TY - JOUR
T1 - Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer
T2 - a multicentre pooled analysis of 5161 patients
AU - I-SPY 2 Trial Consortium
AU - Yau, Christina
AU - Osdoit, Marie
AU - van der Noordaa, Marieke
AU - Shad, Sonal
AU - Wei, Jane
AU - de Croze, Diane
AU - Hamy, Anne Sophie
AU - Laé, Marick
AU - Reyal, Fabien
AU - Sonke, Gabe S.
AU - Steenbruggen, Tessa G.
AU - van Seijen, Maartje
AU - Wesseling, Jelle
AU - Martín, Miguel
AU - del Monte-Millán, Maria
AU - López-Tarruella, Sara
AU - Adamson, Kathi
AU - Albain, Kathy S.
AU - Asare, Adam L.
AU - Asare, Smita M.
AU - Balassanian, Ron
AU - Beckwith, Heather
AU - Berry, Scott M.
AU - Berry, Donald A.
AU - Boughey, Judy C.
AU - Buxton, Meredith B.
AU - Chen, Yunn Yi
AU - Chen, Beiyun
AU - Chien, A. Jo
AU - Chui, Stephen Y.
AU - Clark, Amy S.
AU - Clennell, Julia L.
AU - Datnow, Brian
AU - DeMichele, Angela M.
AU - Duan, Xiuzhen
AU - Edmiston, Kirsten K.
AU - Elias, Anthony D.
AU - Ellis, Erin D.
AU - Esserman, Laura L.
AU - Euhus, David M.
AU - Fadare, Oluwole
AU - Fan, Fang
AU - Feldman, Michael D.
AU - Forero-Torres, Andres
AU - Haley, Barbara B.
AU - Han, Hyo S.
AU - Harada, Shuko
AU - Haugen, Patricia
AU - Helsten, Teresa
AU - Viscusi, Rebecca K.
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S1470-2045(21)00589-1
DO - 10.1016/S1470-2045(21)00589-1
M3 - Article
C2 - 34902335
AN - SCOPUS:85123225548
SN - 1470-2045
VL - 23
SP - 149
EP - 160
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 1
ER -