The 21-gene recurrence score assay (Oncotype DX) was applied to early breast cancer patients with hormone-receptor and axillary lymph node positivity in two studies reported at the 2007 San Antonio Breast Cancer Symposium. Their findings suggest that the recurrence score can identify subsets most likely to benefit from chemotherapy.
SAN ANTONIOThe 21-gene recurrence score assay (Oncotype DX) was applied to early breast cancer patients with hormone-receptor and axillary lymph node positivity in two studies reported at the 2007 San Antonio Breast Cancer Symposium. Their findings suggest that the recurrence score can identify subsets most likely to benefit from chemotherapy.
Kathy S. Albain, MD, professor of medicine, Loyola University Chicago Stritch School of Medicine, reported the correlation of the 21-gene assay with outcomes in patients from the SWOG 8814 study (abstract 10).
SWOG 8814 previously found that six cycles of cyclophosphamide, doxorubicin, and fluorouracil followed by 5 years of tamoxifen (CAF-T) was associated with superior disease-free survival (DFS) and overall survival (OS) over tamoxifen alone in postmenopausal patients with node-positive, estrogen-receptor (ER)-positive breast cancer.
Dr. Albain's group showed that the recurrence score (RS) is prognostic for DFS (P = .017) and OS (P = .003) in patients treated with tamoxifen alone.
Low, intermediate, and high RSs were associated with 10-year DFS of 60%, 49%, and 43%, respectively, and with 10-year OS of 77%, 68%, and 51%, respectively.
Next, they determined the predictive value of the RS. DFS and OS were compared in patients treated with tamoxifen only vs those who also received chemotherapy.
While a significant improvement in DFS and OS was achieved by adding CAF in patients with a high RS, there was no benefit in patients with a low RS. The interaction of RS with treatment effect was true for patients with 1 to 3 positive nodes and 4 or more nodes.
The researchers concluded that benefit from CAF can be predicted when the RS is high, and that a low RS may define a group of node-positive patients who may not benefit from anthracycline-based chemotherapy.
Challenging the mandates
According to Dr. Albain, the data challenge chemotherapy mandates for patients with node-positive, ER-positive disease. Some patients benefit more from chemotherapy than previously predicted while others do not benefit at all, she noted, adding that new strategies are needed for these patients with low RS, given that they have a 10-year event rate of 40% yet get little benefit from chemotherapy.
Dr. Albaine suggested that a prospective randomized trial of chemotherapy plus endocrine therapy vs endocrine therapy alone in node-positive, ER-positive patients with low RS should be an investigative priority.
A somewhat different perspective was provided by an intergroup study in a node-positive, hormone-receptor-positive cohort assayed by the 21-gene RS.
The study, presented by Lori Goldstein, MD, director of the Breast Evaluation Center, Fox Chase Cancer Center (abstract 63), compared the prognostic utility of Oncotype DX RS with classical clinicopathologic features and treatment factors integrated by the Adjuvant! prognostic tool.
"We found that the RS provides additional information that is complementary to clinicopathological features integrated by Adjuvant!," Dr. Goldstein said. Patients with a low RS had excellent outcomes at 5 years when treated with an abbreviated course of chemotherapy, she reported.
The intergroup study included patients with hormone-receptor-positive disease from the E2197 trial. E2197 included 2,885 patients with 0 to 3 positive nodes, randomized to doxorubicin plus cyclophosphamide (AC) or doxorubicin plus docetaxel (Taxotere) (AT) given every 3 weeks for four cycles, plus tamoxifen for 5 years. At a medium follow-up of 76 months, no differences were observed between the regimens.
A subset of E2197 patients (n = 465) had tissue available for the Oncotype DX RS assay and a recurrence risk estimated by the Adjuvant! program.
Five-year recurrence estimates were computed by Adjuvant! and patients were classified as being at "low," "intermediate," or "high" risk. The prognostic utility of RS was evaluated in each Adjuvant! risk group.
Similar to patients with node-negative disease, 46% of patients by the Oncotype DX RS were at low risk (RS < 18), 30% were at intermediate risk (RS 18-30), and 24% were at high risk (RS ≥ 31) for recurrence.
Out of the 465 patients, there were 99 recurrences. RS was a highly significant predictor of recurrence for local and distant disease, both in node-negative patients (P = .0007) and node-positive patients (P = .0004).
A low RS predicted a low chance of recurrence (≤ 5%) irrespective of classical clinicopathologic features such as nodal status, Dr. Goldstein reported.
There was little difference in recurrence rates for patients with 1 vs 0 positive nodes. Recurrences were observed in 3% to 4% of patients with 0 to 1 positive nodes, rising to 8% in patients with 2 to 3 positive nodes.
"The recurrence rates increased as RS increased up to 40, but there was a flattening of the curve in patients with RS higher than 40. This is consistent with previous reports indicating a greater chemotherapy treatment effect for persons with high RS, perhaps reflecting the greater sensitivity of these patients for chemotherapy," she suggested.
The investigators concluded that:
• The RS is positively correlated with recurrence in patients with node-positive disease, independently of classical clinicopathologic features.
• RS > 40 is not associated with recurrence, which probably reflects sensitivity to chemotherapy in this high-risk group of patients.
• Low RS predicts for excellent outcomes at 5 years, and outcomes are comparable for patients with 1 or 0 positive nodes.
"This study has implications for the clinical care of patients with 1 to 3 positive nodes," Dr. Goldstein noted. "For the 46% with a low RS, a shorter course of chemotherapy that is potentially less toxic may be adequate. The findings also suggest for clinical trials that are evaluating more aggressive, novel or prolonged regimens, we might enrich the population with high-risk subjects, selecting only patients with intermediate or high recurrence scores."
She cautioned, however, that the study was exploratory, that neither RS nor Adjuvant! was optimized for 5-year outcomes, that follow-up may be too short to fully appreciate recurrences, and that it did not examine patients who received only endocrine therapy, for whom outcomes may have been different.