Abstract
Breast cancer in young women is associated with poor prognosis. We aimed to define the role of gene expression signatures in predicting prognosis in young women and to understand biological differences according to age. Patients were assigned to molecular subtypes [estrogen receptor (ER)(+)/HER2(-); HER2(+), ER(-)/HER2(-))] using a three-gene classifier. We evaluated whether previously published proliferation, stroma, and immune-related gene signatures added prognostic information to Adjuvant! online and tested their interaction with age in a Cox model for relapse-free survival (RFS). Furthermore, we evaluated the association between candidate age-related genes or gene sets with age in an adjusted linear regression model. A total of 3,522 patients (20 data sets) were eligible. Patients aged 40 years or less had a higher proportion of ER(-)/HER2(-) tumors (P < 0.0001) and were associated with poorer RFS after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR = 1.34, 95% CI = 1.10-1.63, P = 0.004). The proliferation gene signatures showed no significant interaction with age in ER(+)/HER2(-) tumors after adjustment for Adjuvant! online. Further analyses suggested that breast cancer in the young is enriched with processes related to immature mammary epithelial cells (luminal progenitors, mammary stem, c-kit, RANKL) and growth factor signaling in two independent cohorts (n = 1,188 and 2,334). Proliferation-related prognostic gene signatures can aid treatment decision-making for young women. However, breast cancer arising at a young age seems to be biologically distinct beyond subtype distribution. Separate therapeutic approaches such as targeting RANKL or mammary stem cells could therefore be needed.
Highlights
Around 7% of patients in the developed world and 25% of patients in the developing world are diagnosed with breast cancer below the age of 40 [1, 2]
Patients aged 40 years or less had a higher proportion of ERÀ/HER2À tumors (P < 0.0001) and were associated with poorer relapse-free survival (RFS) after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR 1⁄4 1.34, 95% CI 1⁄4 1.10–1.63, P 1⁄4 0.004)
The proliferation gene signatures showed no significant interaction with age in ERþ/HER2À tumors after adjustment for Adjuvant! online
Summary
Around 7% of patients in the developed world and 25% of patients in the developing world are diagnosed with breast cancer below the age of 40 [1, 2]. These women have poorer survival and higher risk of relapse than their older counterparts [3, 4]. Several factors have been linked to the poor prognosis associated with developing breast cancer at a young age. Institut Jules Bordet, Universite Libre de Bruxelles; 2Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium; 3Division of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Canada; and 4Computational Biology and Functional Genomic Laboratory, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston
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