Mortality from breast cancer may be reduced substantially if personalized therapy is instituted.Whole exome capture followed by massively parallel sequencing will soon be available to enumerate all the cancer-specific protein and microRNA structural changes.With this information, therapy can be instituted to leverage the enumerated "weaknesses" of the cancer.Once therapy is instituted, monitoring of therapy or recurrence (MOTOR) can be performed by utilizing the cancer signature in circulating cells.As a model system to demonstrate the efficacy of MOTOR, we analyzed plasma to detect breast cancer mutation signatures of DNA fragments released from apoptotic or necrotic cancer cells and the DNA of circulating cancer epithelial cells.Initially, candidate cancer genes were sequenced in breast cancer tissue samples to identify in each patient a personalized cancer signature of somatic mutations.Subsequently, pyrophosphorolysis activated polymerization (PAP) (www.cityofhope.org/PAP), a method for detecting ultra-rare mutations, was used to detect the cancer-specific signature in DNA isolated from the plasma and circulating epithelial cells of patients with non-metastatic breast cancer.Our data demonstrate the rapid development of PAP assays that routinely detect even a single copy of the cancer-specific somatic mutations in circulation.The selectivity of PAP is extremely high, often ranging from at least 1 part per million to as high as 1 part per billion.Cireulating levels of cancer signature mutations and their rates of increase are being measured at multiple intervals in a multi-year follow up.Our ultimate goal is to achieve effective monitoring of chemotherapy and to predict recurrence months to years earlier than currently possible.