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
Authors: Douglas Yee, Angela M. DeMichele, Christina Yau, Claudine Isaacs, W. Fraser Symmans, Kathy S. Albain, Yunn-Yi Chen, Gregor Krings, Shi Wei, Shuko Harada, Brian Datnow, Oluwole Fadare, Molly Klein, Stefan Pambuccian, Beiyun Chen, Kathi Adamson, Sharon Sams, Paulette Mhawech-Fauceglia, Anthony Magliocco, Mike Feldman, Mara Rendi, Husain Sattar, Jay Zeck, Idris T. Ocal, Ossama Tawfik, Lauren Grasso LeBeau, Sunati Sahoo, Tuyethoa Vinh, A. Jo Chien, Andres Forero-Torres, Erica Stringer-Reasor, Anne M. Wallace, Lajos Pusztai, Judy C. Boughey, Erin D. Ellis, Anthony D. Elias, Janice Lu, Julie E. Lang, Hyo S. Han, Amy S. Clark, Rita Nanda, Donald W. Northfelt, Qamar J. Khan, Rebecca K. Viscusi, David M. Euhus, Kirsten K. Edmiston, Stephen Y. Chui, Kathleen Kemmer, John W. Park, Minetta C. Liu, Olufunmilayo Olopade, Brian Leyland-Jones, Debasish Tripathy, Stacy L. Moulder, Hope S. Rugo, Richard Schwab, Shelly Lo, Teresa Helsten, Heather Beckwith, Patricia Haugen, Nola M. Hylton, Laura J. van’t Veer, Jane Perlmutter, Michelle E. Melisko, Amy Wilson, Garry Peterson, Adam L. Asare, Meredith B. Buxton, Melissa Paoloni, Julia L. Clennell, Gillian L. Hirst, Ruby Singhrao, Katherine Steeg, Jeffrey B. Matthews, Smita M. Asare, Ashish Sanil, Scott M. Berry, Laura J. Esserman, Donald A. Berry
Journal: JAMA Oncology (2020)

<h3>Importance</h3> 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. <h3>Objective</h3> 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. <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> 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. <h3>Main Outcomes and Measures</h3> Pathologic complete response and 3-year EFS and DRFS. <h3>Results</h3> 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. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01042379