Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis.

Despite progress, 2-year pancreatic cancer survival remains dismal. We evaluated a biomarker-driven, combination/N-of-one strategy in 18 patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor Board). Targeted agents administered/patient = 2.

Precision medicine-based therapies in advanced colorectal cancer: The University of California San Diego Molecular Tumor Board experience.

Treatment for advanced colorectal cancer is often limited by complex molecular profiles, which promote resistance to systemic agents and targeted monotherapies. Recent studies suggest that a personalized, combinatorial approach of matching drugs to tumor alterations may be more effective. We implemented a precision medicine strategy by forming a Molecular Tumor Board (MTB), a multidisciplinary team of clinicians, scientists, bioinformaticians and geneticists.

Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study.

Background: Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study.

Establishment of Patient-Derived Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response.

Purpose: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase () subunits (A-D) comprising less than 7.5% (i.e.

Phase I Trial of Stereotactic Body Radiation Therapy Dose Escalation in Pancreatic Cancer.

Purpose: Stereotactic body radiation therapy (SBRT) has demonstrated encouraging local tumor control rates in the treatment of pancreatic cancer, yet we lack prospective clinical trials evaluating dose-escalation strategies among patients treated with 5-fraction SBRT. This phase 1 dose-escalation trial was conducted to determine the maximum tolerated dose of SBRT in patients with pancreatic cancer.

Methods And Materials: Thirty patients with pancreatic cancer were enrolled and treated with 40, 45, or 50 Gy SBRT in 5 fractions with doses determined using a time-to-event continual reassessment method trial design.

Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy.

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies.

Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers.

Biliary tract cancers have dismal prognoses even when cytotoxic chemotherapy is administered. There is an unmet need to develop precision treatment approaches using comprehensive genomic profiling. A total of 121 patients with biliary tract cancers were analyzed for circulating-tumor DNA (ctDNA) and/or tissue-based tumor DNA (tissue-DNA) using clinical-grade next-generation sequencing: 71 patients (59%) had ctDNA; 90 (74%), tissue-DNA; and 40 (33%), both.

Current management of succinate dehydrogenase-deficient gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5-10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate.

Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Colorectal Cancer: Implications for Response and Resistance to Targeted Therapeutics.

Molecular profiling of circulating tumor DNA (ctDNA) is a promising noninvasive tool. Here, next-generation sequencing (NGS) of blood-derived ctDNA was performed in patients with advanced colorectal cancer. We investigated ctDNA-derived genomic alterations, including potential actionability, concordance with tissue NGS, and serial dynamics in 78 patients with colorectal cancer using a clinical-grade NGS assay that detects single nucleotide variants (54-73 genes) and selected copy-number variants, fusions, and indels.

Frequent rectal gastrointestinal stromal tumor recurrences in the imatinib era: Retrospective analysis of an International Patient Registry.

Introduction: Rectal gastrointestinal stromal tumor (GIST) is rare and comprises about 3% of GIST.

Methods: Registry data was collected by the Life Raft Group June 1976 to November 2017. All patients had a histologic GIST diagnosis.

Revisiting Epidermal Growth Factor Receptor () Amplification as a Target for Anti-EGFR Therapy: Analysis of Cell-Free Circulating Tumor DNA in Patients With Advanced Malignancies.

Purpose: To date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response.

Methods: We assessed amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel).

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.

Analysis of Circulating Tumor DNA and Clinical Correlates in Patients with Esophageal, Gastroesophageal Junction, and Gastric Adenocarcinoma.

Purpose: Esophageal, gastroesophageal junction, and gastric adenocarcinoma (herein gastroesophageal adenocarcinomas) are associated with poor prognosis and limited systemic treatment options. To further understand the genomic landscape of gastroesophageal cancers and its clinical correlations, circulating tumor DNA (ctDNA) from patients' plasma was evaluated using next-generation sequencing (NGS).

Experimental Design: We analyzed genomic alterations of 55 patients (mostly advanced disease; 9, surgically resectable) with gastroesophageal adenocarcinomas using clinical-grade NGS performed on plasma-derived ctDNA (54-73 gene panel).

A Novel Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy.

Gastrointestinal stromal tumors (GISTs) are rare in pregnancy, with only 11 reported cases. Adjuvant imatinib therapy, which targets the most common driver mutations in GIST ( and , is recommended for patients with high-risk GIST, but it has known teratogenicity in the first trimester. A 34-year-old G3P2 woman underwent exploratory laparotomy at 16 weeks' gestation for a presumed adnexal mass.

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.

The Mutational Landscape of Gastrointestinal Malignancies as Reflected by Circulating Tumor DNA.

We aimed to assess the utility of a novel, noninvasive method of detecting genomic alterations in patients with gastrointestinal malignancies, i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers.

Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability.

Enhancements in clinical-grade next-generation sequencing (NGS) have fueled the advancement of precision medicine in the clinical oncology field. Here, we survey the molecular profiles of 1,113 patients with diverse malignancies who successfully underwent clinical-grade NGS (236-404 genes) in an academic tertiary cancer center. Among the individual tumors examined, the majority showed at least one detectable alteration (97.

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.

Surgical Management of Adolescents and Young Adults With Gastrointestinal Stromal Tumors: A US Population-Based Analysis.

Importance: There is a dearth of population-based evidence regarding outcomes of the adolescent and young adult (AYA) population with gastrointestinal stromal tumors (GISTs).

Objectives: To describe a large cohort of AYA patients with GISTs and investigate the effect of surgery on GIST-specific survival (GSS) and overall survival (OS).

Design, Setting, And Participants: This retrospective cohort study of 392 AYA patients and 5373 older adult (OA) patients in the Surveillance, Epidemiology, and End Results (SEER) database with GISTs histologically diagnosed from January 1, 2001, through December 31, 2013, with follow-up through December 31, 2015, compared the baseline characteristics of AYA (13-39 years old) and OA (≥40 years old) patients and among AYA patients stratified by operative management.

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic and Notch Pathway Mutations.

Purpose: GI stromal tumors (GISTs) are commonly associated with somatic mutations in and . However, a subset arises from mutations in , most commonly associated with neurofibromatosis type 1. We define the anatomic distribution of alterations in GIST.

FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors.

Background: About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.

Methods: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.

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.