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/NEJMoa 1507643

Motzer et al; NEJM 373: 1803 -13, 2015

Garon et al

Treatment one patient proxy 1. 000 NOK 1/10 patients benefit; cost 10. 000 NOK Machine proxy 7. 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) non-MSI CRC MSI

Colon-kanser: Pembrolizumab; MSI versus non-MSI Le et al: NEJM 372: 25092520, 2015

«Dominant» technology Illumina Solexa technology: Two instruments: Hi. Seq Mi. Seq (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 unpublished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/nature 12477

Validated mutational signatures found in human cancer. Age Lung, Head/Neck BRCA 1/2 mut Melanoma Mismatch Rep LB Alexandrov et al. Nature 000, 1 -7 (2013) doi: 10. 1038/nature 12477

Nik-Zainal S. et al; Nature doi: 10. 1038/nature 17676 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

SAFIR 01/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 Alpha. Med 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 Alpha. Med Press

Bolero-1; Trastuzumab + Paclitaxel + / Everolimus 10 mg / 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 5 FU n = 90 Epirubicin Paclitaxel 2 3 Docetaxel n = 35 n = 228 Sanger ! 4 n = 80 NCGC 24

Relationship TP 53 mutations and Chemoresistance PR/SD TP 53 WT TP 53 MUTATED L 2/L 3 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

TP 53 WT TP 53 MUTATED PR/SD PD 67 14 4 5 1. P 53 a “random correlate” (p = 0. 008) 2. P 53 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 p 53 -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 2003 Knappskog S………. Lønning PE: Mol Oncol 9, 1553– 1564, 2015, 27

«Serendipity» • Over 6 months; 2 patients <30 years of age with germline TP 53 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

P 53 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 TP 53 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 4 cm; p. CR, complete MRI regression liver met • Pat 2; 2 weeks after implementing therapy; partiell response (RECIST) criteria of 7 X 7 cm tumour

Potential explanations many; may be due to chromosomal catastrophy (chromotripsis) known to exist with germline TP 53 mutations other tumours. Rausch T. et al; Cell 148: 59 -71, 2012

Notably, germline TP 53 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? Ø We dont know Ø May be limited to these two patients Ø May be limited to patients with certain germline TP 53 mutations Ø May be limited to patients with TP 53 mutations in general Ø May apply to many breast cancer patients with somatic TP 53 mutations (30% of all BC patients)? Ø May apply to patients with somatic TP 53 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? Ø Personal opinion; I am worried Ø 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) Ø An urgent need to educate clinicians Ø 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) Ø Need the integrated Oncology Unit