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existing pathology tests. This is one important step towards personalized diagnosis
and treatment planning based on an integrated genomic test of an individual tumor.
Resistance to treatment with endocrine therapy occurs in ∼50 % of breast cancer
patients. The transcription factor PBX1, a known NOTCH target gene, is required
for the growth of endocrine therapy-resistant breast cancer cells. The NOTCH path-
way is overactivated in resistant breast cancer cells, whereas classical ERα signal-
ing is epigenetically disengaged. Blocking of NOTCH signaling abrogates growth
of resistant breast cancer cells. A gene expression signature based on NOTCH-
PBX1 activity can determine if breast cancer patients are responsive or not to endo-
crine therapy (Magnani et al. 2013 ).
Results of gene expression studies have confi rmed that breast cancer is not a
single disease with variable morphologic features and biomarkers but, rather, a
group of molecularly distinct neoplastic disorders. This forms the basis of molecu-
lar classifi cation of breast cancer. Profi ling results also support the hypothesis that
ER-negative and ER-positive breast cancers originate from distinct cell types and
point to biologic processes that govern metastatic progression. Moreover, such pro-
fi ling has uncovered molecular signatures that could determine response to chemo-
therapy and infl uence clinical care of patients with breast cancer (Sotiriou and
Pusztai 2009 ).
Unbiased NGS studies have identifi ed several recurrently mutated genes in breast
cancer that represent putative novel therapeutic targets (Russnes et al. 2011 ).
PI3KCA was found as one of the most frequently mutated genes in breast and other
cancer types. Therapeutic targeting of the PI3K/AKT signaling pathway has been a
major focus of several drug companies, leading to the development and clinical test-
ing of several PI3K and AKT inhibitors. Upregulation of phosphorylated HER3 and
partial recovery of phospho-AKT has been observed following XL147 treatment,
leading to incomplete suppression of tumor cell growth (Chakrabarty et al. 2012 ).
Based on follow-up experiments, these authors demonstrated that the combined
inhibition of HER2 and PI3K leads to synergistic effects and more effi cient eradica-
tion of the tumors. These results are an example for the complexity of signaling
pathways in cancer cells complicated by multiple layers of feedback inhibition.
TOP 20 model , licensed by Tiziana Life Sciences from the European Institute of
Oncology for commercial development, is a gene expression signature capable of
predicting disease aggressiveness and prognosis in breast cancer patients. It is dif-
ferent from all other signatures available today because it is derived from cancer
stem cells and therefore it predicts cancer behavior based on its stem cell content.
The TOP 20 genes have been defi ned based on published expression profi les of
breast stem cells. They are further selected based on their levels of expression and
likelihood of translation into practice for patient stratifi cation in breast cancer.
Monitoring of Circulating Tumor Cells in Metastatic Breast Cancer
Because repeated tissue biopsies are invasive, costly and impractical, assessment
of tumor characteristics on circulating tumor cells (CTCs) by a peripheral blood
sample as a ‘liquid biopsy’ provides a better alternative. Molecular and genomic
10 Personalized Therapy of Cancer