Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy.— Fatima Cardoso, MD, and colleagues
In the phase III MINDACT trial reported in The New England Journal of Medicine, Fatima Cardoso, MD, of Champalimaud Clinical Center–Champalimaud Foundation, Lisbon, and colleagues found that adjuvant chemotherapy may be avoidable in women with early-stage breast cancer who are at high clinical risk but low genomic risk as determined by the 70-gene signature assay (MammaPrint).1 In these women who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy.
The study enrolled 6,693 women with early-stage breast cancer (stage T1 or T2 or operable T3) from 112 sites in 9 European countries between 2007 and 2011. Clinical risk was determined using a modified version of Adjuvant! Online, and genomic risk was determined using the 70-gene signature test. Women at low clinical and genomic risk did not receive adjuvant chemotherapy; those at high clinical and genomic risk did receive adjuvant chemotherapy.
Patients with discordant risk assessments were randomized to receive adjuvant chemotherapy or no adjuvant therapy based on either the clinical or genomic result. Those randomized to receive chemotherapy could receive an anthracycline-containing regimen or a docetaxel/capecitabine regimen, and patients with hormone receptor–positive disease could undergo additional randomization to a tamoxifen/letrozole regimen or a letrozole-only regimen.
The primary objective was to determine whether patients with high-risk clinical features and low-risk gene-expression profile who did not receive chemotherapy in the primary-test population (including those adherent to treatment assignment) would have a rate of 5-year distant metastasis–free survival with a lower boundary of the 95% confidence interval (CI) of 92% or higher (noninferiority boundary).
Among all patients, 2,745 (41.0%) had low clinical risk and low genomic risk, 592 (8.8%) had low clinical risk and high genomic risk, 1,550 (23.2%) had high clinical risk and low genomic risk, and 1,806 (27.0%) had high clinical risk and high genomic risk. Among all patients, median age was 55 years, 79.0% had node-negative disease, 88.4% had hormone receptor–positive disease, and 9.5% had HER2-positive disease. Median follow-up was 5 years.
High Clinical/Low Genomic Risk
Among the 1,550 patients with high clinical and low genomic risk, 749 were randomized to receive chemotherapy and 748, not to chemotherapy. At 5 years, the rate of survival without distant metastases among patients at high clinical/low genomic risk in the primary-test population who did not receive chemotherapy was 94.7% (95% CI: 92.5%–96.2%), thus meeting the primary study objective. On intent-to-treat analysis, 5-year rates of distant metastasis–free survival were 95.9% in the chemotherapy group vs 94.4% in the no-chemotherapy group (absolute difference = 1.5%; adjusted hazard ratio [HR] = 0.78, P = 0.27).
Five-year rates of distant metastasis–free survival were 95.7% vs 93.2% in patients with node-negative disease; 96.3% vs 95.6% in those with node-positive disease; and 95.5% vs 93.9% in patients with estrogen receptor–positive, HER2-negative, node-negative disease. No significant differences were observed between the chemotherapy and no-chemotherapy groups with regard to 5-year disease-free (absolute increase of 2.8% with chemotherapy) or overall survival (absolute increase of 1.4% with chemotherapy).
On per-protocol analysis in the high clinical/low genomic risk group (592 received chemotherapy, 636 did not), 5-year rates were 96.7% vs 94.8% (HR = 0.65, P = 0.11) for distant metastasis–free survival, 93.3% vs 90.3% (HR = 0.64, P = .03) for disease-free survival, and 98.8% vs 97.3% (HR = 0.63, P = .25) for overall survival.
Low Clinical/High Genomic Risk
Among the patients who had low clinical/high genomic risk, 5-year rates of distant metastasis–free survival were 95.8% in 344 patients receiving chemotherapy vs 95.0% in 346 patients not receiving chemotherapy (adjusted HR = 1.17, P = 0.66). No significant differences were observed between the chemotherapy and no-chemotherapy groups with regard to disease-free or overall survival.
The investigators concluded: “Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy.” ■
Disclosure: The study was supported by the European Commission Sixth Framework Program, Novartis, F. Hoffmann-La Roche, Sanofi-Aventis, Eli Lilly, Veridex, and others. For full disclosures of the study authors, visit www.nejm.org.