TY - JOUR
T1 - Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer
T2 - An Analysis of Data from the I-SPY2 Randomized Clinical Trial
AU - Symmans, W. Fraser
AU - Yau, Christina
AU - Chen, Yunn Yi
AU - Balassanian, Ron
AU - Klein, Molly E.
AU - Pusztai, Lajos
AU - Nanda, Rita
AU - Parker, Barbara A.
AU - Datnow, Brian
AU - Krings, Gregor
AU - Wei, Shi
AU - Feldman, Michael D.
AU - Duan, Xiuzhen
AU - Chen, Beiyun
AU - Sattar, Husain
AU - Khazai, Laila
AU - Zeck, Jay C.
AU - Sams, Sharon
AU - Mhawech-Fauceglia, Paulette
AU - Rendi, Mara
AU - Sahoo, Sunati
AU - Ocal, Idris Tolgay
AU - Fan, Fang
AU - Lebeau, Lauren Grasso
AU - Vinh, Tuyethoa
AU - Troxell, Megan L.
AU - Chien, A. Jo
AU - Wallace, Anne M.
AU - Forero-Torres, Andres
AU - Ellis, Erin
AU - Albain, Kathy S.
AU - Murthy, Rashmi K.
AU - Boughey, Judy C.
AU - Liu, Minetta C.
AU - Haley, Barbara B.
AU - Elias, Anthony D.
AU - Clark, Amy S.
AU - Kemmer, Kathleen
AU - Isaacs, Claudine
AU - Lang, Julie E.
AU - Han, Hyo S.
AU - Edmiston, Kirsten
AU - Viscusi, Rebecca K.
AU - Northfelt, Donald W.
AU - Khan, Qamar J.
AU - Leyland-Jones, Brian
AU - Venters, Sara J.
AU - Shad, Sonal
AU - Matthews, Jeffrey B.
AU - Asare, Smita M.
AU - Buxton, Meredith
AU - Asare, Adam L.
AU - Rugo, Hope S.
AU - Schwab, Richard B.
AU - Helsten, Teresa
AU - Hylton, Nola M.
AU - Van 'T Veer, Laura
AU - Perlmutter, Jane
AU - Demichele, Angela M.
AU - Yee, Douglas
AU - Berry, Donald A.
AU - Esserman, Laura J.
N1 - Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/11
Y1 - 2021/11
N2 - Importance: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. Objective: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. Design, Setting, and Participants: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Interventions: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Main Outcomes and Measures: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). Results: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. Conclusions and Relevance: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.
AB - Importance: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. Objective: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. Design, Setting, and Participants: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Interventions: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Main Outcomes and Measures: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). Results: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. Conclusions and Relevance: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.
UR - http://www.scopus.com/inward/record.url?scp=85115214292&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85115214292&partnerID=8YFLogxK
U2 - 10.1001/jamaoncol.2021.3690
DO - 10.1001/jamaoncol.2021.3690
M3 - Article
C2 - 34529000
AN - SCOPUS:85115214292
SN - 2374-2437
VL - 7
SP - 1654
EP - 1663
JO - JAMA Oncology
JF - JAMA Oncology
IS - 11
ER -