Abstract: The present invention is directed to a method for detecting somatic mutation in cell free total nucleic acid (cfTNA) in a liquid biological sample by a personalized approach with high sensitivity and specificity. The present invention relates to multiplex amplification of target loci with primers selected from a primer bank for cancer liquid biopsies, including but not limited to minimal residual disease (MRD) monitoring, recurrence monitoring, therapy monitoring, early detecting or screening cancer. Somatic, clonal variants of a patient are first identified by sequencing of the primary tumor and the matched normal sample in the patient. Then customized panel of primer pairs for the patient is selected from a primer bank. Using the selected panel of primer pairs, multiplex polymerase chain reaction and next-generation sequencing are performed on the cfTNA sample from this patient to detect the presence of tumor DNA in the sample.