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

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Lancet Oncol. 2022 Jan;23(1):149-160. doi: 10.1016/S1470-2045(21)00589-1. Epub 2021 Dec 11.

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

The Lancet. Oncology

Christina Yau, Marie Osdoit, Marieke van der Noordaa, Sonal Shad, Jane Wei, Diane de Croze, Anne-Sophie Hamy, Marick Laé, Fabien Reyal, Gabe S Sonke, Tessa G Steenbruggen, Maartje van Seijen, Jelle Wesseling, Miguel Martín, Maria Del Monte-Millán, Sara López-Tarruella, Judy C Boughey, Matthew P Goetz, Tanya Hoskin, Rebekah Gould, Vicente Valero, Stephen B Edge, Jean E Abraham, John M S Bartlett, Carlos Caldas, Janet Dunn, Helena Earl, Larry Hayward, Louise Hiller, Elena Provenzano, Stephen-John Sammut, Jeremy S Thomas, David Cameron, Ashley Graham, Peter Hall, Lorna Mackintosh, Fang Fan, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela M DeMichele, Kimberly Cole, Lajos Pusztai, Mi-Ok Kim, Laura J van 't Veer, Laura J Esserman, W Fraser Symmans

Affiliations

Department of Surgery, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected].
Department of Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Surgery, Institut Curie, Paris, France.
Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
Department of Tumor Biology, Institut Curie, Paris, France.
Department of Medical Oncology, Institut Curie, Paris, France.
Department of Tumor Biology, Institut Curie, Paris, France; Department of Pathology, Université de Rouen Normandie, Rouen, France.
Department of Surgery, Institut Curie, Paris, France.
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
Department of Surgery, Mayo Clinic, Rochester, MN, USA.
Department of Oncology, Mayo Clinic, Rochester, MN, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Department of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
Department of Oncology, University of Cambridge, Cambridge, UK.
Diagnostic Development Program, Ontario Institute for Cancer Research, Toronto, Canada; Deanery of Molecular, Genetic and Population Health Sciences, Edinburgh Cancer Research Centre, Edinburgh, UK; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
Department of Oncology, Western General Hospital, Edinburgh, UK.
Department of Histopathology, University of Cambridge, Cambridge, UK.
Department of Pathology, Western General Hospital, Edinburgh, UK.
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Medical Oncology, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pathology, Yale University, New Haven, CT, USA.
Department of Medical Oncology, Yale University, New Haven, CT, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.

PMID: 34902335 DOI: 10.1016/S1470-2045(21)00589-1

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

Publication Types

Journal Article

Grant support

P50 CA116201/CA/NCI NIH HHS/United States