Gene expression profiles associated with the presence of a fibrotic focus and the growth pattern in lymph node-negative breast cancer
ABSTRACT A fibrotic focus, the scar-like area found in the center of an invasive breast tumor, is a prognostic parameter associated with an expansive growth pattern, hypoxia, and (lymph)angiogenesis. Little is known about the molecular pathways involved.
Sixty-five patients were selected of whom microarray data of the tumor and H&E slides for histologic analysis were available. The growth pattern and the presence and size of a fibrotic focus were assessed. Differences in biological pathways were identified with global testing. The correlations of growth pattern and fibrotic focus with common breast cancer signatures and with clinicopathologic variables and survival were investigated.
Tumors with a large fibrotic focus showed activation of Ras signaling and of the hypoxia-inducible factor-1alpha pathway. Furthermore, unsupervised hierarchical cluster analysis with hypoxia- and (lymph)angiogenesis-related genes showed that hypoxia-inducible factor-1alpha, vascular endothelial growth factor A, and carbonic anhydrase 9 were overexpressed. The presence of a fibrotic focus, especially a large fibrotic focus, was associated with the basal-like subtype (P = 0.009), an activated wound-healing signature (P = 0.06), and a poor-prognosis 76-gene signature (P = 0.004). The presence of a fibrotic focus (P = 0.02) and especially of a large fibrotic focus (P = 0.004) was also associated with early development of distant metastasis.
Our results sustain the hypothesis that hypoxia-driven angiogenesis is essential in the biology of a fibrotic focus. Ras and Akt might play a role as downstream modulators. Our data furthermore suggest that vascular endothelial growth factor A does not only drive angiogenesis but also lymphangiogenesis in tumors with a fibrotic focus. Our data also show an association between the presence of a fibrotic focus and infaust molecular signatures.
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ABSTRACT: Background: Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status. Methods: Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations. Results: Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0–64.6; P=5 × 10−7). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers. Conclusion: This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2.British Journal of Cancer 06/2013; 109(1):154-163. DOI:10.1038/bjc.2013.295 · 4.82 Impact Factor
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ABSTRACT: A minority of early invasive breast cancers show a pattern of central necrosis and fibrosis (CNF). Previous studies have documented an adverse prognostic impact and association with other adverse pathological features, but its predictive importance for therapy selection is unknown. We examined the prognostic and predictive value of CNF in two randomized clinical trials comparing chemoendocrine therapy with endocrine therapy alone in patients with node-negative breast cancer. A total of 1,850 patients randomly assigned to treatment groups comparing endocrine with chemoendocrine therapy, and with centrally-assessed CNF, ER, PgR and HER2 were included in the analytic cohort. The median follow up was 10 years. CNF was present in 84 of 1,850 trial patients (4.5%). It was associated with tumor characteristics suggesting poor outcome, but was an independent adverse factor for disease-free survival. In the presence of CNF outcome was worse regardless of tumor grade, whereas in the absence of CNF, patients with grade 3 tumors had poorer outcome than those with grade 1-2 tumors. Among patients with estrogen receptor-absent tumors chemoendocrine therapy was superior to endocrine therapy alone only in the absence of CNF [HR (chemoendocrine:endocrine) = 0.46 in CNF-absent, 0.90 in CNF-present], while among those with receptor-positive disease chemoendocrine therapy was beneficial only in the presence of CNF [HR = 0.34 CNF-present, 0.96 CNF-absent]. The results suggest that the presence of CNF reflects a biological difference in early breast cancer that is important in modulating the efficacy of standard therapies. Accordingly we believe that its presence should be routinely reported.Breast Cancer Research and Treatment 04/2009; 121(1):211-8. DOI:10.1007/s10549-009-0360-y · 4.20 Impact Factor
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ABSTRACT: Gene expression microarrays allow for the high throughput analysis of huge numbers of gene transcripts and this technology has been widely applied to the molecular and biological classification of cancer patients and in predicting clinical outcome. A potential handicap of such data intensive molecular technologies is the translation to clinical application in routine practice. In using an artificial neural network bioinformatic approach, we have reduced a 70 gene signature to just 9 genes capable of accurately predicting distant metastases in the original dataset. Upon validation in a follow-up cohort, this signature was an independent predictor of metastases free and overall survival in the presence of the 70 gene signature and other factors. Interestingly, the ANN signature and CA9 expression also split the groups defined by the 70 gene signature into prognostically distinct groups. Subsequently, the presence of protein for the principal prognosticator gene was categorically assessed in breast cancer tissue of an experimental and independent validation patient cohort, using immunohistochemistry. Importantly our principal prognosticator, CA9, showed that it is capable of selecting an aggressive subgroup of patients who are known to have poor prognosis.Breast Cancer Research and Treatment 05/2009; 120(1):83-93. DOI:10.1007/s10549-009-0378-1 · 4.20 Impact Factor