De huidige staat van moleculair testen in het behandelen van kankerpatienten met solide tumoren. Een uitstekend overzichtsartikel met de nieuwste ontwikkelingen over RNA, DNA en eiwitten anno 2019

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Op de website van Caris Lifesciences staan hier publicaties van de laatste 5 jaar met moleculaire testen.

18 juni 2019: Bron: Whiley online library

In een uitstekend en gedetailleerd artikel beschrijven een groep van bekende wetenschappers en artsen wat de huidige staat is van moleculair testen. En wat dat betekent voor het behandelen van kanker met solide tumoren. Onafhankelijk van de primaire tumordiagnose. Aan bod komen de verschillen en soms ook overeenkomsten tussen RNA mutaties, DNA mutaties en eiwitexpressie.

Een aantal al bekende mutaties gekoppeld aan de door FDA en EMU geregistreerde medicijnen die horen bij bepaalde mutaties of eiwitexpressie is deze grafiek. En bedenk dat eigenlijk dit los staat van de primaire tumordiagnose al wordt daar nog veel te weinig mee gedaan, maar dit gaat ongetwijfeld veranderen. Dat een medicijn voor BRCA gerelateerde vormen van kanker niet alleen maar voor borstkanker of eierstokkanker gaat gebruikt worden maar ook voor andere vormen van kanker met BRCA mutaties. En zo zijn er veel meer voorbeelden te noemen, zoals HER2 expressie, EGFR mutaties, MSI instabiel enz. , maar zie deze grafiek:

Table 7. Broadening Molecular Profiling Boundaries—Biomarker‐Targeted Therapy Matches

TARGETED MUTATION	DRUG
NCI‐MATCH trial: NCT02465060aNCI‐MATCH trial: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma. Matches are as listed on ClinicalTrials.gov/ct2/show/NCT02465060. Accessed February 6, 2019. After patient tumor molecular testing on a main screening protocol, those with actionable mutations are assigned to 1 of 35 treatment subprotocols.
EGFR activating mutation	Afatinib
HER2 activating mutation	Afatinib
BRCA1 or BRCA2 mutations	Adavosertib (AZD1775)
FGFR pathway aberrations	AZD4547
NRAS12, NRAS13, NRAS61 mutation	Binimetinib
AKT mutation	Capivasertib (AZD 5363)
PIK3CA mutation	Copanlisib
PTEN mutation	Copanlisib
PTEN loss	Copanlisib
MET amplification	Crizotinib
MET exon 14 deletion	Crizotinib
ALK translocation	Crizotinib
ROS1 translocation or inversion	Crizotinib
BRAF V600E/V600R/V600K/V600D mutation	Dabrafenib + trametinib
DDR2 S768R, I638F, or L239R mutation	Dasatinib
NF2 inactivating mutation	Defactinib
PTEN mutation or deletion and PTEN expression	GSK2636771 (PI3Kβ inhibitor)
PTEN loss	GSK2636771 (PI3Kβ inhibitor)
FGFR mutation or fusion	Erdafitinib
FGFR amplification	Erdafitinib
NTRK1, NTRK2, NRTK3 gene fusions	Larotrectinib (LOXO‐101)
Loss of MLH1 or MSH2 (by IHC)	Nivolumab
EGFR T790M or rare activating mutation	Osimertinib
CCND1, CCND2, CCND3 amplification & Rb expression	Palbociclib
CDK4 or CDK6 amplification and Rb protein	Palbociclib
HER2 amplification ≥7 copy numbers	Pertuzumab + trastuzumab
TSC1 or TSC2 mutation	Sapanisertib
mTOR mutation	Sapanisertib
cKIT exon 9, 11, 13, or 14 mutation	Sunitinib
PIK3CA mutation	Taselisib
GNAQ/GNA11 mutation	Trametinib
BRAF fusion or BRAF non‐V600 mutation	Trametinib
NF1 mutation	Trametinib
HER2 amplification	Trastuzumab emtansine
SMO/PTCH1 mutation	Vismodegib
TAPUR trial: NCT02693535bThe American Society of Clinical Oncology's TAPUR trial: Testing the Use of US Food and Drug Administration‐Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer. Matches are as listed on clinicaltrials.gov/ct2/show/NCT02693535. Accessed February 6, 2019.
VEGFR mutation, amplification or overexpression	Axitinib
Bcr‐abl, SRC, LYN, LCK mutations	Bosutinib
ALK, ROS1, MET mutations	Crizotinib
KRAS, NRAS, and BRAF (all wild type)	Cetuximab
Bcr‐abl, SRC, KIT, PDGFRB, EPHA2, FYN, LCK, YES1 mutations	Dasatinib
BRCA1/BRCA2 inactivating mutations; ATM mutations/deletions	Olaparib
MSI‐high, high TML, and others	Nivolumab and ipilimumab
CDKN2A, CDK4, CDK6 amplifications	Palbociclib
POLE/POLD1 mutations; high TML	Pembrolizumab
VEGFR1, VEGFR2, VEGFR3, PDGFRB, RET, KIT, RAF‐1, BRAF mutations/amplifications	Regorafenib
PDGFR, VEGFR, CSF1R	Sunitinib
mTOR, TSC mutations	Temsirolimus
ERBB2 amplifications	Trastuzumab and pertuzumab
BRAF V600E mutations	Vemurafenib and cobimetinib

Het gaat me te ver om alles te vertalen want het is behoorlijk medisch technisch al leest het in sommige delen van het artikel best makkelijk, in ieder geval voor mij. Zo worden de methodes van moleculaire testen ook beschreven in wat de verschillen zijn en overeenkomsten en waar ze toe dienen in relatie tot een behandeling van kanker.

DNA and RNA

Polymerase chain reaction (PCR) is used to amplify and detect DNA and RNA sequences. Standard PCR involves the amplification of one or more copies of a chosen DNA sequence to produce millions of copies and enable detection and analysis. Reverse transcription PCR converts RNA templates into complementary DNA for molecular analysis.
In situ hybridization (ISH) localizes and determines a specific DNA or RNA sequence in a tissue section (in situ) or in circulating tumor cells using a labeled complementary DNA, RNA, or modified nucleic acid strand probe. This technique detects gene deletions, amplifications, translocations, and fusions. Gene fusions commonly occur in epithelial cancers as a result of genomic rearrangements or abnormal mRNA processing. ISH techniques include chromogenic ISH and fluorescence in situ hybridization (FISH).
- Chromogenic in situ hybridization (CISH) uses brightfield microscopes for label detection.
- FISH uses fluorescence microscopes for label detection.
Sanger sequencing examines strands of DNA to identify mutations by analyzing long, contiguous sequencing reads. This DNA sequencing takes place according to the selective incorporation of chain‐terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication. This was the primary sequencing method used for well over 20 years and, although it is still widely used, next‐generation sequencing (NGS) is now preferred for multigene/variant assessment.
NGS is a high‐throughput technique that rapidly examines and more broadly detects DNA mutations (often used for circulating tumor DNA), copy number variations (CNVs), and gene fusions (using an RNA sequencing panel) across the genome. NGS can be performed on a range of cancer types using blood, solid tissue, and bone marrow samples. Precise tissue collection and workup are necessary for accurate results. Laboratory regulatory agencies constantly provide updated guidance documents pertaining to the design, development, and use of NGS‐based tests, recognizing the importance of NGS in cancer diagnostics and therapeutics.
Pyrosequencing detects and quantifies mutations, methylation, etc, through sequencing by synthesis—a method that performs DNA sequencing by detecting the nucleotide that is incorporated by DNA polymerase.
Fragment analysis detects changes in DNA (eg, the length of a specific DNA sequence) or RNA to indicate the presence or absence of an inserted or deleted genomic sequence.

Protein

Immunohistochemistry (IHC) uses the principles of antibody binding to proteins to determine the levels of protein expression in tissue samples. Tumor‐related proteins of interest can include tumor‐specific antigens, protein products of oncogenes and tumor suppressor genes, tumor cell proliferation markers, and enzymes.

Maar leest u verder het artikel door op de volgende link te klikken:

Molecular Profiling Assays and Why Physician Oncologists and Pathologists Should Be Familiar With Them

Hier het abstract van dit artikel met alle genoemde wetenschappers en artsen die hieraan hebben meegewerkt en indeling van het artikel:

The current state of molecular testing in the treatment of patients with solid tumors, 2019

Abstract

The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin. Molecular profiling methodologies have likewise changed such that tests that were performed on patients a few years ago are no longer complete and possibly inaccurate today. As with all rapid change, medical providers can quickly fall behind or struggle to find up‐to‐date sources to ensure he or she provides optimum care. In this review, the authors provide the current state of the art for molecular profiling/precision medicine, practice standards, and a view into the future ahead.

Wafik S. El‐Deiry MD, PhD, FACP

Associate Dean for Oncologic Sciences, Warren Alpert Medical School; Director, Joint Program in Cancer Biology, Brown University and the Lifespan Cancer Institute; Professor of Pathology & Laboratory Medicine and Professor of Medical Science, Brown University, Providence, RI

DNA and RNA

Protein

The current state of molecular testing in the treatment of patients with solid tumors, 2019

Abstract

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