Paneles genómicos en tumores sólidos
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Simposio ACHO de Medicina de Precisión, 15/03/2019
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Paneles genómicos en tumores sólidos
- 1. 1 paneles genómicos en tumores sólidos: ¿cuál, cu Mauricio Lema Medina Clínica de oncología Astorga, Clínica SOMA, Medellín
- 2. 2 Conflicts of interest for this talk Mauricio Lema Medina None @Onconerd
- 5. 5 Conventional genomic Colon cancer Extended RAS BRAF MSI NSCLC EGFR ALK/EML4 ROS1 BRAF Her2 TMB Melanoma BRAF Breast OncoTypeDx MAMMAPRINT PAM50
- 6. 6 Comprehensive Genomic Profile (CGP) * * * Many genes are interrogated in a single test, through the use of DNA sequencers
- 8. Big Data Bio-informatics The SIGNIFICANCE of EVERY mutation MUST be assessed…
- 11. FoundationOne CDx FoundationOne CDx™ (F1CDx™) is a next generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens. https://assets.ctfassets.net/vhribv12lmne/6Rt6csmCPuaguuqmgi2iY8/e3a9b0456ed71a55d2e4480374695d95/FoundationOne_CDx.pdf
- 12. FoundationOne CDx FoundationOne CDx™ (F1CDx™) is a next generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens. https://assets.ctfassets.net/vhribv12lmne/6Rt6csmCPuaguuqmgi2iY8/e3a9b0456ed71a55d2e4480374695d95/FoundationOne_CDx.pdf
- 13. Sample Adequate sample Clinical CGP can be successfully performed for solid tumour samples (generally formalin fixed, paraffin embedded material), bone marrow, and blood, although many other tissue samples such as FNAs can be analysed. In general, a sample approximately 15 mm2 with a minimal depth of 40 mm is adequate for CGP. Ross JS. Pathology, 2016
- 14. Sample Adequate sample Clinical CGP can be successfully performed for solid tumour samples (generally formalin fixed, paraffin embedded material), bone marrow, and blood, although many other tissue samples such as FNAs can be analysed. In general, a sample approximately 15 mm2 with a minimal depth of 40 mm is adequate for CGP. Ross JS. Pathology, 2016
- 15. Sample For assays that measure gene copy number, tumour nuclei should account for at least 20% of the total nuclei present. When tumour nuclei are less than 20%, the risk of missing a copy number gain or homozygous loss increases dramatically Ross JS. Pathology, 2016
- 16. Sample Contamination with non-cancerous tissue or high levels of necrosis can affect detection sensitivity, although macro-dissection can often be used to enrich the sequenced sample for tumour nuclei. Ross JS. Pathology, 2016
- 17. Detecting alteration Point mutations that selectively alter enzyme activity or induce early protein termination, genomic rearrangements that disrupt genes or create novel oncogenic molecules, copy number gains or losses that dramatically change transcript levels, and small insertions and deletions (indels) with various effects depending on the gene and alteration location Ross JS. Pathology, 2016
- 18. Bio-informatics Although managing a clinical CGP assay requires technical expertise across many domains, the computational bioinformatics expertise required for high-quality analysis and interpretation is key Ross JS. Pathology, 2016
- 19. Actionable genomic alterations The term ‘actionable’ describes a sequencing result that can direct a specific action by a treating oncologist Ross JS. Pathology, 2016
- 20. ABL1
- 21. AR ESR1 TOPO1
- 22. BRCA1/2
- 23. ALK
- 24. APC
- 25. ATM
- 26. RB
- 27. TP53
- 28. TSC1/2
- 30. https://www.carismolecularintelligence.com/tumor-profiling-works/ Caris: Comprehensive Tumor Profiling
- 31. https://www.carismolecularintelligence.com/tumor-profiling-works/ Caris: Comprehensive Tumor Profiling
- 32. https://www.carismolecularintelligence.com/tumor-profiling-works/ Caris: Comprehensive Tumor Profiling
- 33. https://www.carismolecularintelligence.com/tumor-profiling-works/ Caris: Comprehensive Tumor Profiling
- 34. https://www.carismolecularintelligence.com/tumor-profiling-works/ Caris: Comprehensive Tumor Profiling
- 35. https://www.carismolecularintelligence.com/tumor-profiling-works/ Caris: Comprehensive Tumor Profiling
- 36. https://www.carismolecularintelligence.com/tumor-profiling-works/ Caris: Comprehensive Tumor Profiling
- 37. Oncomine Based on robust Ion AmpliSeq™ technology, the assay requires only 10 ng of DNA or RNA per pool, enabling analysis of even small and challenging FFPE samples
- 39. Oncomine https://tools.thermofisher.com/content/sfs/brochures/cancer-genomics-research-brochure.pdf
- 42. Options, options… Foundation Medicine Caris Oncomine Institutional: Mayo Clinic Oncotype Mammaprint PAM50 Created by your Molecular Oncologist
- 43. Options, options… Foundation Medicine Oncomine Institutional: ie, Mayo Clinic Oncotype Mammaprint PAM50 Created by your Molecular Oncologist Top bioinformatics Caris
- 45. Adult Low-Grade GliomasPilocytic astrocytoma Glioblastoma Ramiksoon LA. Curr Treat Options Oncol, 2018
- 46. Adult Low-Grade GliomasPilocytic astrocytoma Glioblastoma Grade II and IIIGrade I Grade IV Ramiksoon LA. Curr Treat Options Oncol, 2018
- 47. Adult Low-Grade GliomasPilocytic astrocytoma Glioblastoma Grade I Grade IV OligoastrocytomaAstrocytic Oligodendroglial Grade II and III Astrocytic Oligodendroglioma Anaplastic oligodendroglioma IHD1/2 ++++ +++ +++ TP53 ++++ - +++ ATRX +++ - +++ PI3k/NOTCH1 ++ - - 1p/19q co-deletion - ++++ +++++ TERT promoter mutation - +++ +++ CIC - +++ +++ FUBP1 - +++ +++Ramiksoon LA. Curr Treat Options Oncol, 2018
- 48. Adult Low-Grade GliomasPilocytic astrocytoma Glioblastoma Grade I Grade IV OligoastrocytomaAstrocytic Oligodendroglial Grade II and III Astrocytic Oligodendroglioma Anaplastic oligodendroglioma IHD1/2 ++++ +++ +++ TP53 ++++ - +++ ATRX +++ - +++ PI3k/NOTCH1 ++ - - 1p/19q co-deletion - ++++ +++++ TERT promoter mutation - +++ +++ CIC - +++ +++ FUBP1 - +++ +++Ramiksoon LA. Curr Treat Options Oncol, 2018
- 49. Adult Low-Grade GliomasPilocytic astrocytoma Glioblastoma Grade I Grade IV OligoastrocytomaAstrocytic Oligodendroglial Grade II and III Astrocytic Oligodendroglioma Anaplastic oligodendroglioma IHD1/2 ++++ +++ +++ TP53 ++++ - +++ ATRX +++ - +++ PI3k/NOTCH1 ++ - - 1p/19q co-deletion - ++++ +++++ TERT promoter mutation - +++ +++ CIC - +++ +++ FUBP1 - +++ +++Ramiksoon LA. Curr Treat Options Oncol, 2018
- 50. Adult Low-Grade GliomasPilocytic astrocytoma Glioblastoma Grade I Grade IV OligoastrocytomaAstrocytic Oligodendroglial Grade II and III Astrocytic Oligodendroglioma Anaplastic oligodendroglioma IHD1/2 ++++ +++ +++ TP53 ++++ - +++ ATRX +++ - +++ PI3k/NOTCH1 ++ - - 1p/19q co-deletion - ++++ +++++ TERT promoter mutation - +++ +++ CIC - +++ +++ FUBP1 - +++ +++Ramiksoon LA. Curr Treat Options Oncol, 2018
- 51. Isocitrate alpha-ketoglutarate IDH1/2 Krebs cycle Ramiksoon LA. Curr Treat Options Oncol, 2018
- 52. Isocitrate alpha-ketoglutarate IDH1/2 Isocitrate 2-Hydroxyglutarate mutated IDH1/2 Krebs cycle Blocked differentiation due to histone and DNA hypermethylation Ramiksoon LA. Curr Treat Options Oncol, 2018
- 53. Oligodendrogliomas 1p/19q co-deletion IDH1/2 mutation Median survival + + 8.2 years - + 6.3 years + - 1.5 years L, Knoff DS, Schultz N, et al. Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage IDH1/2 mutations are CRITICAL to prognosis in Oligodendrogliomas. Comprehensive Genomic Profiling is superior to IHC by 20%. Ramiksoon LA. Curr Treat Options Oncol, 2018
- 54. Glioblastoma Chromosome 7 amplifiaction CDKN2A/B homozygous deletion EGFR amplification PTEN-loss TP53 mutation PDGFRA amplification Hemizygous NF1 loss Common, but not actionable, mutations in GBM BRAF mutation Uncommon, but actionable, mutations in GBM Dabrafenib + Trametinib Ramiksoon LA. Curr Treat Options Oncol, 2018
- 55. Glioblastoma TERT IDH1/2 Monticelli M. Clin Neurol Neurosurg, 2018
- 56. IDH1/2 mutation Glioblastoma Secondary GBM IDH1/2 wild-type Primary GBM 5% Worse prognosis Ramiksoon LA. Curr Treat Options Oncol, 2018
- 57. EGFR amplification Glioblastoma No impact in OS TERT mutation EGFR amplification Doubles OS No TERT mutation Ramiksoon LA. Curr Treat Options Oncol, 2018
- 58. Gliomas Mutation Condition Targeted therapy Comment 1p deletion or 1p/19q co-deletion Oligodendroglioma Chemotherapy 1p deletion is a strong predictor of chemosensitivity IDH2 AML Gliomas Enasidenib FDA-approved in IDH2 mutated AML IDH1/2 Glioma Chondrosarcoma Cholangiocarcinoma Ivosidenib Phase I/II studies BRAF mutation Pilicytic astrocytoma Xanthoastrocytoma Epithelioid GBM Vermurafenib, Dabrafenib/Trametini b Scattered reports EGFR amplification GBM Depatuxizumb mafodotin In research Ramiksoon LA. Curr Treat Options Oncol, 2018
- 59. Gliomas Mutation Condition Targeted therapy Comment 1p deletion or 1p/19q co-deletion Oligodendroglioma Chemotherapy 1p deletion is a strong predictor of chemosensitivity IDH2 AML Gliomas Enasidenib FDA-approved in IDH2 mutated AML IDH1/2 Glioma Chondrosarcoma Cholangiocarcinoma Ivosidenib Phase I/II studies BRAF mutation Pilicytic astrocytoma Xanthoastrocytoma Epithelioid GBM Vermurafenib, Dabrafenib/Trametini b Scattered reports EGFR amplification GBM Depatuxizumb mafodotin In research Ramiksoon LA. Curr Treat Options Oncol, 2018
- 63. NSCLC Ali SM. The Oncologist, 2017 1070 NSCLC CGP Non-EML/ALK 6 ALK mutations 47 patients EML4/ALK 41
- 64. NSCLC Ali SM. The Oncologist, 2017 1070 NSCLC CGP Non-EML/ALK 6 ALK mutations 47 patients FISH/ALK+ 20 FISH/ALK- 11 Prior FISH/ALK test 31 EML4/ALK 41
- 65. Ali SM. The Oncologist, 2017 NSCLC
- 66. Ali SM. The Oncologist, 2017 NSCLC FISH negative EIF2AK4/ALK fusion
- 67. Farago AF. JCO Precision Oncology 2018 NSCLC - NTRK NTRK fusions <1% of NSCLC
- 68. Ali SM. The Oncologist, 2017 NSCLC Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases. The Oncologist 2016;21:762–770
- 69. Farago AF. JCO Precision Oncology 2018 NSCLC - NTRK 4/4 responded to Entrectinib Entrectinib Glioneuronal tumor (BCAN-NTRK), NSCLC (SQSTM1-NTRK1), MASC (ETV6-NTRK3), CRC (LMNA-NTRK1)
- 70. Drilon A. NEJM, 2018 NTRK Larotrectinib in tumor agnostic TRK fusion positive
- 71. Drilon A. NEJM, 2018 NTRK Larotrectinib in tumor agnostic TRK fusion positive
- 72. NSCLC Mutation Condition Targeted therapy Comment ALK/EML4 FISH/ALK negative NSCLC Anti-ALK therapy CGP improves EML4/ALK detection by 35% Non-EML4/ALK fusions NSCLC Crizotinib 6 out of 1070 NTRK fusions Sarcomas, NSCLC, Breast, cholangiocarcinomas Larotrectinib Entrectinib FDA approved BRAF mutation Melanoma, Thyroid cancer, Hairy-cell leukemia, NSCLC Dabrafenib/Trametini b 2.6% of NSCLC exhibit BRAF mutation EGFR mutation NSCLC Anti-EGFR In research Cut G. Medicine (Baltimore), 2017
- 74. CRC TERT IDH1/2
- 75. KRAS CRC
- 76. CRC Rankin A. The Oncologist, 2017 4422 CRC CGP 55.6% codon 12/13 RAS mutations 62% RAS/RAF mutations Undetected RAS mutations with conventional: 78/90 (88%) 6.4% (n=90) Non-codon 12/13 RAS mutations
- 77. CRC Rankin A. The Oncologist, 2017 Missed detection of KRAS non-G12/13 mutations by prior focused molecular testing
- 78. CRC Rankin A. The Oncologist, 2017 1644 RAS/RAF wild type by CGP 31% Genomic alteration associated with resistance of anti EGFR therapy PI3KCA PTEN EGFR Her2
- 79. CRC Rankin A. The Oncologist, 2017 Quantitation of CRC cases with potential driver alterations and co-occurrence of KRAS mutations. Breakdown of specific subtypes of RTK, MEK1, PIK3CA, and PTEN alteration classes and overlap with RAS/RAF alterations.
- 83. Melanoma Boussemart L. The Oncologist, 2019 385 BRAF mutations in melanoma detected with CGP Records of prior BRAF testing in 79 (21%) 11/57 (19%) V600+ were BRAF negative with prior testing 16/20 (80%) non-V600 mutated BRAF were negative with prior testing And 2/2 activating BRAF fusions
- 84. Ali SM. The Oncologist, 2017 Melanoma CGP identifies diverse activating BRAF alterations in a significant fraction of cases with prior negative testing. Given the proven clinical benefit of BRAF/ MEK inhibitors in BRAF- mutated melanoma, CGP should be considered for patients with metastatic melanoma, particularly if other testing is negative. The Oncologist 2019;24:1–7
- 85. Breast Ross JS. Pathology, 2016
- 86. Breast cancer
- 87. Breast Ross JS. Pathology, 2016
- 88. Breast Ross JS. Pathology, 2016
- 89. Breast Ross JS. Pathology, 2016 8654 ABC CGP 2697 (31%) mutations in just one pathway 6959 (80%) Mutations in at least one pathway
- 90. Breast Ross JS. Pathology, 2016
- 91. Breast Ross JS. Pathology, 2016
- 92. Breast Ross JS. Pathology, 2016 Prognostic assessment ie TP53 mutation Predicting hormonal therapy resistance AKT1, AKT2, BCAR1, BCAR3, EGFR, ERBB2, GRB7, SRC, TLE3 and TRERF1 Predicting resistance to targeted therapy ESR1 and ERBB2 mutations.
- 93. Breast Ross JS. Pathology, 2016 Base substitution in ESR1 Tamoxifen resistance ESR1 fusions and rearrangements AI resistance Acquired ERBB2 mutation in CDH1 mutated lobular ABC 100% ORR with Neratinib + Fulvestrant in ERBB2/CDH1 co-mutated lobular BC 31% after prolonged anti HR therapy
- 94. Breast Ross JS. Pathology, 2016 ERBB2 amplification Correlates with FISH ERBB2 activating mutations Potential targets to anti-Her2 therapy Acquired ERBB2 mutation in Her2 amplified BC Potential acquired resistance mechanism for patients with HER2+ by IHC 2.4% Acquired PIK3CA/MET/PTEN mutations in Her2 amplified BC Potential acquired resistance mechanism for patients with HER2+ by IHC
- 95. Breast Ross JS. Pathology, 2016 BRCA1/2 mutations Sensitivity to Olaparib or Rucaparib Mutations in other HR- associated genes May be targeted by PARP-inhibition 15% TMB (>20 per megabase) May benefit from Anti-PD(L)1 therapy 5% Rare, potentially actionable mutations EGFR1 amplification, SRC, ALK/EML4, Ret-fusions
- 96. Breast Ross JS. Pathology, 2016 Basal genomics Acquired mutations Implications Lobular CDH1/Pi3k pathway mutations Acquired ERRB2 (30-40%) May benefit from the addition anti Her2 therapy Inflammatory breast cancer ERBB, MTOR, FGFR and DNA repair pathways Mucinous FGFR1 and ERBB2 alterations Secretory breast cancer ETV6-NTRK3 fusion Entrectinib/Larotrecti nib Adenoid Cystic Breast Cancer MYB-NFIB Similar to salivary gland carcinomas Triple-negative and metaplastic BC ERBB2 mutations, RTK pathway mutations, and DNA repair BRCAness pathways. Different targets
- 99. Tumor agnostic
- 100. BRCA1 HR-related genes BRCA2 ATM BARD1 BRIP1 CDK12 CHEK1 CHEK2 FANCL PALB2 PPP2R2A RAD51B RAD51C RAD51D RAD54L Largely tumor agnostic mutations of clinical interest
- 101. BRCA1 HR-related genes BRCA2 ATM BARD1 BRIP1 CDK12 CHEK1 CHEK2 FANCL PALB2 PPP2R2A RAD51B RAD51C RAD51D RAD54L PMS2 MLH1 MSH2 MSH6 POLE MSI + POLE Largely tumor agnostic mutations of clinical interest
- 102. NTRK2 BRCA1 HR-related genes BRCA2 ATM BARD1 BRIP1 CDK12 CHEK1 CHEK2 FANCL PALB2 PPP2R2A RAD51B RAD51C RAD51D RAD54L PMS2 MLH1 MSH2 MSH6 POLE MSI + POLE NTRK1 NTRK3 NTRK1/2/3 Largely tumor agnostic mutations of clinical interest
- 103. Tumor agnostic BRCA1/2 mutations Sensitivity to Olaparib or Rucaparib Mutations in other HR- associated genes May be targeted by PARP-inhibition MSI / POLE May benefit from Anti-PD(L)1 therapy NTRK Larotrectinib/Entrectinib
- 104. SHIVA Le Tourneau, Ann Oncol, 2016
- 105. SHIVA AR over expression Abiraterone MAPK (PTEN/AKT/RICTOR, etc) Everolimus Her2 amplification Trastuzumab + Lapatinib PDGFR Sorafenib ER over expression Tamoxifen Le Tourneau, Ann Oncol, 2016
- 106. SHIVA Le Tourneau, Ann Oncol, 2016 MTA: Molecular targeted agent TPC: Treatment at physicians choice
- 107. SHIVA Le Tourneau, Ann Oncol, 2016
- 108. Le Tourneau, Ann Oncol, 2016
- 109. Le Tourneau, Ann Oncol, 2016
- 110. Le Tourneau, Ann Oncol, 2016 The cross-over analysis of the SHIVA trial identified 37% of patients who crossed over from TPC to MTA with a PFSMTA/PFSTPC ratio exceeding 1.3. SHIVA
- 111. Amarillo Azul Rojo
- 112. Off-label use of medications is essentially banned in Colombia
- 113. Acquisition of a “Vital no disponible” often is a thank-less task
- 114. Get the test done Result interpretation MTA assignment Regulatory obstacles Payer issues
- 115. Get the test done Foundation Medicine Caris Oncomine are ALL performed abroad
- 116. Result interpretation Great knowledge (Andrés Cardona), or Molecular Tumor Board (the rest of us)
- 117. MTA assignment Often Off-label,AND/OR unavailable, AND/OR in early clinical development, and VERY OFTEN of UNPROVED efficacy
- 118. Regulatory obstacles The INVIMA takes at least 4 weeks. In my experience, more than 12 weeks
- 119. Payer issues Insurance wants you out for two reasons: 1. You requested the test (US 4000-5000) 2. They fail to see the point in using an expensive drug, in an unproven setting…
- 120. When should you use it?
- 121. When should you use it? Consider using CGP in PS0/1 patients, in which ALL established treatment options have been tried With a “reasonable” expectation of getting a reliable CGP test (not home-made) Good (ie, not only PBS), insurance International medical coverage With a “reasonable” expectation of getting MTA treatment, should it be advised Today Also, in PS0/1 patients, with non-curable RARE tumors with no clear standard of care
- 123. In the NEAR future, we will use CGPs for the INITIAL treatment in the vast majority of tumors.