ALK gene amplified in most inflammatory breast cancers.

I nflammatory breast cancer (IBC) is a rare form of the disease that differs substantially from noninflammatory breast cancer in presentation and response to therapy. Despite those differences, researchers have uncovered few molecular characteristics that distinguish IBC from noninflammatory breast cancer, and IBC treatment generally relies on standard breast cancer regimens. Cancer Center in Houston, and colleagues report that ALK gene amplifi cation is a common feature of IBC tumors and that small-molecule ALK inhibitors are effective in mouse xenograft models. On the basis of those preclinical data, clinical investigators have started enrolling IBC patients in a phase I trial testing an experimental ALK inhibitor, Robertson reported at the AACR – NCI – EORTC Molecular Targets and Cancer Therapeutics Conference in San Francisco. " This disease is so diffi cult that if we can fi nd something like the ALK amplifi cation and can inhibit it, we should try it in a clinical trial, " said Beth Overmoyer, M.D., from the Breast Oncology Center at the Dana – Farber Cancer Institute in Boston, who was not involved in the work. Robertson ' s discovery came as part of a larger effort in which her team was using genomic and proteomic tools to characterize the biology of IBC (see " Elucidating an Uncommon Disease: Infl ammatory Breast Cancer, " J. noticed that the ALK pathway was as activated in three different IBC cell lines as it was in ALK-driven non – small-cell lung cancer models. Later genomic experiments showed that the ALK gene is amplifi ed in the IBC cell lines and in nine of the 12 patient tumors analyzed. Thus far, the team has not detected activating mutations in the ALK gene, which are common in non – small-cell lung cancer. " This may be a very prevalent genetic change in IBC, " Robertson said. " But we really believe that if we had not been doing this tandem proteomic – genomic approach, we might have missed it. So we really need to use all of the resources that we have. " Crizotinib (Xalkori), a small-molecule inhibitor of ALK that the U.S. Food and Drug Administration recently approved for lung cancer therapy, arrested growth of IBC cells in culture and activated the cell death pathway. Moreover, xenograft IBC tumors were resistant to paclitaxel but sensitive to low doses of crizotinib, which caused tumor shrinkage. Given the preclinical data and the …