymerase chain reaction (PCR) process to quantify the expression of specific mRNA for 16 cancer genes and 5 reference genes in paraffin samples obtained from a breast cancer biopsy, combining the expression results into a single score called the Recurrence Score® result.
Clinical Validation
In order to clinically validate the Oncotype DX assay, prospectively designed trials of archived tissue from the two NSABP studies mentioned on the “Unmet Need in Early-Stage Breast Cancer” sub-page were performed with the Oncotype DX assay. The results of the NSABP B-14 trial supported the prognostic value of the assay while the NSABP B-20 trial supported the predictive value of the assay in determining the magnitude of chemotherapy benefit.2,3 The 2007 ASCO (American Society of Clinical Oncology) Guidelines Committee recently stated that although performed retrospectively, the validation of the Oncotype DX assay may be considered Level of Evidence I.8
Figure 1 below shows the performance of the Recurrence Score result as a continuous predictor of distant recurrence at 10 years; 50% of patients are found to have scores <18 ("Low Risk"). From the Oncotype DX assay NSABP B-14 Study, Figure 2 below shows the ability of the assay to stratify women with LN-, ER+ breast cancer who were treated with 5 years of tamoxifen by risk of distant recurrence. The prognostic value of the Oncotype DX assay has also been evaluated in a community hospital setting, in a large case-control study by Habel et al. among Northern California Kaiser Permanente patients, with consistent clinical results.9
Figure 1. Recurrence Score Result as a Continuous Predictor of Distant Recurrence at 10 Years in a Node-Negative, ER-Positive Population
From Paik et al 2004.
Figure 2. B-14 Overall 10-Year DRFS For the Whole Group (Left) and Recurrence Score Groups (Right)
From Paik et al. 2004
Figure 3 below shows that Low Risk Recurrence Score result patients (Scores <18) are found in the NSABP B-20 study to have minimal benefit from chemotherapy, whereas those with Recurrence Score results ≥31 ("High Risk") have significant benefit (75% relative benefit, 28% absolute benefit). It is important to note that not all prognostic tests or measures are predictive of chemotherapy benefit; each must be independently tested to determine whether it has this ability.
Figure 3. Chemotherapy Absolute Benefit Stratified by Recurrence Score Result Risk
From Paik et al. 2006; DRFS – Distant recurrence-free survival
Benefit of Recurrence Score Result and Relationship to Established Measures
In a study comparing classification, 668 patients from NSABP B-14 were assessed by the Oncotype DX assay (RS low, RS int, RS high) using prior 2004 NCCN guideline criteria for tumors (Nlow, Nhigh). In Figure 4, the Oncotype DX assay reclassified 28% of NCCN low risk patients as intermediate or high risk (and thus high likelihood of chemotherapy benefit), and 49% of the NCCN high-risk patients showed a low Recurrence Score result with low risk of 10-year distant recurrence and minimal benefit from chemotherapy. In total, about 50% of patients were reclassified from NCCN risk groups by the Recurrence Score result. Results from this analysis illustrate that the Oncotype DX multi-gene assay offers additional, quantitative evaluation of recurrence risk beyond the NCCN guidelines, which rely on age, tumor size and tumor grade.3
Figure 4. Recurrence Score Result Reclassification Rates from NCCN Guidelines
From Paik et al. 2005.
Another established method to quantify risk of distant recurrence is Adjuvant!Online. Adjuvant!Online, an established on-line breast cancer model, is a validated computer-based model that estimates 10-year disease-free and overall survival with and without adjuvant chemotherapy using standard measures such as patient age, tumor size, tumor grade and lymph node status as inputs. A recent analysis conducted by Goldstein et al. showed that the Oncotype DX assay predicted recurrence independently from the Adjuvant! risk prediction algorithm adjusted to 5-year outcomes. Recurrence Score result was a highly significant predictor of recurrence for node-negative and node-positive disease (P < 0.001).11
Incorporation into National Guidelines
In a 2007 ASCO update on the use of tumor markers, the ASCO committee recommended that "…the Oncotype DX® assay can be used to predict the risk of recurrence in patients treated with tamoxifen. Oncotype DX may be used to identify patients who are predicted to obtain the most therapeutic benefit from adjuvant tamoxifen and may not require adjuvant chemotherapy. In addition, patients with high Recurrence Scores® appear to achieve relatively more benefit from adjuvant chemotherapy (specifically CMF) than from tamoxifen."8
In its 2008 update, NCCN commented on the validity and usefulness of molecular classifiers to further improve the prediction and classification of risk for women with early-stage breast cancer. The Oncotype DX assay is recommended for HER2-negative, node-negative (pN0) patients characterized as 0.6–1.0 cm (if moderately/poorly differentiated or unfavorable features) or >1 cm tumors or node-positive patients with micrometastatic disease (pN1mi, tumors 0.2mm–2.0mm).12