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Generali D.,Azienda Instituti Ospitalieri Of Cremona | Symmans W.F.,University of Houston | Berruti A.,University of Turin | Fox S.B.,Molecular Pathology Research and Development Laboratory
Journal of the National Cancer Institute - Monographs | Year: 2011

The adoption of personalized medicine has led to the search for prognostic and predictive markers that can be applied to individual patients to give optimal information for their clinical management. We have used samples from randomized clinical trials of hormonal and chemotherapy to identify relevant markers of sensitivity and resistance using a neoadjuvant approach by linking expression of a panel of proteins involved in growth factor receptor signaling, angiogenesis, estrogen receptor signaling, and hypoxia to individual patient response. We evaluated samples from randomized clinical trials of epirubicin with or without tamoxifen, and letrozole with or without metronomic cyclophosphamide, to study chemotherapy, hormonal therapy, and antiangiogenic effects. We present a proof of principle of this approach in identifying several key pathways that are associated with clinical and pathological response. Thus, we have shown that the hypoxia-inducible factor (HIF) pathway, mitogen activated protein kinase, and phosphorylated estrogen receptor-a can identify patients who are likely to respond to hormonal therapy and that HIF signaling is also a marker of resistance for anthracycline-based chemotherapy. To redress the role of HIF, we then evaluated samples from a randomized control trial of an anthracycline chemotherapy with and without erythropoietin. These studies demonstrate that the approach of using primary systemic therapy in breast can identify markers of response and potentially targets for rationale design of new therapies. © The Author 2011. Published by Oxford University Press. All rights reserved.

Fox S.B.,Peter MacCallum Cancer Center | Generali D.,Azienda Instituti Ospitalieri Of Cremona | Berruti A.,University of Turin | Brizzi M.P.,Azienda Instituti Ospitalieri Of Cremona | And 11 more authors.
Breast Cancer Research | Year: 2011

Introduction: The purpose of the present study was to investigate the relationship of expression of hypoxia inducible factor (HIF)-1α-modifying enzymes prolyl hydroxylase (PHD)1, PHD2 and PHD3 to response of tumours and survival in breast cancer patients enrolled in a phase II trial of neoadjuvant anthracycline and tamoxifen therapy.Methods: The expression of PHD1, PHD2 and PHD3 together with HIF-1α and the HIF-inducible genes vascular endothelial cell growth factor (VEGF) and carbonic anhydrase IX were assessed by immunohistochemistry using a tissue microarray approach in 211 patients with T2-4 N0-1 breast cancer enrolled in a randomised trial comparing single-agent epirubicin versus epirubicin and tamoxifen as the primary systemic treatment.Results: PHD1, PHD2 and PHD3 were detected in 47/179 (26.7%), 85/163 (52.2%) and 69/177 (39%) of tumours at baseline. PHD2 and PHD3 expression was moderate/strong whereas PHD1 expression was generally weak. There was a significant positive correlation between HIF-1α and PHD1 (P = 0.002) and PHD3 (P < 0.05) but not PHD2 (P = 0.41). There was a significant positive relationship between VEGF and PHD1 (P < 0.008) and PHD3 (P = 0.001) but not PHD2 (P = 0.09). PHD1, PHD2 and PHD3 expression was significantly increased after epirubicin therapy (all P < 0.000) with no significant difference in PHD changes between the treatment arms. There was no significant difference in response in tumours that expressed PHDs and PHD expression was not associated with survival.Conclusions: Although expression of the PHDs was not related to response or survival in patients receiving neoadjuvant epirubicin, our data provide the first evidence that these enzymes are upregulated on therapy in breast cancer and that the biological effects independent of HIF make them therapeutic targets. © 2011 Fox et al.; licensee BioMed Central Ltd.

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