This multicenter study, randomized, controlled of blood-based biomarker-driven targhet therapy. Patients were selectedm( at Hospital San Giovanni and Celio in Rome) according to CTCs results ( CTCs-guided managment performed at University Magna Graecia) or managed by the treating clinician according to standard pathological criteria (standard management). The participants were assigned to trial groups with the use of block randomization stratified according to the enrolling center location metropolitan) and tumor stage (T3 or T4).

The investigators enroll patients with histologically confirmed advanced stage (T3 or T4, N1/2, M0/1) colorectal adenocarcinoma with molecular analysis on RAS mutant status. The participants are enrolled within 3 weeks at the time of progression disease (PD) from any line of therapy. Blood samples were collected from each participant after obtaining informed consent. Permission to perform CTCs analysis from blood was obtained from the Regional Ethical Committee (No.2013/34) and the study is conducted in accordance with the Declaration of Helsinki.

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 to 2 (scores range from 0 to 5, with higher numbers reflecting greater disability) ,
• medically able to receive chemotherapy.

Exclusion Criteria:

• evidence of infective disease before enrollment ,
• a history of another primary cancer within the previous 3 years,
• the presence of synchronous primary colorectal cancer.