Genomic Assessment of Blood-Derived Circulating Tumor DNA in Patients With Colorectal Cancers: Correlation With Tissue Sequencing, Therapeutic Response, and Survival.

Purpose: Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with colorectal cancers were correlated with clinical outcomes.

Patients And Methods: Next-generation sequencing of ctDNA (54- to 73-gene panel) was performed in 94 patients with colorectal cancer.

Results: Most patients (96%) had metastatic or recurrent disease at the time of blood draw.

Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study.

Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed the outcomes of some malignancies. Tumor complexity and heterogeneity suggest that the 'precision medicine' paradigm of cancer therapy requires treatment to be personalized to the individual patient. To date, precision oncology trials have been based on molecular matching with predetermined monotherapies.

MET alterations detected in blood-derived circulating tumor DNA correlate with bone metastases and poor prognosis.

Background: We analyzed clinical associations of MET alterations in the plasma of patients with diverse malignancies.

Methods: Digital sequencing of circulating tumor DNA (ctDNA) (54-70 genes) was performed in 438 patients; 263 patients also had tissue sequencing (182-315 genes). The most represented tumor types were gastrointestinal (28.

mutations and number of alterations correlate with maximum standardized uptake value (SUVmax) determined by positron emission tomography/computed tomography (PET/CT) [F] fluorodeoxyglucose (F-FDG PET).

Background: Our study explored the relationship between the molecular changes in cancer and the maximum standardized uptake value (SUVmax) determined by positron emission tomography/computed tomography (PET/CT) with [F] fluorodeoxyglucose (F-FDG).

Results: A higher SUVmax correlated with alterations, but not with histologic diagnosis or other gene/pathway mutations or copy number alterations. In data from breast, lung and colon cancer, patients with the highest SUVmax show more genomic anomalies compared to those with the lowest SUVmax ( < 0.

Telomerase reverse transcriptase promoter alterations across cancer types as detected by next-generation sequencing: A clinical and molecular analysis of 423 patients.

Background: Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers.

Methods: This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next-generation sequencing was performed between August 2014 and July 2015.

Genomic Alterations in Circulating Tumor DNA from Diverse Cancer Patients Identified by Next-Generation Sequencing.

Noninvasive genomic profiling of tumors may be possible with next-generation sequencing (NGS) of blood-derived circulating tumor DNA (ctDNA), but proof of concept in a large cohort of patients with diverse cancers has yet to be reported. Here we report the results of an analysis of plasma-derived ctDNA from 670 patients with diverse cancers. The tumors represented in the patient cohort were mainly gastrointestinal (31.

Topoisomerase expression and amplification in solid tumours: Analysis of 24,262 patients.

Background: Topoisomerase I (TOPO1) and topoisomerase IIα (TOP2A) are specific targets of multiple chemotherapy drugs. Increased expression of TOPO1 protein and amplification of the TOP2A gene have been associated with treatment response in colorectal and breast cancers, respectively. TOPO1 and TOP2A may be potential therapeutic targets in other malignancies as well.

Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma.

Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes. Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next-generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications.

An appraisal of drug development timelines in the Era of precision oncology.

The effects of incorporating a biomarker-based (personalized or precision) selection strategy on drug development timelines for new oncology drugs merit investigation. Here we accessed documents from the Food and Drug Administration (FDA) database for anticancer agents approved between 09/1998 and 07/2014 to compare drugs developed with and without a personalized strategy. Sixty-three drugs were included (28 [44%] personalized and 35 [56%] non-personalized).

Association of Biomarker-Based Treatment Strategies With Response Rates and Progression-Free Survival in Refractory Malignant Neoplasms: A Meta-analysis.

Importance: The impact of a biomarker-based (personalized) cancer treatment strategy in the setting of phase 1 clinical trials was analyzed.

Objective: To compare patient outcomes in phase 1 studies that used a biomarker selection strategy with those that did not.

Data Sources: PubMed search of phase 1 cancer drug trials (January 1, 2011, through December 31, 2013).

Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted Therapeutics.

Alterations in the cyclin-dependent kinase (CDK)-retinoblastoma (RB) machinery disrupt cell-cycle regulation and are being targeted in drug development. To understand the cancer types impacted by this pathway, we analyzed frequency of abnormalities in key cell-cycle genes across 4,864 tumors using next-generation sequencing (182 or 236 genes; Clinical Laboratory Improvement Amendments laboratory). Aberrations in the cell-cycle pathway were identified in 39% of cancers, making this pathway one of the most commonly altered in cancer.

Use of Liquid Biopsies in Clinical Oncology: Pilot Experience in 168 Patients.

Purpose: There is a growing interest in using circulating tumor DNA (ctDNA) testing in patients with cancer.

Experimental Design: A total of 168 patients with diverse cancers were analyzed. Patients had digital next-generation sequencing (54 cancer-related gene panel including amplifications in ERBB2, EGFR, and MET) performed on their plasma.

Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience.

By profiling their patients' tumors, oncologists now have the option to use molecular results to match patients with drug(s) based on specific biomarkers. In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated. Outcomes for patients who received a "matched" versus "unmatched" therapy following their NGS results were compared.

Detection rate of actionable mutations in diverse cancers using a biopsy-free (blood) circulating tumor cell DNA assay.

Analysis of cell-free DNA using next-generation sequencing (NGS) is a powerful tool for the detection/monitoring of alterations present in circulating tumor DNA (ctDNA). Plasma extracted from 171 patients with a variety of cancers was analyzed for ctDNA (54 genes and copy number variants (CNVs) in three genes (EGFR, ERBB2 and MET)). The most represented cancers were lung (23%), breast (23%), and glioblastoma (19%).

Molecular inimitability amongst tumors: implications for precision cancer medicine in the age of personalized oncology.

Tumor sequencing has revolutionized oncology, allowing for detailed interrogation of the molecular underpinnings of cancer at an individual level. With this additional insight, it is increasingly apparent that not only do tumors vary within a sample (tumor heterogeneity), but also that each patient's individual tumor is a constellation of unique molecular aberrations that will require an equally unique personalized therapeutic regimen. We report here the results of 439 patients who underwent Clinical Laboratory Improvement Amendment (CLIA)-certified next generation sequencing (NGS) across histologies.

Impact of a Biomarker-Based Strategy on Oncology Drug Development: A Meta-analysis of Clinical Trials Leading to FDA Approval.

Background: In order to ascertain the impact of a biomarker-based (personalized) strategy, we compared outcomes between US Food and Drug Administration (FDA)-approved cancer treatments that were studied with and without such a selection rationale.

Methods: Anticancer agents newly approved (September 1998 to June 2013) were identified at the Drugs@FDA website. Efficacy, treatment-related mortality, and hazard ratios (HRs) for time-to-event endpoints were analyzed and compared in registration trials for these agents.

Impact of Precision Medicine in Diverse Cancers: A Meta-Analysis of Phase II Clinical Trials.

Purpose: The impact of a personalized cancer treatment strategy (ie, matching patients with drugs based on specific biomarkers) is still a matter of debate.

Methods: We reviewed phase II single-agent studies (570 studies; 32,149 patients) published between January 1, 2010, and December 31, 2012 (PubMed search). Response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared for arms that used a personalized strategy versus those that did not.

Genomic landscape of salivary gland tumors.

Effective treatment options for advanced salivary gland tumors are lacking. To better understand these tumors, we report their genomic landscape. We studied the molecular aberrations in 117 patients with salivary gland tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One, Inc.

Breast Cancer Experience of the Molecular Tumor Board at the University of California, San Diego Moores Cancer Center.

Purpose: Multiplex genomic tests are enabling oncologists to interrogate the DNA of their patients. However, few oncologists are proficient with respect to the implications of complex molecular diagnostics. We initiated a Molecular Tumor Board that focused on individual patients with advanced cancer whose tumors underwent genomic profiling, and here report our experience with breast cancer.

Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are transmembrane growth factor receptors with wide tissue distribution. FGF/FGFR signaling is involved in neoplastic behavior and also development, differentiation, growth, and survival. FGFR germline mutations (activating) can cause skeletal disorders, primarily dwarfism (generally mutations in FGFR3), and craniofacial malformation syndromes (usually mutations in FGFR1 and FGFR2); intriguingly, some of these activating FGFR mutations are also seen in human cancers.

Squamousness: Next-generation sequencing reveals shared molecular features across squamous tumor types.

In order to gain a better understanding of the underlying biology of squamous cell carcinoma (SCC), we tested the hypothesis that SCC originating from different organs may possess common molecular alterations. SCC samples (N = 361) were examined using clinical-grade targeted next-generation sequencing (NGS). The most frequent SCC tumor types were head and neck, lung, cutaneous, gastrointestinal and gynecologic cancers.

Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with cancer.

Next generation sequencing is transforming patient care by allowing physicians to customize and match treatment to their patients' tumor alterations. Our goal was to study the association between key molecular alterations and outcome parameters. We evaluated the characteristics and outcomes (overall survival (OS), time to metastasis/recurrence, and best progression-free survival (PFS)) of 392 patients for whom next generation sequencing (182 or 236 genes) had been performed.

On the Road to Precision Cancer Medicine: Analysis of Genomic Biomarker Actionability in 439 Patients.

Despite the increased use of molecular diagnostics, the extent to which patients who have these tests harbor potentially actionable aberrations is unclear. We retrospectively reviewed 439 patients with diverse cancers, for whom next-generation sequencing (mostly 236-gene panel) had been performed. Data pertaining to the molecular alterations identified, as well as associated treatment suggestions (on- or off-label, or experimental), were extracted from molecular diagnostic reports.