Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer.

Unlabelled: Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review.

Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

Purpose: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.

Experimental Design: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models.

Colorectal Liver Micrometastases: Association with RAS/TP53 Co-Mutation and Prognosis after Surgery.

Background: Micrometastases, defined as microscopic cancer cells spatially separated from the macroscopically evident metastasis, are identified in 24% to 56% of resected colorectal liver metastases (CLMs). Somatic gene mutations have emerged as independent prognostic factors in CLM. This study aimed to determine the prognostic impact and risk factors for the presence of micrometastases, including somatic gene mutations.

BCL-X PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRAS-mutated cancers.

KRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRAS, was recently approved for the treatment of KRAS-mutated non-small cell lung cancer (NSCLC). However, the efficacy of sotorasib and other KRAS inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated tumors.

Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer.

Objective: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described.

Design: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin.

Results: We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression.

Preliminary Analysis of Liquid Biopsy after Hepatectomy for Colorectal Liver Metastases.

Background: Liquid biopsies are increasingly tested in patients with colorectal cancer to assess tumor burden, response to therapy, and prognosis. The significance of liquid biopsy results after resection of colorectal liver metastases (CLMs) is not well-defined.

Study Design: Sixty-three patients undergoing CLM resection between 2016 and 2018 had plasma drawn postoperatively for liquid biopsy evaluation.

SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases.

Introduction: Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-β signaling pathway and SMAD4 gene mutations are thought to play a critical role in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for colorectal liver metastases (CLM).

Methods: Between 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified.

Impact of Prior Hepatectomy History on Local Tumor Progression after Percutaneous Ablation of Colorectal Liver Metastases.

Purpose: To test the hypothesis that, given the current resection eligibility criteria for colorectal liver metastasis (CLM), prior hepatectomy would be associated with improved local tumor control and survival after percutaneous ablation of CLMs.

Materials And Methods: This single-institution retrospective study included 82 consecutive patients with 97 CLMs treated with ablation (radiofrequency ablation, microwave ablation, or cryoablation) from January 2005 to December 2014. Local tumor progression-free survival (LTPFS), recurrence-free survival (RFS) at any organ, and overall survival (OS) were calculated using the Kaplan-Meier method from the time of ablation and compared between patients with (n = 49) and without (n = 33) prior hepatectomy.

Preoperative radiation dose escalation for rectal cancer using a concomitant boost strategy improves tumor downstaging without increasing toxicity: A matched-pair analysis.

Purpose: Pathologic complete response to neoadjuvant chemoradiation therapy (CRT) is associated with improved outcomes for patients with locally advanced rectal cancer (LARC). Increased response rates have been reported with higher radiation doses, but these studies often lack long-term outcome and/or toxicity data. We conducted a case-control analysis of patients with LARC who underwent definitive CRT to determine the efficacy and safety of intensified treatment with a concomitant boost (CB) approach.

Impact of RAS Mutations in Metastatic Colorectal Cancer After Potentially Curative Resection: Does Site of Metastases Matter?

Background: RAS mutation status is an important prognostic factor after resection of liver metastases (LiM) from colorectal cancer (CRC). The prognostic significance of RAS after resection of lung (LuM) and peritoneal (PM) metastases from CRC is unknown.

Methods: Between 2005 and 2014, all consecutive patients with known RAS status who underwent potentially curative resection for LiM, LuM, or PM were evaluated.

Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases.

Objective: To assess the impact of somatic gene mutations on survival among patients undergoing resection of colorectal liver metastases (CLM).

Background: Patients undergoing CLM resection have heterogeneous outcomes, and accurate risk stratification is necessary to optimize patient selection for surgery.

Methods: Next-generation sequencing of 50 cancer-related genes was performed from primary tumors and/or liver metastases in 401 patients undergoing CLM resection.

APC and PIK3CA Mutational Cooperativity Predicts Pathologic Response and Survival in Patients Undergoing Resection for Colorectal Liver Metastases.

Objective: The aim of the study was to determine the prognostic impact of co-existence of APC and PIK3CA mutations in patients undergoing preoperative chemotherapy and resection for colorectal liver metastases (CLM).

Background: Co-occurring genetic events have been shown to drive carcinogenesis in multiple malignancies.

Methods: We identified 396 patients with primary colorectal cancer and known somatic mutation status by next-generation sequencing who underwent hepatectomy for CLM (2005-2015).

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology.

Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens.

Methods: The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted.

Molecular Biomarkers for the Evaluation of Colorectal Cancer.

Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. Methods: The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted.

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology.

Purpose Molecular testing of colorectal cancers (CRCs) to improve patient care and outcomes of targeted and conventional therapies has been the center of many recent studies, including clinical trials. Evidence-based recommendations for the molecular testing of CRC tissues to guide epidermal growth factor receptor (EGFR) -targeted therapies and conventional chemotherapy regimens are warranted in clinical practice. The purpose of this guideline is to develop evidence-based recommendations to help establish standard molecular biomarker testing for CRC through a systematic review of the literature.

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology.

Objectives: - To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens.

Methods: - The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted.

Embryonic Origin of Primary Colon Cancer Predicts Pathologic Response and Survival in Patients Undergoing Resection for Colon Cancer Liver Metastases.

Background: The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM).

Methods: We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed.

Planned Treatment of Advanced Metastatic Disease with Completion Ablation After Hepatic Resection.

Purpose: The aim of this study is to describe a modified treatment strategy with image-guided percutaneous ablation after hepatic resection as a completion method to surgical eradication of liver metastases ("completion ablation [CA]").

Methods: We conducted a retrospective analyses of patients who underwent CA within 180 days from the liver surgical resection to eradicate liver metastases present on the pre-surgical cross-sectional imaging or identified during intraoperative ultrasound that were not resected due to various reasons. Lesions treated with CA were evaluated for local tumor progression (LTP).

RAS Mutation Is Associated with Decreased Survival in Patients Undergoing Repeat Hepatectomy for Colorectal Liver Metastases.

Background: The relationship between RAS mutation status and outcome for patients undergoing repeat hepatectomy (RH) for recurrent colorectal liver metastases (CLM) has not been defined.

Objective: The objective of this study was to evaluate the relationship between RAS mutation status and outcome in patients undergoing RH for CLM.

Methods: All patients who underwent RH for CLM with known RAS mutation status between January 2005 and November 2014 were identified, and the outcomes of patients with and without RAS mutations were compared.

RAS Mutation Predicts Positive Resection Margins and Narrower Resection Margins in Patients Undergoing Resection of Colorectal Liver Metastases.

Background: In patients undergoing resection of colorectal liver metastases (CLM), resection margin status is a significant predictor of survival, particularly in patients with suboptimal response to preoperative therapy. RAS mutations have been linked to more invasive and migratory tumor biology and poor response to modern chemotherapy.

Objective: The aim of this study was to evaluate the relationship between RAS mutation and resection margin status in patients undergoing resection of CLM.

Predictors of Safety and Efficacy of 2-Stage Hepatectomy for Bilateral Colorectal Liver Metastases.

Background: In patients with bilateral colorectal liver metastases (CLM) not resectable in 1 operation, 2-stage hepatectomy is the standard surgical approach. The objective of this study was to determine factors associated with safety and efficacy of 2-stage hepatectomy.

Study Design: The study included all 109 patients for whom 2-stage hepatectomy for CLM was planned during 2003 to 2014.

Preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib for rectal cancer: a phase 1 trial.

Purpose: The goal of this phase 1 trial was to determine the maximum tolerated dose (MTD) of concurrent capecitabine, bevacizumab, and erlotinib with preoperative radiation therapy for rectal cancer.

Methods And Materials: Patients with clinical stage II to III rectal adenocarcinoma, within 12 cm from the anal verge, were treated in 4 escalating dose levels, using the continual reassessment method. Patients received preoperative radiation therapy with concurrent bevacizumab (5 mg/kg intravenously every 2 weeks), erlotinib, and capecitabine.