Molecular markers used to guide treatment, assess prognosis, or detect relapse. BRAF BRCA EGFR HER2 KRAS ROS1 ALK PD-L1

Molecular markers used to guide treatment, assess prognosis, or detect relapse.

• BRAF
• BRCA
• EGFR
• HER2
• KRAS
• ROS1
• ALK
• PD-L1

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.[5] Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the adaptive arm of immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the adaptive immune system reacts to antigens that are associated with immune system activation by exogenous or endogenous danger signals. In turn, clonal expansion of antigen-specific CD8+ T cells and/or CD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM) motif [6]. This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells) - further mediated by a lower regulation of the gene Bcl-2.Cancer Micrograph showing a PD-L1 positive lung adenocarcinoma. PD-L1 immunostain. It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of 196 tumor specimens from patients with renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death.[20] Many PD-L1 inhibitors are in development as immuno-oncology therapies and are showing good results in clinical trials.[21] Clinically available examples include Durvalumab, atezolizumab and avelumab.[22] In normal tissue, feedback between transcription factors like STAT3 and NF-κB restricts the immune response to protect host tissue and limit inflammation. In cancer, loss of feedback restriction between transcription factors can lead to increased local PD-L1 expression, which could limit the effectiveness of systemic treatment with agents targeting PD-L1. [23] Listeria monocytogenes In a mouse model of intracellular infection, L. monocytogenes induced PD-L1 protein expression in T cells, NK cells, and macrophages. PD-L1 blockade (using blocking antibodies) resulted in increased mortality for infected mice. Blockade reduced TNFα and nitric oxide production by macrophages, reduced granzyme B production by NK cells, and decreased proliferation of L. monocytogenes antigen-specific CD8 T cells (but not CD4 T cells).[24] This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection. Autoimmunity The PD-1/PD-L1 interaction is implicated in autoimmunity from several lines of evidence. NOD mice, an animal model for autoimmunity that exhibit a susceptibility to spontaneous development of type I diabetes and other autoimmune diseases, have been shown to develop precipitated onset of diabetes from blockade of PD-1 or PD-L1 (but not PD-L2).[25] In humans, PD-L1 was found to have altered expression in pediatric patients with Systemic lupus erythematosus (SLE). Studying isolated PBMC from healthy children, immature myeloid dendritic cells and monocytes expressed little PD-L1 at initial isolation, but spontaneously up-regulated PD-L1 by 24 hours. In contrast, both mDC and monocytes from patients with active SLE failed to upregulate PD-L1 over a 5-day time course, expressing this protein only during disease remissions.[26] This may be one mechanism whereby peripheral tolerance is lost in SLE.

BiomarkersMolecular markers used to guide treatment, assess prognosis, or detect relapse.BRAFBRCAEGFRHER2KRASROS1ALKPD-L1PD-L1May 02, 2019Arcus Biosciences, Strata Oncology Team Up to Advance Anti-PD-1 DrugThe companies are using Strata's biomarker technology to identify genomic subpopulations of cancer patients who respond to Arcus' investigational immunotherapy drug.Apr 17, 2019FDA Approves Expanded Use of Agilent CDx for Keytruda in Lung CancerThe diagnostic can now be used to identify a wider...

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Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene.ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.[6] The deduced amino acid sequences reveal that ALK is a novel receptor tyrosine kinase having a putative transmembrane domain and an extracellular domain. These sequences are absent in the product of the transforming NPM-ALK gene.[7] ALK shows the greatest sequence similarity to LTK (leukocyte tyrosine kinase). Pathology The ALK gene can be oncogenic in three ways – by forming a fusion gene with any of several other genes, by gaining additional gene copies or with mutations of the actual DNA code for the gene itself. Anaplastic large-cell lymphoma The 2;5 chromosomal translocation is associated with approximately 60% anaplastic large-cell lymphomas (ALCLs). The translocation creates a fusion gene consisting of the ALK (anaplastic lymphoma kinase) gene and the nucleophosmin (NPM) gene: the 3' half of ALK, derived from chromosome 2 and coding for the catalytic domain, is fused to the 5' portion of NPM from chromosome 5. The product of the NPM-ALK fusion gene is oncogenic. In a smaller fraction of ALCL patients, the 3' half of ALK is fused to the 5' sequence of TPM3 gene, encoding for tropomyosin 3. In rare cases, ALK is fused to other 5' fusion partners, such as TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9.[8] Adenocarcinoma of the lung The EML4-ALK fusion gene is responsible for approximately 3-5% of non-small-cell lung cancer (NSCLC). The vast majority of cases are adenocarcinomas. The standard test used to detect this gene in tumor samples is fluorescence in situ hybridization (FISH) by a US FDA approved kit. Recently Roche Ventana obtained approval in China and European Union countries to test this mutation by immunohistochemistry.[citation needed] Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended.[citation needed] ALK lung cancers are found in patients of all ages, although on average these patients tend to be younger. ALK lung cancers are more common in light cigarette smokers or nonsmokers, but a significant number of patients with this disease are current or former cigarette smokers. EML4-ALK-rearrangement in NSCLC is exclusive and not found in EGFR- or KRAS-mutated tumors.[9] Gene rearrangements and overexpression in other tumours Familial cases of neuroblastoma[10] Inflammatory myofibroblastic tumor[11][12] Adult[13][14] and pediatric[15][16] renal cell carcinomas Esophageal squamous cell carcinoma[17][18] Breast cancer,[19] notably the inflammatory subtype[20] Colonic adenocarcinoma[19] Glioblastoma multiforme[21][22] Anaplastic thyroid cancer[23] ALK inhibitors Main article: ALK inhibitor Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.[24] Early results of an initial Phase I trial with 82 patients with ALK induced lung cancer showed an overall response rate of 57%, a disease control rate at 8 weeks of 87% and progression free survival at 6 months of 72%. Ceritinib was approved by the FDA in April 2014 for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.[25] Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 is currently underway to test the drug in patients with ROS1/NTRK/ALK gene rearrangements.

BiomarkersMolecular markers used to guide treatment, assess prognosis, or detect relapse.BRAFBRCAEGFRHER2KRASROS1ALKPD-L1ALKMay 16, 2019Roche Drug Shows Benefit in Pediatric Patients With Rare, Molecularly Defined TumorsPremiumIn the Phase I/IB study, only patients with NTRK or ROS1 fusions, or an ALK fusion or mutation responded to entrectinib, while patients without these tumor markers didn’t respond.Apr 10, 2019Foundation Medicine, Flatiron Health Publish Clinical Validity of Clinico-Genomics...

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Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.This proto-oncogene, highly expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor.ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the anaplastic lymphoma kinase (ALK) protein; it is encoded by the c-ros oncogene and was first identified in 1986.[7][8][9][10] The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined.[8] Nonetheless, as gene rearrangement events involving ROS1 have been described in lung and other cancers, and since such tumors have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has been increasing.[7][11] Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive.[12] Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.[13][14] In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient.[15] Since that discovery, multiple studies have demonstrated an incidence of approximately 1% in lung cancers, demonstrated oncogenicity, and showed that inhibition of tumor cells bearing ROS1 gene fusions by crizotinib or other ROS1 tyrosine kinase inhibitors was effective in vitro.[16][17][18] Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions.[19][20] Preclinical and clinical work suggests multiple potential mechanisms of drug resistance in ROS1 + lung cancer, including kinase domain mutations in ROS1 and bypass signaling via RAS and EGFR.[21][22][23] Although the most preclinical and clinical studies of ROS1 gene fusions have been performed in lung cancer, ROS1 fusions have been detected in multiple other tumor histologies, including ovarian carcinoma, sarcoma, cholangiocarcinomas and others.[24] Crizotinib or other ROS1 inhibitors may be effective in other tumor histologies beyond lung cancer as demonstrated by a patient with an inflammatory myofibroblastic tumor harboring a ROS1 fusion with a dramatic response to crizotinib.

BiomarkersMolecular markers used to guide treatment, assess prognosis, or detect relapse.BRAFBRCAEGFRHER2KRASROS1ALKPD-L1ROS1May 16, 2019Roche Drug Shows Benefit in Pediatric Patients With Rare, Molecularly Defined TumorsPremiumIn the Phase I/IB study, only patients with NTRK or ROS1 fusions, or an ALK fusion or mutation responded to entrectinib, while patients without these tumor markers didn’t respond.Apr 10, 2019Foundation Medicine, Flatiron Health Publish Clinical Validity of Clinico-Genomics...

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The KRAS gene provides instructions for making a protein called K-Ras that is part of a signaling pathway known as the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). The K-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. In this way the K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules. To transmit signals, it must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus. The KRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and NRAS. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis).

BiomarkersMolecular markers used to guide treatment, assess prognosis, or detect relapse.BRAFBRCAEGFRHER2KRASROS1ALKPD-L1KRASMay 29, 2019CRISPR Framework Helps Identify Combination Therapies for Optimal Targeting of KRAS MutantResearchers used a genome-scale CRISPRi platform to identify genetic interactions with an inhibitor for a mutant form of KRAS in models of lung and pancreatic cancer.Feb 26, 2019Thermo Fisher Scientific Oncomine Dx Target Test Gets Expanded Regulatory Approval in JapanThe NGS...

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Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers.[8][14] It is strongly associated with increased disease recurrence and a poor prognosis.[15] Over-expression is also known to occur in ovarian,[16] stomach, adenocarcinoma of the lung[17] and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma,[18][19] e.g. HER-2 is over-expressed in approximately 7-34% of patients with gastric cancer[20][21] and in 30% of salivary duct carcinomas.[22] HER2 is colocalised and most of the time, coamplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumours. HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.[23][24] Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.[25] Mutations Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumours and some of these tumours carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerisation of this protein in the absence of a ligand.[26] HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.[27]Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene isolated from avian genome. It is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.[5][6][7] HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients.[8]

BiomarkersMolecular markers used to guide treatment, assess prognosis, or detect relapse.BRAFBRCAEGFRHER2KRASROS1ALKPD-L1HER2Apr 03, 2019Project GENIE Used to Explore Impact of Rare Cancer Mutations on Treatment ResponsePremiumStudies presented at the AACR meeting demonstrated how the registry can be used to evaluate how cancer patients with rare tumor markers respond to treatments.Mar 04, 2019Colon Cancer Patients Could Benefit From HER2 EGFR Non-Response Findings, Investigators SayPremiumBased...

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Mutations that lead to EGFR overexpression (known as upregulation or amplification) have been associated with a number of cancers, including adenocarcinoma of the lung (40% of cases), anal cancers,[16] glioblastoma (50%) and epithelian tumors of the head and neck (80-100%).[17] These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division.[18] In glioblastoma a specific mutation of EGFR, called EGFRvIII, is often observed.[19] Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.[5] The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). In many cancer types, mutations affecting EGFR expression or activity could result in cancer.[6] Epidermal growth factor and its receptor was discovered by Stanley Cohen of Vanderbilt University. Cohen shared the 1986 Nobel Prize in Medicine with Rita Levi-Montalcini for their discovery of growth factors. Deficient signaling of the EGFR and other receptor tyrosine kinases in humans is associated with diseases such as Alzheimer's, while over-expression is associated with the development of a wide variety of tumors. Interruption of EGFR signalling, either by blocking EGFR binding sites on the extracellular domain of the receptor or by inhibiting intracellular tyrosine kinase activity, can prevent the growth of EGFR-expressing tumours and improve the patient's condition.

BiomarkersMolecular markers used to guide treatment, assess prognosis, or detect relapse.BRAFBRCAEGFRHER2KRASROS1ALKPD-L1EGFRApr 10, 2019Foundation Medicine, Flatiron Health Publish Clinical Validity of Clinico-Genomics DatabaseIn the JAMA study, researchers confirmed the previously known clinical and genomic features of NSCLC patients in their large clinico-genomics database.Mar 04, 2019Colon Cancer Patients Could Benefit From HER2 EGFR Non-Response Findings, Investigators SayPremiumBased on the...

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A BRCA mutation is a mutation in either of the BRCA1 and BRCA2 genes, which are tumour suppressor genes. Hundreds of different types of mutations in these genes have been identified, some of which have been determined to be harmful, while others have no proven impact. Harmful mutations in these genes may produce a hereditary breast-ovarian cancer syndrome in affected persons. Only 5-10% of breast cancer cases in women are attributed to BRCA1 and BRCA2 mutations (with BRCA1 mutations being slightly more common than BRCA2 mutations), but the impact on women with the gene mutation is more profound.[1] Women with harmful mutations in either BRCA1 or BRCA2 have a risk of breast cancer that is about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times normal.[2] The risk of breast and ovarian cancer is higher for women with a high-risk BRCA1 mutation than with a BRCA2 mutation. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or imply that any cancer that appears was actually caused by the mutation, rather than some other factor. High-risk mutations, which disable an important error-free DNA repair process (homology directed repair), significantly increase the person's risk of developing breast cancer, ovarian cancer and certain other cancers. Why BRCA1 and BRCA2 mutations lead preferentially to cancers of the breast and ovary is not known, but lack of BRCA1 function seems to lead to non-functional X-chromosome inactivation. Not all mutations are high-risk; some appear to be harmless variations. The cancer risk associated with any given mutation varies significantly and depends on the exact type and location of the mutation and possibly other individual factors. Mutations can be inherited from either parent and may be passed on to both sons and daughters. Each child of a genetic carrier, regardless of sex, has a 50% chance of inheriting the mutated gene from the parent who carries the mutation. As a result, half of the people with BRCA gene mutations are male, who would then pass the mutation on to 50% of their offspring, male or female. The risk of BRCA-related breast cancers for men with the mutation is higher than for other men, but still low.[3] However, BRCA mutations can increase the risk of other cancers, such as colon cancer, pancreatic cancer, and prostate cancer. Methods to diagnose the likelihood of a patient with mutations in BRCA1 and BRCA2 getting cancer were covered by patents owned or controlled by Myriad Genetics.[4][5] Myriad's business model of exclusively offering the diagnostic test led to Myriad growing from being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012;[6] it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit.[7]

BiomarkersMolecular markers used to guide treatment, assess prognosis, or detect relapse.BRAFBRCAEGFRHER2KRASROS1ALKPD-L1BRCAApr 05, 201923andMe DTC Breast and Ovarian Cancer Risk Test Misses Almost 90 Percent of BRCA Mutation CarriersIn 125,000 de-identified Invitae customers with and without a personal or family history of cancer, 23andMe's DTC test would have missed almost 90 percent of BRCA mutations.Apr 04, 2019Myriad Genetics, AstraZeneca, Merck Expand BRCA CDx CollaborationThe test will be...

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BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.[5][6] The B-Raf protein is involved in sending signals inside cells which are involved in directing cell growth. In 2002, it was shown to be faulty (mutated) in some human cancers.[7] Certain other inherited BRAF mutations cause birth defects. Drugs that treat cancers driven by BRAF mutations have been developed. Two of these drugs, vemurafenib[8] and dabrafenib are approved by FDA for treatment of late-stage melanoma. Vemurafenib was the first drug to come out of fragment-based drug discovery.

BiomarkersMolecular markers used to guide treatment, assess prognosis, or detect relapse.BRAFBRCAEGFRHER2KRASROS1ALKPD-L1BRAFMay 16, 2019NCI Pediatric MATCH Trial Interim Data Shows 24 Percent of Patients Eligible for Targeted TherapyPremiumThe actual match rate is significantly higher than the 10 percent rate the researchers anticipated they would see when the study began in 2017.Jan 10, 2019Melanoma BRAF Mutation Type May Affect Response to Targeted Treatments, ImmunotherapyIn a small study, melanoma...

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