![]() ![]() Currently, several randomized TNT‐based trials are ongoing to establish a potentially nonoperative management of patients with locally advanced rectal cancer (e.g., the Organ Preservation in Rectal Adenocarcinoma trial). Currently, the standard treatment for locally advanced rectal cancer irrespective of molecular subtypes is total neoadjuvant treatment (TNT) consisting of (chemo)radiation followed by chemotherapy or vice versa before delayed surgery. In the pivotal Keynote‐177 study, a superior response rate of 43.8% in MSI‐H/dMMR mCRC was demonstrated with first‐line pembrolizumab compared with 33.1% with standard chemotherapy. ![]() Just recently, first‐line therapy with the anti‐programmed death receptor 1 (PD‐1) antibody pembrolizumab was approved for first‐line therapy in metastatic MSI‐H/dMMR CRC. īecause MSI‐H/dMMR is an actionable predictive biomarker for treatment with immune checkpoint inhibitors (ICIs), the detection by fragment length polymerase chain reaction (PCR) analysis and/or immunohistochemistry is recommended for many advanced tumor types. The incidence of MSI‐H/dMMR is 20% in stage II CRC, 11% in stage III, and 3%–4% in metastatic CRC (mCRC). The vast majority of sporadic MSI‐H/dMMR CRCs are caused by methylation of the MLH1 gene promoter, whereas more than two‐thirds of patients with CRC and Lynch syndrome are associated with germline mutations in MLH1 or MSH2. The MSI‐H/dMMR phenotype is present in approximately 15% of all CRCs and is a hallmark of Lynch syndrome, but it is also distinctive in sporadic CRCs and in several other tumor types. Colorectal cancer (CRC) with deficiency in mismatch repair (dMMR) results in a strong mutator phenotype known as high microsatellite instability (MSI‐H) and high mutational burden. ![]()
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