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. 2012:2:227.
doi: 10.1038/srep00227. Epub 2012 Jan 17.

A gene signature for predicting outcome in patients with basal-like breast cancer

Robin M Hallett  1 , Anna Dvorkin-Gheva, Anita Bane, John A Hassell
Affiliations

A gene signature for predicting outcome in patients with basal-like breast cancer

Robin M Hallett et al. Sci Rep. 2012.

Abstract

Basal-like breast cancer is a molecular subtype of breast cancer with a poor prognosis. Follow-up studies of long-term outcome in these patients, demonstrates they can be separated into two clinical groups: those who succumb to their disease within the first 5 years and those expected to show excellent long term survival. Currently available clinical/histopathological variables as well as molecular signatures show little capacity to identify basal breast cancer patients with either a high or low risk of disease relapse. Using data derived from 85 basal-like breast cancer patients, we identified a 14-gene signature, which we subsequently validated on an additional 49 basal breast cancer patient set. The ability to distinguish between these two sub-groups of basal breast cancer patients at the time of initial diagnosis would permit tailoring aggressive therapeutic regimens to those patients with a poor prognosis and conversely avoid such therapy in low risk patients.

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Conflict of interest statement

The authors have filed a provisional patent application on using the described gene signature for prognosis of breast cancer patients.

Figures

Figure 1
Figure 1. Human breast tumors cluster into 6 distinct molecular subtypes of breast cancer with differences in patient survival.
(A) Hierarchical clustering of 547 breast tumors using the ‘intrinsic’ gene set separates tumors into the 6 molecular subtypes of human breast tumors. (B) Kaplan-Meier survival analysis of patients comprising each of the molecular subtypes.
Figure 2
Figure 2. 14 probe sets optimally separate patients into good and poor survival groups.
(A) Experimental strategy to identify an optimal signature to separate patients with BLBC into high and low risk groups. (B) Comparison of relative risk between leave-one-out cross-validation predicted high and low risk groups for n length signatures (n = 1,2,3…,50). 14 probe sets produces maximal risk separation between high and low risk groups (blue arrow).
Figure 3
Figure 3. The Basal 14 signature accurately predicts outcome in independent patients with BLBC.
(A) Rug plot (distribution of predicted probabilities) of proportion of patients experiencing disease relapse increases linearly with probability of relapse predicted by Basal 14 signature. (B) ROC curve to assess the accuracy of the Basal 14 signature in the validation cohort (AUC: 0.76, p = 0.003). (C) Kaplan-Meier survival analysis with the validation (HR: 4.7, [CI95: 1.8–12.3], p = 0.0017, Log-rank test). (D) Kaplan-Meier survival analysis with chemotherapy naïve patients (HR: 4.4, [CI95: 1.1–16.7], p = 0.03, Log-rank test).
Figure 4
Figure 4. Other reported prognostic signatures fail to predict patient outcome in the context of BLBC.
We calculated a signature index for the (A) Basal 14, (B) Genomic Grade Index, (C) NKI-70, (D) Recurrence Score, (E) CSR/Wound response, (F) Triple Negative and (G) MS-14 signatures. Only the Basal 14 signature was prognostic in the validation cohort of BLBC patients HR: 4.7 [CI95: 1.8–12.3], p = 0.0017, Log-rank test). Although, the Triple negative signature did trend to significance (HR: 2.0 [CI95: 0.8–5.4], p = 0.15, Log-rank test).
Figure 5
Figure 5. Basal 14 signature is prognostic in the basal and ERBB2 molecular sutbypes of breast cancer.
Prognostic capacity of the Basal 14 signature was evaluated in the (A) luminal A, (B) luminal B, (C) claudin low, (D) Normal, and (F) ERBB2 molecular subtypes of breast cancer. Notably, the Basal 14 signature was prognostic in patients with the ERBB2 molecular subtype of breast cancer (HR: 2.8 [CI95: 1.3–6.5], p = 0.01, Log-rank test).
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