S3-5: Next Generation Sequencing Reveals Co-Activating Events in the MAPK and P13K/AKT Pathways in Metastatic Triple Negative Breast Cancers.

Abstract

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.

Accelerating Cancer Therapy Development: The Importance of Combination Strategies and Collaboration. Summary of an Institute of Medicine Workshop

“…This patient was subsequently treated on a phase I study with the combination of trametinib and the AKT inhibitor GSK2141795 and, within 2 months, her breast mass had nearly completely regressed. (5,11) The investigators hope to reproduce these data on a larger scale and show multitarget therapeutic advantages.…”

“…Based on preclinical in vitro and in vivo combination data, clinical trials evaluating targeted drug combinations have become a significant focus for early-phase drug therapeutics with preliminary evidence of success being reported (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). As an example, promising results were recently presented from a phase I/II study investigating the BRAF inhibitor dabrafenib in combination with the MEK1/2 inhibitor trametinib in patients with V600 BRAFmutant solid tumors (3).…”

Applied molecular profiling: evidence-based decision-making for anticancer therapy

“…One chemotherapyrefractory mTNBC patient, with a high-level BRAF amplification or overexpression and downregulation of PTEN and INPP4B, had a major response to a combination regimen consisting of an MEK inhibitor and an AKT (protein kinase B) inhibitor in a phase 1 study. 31 The study, which involved comprehensive genomic and transcriptomic sequencing of mTNBCs, shed light on the importance of coactivation of the MAPK and PI3K/AKT pathways (albeit through different mutational mechanisms). In addition, the approach used in this study supports the possible use of combination therapy (ie, MEK inhibitors plus AKT inhibitors) to co-inhibit these pathways in mTNBC.…”

Next-Generation Sequencing in Breast Cancer: Translational Science and Clinical Integration

“…Of interest, several clinical trials of PIK3CA inhibitors are ongoing [101], and these inhibitors may be effective in PIK3CA-mutated breast cancers [16]. In a different trial presented at the 2011 San Antonio Breast Cancer Symposium, metastatic triple-negative breast cancer patients were sequenced by NGS revealing mutations that activate the MAPK and PI3K/AKT pathways in all 14 cases sequenced [17]. Based on this data, the authors have initiated a new Phase I study of combined MEK plus AKT inhibitors in this patient population.…”