Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients

AIM:To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients. METHODS:Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had a partial response. Tumor buds were evaluated from whole tissue sections stained for pan-cytokeratin, evaluated in the densest region using a 40 × objective and "high-grade" tumor budding was defi ned as 15 buds/high-power f ield.RESULTS: Tumor buds and K-RAS mutation both correctly classif ied 68% of patients. All patients with K-RAS mutation (n=7) or high-grade tumor budding (n=11) were non-responsive, of which 4 patients had both features. All 13 partial responders were K-RAS wild-type with low-grade tumor budding. Combined, the predictive value of K-RAS and tumor budding was 80%. Additionally, high-grade tumor budding was significantly related to worse progression-free survival [HR (95% CI): 2.8 (1.3-6.0, P=0.008)].CONCLUSION: If confirmed in larger cohorts, the addition of tumor budding to K-RAS analysis may represent an effective approach for individualized patient management in the metastatic setting.

Research progress on KRAS mutations in colorectal cancer

The RAS gene family,responsible for signal transduction within the mitogen activated protein kinase(MAPK)and phosphatidylinositol 3 kinase(PI3K)pathways,is frequently involved in carcinogenesis,and alterations in its member genes can be detected,with variable frequency,in a wide variety of solid and hematological cancers.These alterations may behave as prognostic-predictive biomarkers and driver mutations,making them an interesting therapeutic target.Since their discovery,many strategies have been pursued to act on their signaling pathways.Indeed,in clinical practice,KRAS,the most prominent member of the RAS gene family,represents an especially elusive target in most malignancies;pathway inhibition is carried out upstream,on the EGFR receptor,or downstream,most frequently on the BRAF/MEK/ERK cascade.Recently,clinically relevant direct RAS inhibition has been successfully achieved with the development of potent and selective covalent inhibitors of KRAS c.34G>T(p.G12C).These latest-generation drugs represent both a new and interesting tool in the therapeutic armamentarium and a symbolic end to the myth of KRAS undruggability.However,their clinical relevance and appropriate place in treatment strategies remain to be determined.