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Background  We previously reported that loss of  KRAS  mutations (“regressive” mutational trajectories) from primary tumors to metastases associated with the oligo-metastatic status in colorectal cancer (CRC). The present study was undertaken in order to analyze the mutational trajectories of  KRAS  in a well-characterized cohort of CRC patients who developed poly- or oligo-metastatic disease.    Material and Methods  Patients were treated and followed-up according to European Society of Medical Oncology guidelines. Primary CRC FFPE tissue and metastatic circulating-free DNA were extracted using the QIAamp DNA specific kits (Qiagen, Hilden, Germany). Samples were sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Plasma collection for liquid biopsy was done from 1 to 14 days before starting first-line chemotherapy. Analysis of the prognostic power of  KRAS  evolutionary trajectories was done with uni- and multivariate analyses.    Results  One-hundred-fourteen patients were enrolled. Sixty-three patients presented with mutated  KRAS  (mut KRAS ) and 51 with wild-type  KRAS  (wt KRAS ).  KRAS  mutational concordance was high (70.1%).Two divergent subsets were identified: mut KRAS  in primary tumors and wt KRAS  in metastatic ones (regressive: mut KRAS  → wt KRAS  in 8.8% of patients), and  vice versa  (progressive: wtK RAS  → mut KRAS  in 21.1% of patients). An association between  KRAS  regressive trajectory and the oligo-metastatic status (P <0.0001) was found. At multivariate analysis, regressive and progressive mutational trajectories emerged as independent prognostic factors for survival, with Hazard Ratios of 0.22 (CI 95%: 0.08–0.61; median survival: not reached) and 2.70 (CI 95%: 1.11–6.56, median survival: 12.1 months), respectively.    Conclusions  Our data provide evidence that the evolutionary trajectories of  KRAS  can have a strong clinical prognostic role and that they can be involved in discriminating between poly-metastatic aggressive  vs  oligo-metastatic indolent CRC.

KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer