Short telomeres (ST) correlate with Background vulnerability, - PowerPoint PPT Presentation

Outline Short telomeres (ST) correlate with Background vulnerability, toxicity and early death in elderly AOC patients receiving carboplatin: a multicenter GINECO study trial. Methods Photo CHLS Results Falandry C., Horard B., Alexandre J., Deplanque D., Cojocarasu O., Salvat J., Legouffe E., Cretin J., Meunier J., Maraval-Gaget R., Micheau-Bonnier D., Conclusions Gilson E., Freyer G.

Outline The telomere connection Background t-loop D-loop circular DNA Strand invasion of 3’ overhang Methods Homologous recombination Non Homologous End Joining End-replication problem High sensitivity to Results Replication fork stalling oxydative stress Hayflick L. Exp Cell Res 1961;25:585-621. Conclusions Olovnikov AM. J Theor Biol 1973;41:181-90. Greider CW. Cell 1987;51:887-98. Rudolph KL. Cell 1999;96:701-12.

Outline Telomere and aging Background Telomerase activation Telomere length ALT telomere lengthening Cancer Chromosomal recombinations – telomere healing Methods Tissue renewal loss Senescence Pro-inflammatory secretory phenotype Pro-tumorogenic potential Age 60 Results - loss of telomerase activity ? - Higher turn over ? - Inflammaging ? - Oxydative stress ? Conclusions PRESENTED BY:

Outline Background Methods Results Conclusions Method

Outline Ovarian cancer in the elderly • Subgroup analyses: standards feasible in selected elderly Background patients : primary surgery, carboplatin-paclitaxel • GINECO experience: treatment completion rate  1999-2003: 72% for carboplatin-cyclophosphamide (n=83) Methods  2004-2006: 68% for carboplatin-paclitaxel (n=75) Multivariate analysis: negative impact of • Age • Stage (IV vs III) Results • Paclitaxel-based treatment • Depression and emotional disorders • Lymphopenia Conclusions Freyer G. Ann Oncol 2005;16:1795-800. Trédan O. Ann Oncol 2007;18:256-62

Outline The telomeric working hypothesis Background Depression Old age Emotional disorders Methods ￬ telomere length Elderly ( = telomere attrition) woman GINECO trials 1 & 2 Lymphocyte dysfunction Results ↓ Survival ? ↑ Toxicities Lymphopenia Conclusions Cawthon RM. Lancet 2003;361:393-5. Epel ES. Proc Natl Acad Sci U S A 2004;101:17312-5.

Outline Elderly woman GINECO trial 3 • 111 patients with stage III/IV ovarian cancer Background included from 08/2007 to 01/2010 treated with 6 cycles of carboplatin monotherapy (AUC5), +/- primary cytoreduction Methods • Primary endpoint: Impact of geriatric covariates on survival • Secondary endpoint: – Impact of telomere length on treatment completion Results rate (TCr), tolerance and overall survival. Standard Terminal Restriction Fragment analysis performed at inclusion, after 3 and 6 cycles Conclusions

Outline Patients characteristics Total (%) 111 (100) Background Age (years) Median 78 ≥ 80 45 (41) Extremes 70-93 Methods Performance status 0-1 63 (57) 2-3 48 (43) ≥ 1 dependence ADL 61 (55) ≥ 1 dependence on IADL Results 93 (75) Emotional disorders Screening 20 (18) HADS ≥ 15 41 (37) Conclusions ≥ 4 co-medications 76 (69)

Outline Development of a Geriatric Vulnerability Score (GVS) in multivariate analysis Background GVS =  vulnerability factors : => Vulnerable if GVS  3 Major : - score ADL < 6 - score IADL < 25 - albuminemia < 35g/L See poster 9079 by Freyer, G. et al.: Methods Minor : - Lymphopenia < 1G/L Patient and survivor care - score HADS > 14 Sat June 2: 8:00-12:00 OS (%) 0 100 GVS<3 GVS>3 Censored 5 Results 50 0 5 0 Conclusions 0 0 10 20 30 40 Time (months)

A weak correlation between Outline telomere length and age 111 patients sampled, 109/111 evaluable (duplicate analysis) • Background Telomere length 8500 8000 Methods 7500 7000 6500 6000 Results y = -26,462x + 8120,9 5500 R 2 = 0,0341 5000 4500 Conclusions 4000 Age 70 75 80 85 90 95

Patient telomere length and Outline treatment completion rate (TCr) • With a cut-off of 5770bp, TL discriminates 2 groups of Background patients with different TCr Treatment completion rate (TCr) Methods 100% 80% 80% 60% 40% 59% p=0.02 Results 20% 0% Long Telomere ST LT Short Conclusions length n = 75 n = 34

Severe toxicity increases Outline with telomere shortening Background Observed Risk: 95% short/long confidence P Methods telomere interval event group Serious Adverse Events 2.69 1.17-6.19 .019 Results Unplanned hospital admissions 2.14 0.92-4.95 .070 Grade > 3 non-hematological 2.04 0.88-4.71 .095 toxicities Conclusions

Vulnerability increases with Outline telomere shortening • No significant correlation with any of the GVS components Background • BUT a correlation between patient telomere length (Short vs Long) and vulnerability (GVS  3;  2 major criteria) Vulnerable pts OR = 2.17, p=0.06 Methods (GVS > 3; > 2 major C, %) 100% 80% 60% GVS =  vulnerability factors : Results 40% Major : - score ADL < 6 20% - score IADL < 25 0% - albuminemia < 35g/L Telomere Short Long Minor : - Lymphopenia < 1G/L Short Long Conclusions length - score HADS > 14 => Vulnerable if GVS  3

Outline Overall survival Stage III, telomere size ≥ 6000bp 1.0 IVvsIII=0, ST5999=0 Stage III, telomere size < 6000bp IVvsIII=0, ST5999=1 Stage IV, telomere size ≥ 6000bp IVvsIII=1, ST5999=0 Background IVvsIII=1, ST5999=1 Stage IV, telomere size < 6000bp 0.8 Overall survival 0.6 Survival 0.4 Methods 0.2 0.0 Results 0 10 20 30 40 Time (months) Time • Multivariate analysis : – Stage (IV vs III) HR=2,53 [1.54-4.27]; p=0,0003 Conclusions – Telomere < 6000bp HR=1,57 [0.98-2.51]; p=0,06

Outline Back to the telomeric working hypothesis • A partial overlap between TL and geriatric vulnerability Background factors Other vulnerability factors ? Depression Old age Methods Emotional disorders ↓ telomerase ￬ telomere length Elderly activity ( = telomere attrition) woman GINECO Results trials 1 & 2 ? Lymphocyte dysfunction ↓ Survival Conclusions ↑ Toxicities Lymphopenia

Outline Dealing with controversies Background Methods From Gilson and Geli, Nat Rev Mol Cell Biol 2007 • Measuring directly DNA damage response Results  In cell nuclei : TIFs (Telomere-dysfunction Induced Foci)  DNA-damage biomarkers Conclusions Jiang et al, Proc Natl Acad Sci U S A 2008;105:11299-304. Augereau et al, Blood 2011;118:1316-22.

Outline Take home messages Background Telomere length estimation  is feasible using standard procedure  Identifies a group of elderly patients with Short Telomeres who: Methods • Have a lower chance to complete their planned 6 chemotherapy courses • Have a higher risk of chemotherapy toxicity (number of serious adverse events, unplanned hospital admissions and severe non- haematological grade 3-4 toxicity) Results • Partially overlaps with patient subsets according to the vulnerability score GVS • Might be a risk factor for premature death independent from FIGO Conclusions stage

Acknowledgements • The patients participating in the trial • The co-investigators Jérôme Alexandre Salima Kalla Eric Pujade-Lauraine Marie-Noëlle Certain Marie-Christine Kaminsky Isabelle Ray-coquard Laure Chauvenet Rémy Largillier Frédérique Rousseau Martin Combe Annick Le Rol Jacques Salvat Jacques Cretin Daniela Lebrun-Jezekova Francesco Savinelli Hervé Curé Eric Legouffe Emmanuel Sevin Philippe Deguiral Catherine Ligeza-Poisson Laëtitia Stefani Gaël Deplanque Elisabeth Luporsi Jean-Marie Tigot Michel Fabbro Jérôme Meunier Olivier Tredan Olivier Gisserot Frank Priou Béatrice Weber Jean-Paul Guastalla Jocelyne Provençal Gabriel Yazbek • The GINECO office • Hospices civils de Lyon study team Raymonde Maraval Gaget Douglas Micheau-Bonnier • The French Ministry of Health Nicolas Gane Bénédicte Votan • Fondation de France