Are we HER-ting for innovation in neoadjuvant breast cancer trial design?

Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium, Universite Libre de Bruxelles, 121 Boulevard de Waterloo, Brussels, Belgium.
Breast cancer research: BCR (Impact Factor: 5.88). 02/2009; 11(1):201. DOI: 10.1186/bcr2209
Source: PubMed

ABSTRACT Through the use of surrogate markers of efficacy, neoadjuvant studies may facilitate the implementation of new treatments into clinical practice. However, disease-free survival is the current standard outcome endpoint for registration of a novel treatment. The coupling of smaller neoadjuvant 'proof of principle' studies with larger adjuvant registration trials offers the promise of speeding up the time to market of new therapies. Clever new designs, such as the 'biological window' and 'learn on the way', can provide valuable insight regarding mechanisms of action and resistance of these novel drugs by identifying patients who are most likely to respond to a novel therapy early in the drug development process. Using the ongoing neoadjuvant trials with HER2 (human epidermal growth factor receptor 2)-directed therapy as a paradigm, this article discusses recent innovations in study design and the challenges of conducting translational research in the neoadjuvant setting.

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    ABSTRACT: Background: Predictive biomarkers offer the potential to improve the benefit:risk ratio of a therapeutic agent. Ixabepilone achieves comparable pathologic complete response (pCR) rates to other active drugs in the neoadjuvant setting. This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent. Patients and methods: Women with untreated, histologically-confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin/cyclophosphamide, followed by 1:1 randomization to ixabepilone (n = 148) or paclitaxel (n = 147). Rates of pCR were compared between treatment arms based on pre-defined biomarker sets: TUBB3, TACC3 and CAPG gene expression, a 20- and 26-gene expression model, MDR1 protein expression and other potential markers of sensitivity. βIII-tubulin protein expression is reported separately, but is referred to here for completeness. All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. Gene expression profiling data was used for molecular subtyping. RESULTS: There was no significant difference in the rate of pCR in both treatment arms in βIII-tubulin-positive patients. Higher pCR rates were observed among βIII-tubulin-positive patients compared with βIII-tubulin-negative patients. Furthermore, no correlation was evident between TUBB3, TACC3 and CAPG gene expression, MDR1 protein expression, multi-gene expression models, and the efficacy of ixabepilone or paclitaxel, even within the estrogen-receptor-negative subset. CONCLUSION: These results indicate that βIII-tubulin protein and mRNA expression, MDR1 protein expression, TACC3 and CAPG gene expression, and multi-gene expression models (20- and 26-gene) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early-stage breast cancer.
    Clinical Cancer Research 01/2013; 19(6). DOI:10.1158/1078-0432.CCR-12-1359 · 8.19 Impact Factor
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    ABSTRACT: Background Luminal breast cancer is a highly endocrine responsive disease. However, the therapeutic benefit of chemotherapy (CT) in this population is not fully characterized. This study investigates the value of CT and hormone therapy (HT) in luminal breast cancer patients in the neoadjuvant setting.Patients and Methods Patients with operable breast cancer and immunophenotypically defined luminal disease (ER+/PR+/HER2-/cytokeratin 8/18+) were recruited. Patients were randomized to CT (epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) 4 cycles followed by docetaxel 100 mg/m(2 )4 cycles [EC-T]) or HT (exemestane 25 mg daily 24 weeks [combined with goserelin in premenopausal patients]). The primary end point was the clinical response measured by magnetic resonance imaging.ResultsNinety-five patients were randomized (47 CT, 48 HT). The clinical response rate was 66% for CT and 48% for HT (P = 0.075). We performed an unplanned analysis based on Ki67 levels (cut-off of 10%). Similar clinical response was seen between arms in patients with low Ki67 (CT: 63%, HT: 58%; P = 0.74); patients with high Ki67 had a better response with CT (67 versus 42%; P = 0.075). Grade 3/4 toxicity was more frequent with CT.Conclusions Luminal immunophenotype is not enough to identify patients who do not benefit from neoadjuvant CT. Luminal patients with low proliferation index could potentially avoid CT.
    Annals of Oncology 06/2012; 23(12). DOI:10.1093/annonc/mds132 · 6.58 Impact Factor
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    ABSTRACT: Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK), including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal growth factor receptor (EGFR) and Src which further contributes to oncogenesis in Herceptin resistant and triple negative breast cancer (TNBC) patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2), a known substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1 cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis, decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.
    PLoS ONE 09/2012; 7(9):e44299. DOI:10.1371/journal.pone.0044299 · 3.53 Impact Factor

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Fatima Cardoso