Chris Womack

To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib ± docetaxel), ZEAL ( NCT00418886 , vandetanib ± pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3–1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n = 3; comparator, n = 4). 2.8% (n = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% (n = 76) had low RET gene copy number gain (4–6 copies in ≥40% of tumor cells) and 8.3% (n = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET-rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with efficacy in the RET rearrangement NSCLC subpopulation. Randomized Phase III clinical trials ( NCT00312377 , ZODIAC; NCT00418886 , ZEAL; NCT00364351 , ZEST; NCT00404924 , ZEPHYR).

Epidermal growth factor receptor (EGFR) overexpression has been associated with prognostic and predictive value in inflammatory breast cancer (IBC). Epidermal growth factor receptor 2 (HER2) overexpression is observed at a higher rate in IBC compared with noninflammatory breast cancer. Current clinically available anti-HER2 therapies are effective only in patients with HER2 amplified breast cancer, including IBC. AZD8931 is a novel small-molecule equipotent inhibitor of EGFR, HER2, and HER3 signaling. In this study, we investigated the antitumor activity of AZD8931 alone or in combination with paclitaxel using preclinical models of EGFR-overexpressed and HER2 non-amplified IBC cells.

2541 Background: AZD5363 is an ATP competitive small molecule inhibitor of AKT1, AKT2 and AKT3 and is currently in phase 1 and 2 clinical trials in breast, gynaecological and prostate cancer. In pre-clinical tumour xenograft models, AZD5363 inhibited the phosphorylation of AKT substrates PRAS40 and GSK3β in tumour tissue. Methods: Tumour biopsies were obtained from patients with advanced solid tumours in Western and Japanese phase 1 studies. Pharmacodynamic activity of AZD5363 in formalin fixed paraffin embedded tumour tissue was measured by immunohistochemistry (IHC) for total and phospho-AKT, phospho-PRAS40 and phospho-GSK3β using commercially available antibodies. IHC was quantified by H-score (sum of % tumour cells with 0=negative; 1=weak; 2=moderate; 3=strong staining) based on the results from 3 sections for each antibody. Inhibition of PRAS40 phosphorylation in hair follicles obtained 4 hours after dosing was measured by immunofluorescence and quantified by image analysis. Results: Paired tumour biopsies at baseline and after approximately 2 weeks dosing were obtained from patients on continuous and intermittent dosing schedules. Inhibition of GSK3β and PRAS40 phosphorylation of >30% or >50% respectively was seen in 4/7 (GSK3β) and 2/8 (PRAS40) tumours at tolerated doses of AZD5363. Phospho-AKT was increased in 4/7 (AKT-Thr308) and 4/5 (AKT-Ser473) tumours commensurate with the mechanism of action of AZD5363. Hair follicle PRAS40 phosphorylation was reduced by >50% in 22/71 patients and showed evidence of an exposure related response with an IC50 of 2μM total plasma concentration. Blood glucose also demonstrated an exposure response relationship with maximum glucose concentration correlating with drug plasma C_max. Conclusions: Inhibition of AKT substrate phosphorylation in tumour biopsies from advanced cancer patients with a range of solid tumours was qualitatively comparable to that observed in preclinical models showing tumour growth inhibition at clinically achievable exposures. Clinical trial information: NCT01226316; NCT01353781.

Advances in scientific understanding of disease together with introduction of new high throughput technologies have led to increased demand for human tissue in research. In general, patients are willing to donate for research, particularly samples that are surplus to diagnostic or therapeutic requirements. New tissue-specific regulations in the UK are intended to facilitate the use of human tissue in research. Despite this positive environment there are challenges to researcher access. Coordinated, systematic collection and storage, via a biobank can provide easier access. However translating a vision for a biobank into reality whether in the public or private sector, has never been simple. But it can be done.

This article details the authors’ experience establishing infrastructure for tissue collection, storage and distribution for biomedical research, firstly within a public healthcare service and latterly in the pharmaceutical industry. Access to human tissue in the context of public-private collaboration in research and development is essential to the provision of high-quality medicines and healthcare and is now supported by a new legal framework in England and Wales. Through collaborations there are opportunities for mutual benefit for patients and professionals alike. Attention to the wishes of tissue donors through informed consent at the outset ensured confidence and continued activity when so-called ‘organ retention scandals’ emerged midway through this period. The overwhelming majority of potential donors support the use of their tissues in biomedical research irrespective of where the research is carried out.