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Personalized Genetics Understanding Your Genetic Test Results

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Personalized Genetics Understanding Your Genetic Test Results Personalized Genetics Understanding Your Genetic Test Results Tracey Evans, MD September 29, 2017 Genetics 101 Punnett Square Genetic Pedigree 2 Genetics 101 Punnett Square Genetic Pedigree 3 It’s not about you! (…or your parents or your kids) It’s about YOUR TUMOR Mutation: Change in the DNA that gets passed on to Cells: they grow and divide, requires daughter cells on subsequent cell divisions replicating the DNA (other DNA changes include translocations, insertions/deletions, copy number changes) 4 Germline vs Somatic Mutations 5 X-Men: Germline Mutations 6 Germline vs Somatic Mutations 7 Mutations that Lead to Cancer 8 Evolution of Tumors 9 Stuff that messes with your genes Inheritable conditions that can predispose to cancers • More likely to mutate/change (MEN2) • Less able to repair mutations/change that inevitably occur (BRCA mutations leading to breast and ovarian cancer) Mutagens • Viruses (HPV) • Toxic exposures (tobacco, asbestos, radon) • Chemotherapy/ radiation Defective immune system • Unable to “take out” cells that go bad (HIV, organ transplants) Bad luck/time: random mistakes during normal replication 10 Cancer: 11 Disease of acquired genetic and molecular abnormalities The Hallmarks of Cancer Mucous hyperplasia Mild dysplasia Severe dysplasia Invasive carcinoma 11 Developments in the Diagnostics and Treatment of Lung Cancer From Plönes T et al, J Pers Med 2016, 6 (1). 12 13 Molecular Events in Lung Cancer Point mutation Single base pair Translocations in Signaling pathway Evasion of mutation in the Amplification of EGFR chromosome 2p alterations immune destruction EGFR gene Chromosome 7 13 Molecular Events in Lung Cancer Point mutation Single base pair Translocations in Signaling pathway Evasion of mutation in the Amplification of EGFR chromosome 2p alterations immune destruction EGFR gene Chromosome 7 14 Recommended approach to Metastatic Non-small Cell Lung Cancer Metastatic disease: requires “systemic” (all over the body) approach 15 Mutations in Lung Adenocarcinomas • These “actionable” mutations are often called “driver mutations” • These mutations happen early in the disease course and are the primary drivers of the cancer • The cancers are “addicted” to the pathways for which they code • Therefore, interfering with this pathway can be very effective 16 NO Overlap in Driver Mutations 17 For Example: the Epidermal Growth Factor Receptor EGFR Invasion P Angiogenesis P MAPK PI3K Signaling cascades Nucleus Gene activation Metastasis Cell cycle progression Proliferation M Myc G1 Fos G2 S Jun Survival Apoptosis MAPK = mitogen-activated protein kinase. Roskoski. Biochem Biophys Res Commun. 2004;319:1. Rowinsky. Annu Rev Med. 2004;55:433. 18 The EGFR story Initial drugs to block the EGFR pathway (contributing factor in many “epithelial” cancers) • Gefitinib: pill, small molecules gets INSIDE the cell and blocks receptor • Cetuximab: IV, Antibody, blocks binding of ligand to receptor from OUTSIDE the cell Initially apparent that gefitinib worked DRAMATICALLY well in SOME lung cancers (about 10%) • Women • Never, distant former, or light tobacco use • Adenocarcinoma • East Asian ethnicity Initial study comparing gefitinib to traditional, IV cytotoxic chemotherapy done in Japan • Overall, gefitinib better at controlling cancer than IV chemo THE CLINICAL OBSERVATION THAT SOME PATIENTS DID REALLY WELL LED TO THE DISCOVERY OF EGFR MUTATIONS THAT STUCK THE RECEPTOR “ON” 19 FDA approved Initial Treatment Options for EGFR mutated Lung Cancer Gefitinib Primary side effects Additional facts • Rash • Similar effectiveness • Hair and nail changes • Recommended starting • Diarrhea dose may be higher than • Rare “interstitial needed pneumonitis” (potentially • Expensive! dangerous inflammation • Provided through of the lungs) specialty pharmacies Afatinib Erlotinib 20 Facts About EGFR Mutation Lung Cancer NOT caused by tobacco exposure • ~10% of lung adenocarcinomas Not all EGFR mutations are the same • Most common (deletion 19, exon 21L858R) almost always respond to initial therapy with the EGFR “TKI’S” (tyrosine kinase inhibitors) • Less common EGFR mutations (exon 18) have variable responses • Some (exon 20 insertion) don’t seem to respond at all Almost inevitably, the cancer at some point develops resistance to the EGFR TKI (meaning the drug stops working to completely control the cancer) • Sometimes this resistance is only in one location that can be managed with a “local treatment” (radiation or surgery) and the drug successfully continued • Even when the cancer is growing on the drug, it often grows faster if the drug is stopped and nothing else started (unique to targeted agents—called “flare”) 21 Why to the EGFR targeted drugs stop working? New molecular changes: Determined by REBIOPSY (or blood or urine te 22 Osimertinib Approved for use in T790M positive EGFR mutated non-small cell lung cancer Gets into blood-brain barrier better than other EGFR TKI’s Inhibits the common EGFR mutations even WITHOUT T790 mutation Less “wild type” EGFR activity (does not affect normal, non- mutated EGFR as much) • Less rash, diarrhea Recently shown to be better in terms of cancer control compared to Gefitinib or Erlotinib when patients treated with this initially (FLAURA) • Not yet FDA approved in this setting 23 Alk Positive Lung Cancer 3-7% of lung adenocarcinomas More common in never/minimal/distant smokers • Not caused by tobacco exposure Treatment with targeted approach leads to better cancer control than traditional IV chemotherapy Alectinib recently shown better at controlling cancer longer than first approved drug crizotinib (Alex) No real consistent side effect profile across class 24 Alk positive lung cancer: Resistance • Many are NOT due to known mutations • And yet, the mutations that CAN occur respond to different drugs….. 25 ….and the rest! 26 ….and the rest! ROS-1 translocation: 1-2%, crizotinib RET translocation: 1-2%, crizotinib, cabozantonib BRAF V600E: 1-3%, dabrafenib and trametinib MET exon 14 skipping: 4%, crizotinib Her2: 2-4%, ado-trastuzumab emtansine, IV KRAS?: NO approved or known effective treatment…yet PD-L1? Not a genetic marker, MORE ABOUT THIS LATER! STAY TUNED FOR MORE! 27 What do we test to figure out tumor genetic profile? • Tissue: Gold standard • Need ENOUGH to do all the tests • Biopsy or resection • Bone biopsies not always eligible for testing • Cytology: • Fine needle biopsy, cells from fluid (pleural effusion) • Blood!: Testing circulating DNA within plasma • In the Lung Cancer Mutation Consortium study (14 U.S. academic centers), only 66% of enrolled patients could have their specimens tested for all 10 genes • Commercially available test for 70 point mutations, 18 amplifications, 6 fusions, 3 internal deletions • Quantitative • Urine • Least invasive of all! • Urine primary route of elimination for circulating DNA and remains stable up to 2 weeks. • Commercially available test evaluates for EGFR, KRAS, BRAF 28 How is the testing done? Next-generation sequencing (NGS), multiplex testing: optimal • Massively parallel sequencing • Get all you need at once, may require more tissue – Generally requires sample be 30%–40% tumor cells – Does not cover translocations – CPD (Center for Personalized Diagnostics) at Penn – Targets 153 genes – TAKES 3-4 WEEKS Sequential sequencing: PCR-based approaches, one gene at a time • Less tissue initially than next gen, may be faster for initial test • More likely to run out of tissue, takes longer overall FISH (fluorescence in situ hybridization) • Used for translocations Antibodies for immunohistochemistry • Requires less tissue, fastest • Variable accuracy • At Penn, used as initial screen for Alk, ROS1, and used for PD-L1 29 When to Rebiopsy or Re-do Molecular Testing When you have reason no to trust your result • Small sample, clinical scenario does not make sense, could not run all desired testing When there is a treatment for particular mode of resistance • EGFR and small cell transformation/T790 • Some Alk mutations in Alk translocated cancers When NOT • Hoping a new driver mutation will pop up 30 Your CPD Report….. 31 Blood-based Molecular Test Report 32 Another commercially available report…. 33 Next Steps Studies incorporating targeted therapies in early stage lung cancer • After surgery in patients with appropriate mutations/translocations • With radiation in patients getting chemoradiation for stage III disease Looking for “actionable” gene mutations in squamous cell Getting more reliable results with smaller samples and with non-invasive samples Figuring out something for KRAS 34 A Case About Why this is Important • 66 yo developed cough late 11/14, fainting episode 12/14 • Found to have lung adenocarcinoma with fluid 9/18/15 surrounding heart. 2 small brain mets diagnosis. • Tobacco: 1ppd 15 yrs quit 1988 • CPD at Penn reported 2/21/15 “deletion of 3 nucleotides in the intron of MET involving the canonical splice donor site” • Chemotherapy through 6/23/15, brain radiation 10/30/15 • 6/15 ASCO: Response to crizotinib…with mutations that cause MET exon 14 skipping • Sudden shortness of breath 9/15 with new, large pleural effusion requiring drainage • Crizotinib on 9/18/15 • Able to attend daughter’s wedding 5/16 35 36 .
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