Age-Independent Preoperative Chemosensitivity and 5-Year Outcome Determined by Combined 70- and 80-Gene Signature in a Prospective Trial in Early-Stage Breast Cancer

Abstract

Background: The Neoadjuvant Breast Symphony Trial (NBRST) demonstrated the 70-gene risk of distant recurrence signature, MammaPrint, and the 80-gene molecular subtyping signature, BluePrint, precisely determined preoperative pathological complete response (pCR) in breast cancer patients. We report 5-year follow-up results in addition to an exploratory analysis by age and menopausal status.

Methods: The observational, prospective NBRST (NCT01479101) included 954 early-stage breast cancer patients aged 18-90 years who received neoadjuvant chemotherapy and had clinical and genomic data available. Chemosensitivity and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed. In a post hoc subanalysis, results were stratified by age (≤ 50 vs. > 50 years) and menopausal status in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors.

Results: MammaPrint and BluePrint further classified 23% of tumors to a different subtype compared with immunohistochemistry, with more precise correspondence to pCR rates. Five-year DMFS and OS were highest in MammaPrint Low Risk, Luminal A-type and HER2-type tumors, and lowest in MammaPrint High Risk, Luminal B-type and Basal-type tumors. There was no significant difference in chemosensitivity between younger and older patients with Low-Risk (2.2% vs. 3.8%; p = 0.64) or High-Risk tumors (14.5% vs. 11.5%; p = 0.42), or within each BluePrint subtype; this was similar when stratifying by menopausal status. The 5-year outcomes were comparable by age or menopausal status for each molecular subtype.

Conclusion: Intrinsic preoperative chemosensitivity and long-term outcomes were precisely determined by BluePrint and MammaPrint regardless of patient age, supporting the utility of these assays to inform treatment and surgical decisions in early-stage breast cancer.

Fig. 1

Sankey diagram depicting further stratification of IHC/FISH-defined tumors (left) by BluePrint/MammaPrint (right) in patients with early-stage breast cancer who received NCT (n = 954; *one patient with Basal-type tumor and missing pathologic subtype information was excluded). IHC immunohistochemistry, FISH fluorescence in situ hybridization, NCT neoadjuvant chemotherapy, HR hormone receptor, HER2 human epidermal growth factor receptor 2, TNBC triple-negative breast cancer

Fig. 2

Treatment response in breast cancer patients who received NCT (n = 954). A Probability of pCR (ypT0/isN0) to NCT as a function of the MammaPrint index (n = 954). Red and yellow circles represent patients who did and did not have a pCR, respectively. Grey circles represent 95% confidence intervals. B pCR rates in IHC/FISH-defined tumors (lined bar graphs) compared with pCR rates of their respective BluePrint classifications (solid bar graphs) in NCT-treated patients (n = 953; 1 patient missing pathologic subtype information). Light blue represents Luminal A-type, dark blue represents Luminal B-type, orange represents HER2-type, and red represents Basal-type. Significance was assessed by a two-tailed z-test for proportions. Numbers (n) along the x-axis represent the total number of patients in each subgroup. ^aTwo patients with IHC-defined HR+/HER2− tumors that were classified as BluePrint HER2-type are not shown. ^bEleven patients with IHC-defined TNBC tumors that were classified as non-Basal type are not shown. NCT neoadjuvant chemotherapy, pCR pathological complete response, IHC immunohistochemistry, FISH fluorescence in situ hybridization, HER2 human epidermal growth factor receptor 2, HR hormone receptor, TNBC triple-negative breast cancer

Fig. 3

Five-year DMFS probability according to A MammaPrint, B BluePrint/MammaPrint, and C IHC/FISH subtyping in NCT-treated early-stage breast cancer patients with follow-up data available (n = 841). Significance was assessed by log-rank test. DMFS distant metastasis-free survival, IHC immunohistochemistry, FISH fluorescence in situ hybridization, NCT neoadjuvant chemotherapy, CI confidence interval, HER2 human epidermal growth factor receptor, HR hormone receptor, TNBC triple-negative breast cancer

Fig. 4

pCR rates in patients ≤ 50 years of age and patients > 50 years of age with HR+/HER2− tumors who received NCT (n = 426) based on their A MammaPrint risk and B BluePrint/MammaPrint classification. Significance was evaluated by a two-tailed z-test for proportions. C–F Five-year DMFS probability in patients with HR+/HER2− tumors who received NCT and had follow-up data available (n = 370) stratified by age: c MammaPrint Low-Risk, Luminal A-type tumors; D MammaPrint High-Risk tumors; E Luminal B-type tumors, and F Basal-type tumors. Significance was evaluated by log-rank test. pCR pathological complete response, HR hormone receptor, HER2 human epidermal growth factor receptor, NCT neoadjuvant chemotherapy, DMFS distant metastasis-free survival, CI confidence interval

Fig. 5

pCR rates in premenopausal and postmenopausal patients with HR+/HER2− tumors who received NCT (n = 423; three patients with unknown menopausal status were not included in the analysis) based on their A MammaPrint risk and B BluePrint/MammaPrint classification. Significance was evaluated by a two-tailed z-test for proportions. C–F Five-year DMFS probability in NCT-treated patients with HR+/HER2− tumors who had follow-up data available (n = 367) stratified by menopausal status: c MammaPrint Low-Risk, Luminal A-type tumors; D MammaPrint High-Risk tumors; E Luminal B-type tumors; and F Basal-type tumors. Significance was evaluated by log-rank test. pCR pathological complete response, HR hormone receptor, HER2 human epidermal growth factor receptor, NCT neoadjuvant chemotherapy, DMFS distant metastasis-free survival, CI confidence interval