Foundation Medicine

About: Foundation Medicine is a based out in . It is known for research contribution in the topics: Cancer & Targeted therapy. The organization has 430 authors who have published 1085 publications receiving 41789 citations.

Landscape of Cyclin Pathway Genomic Alterations Across 5,356 Prostate Cancers: Implications for Targeted Therapeutics

Abstract: The cyclin pathway may confer resistance to standard treatments but also offer novel therapeutic opportunities in prostate cancer. Herein, we analyzed prostate cancer samples (majority metastatic) using comprehensive genomic profiling performed by next-generation sequencing (315 genes, >500× coverage) for alterations in activating and sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), androgen receptor (AR) gene, and coalterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). Overall, cyclin sensitizing pathway genomic abnormalities were found in 9.7% of the 5,356 tumors. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Alterations in possible resistance genes, RB1 and CCNE1, were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, whereas AR alterations were seen in 20.9% of tumors (~27.3% in anaplastic). Cyclin sensitizing alterations were also more frequently associated with concomitant AR alterations.

Molecular Profiling of Synchronous Colon Cancers and Anaplastic Thyroid Cancer in a Patient with Lynch Syndrome

Abstract: Lynch syndrome is an autosomal dominant cancer susceptibility disorder caused by either a germ line mutation in a DNA mismatch repair gene: MLH1, MSH2, MSH6, or PMS2 or deletion of the last few exons of the EPCAM gene leading to epigenetic silencing of MSH2 [1]. The deficient mismatch repair leads to a hyper mutated state as exemplified by microsatellite instability and eventual carcinogenesis. Clinically, the hallmark of Lynch syndrome is an increased predisposition to the development of colorectal cancers at a significantly younger age relative to their sporadic counterparts, metachronous and synchronous colonic primaries [1]. An increased frequency of neoplasia is also observed in the endometrium, ovary, upper urinary tract, stomach, hepatobiliary, pancreas, small intestine, brain/CNS, sebaceous glands, and keratoacanthomas [1]. Notably,MSH6mutations are associated with a higher proportion of extracolonic neoplasms, a later age of onset of these cancers, and a slightly lower risk of colorectal cancer [2, 3]. Thyroid carcinomas are not traditionally considered to be a part of the Lynch syndrome spectrum, and only two reports describe Lynch patients with thyroid cancer, both harboringMSH2 mutations and without synchronous colorectal carcinomas [4–6]. Recent data has linked tumors driven by microsatellite instability to response to immune-oncology approaches, such as anti-PD1 therapies [7, 8]. We describe here two synchronous colonic and an anaplastic thyroid carcinoma assessed by comprehensive genomic profiling (CGP) in the course of clinical care to demonstrate a hypermutated state thus presenting a potential therapeutic option for this unique clinical presentation.

Clinical Activity of Nivolumab for Human Papilloma Virus‐Related Juvenile‐Onset Recurrent Respiratory Papillomatosis

Abstract: Background Juvenile-onset recurrent respiratory papillomatosis (JO-RRP) is a human papilloma virus-mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO-RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth. Materials and methods We treated two patients with refractory JO-RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling. Results Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on-treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma. Conclusion Nivolumab appears to have promising activity in JO-RRP, and further clinical investigation with more patients in clinical trials is warranted. Implications for practice To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death-1 (PD-1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD-1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.

Discovery of recurrent KIF5B-RET fusions and other targetable alterations from clinical NSCLC specimens.

Abstract: 7510 Background: Many NSCLCs have driving oncogenic alterations including in EGFR, KRAS, ERBB2, BRAF, ALK and ROS1. Clinically effective drugs are approved for EGFR and ALK and clinical trials are underway for other genomic targets. Thus having a means of identifying genomic alterations in routine formalin fixed paraffin embedded (FFPE) clinical specimens is critical. Methods: We sequenced 24 FFPE NSCLC specimens with a next generation sequencing (NGS) assay that captures and sequences 2574 coding exons of 145 cancer relevant genes plus 37 introns from 14 genes often rearranged in cancer. Tumors from 643 additional patients were genotyped for KIF5B-RET. Results: We identified 50 alterations in 21 genes with at least one in 83% (20/24) of tumors (range 1-7). In 72% (36/50) of NSCLCs, at least one alteration was associated with a current clinical treatment or targeted therapy trial, including mutations in KRAS, BRAF, EGFR, MDM2, CDKN2A, CCNE1, CDK4, NF1 and PIK3CA. We also found an 11,294,741 bp pericentric...