In a 3-year follow-up analysis of the phase II I-SPY 2 trial reported in JAMA Oncology, researchers in the I-SPY 2 Trial Consortium found that pathologic complete response was associated with improved event-free and distant recurrence–free survival—irrespective of molecular subtype or neoadjuvant regimen received—in women with high-risk stage II or III breast cancer.
"The 3-year outcomes from the I-SPY 2 trial show that, regardless of subtype and/or treatment regimen, including nine novel therapeutic combinations, achieving pathologic complete response after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate."— I-SPY2 Trial Consortium
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Study Details
In the trial, 950 women who had not undergone prior surgery or received prior systemic therapy with primary tumors ≥ 2.5 cm were adaptively randomly assigned from March 2010 through 2016 to receive neoadjuvant therapy with one of nine investigational agents or combinations or control treatment within molecular subtypes. Women with tumors that were HER2-negative/hormone receptor (HR)-positive with a low 70-gene assay score were excluded. All patients received standard neoadjuvant taxane treatment with or without an investigational regimen followed by doxorubicin and cyclophosphamide.
Key Findings
Overall, pathologic complete response was achieved in 330 women (34.7%). Rates of pathologic complete response ranged from 17% in HR-positive/HER2-negative patients to 68% in HR-negative/HER2-positive patients. Rates were higher in investigational vs control groups.
Among all patients, 3-year event-free survival was 95% in those with pathologic complete response vs 78% in those without pathologic complete response (hazard ratio [HR] = 0.19, 95% confidence interval [CI] = 0.12–0.31). Range by molecular subtypes was 93% to 97% vs 57% to 89%. By molecular subtypes, hazard ratios were 0.14 (95% CI = 0.03–0.55) for HR-positive/HER2-negative disease, 0.15 (95% CI = 0.03–0.63) for HR-positive/HER2-positive disease, 0.18 (95% CI = 0.09–0.34) for HR-negative/HER2-negative disease, and 0.14 (95% CI = 0.05–0.41) for HR-negative/HER2-positive disease.
Among all patients, 3-year distant recurrence-free survival was 95% in those with pathologic complete response vs 81% for those without pathologic complete response (HR = 0.21, 95% CI = 0.13–0.34). By molecular subtypes, hazard ratios were 0.16 (95% CI = 0.04–0.64) for HR-positive/HER2-negative disease, 0.10 (95% CI = 0.01–0.77) for HR-positive/HER2-positive disease, 0.20 (95% CI = 0.10–0.40) for HR-negative/HER2-negative disease, and 0.18 (95% CI = 0.06–0.53) for HR-negative/HER2-positive disease.
The investigators concluded, “The 3-year outcomes from the I-SPY 2 trial show that, regardless of subtype and/or treatment regimen, including nine novel therapeutic combinations, achieving pathologic complete response after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY 2 trial is to rapidly identify investigational therapies that may improve pathologic complete response when validated in a phase III confirmatory trial. Whether pathologic complete response is a validated surrogate in the sense that a therapy that improves pathologic complete response rate can be assumed to also improve long-term outcome requires further study.”
Laura J. Esserman, MD, MBA, of the University of California, San Francisco, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by Quantum Leap Healthcare Collaborative, Foundation for the National Institutes of Health, and National Cancer Institute. For full disclosures of the study authors, visit jamanetwork.com.
