Abstract
The association between breast cancer risk defined by the Tyrer‐Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5‐year TC and disease aggressiveness and then characterized underlying molecular processes. In a case‐only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low‐risk TC gene expression (TC‐Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low‐risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P < .05) including Ki‐67 proliferation status (P < 5 × 10−07). Our low‐risk TC‐Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal‐like (P < 5 × 10−13), HER2‐enriched subtype (P < 5 × 10−07) and worse 10‐year breast cancer‐specific survival (log‐rank P < 5 × 10−04). Associations between low‐risk TC‐Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR < 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes.
Highlights
Breast cancer is a complex disease involving genetic and nongenetic risk factors
We have previously observed that women at high risk as predicted by risk assessment tools are more likely to have tumors of more favorable tumor characteristics,[4] prompting the question whether the association persists for breast cancer subtypes, which are known to differ in their etiology.[5]
The goal of this study is to investigate the association between Tyrer-Cuzick risk score and breast cancer subtypes, tumor characteristics and prognosis, and to gain biological understanding of underlying
Summary
Breast cancer is a complex disease involving genetic and nongenetic risk factors. Risk assessment tools have been developed to estimate individual breast cancer risk over time.[1]. More aggressive breast cancers tend to be of basal-like and human epidermal growth factor receptor 2 (HER2)enriched intrinsic molecular subtypes,[6] hormone-receptor (ER) negative,[7] higher grade and proliferation status, larger tumor size and lymph node-positive involvement.[8,9] Currently, no risk assessment tool is sensitive for predicting risk of aggressive breast cancer subtypes.[10] The lack of such an algorithm can be partially attributed to a bias because overrepresentation of ER positive and less aggressive cancers in most populations where etiology has been studied and risk prediction tools have been established. The goal of this study is to investigate the association between Tyrer-Cuzick risk score and breast cancer subtypes, tumor characteristics and prognosis, and to gain biological understanding of underlying. The relationship between Tyrer-Cuzick score and specific breast cancer subtypes, remains unclear In this investigation, fiveyear, low-risk Tyrer-Cuzick gene expression profile, expected to be negatively correlated with risk, was associated with certain, more aggressive breast cancer subtypes, including basal-like and HER2-enriched subtypes. Molecular processes by leverage of gene expression data in samples from a clinically representative study population
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