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Breast Cancer Biomarkers: from Identification to Application to FFPE tissues
Pracella, Danae
2013-04-22
Abstract
Background: Breast carcinoma (BC) is the most common form of malignancy in women and the leading cause of cancer-related mortality among females internationally. BC includes a series of heterogeneous tumours with a great variability at histological level, biological level and clinical evolution. Because its complexity, BC treatment recommendations are continually changing with the new advances in this field. However there are still a significant number of patients with similar features that show distinct outcome. In order to detect the existing molecular differences and address patients to more personalized treatment, there is a need to find out new cancer biomarkers.
Aim: The main goal of my PhD project is to investigate on the possibility of combining traditional clinical and pathological features with new candidate biomarkers for the prognostication of breast cancer. The first part concerns the prognostic role of molecular classification of primary tumours, according to luminal A, luminal B, HER-2+ and basal-like subtypes. In the second part, the prognostic value of nine candidate genes was investigated at mRNA level. The genes of interest belong to the RB pathway (CDK2, RB1), the RAS pathway (HER-2, PI3K, AKT1, AKT2, AKT3, RAF1) and cellular differentiation mechanism (CK8).
Methods: This retrospective study comprises 305 BC patients, both lymph node negative (LN-) and lymph node positive (LN+). The molecular classification of primary tumours was performed by means of immunohistochemistry (IHC), using seven surrogate markers: ER, PR, HER-2, Ki67, CK8 and CK5/6, plus vimentin. Results of molecular classification were analysed with respect to morphologic and pathological features, and outcome. Moreover, the molecular characterization was also performed in a set of loco-regional metastatic lymph nodes, to compare the phenotype of primary tumour cells with their matched metastatic cells colonizing regional nodes. To the second purpose, gene’s expression was investigated in the entire cohort of primary tumours by means of real-time PCR, using the TaqMan chemistry. The expression of the nine genes was investigated in connection with the clinical-pathological factors, molecular classification and BC specific patient’s survival.
Results: Regarding molecular classification of primary tumours, luminal A, luminal B, HER-2+ and basal-like accounted for 46%, 34%, 8% and 12% respectively. Luminal A tumours were mainly LN-, well differentiated and stage I, while luminal B and HER2+ showed higher tumour grade, nodal metastases as well as higher proliferation status and stage. Luminal A exhibited better survival in comparison to the other subtypes (p<0.001). HER2+ and basal-like showed a poorer outcome. Despite of the longer survival of patients with luminal tumours, they are the only one that underwent long-term recurrences. The molecular classification at the level of loco-regional metastasis, revealed that HER-2, Ki67, CK8 and vimentin positivity was significantly decreased with respect primary tumour, whereas CK5/6 positivity was increased. No significant differences for ER and PR positivity between primary and metastatic lesions were found. Regarding gene’s expression, we found a significant different distribution for all genes, except RAF-1, among LN- and LN+ groups. We also found specific pattern of genes’ expression among molecular classes for: CDK2, HER-2, PI3K, AKT2, AKT3 and CK8. Survival analysis revealed a significant and independent role on patient’s survival for one gene in luminal A tumours.
Conclusions: We believe that the use of the traditional biomarkers ER, PR, HER-2 and Ki67 is essential for BC characterisation and prognostication in association with clinical pathological features. Nevertheless, we identified new molecular markers that could better distribute patients into more homogeneous subgroups of BC.
Insegnamento
Publisher
Università degli studi di Trieste
Languages
en
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