"There is a group of metastatic breast cancers that has the HER gene amplified  the cells have many copies of it  which leads to enhanced activity of the product enzyme a tyrosine kinase. HER has been established as a therapeutic target in breast cancer and breast cancers in which the HER gene is not amplified do not in general respond to HERdirected therapeutic approaches.    A few years ago when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors they found a new mutation in HER that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.    In this particular activation mechanism the cells develop a subtle mutation within the functional part of the HER gene that activates the enzyme said Ellis professor and director of the Lester and Sue Smith Breast Center part of the National Cancer Institutedesignated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. The mutation locks the enzyme into an on position.    Ellis and his colleagues developed a preclinical model to study this new HER mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore these tumor cells were sensitive to an experimental drug neratinib. With this information in hand the researchers took the next step.    We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER mutation Ellis said. Finding patients that are positive for a HER mutation required a national collaboration because we had to screen hundreds of patients to identify the  to  percent that have a tumor driven by a HER mutation. The results of the clinical trial were encouraging in that about  percent of the  patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.    This is the first time we had a reasonable number of patients treated for HER mutations in whom we could estimate the response rate.    The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as  patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in  to  percent of cases the researchers calculated that approximately  to  patients with metastatic breast cancer carry a HER mutation and are therefore potential candidates for neratinib treatment.    Circulating tumor DNA analysis a promising diagnostic tool    To identify the patients in this study who carried the new HER mutation the researchers required tissue from the tumor a biopsy from which they could extract and sequence the genetic material to determine the presence of the HER mutation. This task turned out to be a major challenge because for  to  percent of the patients the researchers did not have sufficient material to make the diagnosis.    To assist in our ability to identify patients with HER mutationpositive tumors we conducted circulating tumor DNA analysis Ellis said. The tumors DNA is released into the human bloodstream and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results and they were much easier to determine. Notably the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.    In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER mutation the researchers have tested the value of the circulating tumor DNA as a diseasemonitoring marker.    A circulating tumor DNAbased blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy Ellis said.    Ellis also is a McNair Scholar at Baylor.    Read all the details of this study the full list of contributors and their financial support in Clinical Cancer Research."