Abstract: Methods and systems for predictive measures of anti-EGFR therapy response in wild type RAS/EGFR+ samples, e.g., histochemical staining methods for staining EGFR, AREG, and EREG, digital analysis of stained slides, and scoring algorithms that allow prediction of a response to anti-EGFR therapies. Analysis of the stained slides and scoring algorithms may include but are not limited to: a percent tumor cell positivity, computerized clustering algorithms, area density (e.g., area of tumor positive for one or more markers over total tumor area), average intensity (e.g., computerized methodology measuring average gray scale pixel intensity), average intensity broken down according to membrane, cytoplasmic, or punctate staining patterns), or any other appropriate parameter or combination of parameters. The methods of the present invention allow for resolving spatial expression patterns of the ligands and the receptor to determine what patterns are predictive for response to anti-EGFR therapies.