Age-specific differences in oncogenic pathway deregulation seen in human breast tumors

Abstract

Purpose: To define the biology driving the aggressive nature of breast cancer arising in young women.

Experimental design: Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young <or=45 years; older >or=65 years), 411 eligible patients (n = 200<or=45 years; n = 211>or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts.

Results: In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value.

Conclusion: Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.

Figure 1. Patterns of pathway deregulation in human breast tumors arising in women aged ≤45 years.

A) Prediction of PI3K, Myc, Ras, β-catenin, Src and E2F pathway deregulation. Red represents high probability of pathway deregulation, blue represents low probability of pathway deregulation. Five clusters emerge based on pathway patterns. B) Kaplan Meier survival analysis based on pathway patterns: good prognosis (cluster 4), intermediate prognosis (clusters 2, 3, 5), and poor prognosis (cluster 1), (p = 0.14). C) Kaplan Meier survival analysis comparing clinically-significant differences between clusters 1 and 4 (HR 4.15).

Figure 2. Patterns of pathway deregulation in human breast tumors arising in women ≥aged 65 years.

A) Prediction of PI3K, Myc, Ras, β-catenin, Src and E2F pathway deregulation. Red represents high probability of pathway deregulation, blue represents low probability of pathway deregulation. Six clusters emerge based on pathway patterns. B) Kaplan Meier survival analysis for breast cancer patients aged ≥65 years based on pathway patterns: good prognosis (clusters 3,5) and poor prognosis (clusters 1,6), (p = 0.04). C) Kaplan Meier survival analysis for breast cancer patients comparing clinically-significant differences between clusters 1 and 3 (HR = 2.7).

Figure 3. Non-parametric T test evaluating pathway probability between tumors arising in younger versus older women.

Red represents women aged ≤45 years. Blue represents women aged ≥65 years. The line represents the median.

Figure 4. Chemosensitivity patterns among women aged ≤45 years and ≥65 years with early stage breast cancer.

A) LEFT PANEL Hierarchical clustering of the probability of sensitivity to 5-fluorouracil (5-FU), paclitaxel, docetaxel, adriamycin and cyclophosphamide among 200 breast tumors arising in women aged ≤45 years; RIGHT PANEL Linear regression analysis of sensitivity to adriamycin among women in genomic cluster 1 (poor prognosis) vs. 4 (good prognosis) aged ≤45 years. B) LEFT PANEL Hierarchical clustering of the probability of sensitivity to 5FU, paclitaxel, docetaxel, adriamycin and cyclophosphamide among 211 breast tumors arising in women aged ≥65 years. RIGHT PANEL Linear regression analysis of sensitivity to adriamycin among women in genomic cluster 1 (poor prognosis) vs. genomic cluster 3 (good prognosis), demonstrating a statistically significant (p = 0.02, log rank) relationship between clusters (of pathway deregulation) and adriamycin sensitivity.