Oncotype DX Breast Recurrence Score Clinical Evidence
Clinical Evidence
Landmark TAILORx Results Published!
The long-awaited results of the Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx) definitively identified the 70% of women with early stage breast cancer who will receive no benefit from chemotherapy, and the 30% for whom chemotherapy can be life-saving.
Read the ASCO and ECOG-ACRIN press releases.
Pre-TAILORx Clinical Validation Studies
The Oncotype DX Breast Recurrence Score test assesses the risk of distant breast cancer recurrence and predicts the benefit of adjuvant chemotherapy.1-6 It is the only genomic assay to fulfill the criteria for level 1 evidence for prognosis and prediction of chemotherapy benefit in patients with early-stage, hormone receptor-positive invasive breast cancer.7
In total, six validation studies—involving nearly 4,000 patients1-6—have been performed. The studies show:
- The Recurrence Score result is strongly associated with the rate of distant recurrence, with a low score indicating a significantly lower rate of distant recurrence.1,3
- The Recurrence Score result predicts the likelihood of benefit from chemotherapy, with a high score predicting a significant benefit from chemotherapy.2,4
The Breast Recurrence Score predicts distant recurrence and chemotherapy benefit
Early studies showed the key benefits of the Breast Recurrence Score—the ability to assess the risk of distant recurrence and the benefit of chemotherapy.
- NSABP B-14 Study1: The first clinical validation of the Breast Recurrence Score test, the NSABP B-14 study demonstrated that the Recurrence Score result quantifies the risk of distant recurrence in node-negative patients. It showed that the 10-year rate of distant recurrence was significantly lower for patients with low Recurrence Score results compared to patients with higher scores.
- NSABP B-20 Study2: This study determined that the Breast Recurrence Score test predicts the likelihood of chemotherapy benefit for node-negative patients: a low Recurrence Score result predicted little to no benefit from chemotherapy, while a high score predicted a larger benefit from chemotherapy.
- TransATAC Study3: Consistent with NSABP B-14 results for node-negative patients, this study confirmed that the Breast Recurrence Score test provides an improved estimate of risk of distant recurrence for node-positive patients. It found that a low Recurrence Score result was associated with a lower rate of distant recurrence, while a high Recurrence Score result was associated with a higher rate of distant recurrence.
- SWOG 88144: This study determined that the Breast Recurrence Score test is associated with the likelihood of chemotherapy benefit in node-positive patients. A Recurrence Score result <18 predicted little to no benefit from chemotherapy, while a score ≥31 predicted a larger benefit from chemotherapy.
Patients with low Recurrence Score results can avoid chemotherapy
Several separate studies, with a total of more than 63,000 patients, found that patients with a low Recurrence Score result may be effectively treated with hormonal therapy alone and safely spared chemotherapy.8-15 Four key studies are described below. Download a detailed summary of all four studies (PDF).
| TAILORx Trial pN0 |
SEER Study pN0-pN1 |
Clalit Study pN0, pN1mi |
WSG PlanB Trial pN0-pN1 |
|||
|---|---|---|---|---|---|---|
| 1,626 Patients | > 44,500 Patients | 2,028 Patients | 2,642 Patients | = | > 50K Patients | |
| Recurrence Score result < 11 | Recurrence Score result < 18 | Recurrence Score result < 18 | Recurrence Score result ≤ 11 | |||
| 5-year distant recurrence-free survival rate of > 99% | 5-year breast cancer-specific survival rate of > 99% | 5-year distant recurrence-free survival and breast cancer-specific survival rates of > 99% | 5-year disease-free survival rate of 94% | |||
- TAILORx Trial8: The first prospective outcomes study providing Level 1A evidence, the TAILORx Trial (Arm A) confirmed that patients with Recurrence Score results <11 may be effectively and safely treated with hormonal therapy alone.
- SEER9, 10, 15, 16: The analysis of the SEER database is the largest molecularly characterized cohort of patients (>40,000 patients) with prospective outcomes in Breast Recurrence Score tested patients. It confirms the clinical utility of the Breast Recurrence Score test, with outcomes for patients with Recurrence Score results <18 that are consistent with the results in the TAILORx Trial for node-negative patients with Recurrence Score results <11.
- Clalit13-14: An analysis of a prospective registry in over 2,100 patients, the Clalit data shows that the Recurrence Score result identifies patients who can safely be spared the addition of chemotherapy.
- WSG PlanB Trial11-12: The WSG PlanB Trial is a confirmation of the clinical utility of the Recurrence Score result in node-positive and clinically high-risk node-negative patients with Level 1A evidence. It shows that patients with Recurrence Score results ≤11 can be safely spared chemotherapy.
NSABP B-14 Study details1
The first clinical validation of the Breast Recurrence Score test for patients with invasive, node-negative breast cancer was performed on a cohort of 668 patients who had participated in the NSABP B-14 trial. The primary objective of this study was to determine whether the Recurrence Score result was prognostic providing 10-year risk of distant recurrence. Among the 668 tamoxifen-treated patients with ER+, node-negative disease, 51%, 22%, and 27% fell into the low-, intermediate-, and high-risk Recurrence Score groups, respectively.
Analyses demonstrated that the Recurrence Score result quantified the 10-year risk of distant recurrence, independent of age and tumor size. The 10-year rate of distant recurrence was significantly lower in the low-risk (Recurrence Score result <18) group (6.8%) compared with the high-risk (Recurrence Score result ≥31) group (30.5%, p<0.001). The Recurrence Score result was also significantly associated with distant relapse-free interval (DRFI) and overall survival (p<0.001 for both). In a multivariate Cox proportional hazards analysis, the Recurrence Score result and tumor grade were the only significant predictors of distant recurrence (p<0.001).
| Risk Group (Recurrence Score) | % of Patients (N) | 10-Year Rate of Distant Recurrence | 95% Confidence Interval |
|---|---|---|---|
| Low (<18) | 51% (338) | 6.8% | 4.0%-9.6% |
| Intermediate (18-30) | 22% (149) | 14.3% | 8.3%-20.3% |
| High (≥31) | 27% (181) | 30.5% | 23.6%-37.4% |
NSABP B-20 Study details2
The NSABP B-20 Study was performed on a cohort of 651 patients with ER+, node-negative breast cancer from the NSABP B-20 trial. The objective of this study was to determine whether the Recurrence Score result predicted the likelihood of chemotherapy benefit. In the parent trial, tamoxifen-treated patients had been randomized to receive either no chemotherapy or chemotherapy. Upon analysis of clinical variables, including age, tumor size, grade (assigned by three independent pathologists), and hormone receptor status, the Breast Recurrence Score value was the strongest predictive factor of chemotherapy benefit and was the only variable that had a statistically significant interaction with chemotherapy treatment (p=0.038).
The results of this study demonstrated that the Breast Recurrence Score result was predictive of the likelihood of chemotherapy benefit. Patients with low Recurrence Score results (<18) had minimal, if any benefit from chemotherapy, compared to patients with high scores (≥31), who demonstrated a significant benefit. Specifically, the group of 218 patients with low Breast Recurrence Score results treated with tamoxifen and chemotherapy showed minimal if any chemotherapy benefit when compared with 135 patients with low-risk results treated with tamoxifen only (p=0.61). In contrast, among patients with high Recurrence Score results, there was a significant treatment benefit in the 117 patients who received chemotherapy compared to 47 patients treated with tamoxifen alone (p<0.001).
| Recurrence Score Risk Group | % of Patients (N) | Distant Recurrence Free at 10 Years (%) | 95% Confidence Interval |
|---|---|---|---|
| Tamoxifen Alone | |||
| All Patients | 227 | 87.8% | 83.3%-92.3% |
| Low (<18) | 59% (135) | 96.8% | 93.7%-99.9% |
| Intermediate (18-30) |
20% (45) | 90.9% | 82.5%-99.4% |
| High (≥31) | 21% (47) | 60.5% | 46.2%-74.8% |
| Tamoxifen Plus Chemotherapy | |||
| All Patients | 424 | 92.2% | 89.4%-94.9% |
| Low (<18) | 51% (218) | 95.6% | 92.7%-98.6% |
| Intermediate (18-30) | 21% (89) | 89.1% | 82.4%-95.9% |
| High (≥31) | 28% (117) | 88.1% | 82.0%-94.2% |
TransATAC Study details3
The TransATAC Study further validated that the Recurrence Score result provides the risk of distant recurrence. It was conducted in samples from 1,231 post-menopausal patients with ER+ node-negative and node-positive disease enrolled in the ATAC trial.
Consistent with the NSABP B-14 study results for node-negative patients, the TransATAC study found that the Recurrence Score result was a statistically significant indicator of the risk of distant recurrence in patients with node-negative (p<0.001) or node-positive (p=0.002) disease, treated with either tamoxifen or anastrozole. In a multivariate analysis of node-negative patients that included tumor size, central grade, and age, the Recurrence Score result and tumor size were the only variables that were statistically significant in predicting time to distant recurrence (p<0.001). In addition, it was found that the 9-year risk of distant recurrence increases with the number of positive nodes for all Recurrence Score values. For patients with low Recurrence Score results and 1-3 positive nodes, the 9-year risk of distant recurrence was similar to that of patients with node-negative disease.
SWOG 8814 Study details4
The SWOG 8814 study analyzed archived tissue from 367 post-menopausal, hormone receptor-positive, node-positive patients with invasive breast cancer treated with tamoxifen or tamoxifen plus cyclophosphamide/doxorubicin/ fluorouracil (CAF).
In the study, the Recurrence Score result was shown to be prognostic for disease-free survival, overall survival, and breast-cancer specific survival in node-positive patients treated with tamoxifen alone as well as predictive of CAF therapy benefit. In addition, the SWOG 8814 study showed that the Recurrence Score result is also predictive of which node-positive patients will likely benefit from the addition of chemotherapy.
The analysis of chemotherapy benefit in disease-free survival by Breast Recurrence Score risk groups showed that only patients with a high Recurrence Score benefitted (p=0.033) and there was no significant benefit in patients in low or intermediate risk groups. Results were similar for overall survival and breast-cancer specific survival.
TAILORx Trial details8
The TAILORx Trial is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and is coordinated by the Eastern Cooperative Oncology Group (ECOG). The trial enrolled 10,253 node-negative, ER-positive, HER2-negative patients at 1,182 sites in six countries from April 2006 to October 2010. It provided the highest level of evidence (Level 1A)7 — a prospective, randomized phase 3 trial—finding less than 1% risk of distant recurrence at five years in patients with Recurrence Score results <11 (Arm A) who were treated with hormonal therapy alone.
Two remaining arms of the trial, B and C, which randomized patients with Recurrence Scores from 11 to 25 to chemotherapy or no chemotherapy in addition to hormonal therapy, are still accruing events and will report when the pre-specified number of events is reached.
5-Year Distant Recurrence-Free Interval (DRFI)
SEER Registry details9, 10, 15, 16
The analysis of the SEER database was a real-world observational study in over 46,000 node-negative and node-positive, HR-positive, HER2-negative patients. It showed that the Breast Recurrence Score test accurately identifies patients that do well with hormonal therapy alone.
Data showed that patients with Recurrence Score results <18 are unlikely to get additional clinical benefit from chemotherapy. In more than 21,000 node-negative patients who received Recurrence Score results <18, less than 1% breast-cancer specific mortality (BCSM) at five years was observed. The BCSM in patients with:
- Recurrence Score <18 was 0.4% (45 events), where 7% of patients were treated with chemotherapy.
- Recurrence Score 18-30 was 1.4% (107 events), where 34% of patients were treated with chemotherapy.
- Recurrence Score ≥31 was 4.4% (71 events), where 69% of patients were treated with chemotherapy.
In more than 3,600 node-positive patients with a Recurrence Score result <18 the results for breast-cancer specific survival (BCSS) at 5 years were16:
- >98% in more than 3,100 patients with micrometastases and one positive node who received Recurrence Score results <18, where <25% were treated with chemotherapy.
- >97% in 458 patients with 2 positive nodes who received Recurrence Score results <18, where 31% were treated with chemotherapy.
- >95% in 139 patients with 3 positive nodes who received Recurrence Score results <18, where 41% were treated with chemotherapy.
5-Year Breast Cancer-Specific Mortality (BCSM) By Recurrence Score Group
Analysis in patients with node-positive (mic, 1-3) disease
In SEER, outcomes for patients with Recurrence Score results <18 are consistent with those in the TAILORx Trial among patients with Recurrence Score results <11: the Recurrence Score result accurately identifies patients who may be spared chemotherapy.
Clalit Registry details13,14
The Clalit registry was a real-world, observational cohort of over 2,000 node-negative, pN1mi and node-positive patients, who used the Recurrence Score result to guide their treatment decisions. The study’s findings are consistent with previously reported results in the TAILORx Trial8 and the SEER Study9, 10, 15, 16: the Recurrence Score result accurately identifies patients who may be spared chemotherapy.
After 6.1-year median follow up, patients who were either node-negative or had micrometastases and Recurrence Score results <18 had a 0.8% (95% CI 0.4% - 1.6%) 5-year risk of distant recurrence when treated with hormonal therapy alone.
5-Year Distant Recurrence (DR)
Data further showed that greater than 95% of patients with micromets or 1 positive node and Recurrence Score results <18 were distant recurrence free at 5 years.
WSG PlanB Trial details11,12
The WSG PlanB Trial was a prospective, randomized trial of patients with high clinical risk disease (early-stage HER2-negative breast cancer, node-positive†, or high-risk node negative‡). The study found that clinically high-risk patients with Recurrence Score results ≤11 may be safely spared chemotherapy. The results showed:
- Only 21% of clinically high-risk patients had high Recurrence Score results.
- 5-year disease-free survival in node-positive and high-risk node-negative patients with Recurrence Score results ≤11 (94%) is similar to the TAILORx Trial result in node-negative patients with Recurrence Score results <11 (93.8%)8, further confirming that patients with Recurrence Score results <11 can be safely spared chemotherapy.
- These patients with Recurrence Score results ≤11 also have the same five-year disease-free survival as patients with Recurrence Score results 12-25 (94%), who were all treated with chemotherapy, which suggests that there may be little benefit of chemotherapy in the 12-25 Recurrence Score group.
5-Year Disease-Free Survival (DFS)
Chemotherapy (CT) use is reported as a percentage of all patients (N-/N+) in each Recurrence Score risk group.
†Node-positive (N+) patients had T1-4, grade 1-3, and HR+ or HR- disease.
‡High-risk node-negative (N0) had T > 2 cm, grade 2-3, or HR- disease, had elevated uPA/PAI-1 levels, or were ≤ 35 years of age.
Clinical validation references
A Multigene Assay to Predict Recurrence of Tamoxifen Treated Node-Negative Breast Cancer
Paik S, Shak S, Tang G, et al.
N Engl J Med. 2004.
Gene Expression and Benefit of Chemotherapy in Women with Node-Negative, Estrogen Receptor-Positive Breast Cancer
Paik S, Tang G, Shak S, et al.
J Clin Oncol. 2006.
Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in Postmenopausal, Node-Positive, Estrogen Receptor-Positive Breast Cancer
Albain K, Barlow W, Shak S, et al.
Lancet Oncol. 2010.
Prediction of Risk of Distant Recurrence Using the 21-Gene Recurrence Score in Node-Negative and Node-Positive Postmenopausal Breast Cancer Patients Treated with Anastrozole or Tamoxifen: A TransATAC Study
Dowsett M, Cuzick J, Wale CJ, et al.
J Clin Oncol. 2010.
A Population-Based Study of Tumor Gene Expression and Risk of Breast Cancer Death Among Lymph Node-Negative Patients
Habel LA, Shak S, Jacobs M, et al.
Breast Cancer Res. 2006.
Clinical Significance of the 21-Gene Signature (Oncotype DX) in Hormone Receptor-Positive Early Stage Primary Breast Cancer in the Japanese Population
Toi M, Iwata H, Yamanaka T, et al.
Cancer. 2010.