Transcript Do we see the practical consequences of clinical

Do we see the practical consequences of
clinical implementation?
Per Eystein Lønning
Section of Oncology, Institute of Medicine University of Bergen
Department of Oncology, Haukeland University Hospital
«Hottest Controversy» i 2015
Change in Tumor Burden, Durability of Tumor
Regressions, and Progression-free Survival.
Postow MA et al. N Engl J Med 2015;372:2006-2017.
Lung cancer and Nivolumab; Overall Survival, Duration of
Response, and Progression-free Survival.
Borghaei H et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1507643
Motzer et al; NEJM 373: 1803-13, 2015
Garon et al
Treatment one patient proxy 1.000.000 NOK
1/10 patients benefit; cost 10.000.000 NOK
Machine proxy 7.000.000
400 gene list:
3.000
Exome (coding) 10.000
Full genome
20.000
Bioinformatics and additional costs
The most expensive therapy = «the one that does not work»
Exome sequencing of different cancer forms
Alexandrov et al. Nature (2013)
Exome sequencing of different cancer forms
Alexandrov et al. Nature (2013)
CRC
non-MSI
MSI
Colon-kanser: Pembrolizumab; MSI versus non-MSI
Le et al: NEJM 372: 25092520, 2015
«Dominant» technology
Illumina Solexa technology:
Two instruments:
HiSeq
MiSeq
(Mass production of seq. data)
(«Personal» sequencer)
Exom or Genome Seq
«Gene list (Cancer 3-400) Seq
«Bør vi ikke klare oss med en enkel genliste med «nøkkelmutasjonene?»
Nature 2009: 462; 1005 -
Identification of
hypermutated regions
of tumour genomes
Knappskog et al. unpublished
Validated mutational signatures found in human cancer.
LB Alexandrov et al. Nature 000, 1-7 (2013) doi:10.1038/nature12477
Validated mutational signatures found in human cancer.
Age
Lung,
Head/Neck
BRCA1/2 mut
Melanoma
Mismatch Rep
LB Alexandrov et al. Nature 000, 1-7 (2013) doi:10.1038/nature12477
Nik-Zainal S. et al; Nature doi:10.1038/nature17676
Epigenetics?
Hvor skal vi angripe…??
Yates et al; Nature Med 21: 751-9, 2015
Tumours in dynamic evolution
This relates to epigenetic events as well
SAFIR01/UNICANCER
SHIVA
.
13/423 responders
André F. et al: Lancet
Oncol 15: 267–274, 2014
Le Tourneau C et al. Lancet Oncol 16; 1324–
1334, 2015
l
brystkreft
Baselga J The Oncologist 2011;16:12-19
©2011 by AlphaMed Press
Trastuzumab
Behandling av brystkreft med trastuzumab (fra 2006); ytterligere 40% reduksjon I risiko
for tilbakefall I tillegg til både cellegift og hormonbehandling.
Realitet;
Tilbakefall
reduseres
med 40%
Død:
= resistens
mot terapi
Perez E A et al. JCO 2011;29:3366-3373
©2011 by American Society of Clinical Oncology
Everolimus
Trastuzumab
Baselga J The Oncologist 2011;16:12-19
©2011 by AlphaMed Press
Bolero-1;
Trastuzumab +
Paclitaxel + / Everolimus 10mg /
Placebo
Here; all patients
Lancet Oncol 16:
816-29, 2015
Studies of chemoresistance in «in-house» biobanks
Unique biobanks - Monotherapy
Pretreatment
Biopsi (snap-frozen!)
Tumourbanking!
Doxorubicin
Mitomycin
1
5FU
n = 90
Epirubicin
Paclitaxel
Docetaxel
2
3
n = 35
n = 228
Sanger
!
4
n = 80
NCGC
24
Relationship TP53 mutations and
Chemoresistance
PR/SD
TP53 WT
TP53 MUTATED L2/L3
67
14
PD
4
5
P = 0.008
T. Aas et al: Nature Med 2:1996;811-4
S. Geisler et al: Cancer Research 61: 2001; 2505-2512
TP53 WT
TP53 MUTATED
PR/SD
PD
67
14
4
5
1. P53 a “random correlate” (p = 0.008)
2. P53 one mechanisms, totally different mechanisms
involved in other tumors
3. Systematic analysis looking for “the logics”
Nature Med 2:1996;811-4; Cancer Research 61: 2001; 2505-2512
Main hypothesis: Chemoresistance toward anthracyclines is caused by defects
in central pathways involved in apoptosis, growth arrest and DNA repair, e.g.
«the p53-pathway» and the «retinoblastoma-way» in concert
Staalesen et al 2006
Knappskog et al 2007
Knappskog et al 2012
Chrisanthar et al 2008
Knappskog et al 2011
Knappskog et al 2012
Berge et al 2010
Berge et al 2011
Geisler et al 2001
Geisler et al 2003
Knappskog S……….Lønning PE: Mol Oncol 9, 1553–1564, 2015,
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«Serendipity»
• Over 6 months; 2 patients <30 years of age with germline
TP53 mutations
• Locally advanced breast cancers; first one with liver mets in
concert
• Both failed standard regimens including epirubicin and
taxotere
Olivier M et al; Cold Spring Harbour Perspec 2010;
Petitjean et al; Hum Mut 28:622-9, 2007
Toledo F and Wahl GM; Nature Rev Cancer 6:909-923, 2006
P53 required;
Gives growth arrest
And interacts with
DNA repair in manners
Incompletely
understood
Martin et al: Curr Opinions Genetics & Dev 18: 80-86, 2008
«Synthetic
Lethality»
Anders et al; Clin Cancer Res 16:
4702-10, 2010
Mechanism of action:
PARP-inhibitors
«Serendipity»
• Over 6 months; 2 patients <30 years of age with germline
TP53 mutations
• Locally advanced breast cancers; first one with liver mets on
concert
• Both failed standard regimens including epirubicin and
taxotere
• Experimental new approach based on «enhancing the defect»
• Pat 1; prim tumour > 6 X 6 cm , axillary mets 4 X 4cm; pCR,
complete MRI regression liver met
• Pat 2; 2 weeks after implementing therapy; partiell response
(RECIST) criteria of 7 X 7cm tumour
Potential explanations many; may be due to chromosomal catastrophy
(chromotripsis) known to exist with germline TP53 mutations other tumours.
Rausch T. et al; Cell 148: 59-71, 2012
Notably, germline TP53 mutations are «first event»; may cause a
different biology as compared to later somatic events.
Yates et al; Nature Med 21: 751-9, 2015
The explanation to these responses?
 We dont know
 May be limited to these two patients
 May be limited to patients with certain germline
TP53 mutations
 May be limited to patients with TP53 mutations
in general
 May apply to many breast cancer patients with
somatic TP53 mutations (30% of all BC patients)?
 May apply to patients with somatic TP53
mutations across different tumour forms?
Message
• Take the lesson from biology and explore it in
the «Translational Unit»
Tumour sample
Platforms
Tumour sample
Platforms
The Translational
Oncology Unit
Breast Ca
Colorectal Ca
Melanoma
Lung Ca
Do we see the practical implications of clinical
implementation?
 Personal opinion; I am worried
 To generate large datasets; key as «backgrounds to our biological
understanding», but naivistic to believe «genomic mass-screening»
and data banking may solve the problems of therapy resistance in
cancer and personalized therapy in cancer; needs the integrated
work across clinical well designed approaches, multiple
methodological approaches (genomics, epigenomics, proteomics)
 An urgent need to educate clinicians
 Investing in biomarkers and genomics; increase costs in the short
run, but become highly cost-effective in the long run (the most
expensive treatment = one that doesn’t work)
 Need the integrated Oncology Unit