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Understanding the landscape of KRAS mutations in #CRC is crucial with over 2.8M annual diagnoses worldwide. Explore promising therapies and ongoing challenges in this comprehensive review. #CancerResearch #KRAS #ColorectalCancer.

Background: Neoadjuvant immune checkpoint blockade (IO) is emerging as a therapeutic option for patients with deficient mismatch repair (dMMR) colorectal cancer (CRC) given high pathological response rates. The aim of the study was to characterise imaging and endoscopic response to IO., Methods: A retrospective analysis of patients with localised dMMR CRC that received at least one cycle of neoadjuvant anti-PD-1 therapy was conducted. Endoscopy, imaging, and pathological outcomes were reviewed to determine response to treatment according to standardised criteria., Results: Thirty-eight patients had received IO for the treatment of localised CRC (median eight cycles). Among evaluable cases (n = 31 for endoscopy and n = 34 for imaging), the best endoscopic response was complete response (CR) in 45% of cases, and the best radiographic response was CR in 23% of cases. Imaging CR rate after ≤4 cycles of IO (n = 1) was 6% compared to 44% after >4 IO cycles (n = 7). Among 28 patients with imaging and endoscopy available, a discrepancy in best response was noted in 15 (54%) cases. At a median follow-up of 28.2 months from IO start, 18 patients underwent surgical resection of which 11 (61%) had pathological CR (pCR). Despite pCR or no evidence of progression ≥6 months after completion of IO among non-operatively managed patients, 72% and 42% of patients had non-CR on imaging and endoscopy, respectively., Conclusions: Discrepancies between imaging and endoscopy are prevalent, and irregularities identified on these modalities can be identified despite pathological remission. Improved clinical response criteria are warranted., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Tsuyoshi Konishi: travel, accommodations, expenses – advent health; Michener Institute of Education at UHN. Kanwal Pratap Singh Raghav: Honoraria - Bayer; Daiichi Sankyo/Astra Zeneca; Eisai; Merck; Seagen. Consulting or advisory role – Bayer; Daiichi Sankyo/Astra Zeneca; Eisai; Merck; Seagen. Research funding – Abbvie (Inst); Abbvie (Inst); Bayer (Inst); Daiichi Sankyo/Astra Zeneca (Inst); Eisai (Inst); Guardant Health (Inst); HiberCell (Inst); Innovent Biologics (Inst); Janssen (Inst); Merck Serono (Inst); Roche/Genentech (Inst); UCB (Inst); Xencor (Inst). Phillip S. Ge: consulting or advisory role – Alira Health; Boston Scientific; Neptune Medical; Ovesco Endoscopy. Benny Johnson: consulting or advisory role – Gritstone Bio; Incyte; Insmed; Pfizer; Taiho Oncology. Research funding – Bristol-Myers Squibb (Inst); Gateway Foundation (Inst); Syntrix Biosystems (Inst). Van K. Morris: consulting or advisory role – Axiom Healthcare Strategies; Bicara Therapeutics; BioMedical Insights; Boehringer Ingelheim; Incyte. Research funding – Bicara Therapeutics (Inst); BioNTech (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Immatics; Pfizer (Inst). Scott Kopetz: stock and other ownership interests – Frontier Medicines; Iylon; Lutris; Navire; Xilis. Consulting or advisory role – Abbvie; Accademia Nazionale Di Medicina; Amal Therapeutics; Amgen; Astra Zeneca/MedImmune; Bayer Health; Bicara Therapeutics; Black Diamond Therapeutics; Boehringer Ingelheim; Bristol-Myers Squibb/Medarex; Cardiff Oncology; Carina Biotech; CureTeq; EMD Serono; Endeavor BioMedicines; Flame Biosciences; Foundation Medicine; Frontier Medicines; Genentech; Genomic Health; Gilead Sciences; GlaxoSmithKline; HalioDx; Harbinger Oncology, Inc; Holy Stone Healthcare; Inivata; Ipsen; Iylon; Jacobio; Jazz Pharmaceuticals; Johnson & Johnson/Janssen; Lilly; Lutris; Merck; Mirati Therapeutics; NeoGenomics Laboratories; Novartis; Numab; Ono Pharmaceutical; Pfizer; Redx Pharma; Repare Therapeutics; Replimune; Servier; Taiho Pharmaceutical; Takeda; Tempus; Xilis; Zentalis. Research funding – Amgen; Array BioPharma; Biocartis; Daiichi Sankyo; EMD Serono; Genentech/Roche; Guardant Health; Lilly; MedImmune; Novartis; Sanofi. George J. Chang: consulting or advisory role – Medicaroid. Kaysia Ludford: research funding – Merck (Inst). Michael J. Overman: consulting or advisory role – 3D Medicines; Array BioPharma; Bristol-Myers Squibb; Eisai; Gritstone Bio; Janssen; Janssen; MedImmune; Merck; Novartis; Pfizer; Pfizer; Promega; Roche/Genentech; Spectrum Pharmaceuticals. Research funding – Bristol-Myers Squibb; MedImmune; Merck; Roche. The remining authors do not have any disclosures., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) represents a distinct phenotype among solid tumors characterized by frequent frameshift mutations resulting in the generation of neoantigens that are highly immunogenic. Seminal studies identified that dMMR/MSI-H tumors are exquisitely sensitive to immune checkpoint inhibitors, which has dramatically improved outcomes for patients harboring dMMR/MSI-H tumors. Nevertheless, many patients develop resistance to single-agent immune checkpoint blockade, prompting the need for improved therapeutic options for this patient population. In this review, we highlight key studies examining the efficacy of PD1 inhibitors in the metastatic and neoadjuvant setting for patients with dMMR/MSI-H tumors, describe resistance mechanisms to immune checkpoint blockade, and discuss novel treatment approaches that are currently under investigation for dMMR/MSI-H tumors., Competing Interests: Declaration of interests V.S. is on the advisory board of Illumina, Labcorp, Relay Therapeutics, Bayer, Jazz Pharmaceuticals, and Aadi Bioscience. The remaining authors have no interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)