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DNA repair as a treatment target

Judith Balmana of the Department of Medical Oncology, Vall d’Hebron Hospital, Barcelona, Spain spoke today about early data and future plans for combinations of PARP inhibitors with cisplatin, carboplatin, carboplatin plus gemcitabine, taxanes, irinotecan, temozolomide, bevacizumab and others that are currently under investigation in several phase I-III trials. In addition, recent preclinical data encourages the assessment of PARP inhibitors in monotherapy in tumours with homologous recombination defects other than BRCA-mutants (i.e., PTEN, RAD51, ATM, and CHK). The search for the most synergistic drug combinations with PARP inhibitors has recently been assessed in vitro and in vivo mice with BRCA2-deficient mammary tumors. Current challenges with these compounds include identification of biomarkers of response, recognition of adequate combination regimens without an increasing toxicity, and overcoming of potential mechanisms of resistance.

Circulating tumour cells and artificial neural network in metastatic breast cancer patients

Antonio Giordano of the MD Anderson Cancer Center, Houston, USA and colleagues used a training dataset from 310 (60%) of 516 consecutive metastatic breast cancer patients treated in their institution, with the aim to develop an artificial neural network (ANN) and predict the probability of death. Predictions obtained in the training dataset were validated in a test set comprising the other 40% (206) of patients. They presented study results, on covariates evaluated by ANN, at the Best abstracts session today. ANN shows a linear increase of risk of death in metastatic breast cancer patients with increasing number of circulating tumour cell (CTCs) within all immunohistochemically defined molecular tumour subtypes. Moreover, the increased rate in risk of death becomes significantly higher after the threshold of 40 CTCs and continues to increase with higher CTC numbers. The authors concluded that BioNeural is a new sophisticated technique for analysing survival according to continuous variables and is able to model complex interactions among covariates.

DASL assay could be a valid approach to identify/validate gene expression signatures using formalin, paraffin embedded material

Lorenza Mittempergher of The Netherlands Cancer Institute, Amsterdam, The Netherlands presented during the Best abstracts session results of the project which evaluated if the DASL gene expression assay, specifically designed to generate reproducible data from degraded RNAs, as a reliable method to apply to RNA from formalin, paraffin embedded (FFPE) tissues. The results show that the 502 genes-DASL assay provides a reliable platform for gene expression profiling in FFPE as well as in fresh-frozen (FF) tissues. Because of the promising results with the 502 genes-DASL assay, the investigators increased the number of matched FFPE and FF samples for analysis on the Whole Genome DASL platform and all the samples show a good RNA quality.

Practice-changing discoveries in translational research

During the session, speakers covered topics on cytotoxics as targeted agents, resistance to anti-HER2 agents, and how to overcome resistance to hormonal therapy. John Bartlett of the Edinburgh Cancer Research Centre, UK debated the potential value of biomarkers to aid selection of patient groups most likely to benefit from cytotoxic treatments. Recent advances in biomarkers of anthracycline response may indicate fresh directions for future research and potential clinical utility. Biologically targeted agents, such as PARP inhibitors, when combined with appropriately selected cytotoxic agents, are being used to target pathways to increase the therapeutic efficacy of both the biological and cytotoxic treatments. Such combinations of targeted delivery of cytotoxic agents with biological agents represent a significant potential for future progress in treating early breast cancer.

Will neo-adjuvant trial results impact on future treatment practice?

Eric Winer of the Department of Medicine, Dana Farber Cancer Institute, Boston, USA spoke about neoadjuvant trials that can be used to identify the most active treatment schedule/regimen, to estimate an effective size, and to narrow the population included in a definitive study by correlating clinical and biologic parameters with response. While early phase trials will generally not lead directly to a change in clinical practice, they can speed the conduct of the definitive phase III trial. At present, studies must show an improvement in disease-free and overall survival to result in a change in clinical practice, but ultimately oncologists hope to use response in the breast and/or regional lymph nodes to define new standards of care. Before adopting such an approach, there is a need for additional studies that demonstrate a strong association between improvement in breast response and long-term outcomes.

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