Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in -mutated colorectal cancer.

Background: is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with -mutated mCRC.

Oncogenic KRAS Mutations Confer a Unique Mechanotransduction Response to Peristalsis in Colorectal Cancer Cells.

Colorectal cancer (CRC) tumors start as polyps on the inner lining of the colorectum, where they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in CRC cells. However, this malignant mechanotransductive response was confined to select CRC lines that harbored an oncogenic mutation in the KRAS gene.

Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in -mutated colorectal cancer.

Background: is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with -mutated mCRC.

Endoscopy for the diagnosis and treatment of gastrointestinal bleeding caused by malignancy.

Background And Aim: The diagnosis and treatment of gastrointestinal (GI) bleeding secondary to malignancy can be challenging. Endoscopy is the gold standard to diagnose and treat gastrointestinal bleeding but clinical characteristics and outcomes of patients with malignancy-related bleeding are not well understood. This study aims to look at clinical characteristics, endoscopic findings, safety and clinical outcomes of endoscopic interventions for GI malignancy-related bleeding.

PIK3CA mutations in plasma circulating tumor DNA predict survival and treatment outcomes in patients with advanced cancers.

Background: Oncogenic mutations in PIK3CA are prevalent in diverse cancers and can be targeted with inhibitors of the phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Analysis of circulating tumor DNA (ctDNA) provides a minimally invasive approach to detect clinically actionable PIK3CA mutations.

Patients And Methods: We analyzed PIK3CA hotspot mutation frequency by droplet digital PCR (QX 200; BioRad) using 16 ng of unamplified plasma-derived cell-free DNA from 68 patients with advanced solid tumors (breast cancer, n = 41; colorectal cancer, n = 13; other tumor types, n = 14).

Differential Outcomes in Codon 12/13 and Codon 61 -Mutated Cancers in the Phase II NCI-MATCH Trial of Binimetinib in Patients with -Mutated Tumors.

Purpose: Preclinical and clinical data suggest that downstream inhibition with an MEK inhibitor, such as binimetinib, might be efficacious for -mutated cancers.

Patients And Methods: Patients enrolled in the NCI-MATCH trial master protocol underwent tumor biopsy and molecular profiling by targeted next-generation sequencing. Patients with -mutated tumors, except melanoma, were enrolled in subprotocol Z1A, a single-arm study evaluating binimetinib 45 mg twice daily.

Tumor Sidedness, Recurrence, and Survival After Curative Resection of Localized Colon Cancer.

Background: Right-sided primary tumor location is associated with worse prognosis in metastatic colon cancer, but the effect of sidedness on recurrence and prognosis for non-metastatic disease is less understood. The purpose of this study was to examine the relationship between sidedness, recurrence, and survival among patients with localized colon cancer.

Patients And Methods: Consecutive patients who underwent curative resection of colon cancer (2006-2013) were identified from a prospective database and retrospectively analyzed.

Targeted methylation sequencing of plasma cell-free DNA for cancer detection and classification.

Background: Targeted methylation sequencing of plasma cell-free DNA (cfDNA) has a potential to expand liquid biopsies to patients with tumors without detectable oncogenic alterations, which can be potentially useful in early diagnosis.

Patients And Methods: We developed a comprehensive methylation sequencing assay targeting 9223 CpG sites consistently hypermethylated according to The Cancer Genome Atlas. Next, we carried out a clinical validation of our method using plasma cfDNA samples from 78 patients with advanced colorectal cancer, non-small-cell lung cancer (NSCLC), breast cancer or melanoma and compared results with patients' outcomes.

Liquid Biopsies Using Plasma Exosomal Nucleic Acids and Plasma Cell-Free DNA Compared with Clinical Outcomes of Patients with Advanced Cancers.

Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Commonly used cell-free DNA (cfDNA) originates from dying cells. Exosomal nucleic acids (exoNAs) originate from living cells, which can better reflect underlying cancer biology.

Development and Validation of an Ultradeep Next-Generation Sequencing Assay for Testing of Plasma Cell-Free DNA from Patients with Advanced Cancer.

Tumor-derived cell-free DNA (cfDNA) in plasma can be used for molecular testing and provide an attractive alternative to tumor tissue. Commonly used PCR-based technologies can test for limited number of alterations at the time. Therefore, novel ultrasensitive technologies capable of testing for a broad spectrum of molecular alterations are needed to further personalized cancer therapy.

Mutation-Enrichment Next-Generation Sequencing for Quantitative Detection of Mutations in Urine Cell-Free DNA from Patients with Advanced Cancers.

Tumor-derived cell-free DNA (cfDNA) from urine of patients with cancer offers noninvasive biological material for detection of cancer-related molecular abnormalities such as mutations in Exon 2 of A quantitative, mutation-enrichment next-generation sequencing test for detecting mutations in urine cfDNA was developed, and results were compared with clinical testing of archival tumor tissue and plasma cfDNA from patients with advanced cancer. With 90 to 110 mL of urine, the cfDNA test had an analytical sensitivity of 0.002% to 0.

Multiplex KRASG12/G13 mutation testing of unamplified cell-free DNA from the plasma of patients with advanced cancers using droplet digital polymerase chain reaction.

Background: Cell-free DNA (cfDNA) from plasma offers easily obtainable material for KRAS mutation analysis. Novel, multiplex, and accurate diagnostic systems using small amounts of DNA are needed to further the use of plasma cfDNA testing in personalized therapy.

Patients And Methods: Samples of 16 ng of unamplified plasma cfDNA from 121 patients with diverse progressing advanced cancers were tested with a KRASG12/G13 multiplex assay to detect the seven most common mutations in the hotspot of exon 2 using droplet digital polymerase chain reaction (ddPCR).

Impact of multimodal therapy in locally recurrent rectal cancer.

Background: The practice of salvaging recurrent rectal cancer has evolved. The aim of this study was to define the evolving salvage potential over time among patients with locally recurrent disease, and to identify durable determinants of long-term success.

Methods: The study included consecutive patients with recurrent rectal cancer undergoing multimodal salvage with curative intent between 1988 and 2012.

BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies.

Despite new and more effective cytotoxic chemotherapy, limitations to conventional agents have been reached in a subset of patients with advanced colorectal cancer (CRC). The identification of novel prognostic and predictive biomarkers to guide individualized treatment plans is critical to overcoming therapeutic resistance. Mutation of the BRAF proto-oncogene is linked to a variety of cancers and is increasingly being used as a prognostic tool and therapeutic target.

Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA.

Next-generation sequencing of cell-free circulating solid tumor DNA addresses two challenges in contemporary cancer care. First this method of massively parallel and deep sequencing enables assessment of a comprehensive panel of genomic targets from a single sample, and second, it obviates the need for repeat invasive tissue biopsies. Digital Sequencing™ is a novel method for high-quality sequencing of circulating tumor DNA simultaneously across a comprehensive panel of over 50 cancer-related genes with a simple blood test.

Erratum: Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies.

The Abstract is incorrect in PubMed. The corrected Abstract is provided here.

BRAF mutation testing with a rapid, fully integrated molecular diagnostics system.

Fast and accurate diagnostic systems are needed for further implementation of precision therapy of BRAF-mutant and other cancers. The novel IdyllaTMBRAF Mutation Test has high sensitivity and shorter turnaround times compared to other methods. We used Idylla to detect BRAF V600 mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples and compared these results with those obtained using the cobas 4800 BRAF V600 Mutation Test or MiSeq deep sequencing system and with those obtained by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory employing polymerase chain reaction-based sequencing, mass spectrometric detection, or next-generation sequencing.

Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies.

Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable source of biologic material for mutation analysis. Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures. Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.

Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors.

Purpose: We used a clinical next-generation sequencing (NGS) hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors.

Experimental Design: A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single-nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interval between onset of primary tumor and metastasis, and neoadjuvant therapy status.

Postoperative chemotherapy use after neoadjuvant chemoradiotherapy for rectal cancer: Analysis of Surveillance, Epidemiology, and End Results-Medicare data, 1998-2007.

Background: Neoadjuvant chemoradiotherapy followed by tumor resection and postoperative chemotherapy is the standard of care for patients with clinical stage II or III adenocarcinoma of the rectum. Significant variation exists in the receipt of postoperative chemotherapy after resection in this population. The objective of this study was to determine the demographic and clinicopathologic factors associated with the initiation of postoperative chemotherapy in elderly patients with rectal cancer and to identify potential targets for reducing treatment variation.

Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations.

Target-matched treatment with PI3K/AKT/mTOR pathway inhibitors in patients with diverse advanced cancers with PIK3CA mutations have shown promise. Tumors from patients with colorectal cancer were analyzed for PIK3CA, KRAS, and BRAF mutations. PIK3CA-mutated tumors were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway.

GWAS-identified colorectal cancer susceptibility loci associated with clinical outcomes.

Recent genome-wide association studies (GWAS) have identified several common susceptibility loci associated with the risk of colorectal cancer (CRC). However, whether these loci affect clinical outcomes of CRC is not clear. In this study, we genotyped 26 single nucleotide polymorphisms (SNPs) in 10 GWAS-identified CRC susceptibility regions and evaluated their associations with survival and recurrence in 285 stage II and III patients receiving fluorouracil-based adjuvant chemotherapy.

Survival benefit associated with surgical oophorectomy in patients with colorectal cancer metastatic to the ovary.

Background And Objectives: The purpose of this study was to determine the outcome of patients with colorectal cancer metastatic to the ovary and the impact of surgical oophorectomy on the outcome.

Methods: We conducted a retrospective evaluation of patients with metastatic colorectal cancer to the ovary. Of 3776 female patients with colorectal cancer seen at MD Anderson from 2001-2008, 110 (2.

Endothelin-1 as a target for therapeutic intervention in prostate cancer.

The endothelins, a family of potent vasoconstricting peptides, have been implicated in the pathophysiology of advanced prostate cancer. Two endothelin receptors, ET-A and ET-B are found in normal prostate tissue. Malignant prostate cells are notable for the loss of ET-B receptors and increased levels of endothelin-1 [ET-1]; this distortion of the endothelin system may be a significant factor in the progression of prostate cancer.