claire falandry, md, phd geriatrics unit, lyon sud ...preliminary data of fag3 study: telommgere...
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Telomere and aging
Claire FALANDRY, MD, PhDGeriatrics Unit, Lyon Sud Hospital, France
Lyon University, France
Conflict of interests
• None to declare
The telomere connection
Homologous recombinationNon Homologous End Joining
Replication fork stalling
High sensitivity to oxydative stress
End-replicationproblem
• 1938-9 : Muller -McClintock : telomere « telos » « meros »• 1961 : Hayflick Hypothesis (Mitotic clock)• 1973 : Olovnikov – A theory of marginotomy – the end-replication
p
y f m g my pproblem
• 1997 : Telomerase gene discovery• 1999 : Terc null mice display a premature aging phenotype p y p g g p yp• 2009 : Nobel prize pour E. Blackburn, C. Greider et J. Scoztack• 2011 : « telomere »: 13182 PubMed references
Telomerase activationALT telomere lengtheningChromosomal recombinations –telomere healing
SenescenceTissue renewal lossPro-inflammatory secretory phenotypePro-tumorogenic potential
Measuring telomere health ?
DNA damage response Senescence
60
DNA damage response signaling
- loss of telomerase activity ?- Higher turn over ?- Inflammaging ? - Oxydative stress ?Oxydative stress ?
PBMC length
• Mortality : controversial data:Cawthon RM & al: Association between telomere length in blood and mortality in people – Cawthon RM & al: Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003;361:393-5
– Fitzpatrick AL, Kronmal RA, Kimura M, Gardner JP, Psaty BM, Jenny NS, Tracy RP, Hardikar S, Aviv A: Leukocyte telomere length and mortality in the cardiovascular health study. J Gerontol A Biol Sci Med Sci 2011;66:421-9.
– Martin-Ruiz C & al: Assessment of a large panel of candidate biomarkers of ageing in the newcastle 85+ study. Mech Ageing Dev 2011;132:496-502.
– Eisenberg DT & al: Substantial variation in qpcr measured mean blood telomere lengths in young men from eleven european countries. Am J Hum Biol 2011;23:228-31.
– Willeit P & al: Telomere length and risk of incident cancer and cancer mortality Jama Willeit P & al: Telomere length and risk of incident cancer and cancer mortality. Jama 2010;304:69-75.
• Degenerative diseases :– Brouilette SW & al: Telomere length, risk of coronary heart disease, and statin treatment
in the West of Scotland primary prevention study: a nested case-control study. Lancet f p m y p y y2007;369:107–114
– van der Harst P & al: Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol 2007;49:1459–1464
– van der Harst P & al: Possible association between telomere length and renal dysfunction in patients with chronic heart failure Am J Cardiol 2008;102:207–210patients with chronic heart failure. Am J Cardiol 2008;102:207–210
Telomerase activity
• Epel ES & al: Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A 2004;101:17312-5.
• Atzmon G & al: Evolution in health and medicine sackler colloquium: Genetic variation in human telomerase is associated with telomere length in ashkenazi centenarians. Proc Natl Acad Sci U S A 2010;1:1710-7.
• Ornish D & al: Increased telomerase activity and comprehensive • Ornish D & al: Increased telomerase activity and comprehensive lifestyle changes: A pilot study. Lancet Oncol 2008;9:1048-57.
Telomere-dysfunction Induced foci (TIFs)( )
• Measuring directly DNA damage response
Augereau et al, Blood 2011From Gilson et al, Nat Rev Mol Cell Biol 2007
DNA-damage biomarkers
• Proteins induced by telomere dysfunction and DNA damage y yrepresent biomarkers of human aging and disease
Jiang et al PNAs 2008Jiang et al, PNAs 2008
Any clinical relevance of telomere analysis in oncogeriatrics ?analysis in oncogeriatrics ?
Metastatic
Feasibility
T tm t
ToxicitiesBenefit/
risk ratio
Treatment decision Expected
survival out of cancer
Adjuvant
Short
Long
f
term Toxicities
term Toxicities
GINECO’s experience
• 1999-2003 (FAG1) : CC treatment feasibility– 73 patients - Feasibility 72%
• 2004-2006 (FAG2): CP treatment feasibility2004 2006 (FAG2): CP treatment feasibility– 82 Patients - Feasibility 68%
• Multivariate analysis: negative impact of:– Age– Age– Depression and emotional disorders– Paclitaxel-based treatment
Stage (IV vs III)– Stage (IV vs III)• 2007-2010 (FAG3): C – Impact of emotional disorders
– Feasibility 74%
Working hypothesis
Other vulnerability
Old ageDepressionEmotional
factors ?
↓ telomere length ↓ telomerase
disorders
↓ telomere length ( = telomere attrition)
↓ telomeraseactivity
?
FAG 1 et FAG 2
Lymphocyte dysfunction
↓ Survival↑ Toxicities
Lymphopenia
Preliminary data of FAG3 study:telomere lengthm g
111 ti ts 111 bl d s li s
ALL (n=109)
- 111 patients, 111 blood samplings
7200
7700
8200ALL (n 109)
Short (n=36)
Linear
y = -25,934x + 8082,3R2 = 0,0326
5700
6200
6700
4700
5200
5700
420068 73 78 83 88 93
Short telomere are associated with a decreased feasibility of treatmenty
F ibilit f 6 C b l ti
60%70%80%90%
100%
p=0,0419
Feasibility of 6 Carboplatin coursesPts characteristics
Total (%) 111 (100)
Age (years)
Median 78
10%20%30%40%50%60%Median 78
≥ 80 45 (41)
Extremes 70-93
Performance status0%
LT ST
60%
p=0 0713Non hematological toxicities
0-1 63 (57)
2-3 48 (43)
≥ 1 dependance ADL 61 (55)
≥ 1 dependance on IADL 93 (75)
20%
30%
40%
50%p=0,0713≥ 1 dependance on IADL 93 (75)
Emotional disorders
Screening 20 (18)
HADS ≥ 15 41 (37)
0%
10%
LT ST
≥ 4 co-medications 76 (69)
And have a nearly significant impacton survival
1.0 ST5800=0
ST5800=1Long telomeres
Short telomeres.6
0.8 Median OS 13,5 vs 19,2mths
p=0,15
Sur
viva
l
0.4
00.
00.
2
• Multivariate analysis :– Stage (IV vs III) HR=2 53 (p=0 0004)
Time
0 10 20 30 40
Stage (IV vs III) HR 2,53 (p 0,0004)– Short telomeres HR=1,53 (p=0,09)
Towards a future challenge
Observational study of every elderly patient with
NOFIT patient: on going trialsevery elderly patient with
AOC assesses the pre-inclusion criteria
FIT patient: on-going trials
Standard Carboplatin AUC5 +
at least one “factor of vulnerability
Lymphopenia
YESVULNERABLE pts Single agent Carboplatin AUC 5R
pPaclitaxel 175mg/m² J1=J21, 6 cycles
-Lymphopenia-Albuminemia < 35g/l-≥ 1 ADL- IADL ≤ 27- emotional disorders
N = 240
Single agent Carboplatin AUC 5 J1=J21, 6 cycles
R
Weekly Carboplatin AUC2 + Paclitaxel 60mg/m² d1 d8 d15Biomarkers Paclitaxel 60mg/m² d1, d8, d15, J1=J28, 6 cycles
Biomarkers of aging