W Fraser Symmans1, Christina Yau2, Yunn-Yi Chen3, Ron Balassanian3, Molly E Klein4, Lajos Pusztai5, Rita Nanda6, Barbara A Parker7, Brian Datnow8, Gregor Krings3, Shi Wei9, Michael D Feldman10, Xiuzhen Duan11, Beiyun Chen12, Husain Sattar13, Laila Khazai14, Jay C Zeck15, Sharon Sams16, Paulette Mhawech-Fauceglia17, Mara Rendi18, Sunati Sahoo19, Idris Tolgay Ocal20, Fang Fan21, Lauren Grasso LeBeau22, Tuyethoa Vinh23, Megan L Troxell24, A Jo Chien25, Anne M Wallace26, Andres Forero-Torres27, Erin Ellis28, Kathy S Albain29, Rashmi K Murthy30, Judy C Boughey31, Minetta C Liu32, Barbara B Haley33, Anthony D Elias34, Amy S Clark35, Kathleen Kemmer36, Claudine Isaacs37, Julie E Lang38, Hyo S Han39, Kirsten Edmiston40, Rebecca K Viscusi41, Donald W Northfelt42, Qamar J Khan43, Brian Leyland-Jones44, Sara J Venters45, Sonal Shad2, Jeffrey B Matthews2, Smita M Asare46, Meredith Buxton47, Adam L Asare46, Hope S Rugo25, Richard B Schwab7, Teresa Helsten7, Nola M Hylton48, Laura van 't Veer45, Jane Perlmutter49, Angela M DeMichele35, Douglas Yee50, Donald A Berry47, Laura J Esserman2. 1. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston. 2. Department of Surgery, University of California, San Francisco. 3. Department of Pathology, University of California, San Francisco. 4. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis. 5. Department of Medicine, Medical Oncology, Yale University, New Haven, Connecticut. 6. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. 7. Division of Hematology-Oncology, Department of Medicine, University of California, San Diego, La Jolla. 8. Department of Pathology, University of California, San Diego, La Jolla. 9. Department of Anatomic Pathology, University of Alabama at Birmingham. 10. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia. 11. Department of Pathology, Loyola University, Chicago, Illinois. 12. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. 13. Department of Pathology, University of Chicago, Chicago, Illinois. 14. Department of Pathology, Moffitt Cancer Center, Tampa, Florida. 15. Department of Pathology, Georgetown University, Washington, DC. 16. Department of Pathology, University of Colorado Anschutz Medical Center, Aurora. 17. Department of Pathology, University of Southern California, Los Angeles. 18. Department of Anatomic Pathology, University of Washington, Seattle. 19. Department of Pathology, University of Texas Southwestern, Dallas. 20. Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona. 21. Department of Pathology, University of Kansas Medical Center, Kansas City. 22. Department of Pathology, University of Arizona Health Sciences, Tucson. 23. Department of Pathology, Inova Health System, Fairfax, Virginia. 24. Department of Pathology, Oregon Health and Science University, Portland. 25. Division of Hematology-Oncology, Department of Medicine, University of California, San Francisco. 26. Department of Surgery, University of California, San Diego, La Jolla. 27. Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham. 28. Medical Oncology, Swedish Cancer Institute, Seattle, Washington. 29. Division of Hematology-Oncology, Department of Medicine, Loyola University Chicago Stritch School of Medicine, Chicago, Illinois. 30. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 31. Department of Surgery, Mayo Clinic, Rochester, Minnesota. 32. Department of Oncology, Mayo Clinic, Rochester, Minnesota. 33. Division of Hematology-Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas. 34. Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora. 35. Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia. 36. Division of Hematology-Oncology, Department of Medicine, Oregon Health & Science University, Portland. 37. Division of Hematology-Oncology, Department of Medicine, Georgetown University, Washington, DC. 38. Department of Surgery, University of Southern California, Los Angeles. 39. Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. 40. Department of Surgery, Inova Schar Cancer Institute, Fairfax, Virginia. 41. Department of Surgery, University of Arizona Health Sciences, Tucson, Arizona. 42. Department of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona. 43. Division of Oncology, Department of Medicine, University of Kansas, Kansas City. 44. Medical Oncology, Avera Cancer Institute, Sioux Falls, South Dakota. 45. Department of Laboratory Medicine, University of California, San Francisco. 46. Quantum Leap Healthcare Collaborative, San Francisco, California. 47. Berry Consultants, LLC, Houston, Texas. 48. Department of Radiology and Biomedical Imaging, University of California, San Francisco. 49. Gemini Group, Ann Arbor, Michigan. 50. Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis.
Abstract
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.
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.
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