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Original Investigation
July 23, 2020

Association of Event-Free and Distant Recurrence–Free Survival With Individual-Level Pathologic Complete Response in Neoadjuvant Treatment of Stages 2 and 3 Breast Cancer: Three-Year Follow-up Analysis for the I-SPY2 Adaptively Randomized Clinical Trial

I-SPY2 Trial Consortium
JAMA Oncol. Published online July 23, 2020. doi:10.1001/jamaoncol.2020.2535
Key Points

Question  Is there an association between pathologic complete response (pCR) and survival end points in neoadjuvant treatment of early breast cancer with various novel therapeutics?

Findings  In this follow-up analysis of a randomized clinical trial of 950 patients with breast cancer, a strong individual-level association was found between pCR and event-free survival and distant recurrence–free survival. Excellent outcomes were associated with pCR for all standard subtypes of breast cancer, including pCR owing to experimental regimens.

Meaning  The findings of this study suggest that pCR may be a robust prognostic biomarker for excellent long-term outcomes at the individual patient level for patients with early, high-risk breast cancer.


Importance  Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial.

Objective  To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence–free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents.

Design, Setting, and Participants  Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019.

Interventions  Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide.

Main Outcomes and Measures  Pathologic complete response and 3-year EFS and DRFS.

Results  Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS.

Conclusions and Relevance  The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study.

Trial Registration  ClinicalTrials.gov Identifier: NCT01042379

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