Combined modularized therapies for metastatic cancer are pointing to central problems of communication among ‘systems participators’. A communication theory explains ''social engineering'', endogenously induced or by implementing non-normative boundary conditions. Evolution-adjusted tumor pathophysiology is borne by an evolution theory, which contrasts narrative evolution histories. The tool of rationalizations constituting the tumor''s normativity (inflammation, immune response etc.) represents the non-genomic counterpart of the tumor genome and should be additionally assessed during tumor staging. Evolution-adjusted tumor pathophysiology allows implementing applied systems biology, a novel clinical and pharmaceutical technology for bioengineering tumor response and personalizing tumor therapy. Combined modularized therapy, evolution-adjusted tumor pathophysiology, and ‘universal’ biomarkers concertedly address genetically based tumor heterogeneity.