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Turner N.C.,Institute of Cancer Research | Turner N.C.,Breast Unit | Reis-Filho J.S.,Sloan Kettering Cancer Center
Clinical Cancer Research | Year: 2013

Triple-negative breast cancer (TNBC) comprises a highly diverse collection of cancers. Here, we review this diversity both in terms of gene expression subtypes and the repertoire of genetic events. Transcriptomic analyses of TNBC have revealed at least six subtypes, with the luminal androgen receptor (luminal AR) or molecular apocrine cancers forming a distinct group within triple-negative disease. Distinct from the gene expression subtypes, a diverse set of genetic events have been described in TNBC, with a number of potentially targetable genetic events found although all at relatively low frequency. Clinical trials to define the clinical utility of therapies targeting these low-frequency events will require substantial screening efforts to identify sufficient patients. Set against the diversity of TNBC, clinical studies of patients with triplenegative disease will need to be either focused on molecularly defined subsets with upfront molecular stratification, or powered for a secondary endpoint analysis of a molecularly defined subset. Such approaches will be crucial to realize the potential of precision medicine for patients with TNBCs. © 2013 American Association for Cancer Research. Source

Constitutive activation of the EGFR/RAS/PI3K cell-signaling pathway that may occur through molecular aberrations in core pathway components occurs in many solid tumours, including colorectal cancer(CRC), non-small-cell lung cancer(NSCLC) and breast cancer. Predictive biomarkers of response to therapeutics targeting this pathway are necessary to select patients more likely to respond, and importantly, to avoid treating patients likely to suffer a worse outcome with therapy compared to standard of care. Determination of EGFR by immunohistochemistry(IHC) is not strongly predictive of response to EGFR-targeted therapy in CRC and NSCLC. EGFR gene mutations in the tyrosine kinase(TK) binding domain are predictive of response to EGFR tyrosine kinase inhibitors(TKIs) in NSCLC, and the acquisition of a point mutation in a gene encoding an amino acid in an adjacent area, T790M, is predictive of resistance. However, novel irreversible EGFR inhibitors such as BIBW-2992 and HKI-272 may retain activity in tumours with T790M mutations. It is well established in CRC that mutations in KRAS are predictive of resistance to EGFR pathway inhibition, and may predict for a poorer outcome with therapy. Other potentially useful biomarkers of resistance to EGFR-targeted therapy in the process of clinical validation include mutations in BRAF, PTEN loss and PI3KCA mutations, nuclear factor-kappa beta(NF-Κβ) pathway activity, and expression of alternative EGFR ligands. Functional genomics elucidation of drug resistance pathways using RNA interference (RNAi) techniques may provide novel therapeutic approaches in disease resistant to EGFR pathway targeting and accelerate predictive biomarker development. Source

Jain V.K.,GI Unit | Turner N.C.,Breast Unit | Turner N.C.,Institute of Cancer Research
Breast Cancer Research | Year: 2012

Activation of the fibroblast growth factor receptor pathway is a common event in many cancer types. Here we review the role of fibroblast growth factor receptor signalling in breast cancer, from SNPs in FGFR2 that influence breast cancer risk and SNPs in FGFR4 that associate with breast cancer prognosis, and potential therapeutic targets such as receptor amplification and aberrant autocrine and paracrine ligand expression. We discuss the multiple therapeutic strategies in preclinical and clinical development and the current and future challenges to successfully targeting this pathway in cancer. © 2012 BioMed Central Ltd. Source

Tryfonidis K.,European Organization for Research and Treatment of Cancer EORTC Headquarters | Zardavas D.,Breast International Group Headquarters BIG aisbl | Cardoso F.,Breast Unit
Cancer Treatment Reviews | Year: 2014

Small (T1a, b), lymph node negative breast tumors represent an entity diagnosed with increasing frequency due to the implementation of wide-scale screening programs. Patients bearing such tumors usually exhibit favorable long-term outcomes, with low breast cancer mortality rates at 10. years, even in the absence of adjuvant chemotherapy. However, most available data derive from retrospective studies. Additionally, a subset of patients with these tumors experience recurrence of the disease, indicating that early tumor stage itself is not a sufficient prognosticator. It is of paramount importance to refine the prognosis of this population, identifying patients with high risk of recurrence, for whom adjuvant treatment is needed. The underlying biology of the disease provides relevant information, such as grade and status of hormone receptors and HER-2 (human epidermal growth factor receptor 2), with high grade, triple negative and HER-2-positive tumors having worse prognosis. Additionally, multigene signatures may improve further the prognostication of patients with small, node negative breast cancers. Further research for this increasingly frequent group of patients is urgently needed, so that better informed clinical decision making, in particular regarding adjuvant chemotherapy, can occur. © 2014 Elsevier Ltd. Source

Senkus E.,Medical University of Gdansk | Cardoso F.,Breast Unit | Pagani O.,Institute of Oncology of Southern Switzerland and Breast Unit of Southern Switzerland
Cancer Treatment Reviews | Year: 2014

Treatment of metastatic breast cancer has substantially changed in the last decades. Availability of new cytotoxics and targeted therapies as well as changes in treatment philosophy and strategy have all contributed to a significant improvement in both survival and patients' quality of life. The multidisciplinary approach, personalised treatments based on tumour characteristics, patient's and disease history, as well as re-definition of treatment goals, aiming at the lowest possible impact on patients' life by replacing aggressive multidrug chemotherapy with single-agent cytotoxic treatment or endocrine. ±. targeted therapies, have all been the bases of the new treatment paradigm. More recently the development of the international advanced breast cancer (ABC) consensus guidelines have further contributed to this improvement. This review will focus on the major achievements and challenges in the different tumour subtypes and sites, with a focus on future research topics and trends. © 2013 Elsevier Ltd. Source

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