Prof Mark McKeage

Transcript

1. Research – Current Lung Health Research (Lung Cancer) Mark McKeage Professor and Co-Director, Department of Pharmacology and Clinical Pharmacology and Auckland Cancer Society Research Centre, University of Auckland Medical Oncology Specialist, Auckland City Hospital m.mckeage@auckland.ac.nz Lung Foundation New Zealand Lung Health Seminar 11 Nov 2015
2. Lung Cancer Global Statistics • The major cancer in the world today • The most common cancer type – 1.8 million new cases per annum • The most common cause of cancer death – 1.6 million cancer deaths per annum 0 0.5 1 1.5 2 Millions Incidence Deaths Adapted from Torre et al CA Cancer J Clin 2015 65 87-108
3. Lung Cancer in New Zealand • Leading cause of cancer death – ≈ 20% of all cancer deaths • Fifth most common cancer – ≈ 2000 cases/annum • Survival outcomes poor – One year survival ≈ 30% Ministry of Health. 2015. Cancer Patient Survival: 1994 to 2011. Wellington: Ministry of Health
4. Cancer Mortality Rates for Maori versus non-Maori: 2012 Males Females Ministry of Health. 2015. Cancer: New registrations and deaths 2012. Wellington: Ministry of Health
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6. Lung cancer: an important opportunity for improving lung health • Tobacco control • Earlier diagnosis • Improving treatments British Medical Journal1995;311:899-909 1995 Lung cancer meta-analysis
7. Genetically-directed lung cancer targeted therapies Garraway et al Journal of Clinical Oncology 2013 31 1803-5
8. EGFR mutation-positive lung cancer Mutations Targeted therapy Nature Reviews Cancer 2007: 7 169–81 N Engl J Med 2010;362:2380-8 EGFR, Epidermal Growth Factor Receptor
9. Results of EGFR mutation testing in eligible cohort patients (n=429) Mutation detected, 86, 20% No mutation detected, 328, 76% No result, 15, 4% EGFR mutation testing Mutation detected No mutation detected No result 64 22 171 157 0% 20% 40% 60% 80% 100% Female Male Gender P<0.001 43 6 11 19 7 201 53 34 29 11 0% 20% 40% 60% 80% 100% Euro Maori Pacific Asian Other Ethnicity P=0.001 26 42 9 123 39 41 0% 20% 40% 60% 80% 100% Ex Non Smoker Smoking P<0.001 Population-based prevalence estimate = 20% (95%CI 16.5 to 24.5%) http://nhc.health.govt.nz/our-work/epidermal-growth-factor-receptor-gene-mutation-testing
10. Multiplexed array mass spectrometry genotyping assay EGFR Missense R108K, T263P, A289V, A289D, GS98V, E709K, E7090/H, E709A, E709G, E709V, E709fs 1111, G719S, G719C, G719A, G719D, E746K, E746V, L747P, L747S, T7511, S752P, S752Y, P753Q, P753S, 1759N, D761N, D761Y, S768I, S768N, D770N, R776C, R776H, T790M, T854A, L858M/K/R, L858R, L861Q, L861R EGFR Exon 19 K745_E749del, E746_E749del, E746_A750del, E746_T751del, E746_T751>1, E746_A750>1P, E746_T751>1P, E746_S752>1, E746_T751>A, E746deV1744_K7451nsKIPVA1I , E746_S752del, E746_T751>1, E746_P753>1S, E746_T751>0, E746_A750>QP, E746_T751>L, E746_P753>LS, E746_T751>S, E746_S752>A, E746_T751>V, E746_T751>VAorvP, E746_P753>VS, E746_S752>V, E746_A750>VP, E746_T751>VA, E746_T751>VP, E746_P753>VQ, E746V/K74S_E746insVPVAIK1, E746_S752>D, L747_A750>P, L747_T751>Q, E746_A750>DP, L747_T751>P, L747_S752>Q, L747_S752>QH, L747_E749del, L747_S752del /L747_S752>Q, L747_P753>Q, L747_T751>A, L747_K754del, L747_K754>N 1, L747_T751>S, L747_T751del, L747_P753>S, L747S/l747_1<754>ST1, T751_1759>N, T751_1759>REA, T751_1759>St, T751_1759del1, S752_1759del, P753_1759del,1751_1759>5 1 EGFR Exon20 M766_A767insAI, A767_S768insll.A1, S768_V769>1L1, V769_0770insMASVD, 0770_P772>ASVDNR, V769_D770inscvt, V769_D770insASV, D770_N771>AGG, V769_D7701nsASV1, V769_D7701nsGSV/ V769_D7701nsGVV/D770>GY 1, D770_N7711nsG, D770_N7711nsAPW, D770_N7711nsGL, N771>GF, N771>GY, D770_N771insG, D770_N771insGD1, D770_N771insSVD, N771_P772>SVQNR, N771>TH, N771>SH, D770_N771insMATPl, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insQ 1, V774_C775insHV,N771_P772insN1, D770fs•611, N771_P772insRH/ P772_H773insTHP1, P772_H773insV1, P772_H773insHvt, H773>NPY 1, V774_C77SinsHvt BRAF D594G, D594V, G469S, G469E, G469A, G469V, G469R, G469R/S, L5970, L597V, L597R, L597S, V600E, V600K, V600M, V600L KRAS G12S, G12R, G12T, G12V, G12F, G12P, G12A, G12C, G12W, G12D, Gl2N, G121, G12L, G12Y, G12E, G12D/V, G13C, G13S, G13A, G13V/I, G13D/N, G13R, AS9T, Q61K, Q61E, Q61L, Q61R, Q61P, Q61H NRAS G12S/N, G12R/P, G12C/Y, G12D/E, G12A, G12V, G13S/NG, G13R, G13C/Y, G13D, G13A, G13V, Q61H, Q61L, Q61R, Q61PQ, Q61K, Q61E
11. Mass spectrometry genotyping retesting results Test results n=532 Mutations detected n=239 EGFR mutation detected, 91 No Mutation detected, 293 Invalid, 2 KRAS mutation detected, 135 NRAS mutation detected, 8 BRAF mutation detected, 5 (result, number) EGFR Exon 18, 4 EGFR Exon 19 Del, 42 EGFR Exon 20 Ins, 6 EGFR L858R, 33 EGFR compound mutations, 4 EGFR other, 2 KRAS G12C, 47 KRAS other, 31 KRAS G12V, 35 KRAS G12D, 22 NRAS, 8 BRAF, 5 (mutation, number) http://nhc.health.govt.nz/our-work/epidermal-growth-factor-receptor-gene-mutation-testing
12. ALK, Anaplastic Lymphoma Kinase. NEJM 2010; 363: 1693-703. Clinical Diagnosis Treatment Response ALK gene rearrangement-positive lung cancer
13. Journal of Thoracic Oncology 10, 6, June 2015 Second generation ALK inhibitor drugs Activity against CNS disease Intracranial Response Rate [n (%)] Total 17 (100%) Complete 1 (6%) Partial 9 (53%) Stable 4 (23%) Progression 0 (0%) Unknown 3 (17%) ASCEND-3 ASCO 2015 Abs #8060 Treatment response
14. Lung cancer genes, mutations and targeted therapies • Potential for improving outcomes and addressing inequalities from lung cancer in New Zealand • Need to understand lung cancer at a molecular level, and the potential of genetically-directed targeted therapies, in the local context Gene Mutation Targeted therapy EGFR Substitutions Indels Gefitnib, Erlotinib, Afatinib ALK Fusions Crizotinib, Ceritinib, Alectinib ROS-1 Fusions Crizotinib RET Fusions Vandetinib MET Amplification Crizotinib ERBB2 Indels Lapadinib BRAF Substitutions Dabrafenib
15. Acknowledgements • Patients and their families • Auckland UniServices Sequenom Facility – Phillip Shepherd • Lung cancer EGFR testing investigators – Don Love (LabPLUS) – Mark Elwood (UOA) – George Laking, Chris Lewis, Nicki Kingston (ADHB) • Auckland UniServices • Study Coordinators – Prashannata Khwaounjoo, Luisa Bituin • Health Innovation Partnership • Health Research Council