分子标记物指导下的结直肠癌治疗.pptVIP

* *All responses were confirmed no earlier than 28 days after the response criteria were first met; Evaluable patients for ORR: KRAS WT, FOLFOX (n=324);Pan+FOLFOX(n=317) and KRAS MUT, FOLFOX (n=212);Pan+FOLOFOX(n=215) * * * In 2002, Davies et al. reported that BRAF is mutated in approximately 8% of human tumors, BRAF mutations are found clustered within the P-loop (exon 11) and activation segment (exon 15) of the kinase domain (see Figure 2). A single glutamic acid for valine substitution at residue 600 (V600E, initially designated V599E) within the activation segment of the kinase domain is observed in approximately 90% of cases [2,5]. V600E BRAF mutations are with rare exception found in a non-overlapping pattern with RAS mutations suggesting that each of these genetic alterations are sufficient to activate common downstream effectors of transformation. pharmacologic inhibition of BRAF and MEK, abrogates tumor growth in BRAF mutant xenografts and transgenic mice [17,18,19]. Overall, these data suggest that V600E BRAF plays an important role in both tumor initiation and maintenance and that targeting BRAF or its downstream effectors may have therapeutic benefit. * * * A defective DNA mismatch repair (MMR) mechanism is a key biologic characteristic of ~15% of stage II colon cancer patients. This biological characteristic, also called MMR deficiency, represents one of two distinct mechanisms for producing colon tumors, with the other mechanism being chromosomal instability – both mechanisms lead to accumulation of genetic changes in tumors which ultimately drive tumor formation. In normal cells, the presence of a multi-protein “machine” (panel at left) allows for repair of routinely encountered errors in DNA replication. This machine ceases to function if any of its components (e.g. MLH1, MSH2 or the other proteins depicted) is missing. Loss of expression of MMR proteins in tumor, especially MLH1 and MSH2 (accounting for 95% of patients with this character