Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients

Abstract

Background: Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings.

Methods: In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype.

Findings: We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41-1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79-2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0·0001 for all subtypes). RCB score remained prognostic for event-free survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1·52 (1·36-1·69) in the hormone receptor-positive, HER2-negative group to 2·09 (1·73-2·53) in the hormone receptor-negative, HER2-positive group (p<0·0001 for all subtypes).

Interpretation: RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be considered to become part of standard pathology reporting after neoadjuvant therapy.

Funding: National Cancer Institute at the US National Institutes of Health.

Conflict of interest statement

Declaration of interests AKG reports personal fees from Sinochips Diagnostics. CC reports institutional funding from Genentech, Roche, Servier, and AstraZeneca; and participation in a data and safety monitoring advisory board for iMED External Science Panel. CY reports institutional funding from Quantum Leap Healthcare Collaborative. DC reports institutional research funding from Novartis, AstraZeneca, Pfizer, Roche, Eli-Lilly, Puma Biotechnology, Daiichi Sankyo, Synthon, Seagen, Zymeworks, Elsevier, European Cancer Organisation, Celgene, Succinct Medical Communications, Prima BioMed (now Immutep), Oncolytics Biotech (US), Celldex Therapeutics, San Antonio Breast Cancer Consortium, Highfield Communication, Samsung Bioepis, prIME Oncology, Merck Sharp & Dohme, Prima BioMed (now Immutep), RTI Health Solutions, and Eisai. WFS owns stocks in Delphi Diagnostics; and reports the patent “method of measuring residual cancer and predicting patient survival” (US Patent and Trademark Office [USPTO] number 7711494B2). GSS reports institutional research funding from AstraZeneca, Merck, Novartis, and Roche. HE reports institutional research funding from Roche Sanofi-Aventis; is a consultant for Daiichi-Sankyo, AstraZeneca, Intas Pharmaceuticals, and prIME Oncology; and reports travel support from Daiichi-Sankyo, AstraZeneca, Intas Pharmaceuticals, Pfizer, and Amgen. JEA reports institutional research funding from AstraZeneca; and honoraria from Pfizer and Eisai. JMSB reports grants from Thermo Fisher Scientific, Geoptix, Agendia, NanoString Technologies, Stratifyer, and Biotheranostics; is a consultant for Insight Genetics, BioNTech, Biotheranostics, Pfizer, RNA Diagnostics, and OncoXchange; reports honoraria from NanoString Technology, Oncology Education, and Biotheranostics; reports travel support from Biotheranostics and Nanostring Technologies; reports patents “histone gene module predicts anthracycline benefit” (Patent Cooperation Treaty [PCT] number CA2016/000247); “95-gene signature of residual risk following endocrine treatment” (PCT number CA2016/000304); “immune gene signature predicts anthracycline benefit” (PCT number CA2016/000305); and applied for patents “methods and devices for predicting anthracycline treatment efficacy” (USPTO application number 15/325,472; European Patent Office number 15822898.1; Canada, not yet assigned) and “systems, devices and methods for constructing and using a biomarker” (USPTO application number 15/328,108; European Patent Office number 15824751.0; Canada, not yet assigned). JCB reports institutional research funding from Eli Lilly. LP is a consultant for and receives honoraria from AstraZeneca, Merck, Novartis, Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Almac, H3 Biomedicine, Clovis, and Syndax; and reports the patent “method of measuring residual cancer and predicting patient survival” (US Patent Number 7711494B2). LaH reports individual research grants from Roche and Sanofi-Aventis; and travel support from Roche, AstraZeneca, Pfizer, and Sanofi-Aventis. LJE reports institutional research funding from Merck; participation in an advisory board for Blue Cross Blue Shield; and personal fees from UpToDate. LJvV is an employee of and owns stock in Agendia. MPG reports individual research grants from Pfizer, Sermonix, and Eli Lilly; and is a consultant for Pfizer, Eli Lilly, Novartis, Biotheranostics, Sermonix, Context Therapeutics, and Eagle Therapeutics. MM reports grants from Roche, Puma, and Novartis; is a consultant for AstraZeneca, Amgen, Glaxo, Taiho Oncology, Roche, Novartis, PharmaMar, Eli Lilly, Puma Biotechnology, Daiichi Sankyo, and Pfizer; reports honoraria from AstraZeneca, Amgen, Roche, Novartis, and Pfizer; and reports personal fees from Pfizer and Eli Lilly. PS reports institutional research funding from Novartis, Merck, and Bristol Myers Squibb; and is a consultant for Merck, Novartis, Seattle Genetics, Gilead Immunomedics, AstraZeneca, and ExactSciences. SL-T has received consulting fees from AstraZeneca, Novartis, Roche, Pfizer, Celgene, Pierre-Fabre, Eisai, and Eli Lilly; reports honoraria from Eli Lilly; and reports travel support from Novartis, Celgene, Merck Sharp & Dohme, Roche, and Pfizer. SBE reports institutional research funding from Pfizer. All other authors declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1:. Study profile

RCB=residual cancer burden.

Figure 2:. Prognostic value of RCB score and RCB class in the overall pooled analysis cohort

Plots of log relative hazard rate for event-free survival events (A) and distant relapse-free survival events (B) as a function of RCB score. Splines approximation of RCB with two degrees of freedom was used to allow for non-linear effect. A log linear increase in relative hazard rate implies that the hazard ratio associated with change in RCB remains constant over the range of RCB. Thresholds for corresponding RCB classes (RCB-0 to RCB-3) are shown for reference (vertical dashed lines). Vertical bars represent all RCB scores recorded on a continuous scale. Kaplan-Meier plots of event-free survival (C) and distant relapse-free survival (D) stratified by RCB class. Crosses denote patients censored. RCB=residual cancer burden. pCR=pathological complete response.

Figure 3:. Prognostic value of RCB score within hormone receptor and HER2 subtypes

Plots of log relative hazard rate for event-free survival events as a function of RCB score among breast cancer subtypes. For the two HER2-positive subtypes, plots of the subset of patients who received neoadjuvant HER2-targeted therapy are shown (plots for all HER2-positive patients, with or without HER2-targeted therapy, are presented in the appendix p 11). Splines approximation of RCB with two degrees of freedom was used to allow non-linear effect. A log linear increase in relative hazard rate implies that the hazard ratio associated with change in RCB remains constant over the range of RCB. Thresholds for corresponding RCB classes (RCB-0 to RCB-3) are shown for reference (vertical dashed lines). Vertical bars represent all RCB scores recorded on a continuous scale. RCB=residual cancer burden. pCR=pathological complete response.

Figure 4:. Prognostic value of RCB class for hormone receptor and HER2 subtypes

Kaplan-Meier plots of event-free survival by RCB classes among breast cancer subtypes. For the two HER2-positive subtypes, plots of the subset of patients who received neoadjuvant HER2-targeted therapy are shown (plots for all HER2-positive patients, with or without HER2-targeted therapy, are presented in the appendix p 13). Crosses denote patients censored. RCB=residual cancer burden.