Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival

Abstract

Based on the hypothesis that features of the molecular program of normal wound healing might play an important role in cancer metastasis, we previously identified consistent features in the transcriptional response of normal fibroblasts to serum, and used this ''wound-response signature'' to reveal links between wound healing and cancer progression in a variety of common epithelial tumors. Here, in a consecutive series of 295 early breast cancer patients, we show that both overall survival and distant metastasis-free survival are markedly diminished in patients whose tumors expressed this wound-response signature compared to tumors that did not express this signature. A gene expression centroid of the wound-response signature provides a basis for prospectively assigning a prognostic score that can be scaled to suit different clinical purposes. The wound-response signature improves risk stratification independently of known clinico-pathologic risk factors and previously established prognostic signatures based on unsupervised hierarchical clustering (''molecular subtypes'') or supervised predictors of metastasis (''70-gene prognosis signature'').microarray ͉ prognosis ͉ wound healing ͉ metastasis ͉ treatment decision

The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1–3 positive lymph nodes in an independent validation study

“…Some previously identified markers do have prognostic value in nodepositive breast cancer, however, since they do not identify a substantial group of patients with an excellent disease outcome, the clinical relevance as prognostic marker for this node-positive patients' group seems to be limited [13,17,18]. The only other signature that could identify a low risk group with a sufficiently good outcome within node-positive patients was the wound signature [9]. Since this wound signature is not available as a diagnostic test, its value for clinical practice seems to be limited at this moment.…”

“…To allow more extensive analyses, follow-up data of all patients with 1-3 positive nodes from the previously described series by Van de Vijver [8], were updated, blinded to the 70-gene prognosis-signature [9].…”

“…To be able to do more extensive analyses we selected all patients with only 1-3 positive nodes from this series (n = 106) [8]. Follow-up was updated from a median of 7.4 years to 10.3 years (range, 1.6 to 21.2 years) [9]. This patient series was significantly different from our here described new series, with regard to age (median age 45 vs. 50 years, respectively; P \ 0.001), axilllary procedure (all ALND), adjuvant systemic therapy and survival probabilities (Supplementary Tables 3 and 4).…”

Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer

“…Moreover, the molecular features that define this wound-like phenotype are evident at an early cancer and predict increased likelihood of metastasis and death in breast, lung, and gastric cancer. 29 In a subsequent study of 295 early breast carcinomas, Chang et al 30 showed that both overall survival and distant metastasis-free survival are significantly diminished in patients whose carcinomas expressed this 'wound-response signature' compared to tumors that did not express this signature. 30 At this point, it is not clear whether the observed genetic changes in our current study are related to breast cancer initiation or are acquired 'reactive' genetic alterations which are more associated with tumor progression.…”

Comparative and integrative functional genomics of HCC

“…Cancer cells do not invent new pathways, but resurrect the pre-existing but dormant signaling pathways that were active during embryonic development or normal physiological condition. In recent studies (Chang et al, 2004(Chang et al, , 2005, gene expression signatures from experimental condition mimicking wound healing process were used to measure how much tumors may be like wounds, and developed a model to predict cancer progression based on wound healing gene expression signature. Patients carrying the wound healing signature had a significantly increased risk of metastasis when compared with patients who lack the signature, indicating that genomic data from normal physiological condition can help to predict the prognosis of cancer patients.…”