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. MethodsIn 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 betweenstudy 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. FindingsWe 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 eventfree 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 c...

Molecular Assessment of HER2 to Identify Signatures Associated with Therapy Response in HER2-Positive Breast Cancer

“…At the time of surgery (approximately 6 months following core biopsy collection and after all qSMLM data were computed), clinical outcomes and residual cancer burden (RCB) indices were noted. The RCB index (RCB-0 to RCB-III) was designed to quantify residual disease in the tumor bed and lymph nodes after neoadjuvant therapy; it is a well validated prognostic indicator for breast cancer [ 112 , 113 ]. Our sample cohort comprised the following: P18 had RCB-I, P20 had RCB-II, and all other women had achieved a pathological complete response (pCR) equivalent to RCB-0.…”

Post-Neoadjuvant Treatment Strategies in Breast Cancer

“…It has recently been recognized that the binary approach of pCR and non-pCR does not stratify the risk groups optimally. Yau et al introduced a categorization according to the residual disease burden, which categorizes the tumor into three grades, according to the size of the residual tumor [ 32 ]. The authors recently found that with an increase in the residual cancer burden, the outcome worsened.…”

Digital phenotyping in young breast cancer patients treated with neoadjuvant chemotherapy (the NeoFit Trial): protocol for a national, multicenter single-arm trial

“…Neoadjuvant chemotherapy (NAC), is currently used for the treatment of aggressive breast carcinomas that are nonetheless operable [ 6 ], to increase conservative breast surgery rates [ 7 ]. Neoadjuvant chemotherapy has many advantages such as a less extensive breast and axillary surgery and a monitoring of the treatment response [ 8 , 9 ]. Pathological complete response (pCR) has been reported to occur in about 20–60% of patients on NAC, and is associated with better survival outcomes [ 10 – 13 ].…”