Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer: An Analysis of Data From the I-SPY2 Randomized Clinical Trial

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Symmans reported shares in IONIS Pharmaceuticals, Eiger Biopharmaceuticals, and Delphi Diagnostics as well as personal fees from Merck and a patent for method for calculating residual cancer burden issued outside the submitted work. Dr Yau reported grants from the National Institutes of Health (NIH)/National Cancer Institute (NCI) and personal fees from Quantum Leap Healthcare Collaborative during the conduct of the study. Dr Nanda reported personal fees from Aduro, Athenex, Clovis, Daiichi Sankyo, Genentech, Immunomedics, MacroGenics, Merck, Pfizer, Seattle Genetics, and G1 Therapeutics as well as grants from AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharm, Odonate Therapeutics, Pfizer, and Seattle Genetics outside the submitted work. Dr Parker reported research support from Pfizer, Novartis, Genentech/Roche, and Oncternal outside the submitted work; additionally, her spouse is a consultant for Bioatla Incorporated and Samumed LLC. Dr B. Chen reported grants from Quantum Leap Healthcare Collaborative during the conduct of the study. Dr Troxell reported personal fees from the United States and Canadian Academy of Pathology, College of American Pathologists, American Society of Nephrology, and Pathology Learning Centers outside the submitted work. Dr Forero-Torres reported employment with Seagen outside the submitted work. Dr Albain reported research support from Quantum Leap Healthcare Collaborative and nonfinancial support from Merck and Seattle Genetics during the conduct of the study as well as research support from Seattle Genetics, AstraZeneca, and Daiichi-Sankyo and personal fees from Genentech/Roche, Genomic Health/Exact Sciences, and Seattle Genetics/Axio outside the submitted work. Dr Murthy reported personal fees from Puma, Genentech, Seattle Genetics, Novartis, AstraZeneca, and Pfizer and grants from Genentech, Daiichi Sankyo, Pfizer, EMD Serono, Seattle Genetics, and AstraZeneca outside the submitted work. Dr Boughey reported research support from the I-SPY2 Foundation, Quantum Leap, and Lilly outside the submitted work. Dr Liu reported research funding from Eisai, Genentech, Merck, Novartis, Seattle Genetics, and Tesaro as well as board participation with AstraZeneca and Pfizer outside the submitted work. Dr Haley reported grants from UT Southwestern Medical Center during the conduct of the study and grants from Pfizer, Lilly, Daiichi Sankyo, Roche, Puma, and Sanofi outside the submitted work. Dr Clark reported grants from Novartis during the conduct of the study. Dr Isaacs reported grants from NCI/NIH during the conduct of the study and personal fees from Genentech, PUMA, Seattle Genetics, AstraZeneca, Novartis, Pfizer, Tesaro, and Eisai outside the submitted work, as well as royalties from Wolters Kluwer and Macmillan Publishing. Dr Lang reported grants from ANGLE Parsortix and personal fees from Genomic Health outside the submitted work. Dr Han reported research funding from Quantum Leap Healthcare Collaborative during the conduct of the study and personal fees from Lilly and research support from Arvinas, AbbVie, BMS, Daiichi Pharma, G1 Therapeutics, GSK, Horizon, Marker Therapeutics, Novartis, Pfizer, Prescient, Seattle Genetics, and Zymeworks outside the submitted work. Dr Leyland-Jones reported participation on the speakers bureau for PUMA, Genentech, Exelixis, and Bayer. Dr S. Asare reported being an employee of Quantum Leap Healthcare Collaborative. Dr Buxton reported research support from Puma Biotechnology, Amgen, Merck, Genentech, Synta Pharmaceuticals, Plexxikon, Pfizer, and Daiichi Sankyo, Bayer, Kintara Therapeutics, Eisai, QED Therapeutics, Taiho Pharmaceutical, Incyte, and the National Brain Tumor Society; grants from the Breast Cancer Research Foundation, Wiliam K. Bowes, Jr. Foundation, Safeway Foundation, National Foundation for Cancer Research, and Asian Fund For Cancer Research; and personal fees from Eli Lilly and the Pancreatic Cancer Action Network outside the submitted work. Dr Rugo reported grants from Roche, Odonate, Immunomedics, Sermonix, Merck, Pfizer, Novartis, Lilly, AstraZeneca, and Daiichi and personal fees from Puma, Mylan, Samsung, and OBI outside the submitted work. Dr Schwab reported research support from Quantum Leap Healthcare Collaborative during the conduct of the study. Dr Hylton reported grants from NIH/NCI during the conduct of the study. Dr van 't Veer reported personal fees from and holding stocks in Agendia NV during the conduct of the study. Dr DeMichele reported grants from Pfizer, Novartis, Genentech, and Menarini and personal fees from Context Therapeutics outside the submitted work. Dr Yee reported research support from Quantum Leap and Boehringer Ingelheim outside the submitted work. Dr Berry reported being a coowner of Berry Consultants, LLC outside the submitted work. Dr Esserman reported being a study sponsor for Quantum Leap Healthcare and grants from the NHI, NCI Center for Biomedical Informatics and Information Technology, Safeway Foundation, William K Bowes Jr. Foundation, Give Breast Cancer the Boot, Quintiles Transnational, Johnson & Johnson, Genentech, Amgen, San Francisco Foundation, Eli Lilly, Eisai, Pfizer, Side Out Foundation, Harlan Family, Avon Foundation for Women, and Alexandria Real Estate Equities during the conduct of the study as well as grants from Merck and Quantum Leap, board membership with Quantum Leap, and personal fees from Blue Cross/Blue Shield outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Distribution of Residual Cancer Burden (RCB) Within Each Phenotypic Subtype as Landscape Plots of Continuous RCB Values and MOSAIC Plots of RCB Classes

HR indicates hormone receptor; pCR, pathologic complete response.

Figure 2.. Association Between Residual Cancer Burden (RCB) and Estimated Rate for Event-Free Survival (EFS) Event Within 3 Years for the Overall I-SPY2 Population, Each Phenotypic Subtype, and Each Category of Treatment After Adjustment for Phenotypic Subtype

The estimated 3-year event rate was plotted on a log scale as a function of RCB index, using smoothing splines approximation from a Cox model. Shaded areas indicate 95% CIs. The cut points that define RCB classes are represented as vertical lines. HR indicates hormone receptor; pCR, pathologic complete response.

Figure 3.. Kaplan-Meier Plots of Event-Free Survival (EFS) in Hormone Receptor (HR)–Positive/ERBB2-Negative, HR-Negative/ERBB2-Negative, HR-Positive/ERBB2-Positive, and HR-Negative/ERBB2-Positive Subtypes

pCR indicates pathologic complete response; RCB, residual cancer burden.

Figure 4.. Landscape Plots of the Distribution of Residual Cancer Burden (RCB) in 3 Categories of Treatments From I-SPY2 Within Hormone Receptor (HR)–Positive/ERBB2-Negative, HR-Negative/ERBB2-Negative, and ERBB2-Positive Subtypes

P values describe the Wilcoxon rank sum analysis of each experimental treatment group compared with the control group for that subtype; pCR indicates pathologic complete response.