Abstract. The Conference Report of the 3rd AAPS/FDA Bioanalytical Workshop (Crystal City III) endorsed the concept that assay methods supporting bioanalytical data in submissions must demonstrate assay reproducibility by using incurred samples. The present Workshop was convened to provide a forum for discussion and consensus building about incurred sample assay reproducibility for both nonclinical and clinical studies. Information about current regulatory perspectives on incurred sample reanalysis (ISR) was presented, implications of ISR for both large and small molecules were discussed, and the steering committee put forth recommendations for performing ISR. These recommendations from the Workshop, along with the subsequent evolution of approaches leading to a robust ISR program, may be used by scientists performing bioanalytical assays for regulated studies to provide additional confirmation of assay reproducibility for incurred samples.

Expeditious clinical development and approval of new drugs that are beneficial to patients are matters of high priority. There has been a great deal of discussion within the oncology community about what should constitute evidence of effectiveness of new anticancer agents for purposes of drug approval. This commentary is intended to illustrate a variety of end points that can lead to approval of new anticancer agents for specific clinical situations. Although the ultimate hope of antineoplastic therapy is prolongation of life, there are other effects of anticancer drugs that constitute clear clinical benefit and represent evidence of effectiveness. The guiding principle is that the beneficial effects obtained from a new drug should sufficiently outweigh the adverse effects such that the potential risk:benefit ratio achieved by an individual patient is favorable. The assessment of a new drug should flexibly evaluate safety and efficacy in the context of the specific clinical condition being treated. Early discussions with the Food and Drug Administration (FDA) and the National Cancer Institute (NCI) are recommended to identify prospectively the end points and trial designs needed to demonstrate effectiveness of a new drug. The general principles discussed will likely apply to the drug approval process for other medical disciplines as well.

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INTRODUCTION: The clinical application of next generation sequencing to comprehensively characterize groups of driving mutations in individual metastatic triple negative breast cancer (mTNBC) genomes has the potential to reveal therapeutically relevant pathway dependencies. Towards this end, we harvested tissue from 14 patients with mTNBC and are conducting deep whole genome and transcriptome sequencing for each case to identify mutations that can guide therapeutic targeting within available phase I/II clinical trials. METHODS: Metastatic tumor tissue was harvested from 14 mTNBC patients, and 7 samples have undergone total genome and transcriptome sequencing with the others currently underway. We are utilizing the Life Technologies SOLiD® system to sequence germline and tumor DNA to sufficient depth to identify somatic genome alterations including point mutations, indels, and structural events including translocations. Furthermore, RNA-seq is being performed on these tumors, along with a series of age- and ethnicity-matched normal breast controls to perform deep differential expression analysis, isoform expression analysis, and fusion transcript detection. Our team of genome scientists and clinical oncologists are evaluating the sequencing findings and are prioritizing the investigational therapeutic options for each patient. RESULTS: Our whole genome and transcriptome sequencing study has revealed numerous known and novel mutations in mTNBC. However, all patients’ cancers analyzed to date had alterations that would activate the MAPK pathway, but through various mechanisms in different patients. These include BRAF amplification and overexpression, NF1 homozygous deletion, and consistent IQGAP3 overexpression. Furthermore, all patients’ cancers also harbor mutations that would activate the PI3K/AKT pathway including PTEN homozygous deletion or down-regulation, consistent INPP4B down-regulation, FBXW7 homozygous deletion, and ERAS overexpression. Moreover, although we and others show ERBB4 down-regulation in breast tumors, we are the first to report unique somatic genomic events that significantly alter the ERBB4 locus leading to its loss in the majority (5/7) of our patients’ tumors. Importantly, we are beginning to use these insights to prioritize therapeutic targeting and have observed that one chemotherapy-refractory mTNBC patient, with a high-level BRAF amplification/overexpression along with down-regulation of PTEN and INPP4B, had a major response to combined mek plus akt inhibitors on a phase I study. CONCLUSIONS: Comprehensive genomic and transcriptomic interrogation of mTNBCs has revealed events supporting co-activation of the MAPK and PI3K/AKT pathways in all the tumors albeit by different mutational mechanisms and supports potential effectiveness of combination therapy in the treatment of mTNBC. We plan to treat these patients with combined mek plus akt inhibitors on a new phase I study beginning in August 2011 to determine the effectiveness of co-inhibition of these pathways based on this frequent genomic context. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-5.