In February 2015, a 41-year-old man was diagnosed with stage IV, RAS and BRAF WT, ERBB2 not-amplified, MSS rectal cancer with synchronous liver metastases. As presented in  Figure 1  and  Table 1 , the patient underwent multimodal treatment with initial first-line therapy with FOLFOX and panitumumab, achieving partial response (PR) after 4 cycles, followed by short-course radiotherapy (RT) on the pelvis and radical surgery on both the primary tumor and liver metastases in June 2015. Thereafter, the patient received post-surgical treatment with FOLFOX for further 8 cycles. After 11 months of follow-up, a liver recurrence occurred and the patient underwent a second metastasectomy in November 2016. However, due to nodal relapse soon after surgery, FOLFOX and bevacizumab was then reintroduced as second line therapy, achieving stable disease (SD) as best response. Treatment had to be interrupted after 6 courses due to persistent G4 thrombocytopenia, that was interpreted as secondary to 5-fluorouracil infusion. Due to oligo-progressive disease (PD) in a single lymph node, the patient underwent stereotactic RT in October 2017, with no further PD until July 2018. Then, the patient received panitumumab monotherapy as a reintroduction strategy with PD after 6 cycles, developing a severe mediastinal syndrome requiring palliative thoracic surgery and RT. At this stage, aiming to extent the spectrum of druggable therapeutic targets, the patient was screened for the GO40872/STARTRK-2 clinical trial (NCT02568267) at Niguarda Cancer Center, Milan, Italy. Thus, a FoundationOne CDx NGS assay (, Foundation Medicine, Inc.) was obtained from the archival formalin-fixed paraffin-embedded (FFPE) tissue derived from the first liver metastasectomy. The case was presented for MTB discussion, revealing no actionable targets. Of note, a somatic tumor MAP2K1 K57N mutation was found on tissue with 17.1% variant allelic frequency (VAF), and confirmed also on liquid biopsy (LB) at progression to anti-EGFR therapy, assessed as reported elsewhere through droplet digital polymerase chain reaction (ddPCR), with a 16.9% minor allelic frequency (MAF). Further treatment with weekly irinotecan and cetuximab was administered, achieving SD as best response. Finally, regorafenib was initiated after PD but soon interrupted due to the deterioration of the clinical conditions. The patient died on March 31th, 2020.