Prevalence of bone metastases and bone-targeting agent use among solid tumor patients in the United States.

PURPOSE: Patients with bone metastases are at an increased risk of experiencing morbidity due to bone complications, and bone-targeting agents (BTA) are indicated for the prevention of these complications. Population-based estimates of the prevalence of bone metastases associated with solid tumors, and current treatment patterns for these patients, are limited. This study was undertaken to estimate the prevalence of bone metastases from solid tumors and to describe recent trends in the use of BTA in the US. METHODS: We estimated the prevalence of bone metastases in the US in 2012 using data from Medicare fee-for-service and PharMetrics Plus, a large commercial claims database. We evaluated the proportion of patients with bone metastases who were treated with BTA in 2012, timing of initiation of BTA relative to bone metastasis diagnosis, and persistence on BTA, overall and by primary tumor type and treatment. RESULTS: There were ~330,000 (168,063 Medicare fee-for-service; 162,239 other) patients aged ≥18 years living with solid tumors and bone metastases in 2012. BTA were used by 43% (Commercial) to 47% (Medicare) of patients in 2012, with the greatest use among breast cancer patients. Over half (Medicare: 57%; Commercial: 53%) of BTA-treated patients initiated BTA after experiencing a bone complication. CONCLUSION: Of the estimated 330,000 solid tumor patients living with bone metastases in the US in 2012, many may have received less than optimal care to prevent bone complications during the calendar year.

Impact of genetic diagnostics on drug development strategy.

Innovation in diagnostics will be essential for the successful adoption of personalized medicine and will also have a major impact on the success of drug development strategies. To remain competitive, companies will need to embrace the rapid innovation in the diagnostic market, utilize diagnostic tools concurrently with research and development, and re-invent how new drugs are brought to market. In this article, specific examples of targeted oncology drugs are used to illustrate the general impact of genetic diagnostics on drug development.

A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase.

A direct binding site for the Grb2 adapter protein is required for the induction of fatal chronic myeloid leukemia (CML)-like disease in mice by Bcr-Abl. Here, we demonstrate direct binding of Grb2 to the Tel-Abl (ETV6-Abl) fusion protein, the product of complex (9;12) chromosomal translocations in human leukemia, via tyrosine 314 encoded by TEL exon 5. A Tel-Abl point mutant (Y314F) and a splice variant without TEL exon 5 sequences (Deltae5) lacked Grb2 interaction and exhibited decreased binding and phosphorylation of the scaffolding protein Gab2 and impaired activation of phosphatidylinositol 3-kinase, Akt, and extracellular signal-regulated kinase/mitogen-activated protein kinase in hematopoietic cells. Tel-Abl Y314F and Deltae5 were unable to transform fibroblasts to anchorage-independent growth and were defective for B-lymphoid transformation in vitro and lymphoid leukemogenesis in vivo. Previously, we demonstrated that full-length Tel-Abl induced two distinct myeloproliferative diseases in mice: CML-like leukemia similar to that induced by Bcr-Abl and a novel syndrome of small-bowel myeloid infiltration endotoxemia and hepatic and renal failure. Lack of the Grb2 binding site had no effect on development of small bowel syndrome but significantly attenuated the induction of CML-like disease by Tel-Abl. These results suggest that direct binding of Grb2 is a common mechanism contributing to leukemogenesis by oncogenic Abl fusion proteins.

The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice.

Several patients with clinical features of chronic myeloid leukemia (CML) have fusion of the TEL (ETV6) gene on 12p13 with ABL on 9q34 and express a chimeric Tel-Abl protein that contains the same portion of the Abl tyrosine kinase fused to Tel, an Ets family transcription factor, rather than Bcr. In a murine retroviral bone marrow transduction-transplantation model, a Tel (exon 1-5)-Abl fusion protein induced 2 distinct illnesses: a CML-like myeloproliferative disease very similar to that induced by Bcr-Abl but with increased latency and a novel syndrome characterized by small-bowel myeloid cell infiltration and necrosis, increased circulating endotoxin and tumor necrosis factor alpha levels, and fulminant hepatic and renal failure. Induction of both diseases required the Tel pointed homology oligomerization domain and Abl tyrosine kinase activity. Myeloid cells from mice with both diseases expressed Tel-Abl protein. CML-like disease induced by Tel-Abl and Bcr-Abl was polyclonal and originated from cells with multilineage (myeloid, erythroid, and B- and T-lymphoid) repopulating ability and the capacity to generate day-12 spleen colonies in secondary transplantations. In contrast to findings with Bcr-Abl, however, neither Tel-Abl-induced disease could be adoptively transferred to irradiated secondary recipient syngeneic mice. These results show that Tel-Abl has leukemogenic properties from distinct from those of Bcr-Abl and may act in a different bone marrow progenitor.