Targeting RAS mutants in malignancies:successes,failures,and reasons for hope

RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies.The mutation,isoform(KRAS,HRAS,and NRAS),position,and type of substitution vary depending on the tissue types.Despite decades of developing RAS-targeted therapies,only small subsets of these inhibitors are clinically effective,such as the allelespecific inhibitors against KRASG12C.Targeting the remaining RAS mutants would require further experimental elucidation ofRAS signal transduction,RASaltered metabolism,and the associated immune microenvironment.This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants,including KRAS allele-specific inhibitors,combination therapies,immunotherapies,and metabolism-associated therapies.

Postoperative chemotherapy use and survival in non-high-risk young and high-risk old-aged patients with stageⅡcolon cancer

Purpose Intensive postoperative chemotherapy treatment use in early-onset colon cancer and late-onset colon cancer remains to be defined and their effects on prognosis were unclear.This study aims to investigate whether intensive adjuvant chemotherapy for stageⅡcolon cancer would result in matched survival improvement in young patients(<50 years)without risk factors and old-aged(70–85 years)patients with risk factors defined by guidelines.Methods We extracted eligible patients with pathologically confirmed TNM stageⅡcolon cancer from the Surveillance,Epidemiology,and End Results database between 2004 and 2015.Patients aged<50 years old without risk factors were defined as non-high-risk early-onset colon cancer(non-HREOCC),and those aged 70 to 85 years with risk factors were defined as high-risk late-onset colon cancer(HRLOCC).Kaplan–Meier(KM)method with log-rank test was performed to calculate the overall survival(OS)and cancer-specific survival(CSS).Multivariate Cox model was used to estimate the association of adjuvant chemotherapy with CSS by adjusting potential confounding factors.Results Of 55,366 eligible stageⅡcolon cancer patients,3341 non-HREOCC patients and 11,722 HRLOCC patients were included.37.68%and 16.8%of patients received adjuvant chemotherapy among non-HREOCC and HRLOCC patients,respectively.For non-HREOCC patients,there was no significant association between adjuvant chemotherapy and CSS(HR=1.09,95%CI0.83–1.44).For HRLOCC patients,adjuvant chemotherapy was associated with a better CSS(HR=0.88,95%CI0.79–0.99).Conclusion Our findings suggested that potential overuse of adjuvant chemotherapy among non-high-risk young patients with stageⅡcolon cancer did not lead to survival improvement,and caution should be called when using chemotherapy in these patients.However,chemotherapy can be used appropriately for high-risk stageⅡcolon cancer patients aged 70 to 85 years.