Transforming patient care through translational research in hormone receptor positive breast cancer

88 Pages·2017·5.82 MB·English

Transforming patient care
through translational research
in hormone receptor positive
breast cancer
Professor Aleix Prat Professor Erik Knudsen
Hospital Clinic of Barcelona University of Arizona Cancer Center
Barcelona, Spain Tucson, United States
170271
Disclaimer
“The statements, views and opinions contained in this symposium are
those of the authors and are not endorsed by, nor do they necessarily
reflect, the opinions of Pfizer.”

“This symposium contains information on investigational products in
development from a research perspective. The information aims to be
truthful, accurate, balanced, fair and not misleading. It is supported by
relevant scientific data and is non-promotional.”
Agenda
The many faces of CDK4/6 inhibition
Erik Knudsen
10 minute introduction to the keynote presentation
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat
40 minute keynote presentation with audience questions
Audience questions and discussion
Closing remarks

Question cards are provided or please raise your hand
Remember to complete your evaluation form
The many faces of CDK4/6
inhibition
Professor Erik Knudsen
University of Arizona Cancer Center
Tucson, United States
170271
Disclosures
Applicability Company
Pfizer, Eli Lilly,
(1) Advisory role Yes
HTG Diagnostics, Novartis
(2) Stock ownership/profit None
(3) Patent royalties/licensing fees None
(4) Lecture/speaker engagement fees Yes Pfizer, Eli Lilly
(5) Manuscript fees None
(6) Scholarship fund None
(7) Other remuneration None
The many faces of CDK4/6 inhibition
Erik Knudsen
University of Arizona Cancer Center
Tucson, United States
• Historical perspective surrounding CDK4/6 inhibition

• Translation to the clinic: Targeting CDK4/6 in HR+/HER2- breast cancer

• Key questions related to CDK4/6 inhibition in breast cancer
– Biomarkers determinants of durable response?
– Nature of progressive disease?
– Combination approaches to prevent progression?
– Additional indications in breast cancer?
Defining CDK in control of proliferation
1902 1970-1990 2001
Cell Division Cell Cycle CDK/Cyclins
Experiments
1900 1970 1990 2000
Genetic control of cell- Cdc2+ encodes a protein Purified maturation CDK/Cyclins
division cycle in yeast, kinase regulated by promoting factor contains
Drive the cell cycle
Hartwell, 1970 PNAS. phosphorylation, cdc2+, Gautier, 1988 Cell.
Simanis , 1986 Cell.
Complementation used
to clone human cdc2,
Lee, 1987 Cell.
A cytoplasmic factor Cyclin in sea urchin eggs is A family of cyclin Role of CDC28 and
promoting oocyte maturation, destroyed at cleavage homologs that control G1 cyclins during mitosis,
Wasserman, 1976 Science. division, Evans, 1983 Cell. phase Hadwiger, 1989 Surana, 1991 Cell.
PNAS.
An essential G1 function
for cyclin-like proteins,
Richardson, 1989 Cell .
Characterisation of CDK4/6: Kinases, cyclins, inhibitors
1991 1992-1994 1993-1994
Cloning of Discovery of CDK4/6 Cellular CDK4/6
Cyclin D1 Inhibitors
CycD p16INK4A
cBioPort al fo r Canc er Genomic s 4 /20/17, 12:46 PM
Cyclin D1 CDK4 or CDK6
Data Sets (data_sets.jsp) Web API (web_api.jsp) R/MATLAB (cgds_r.jsp) Tutorials (tutorial.jsp) FAQ (faq.jsp) News (news.jsp) Tools (tools.jsp) About (about_us.jsp)
(index.do)
Visualize Your Data (visualize_your_data.jsp)
1991 1992 1993 1994
Modify Query
OverviewCKM/dutatiopnsi Expression Dow1nlaoa/ddapBoio kmark CK/D1a CK/D1a/dapi
Human D-type cyclCinr oclsosn-ecda nceIdr eanlteifricaattiioonn saunmd m ary for CCExNpDre1s,s CioDnK a4n,d C DKN2 A ( 1 5 0 sCtuDdKi4e/s6 /d e3f ignen ae csl)ass oPf D F SVG Dysregulation of
Y-Axis vbalyu ec:o mAltperlaetmione fnretqauteinocyn, XionMgin, . % palrteorpede sratmiepsle os:f an atypic3a6l % aMminp. #li ftioctalt sioamnp olesf: cyclin gen0es CDK S bhionwd ailntegra tion D ty pCeysclins , Cyclin D, CDK4/6, p16ink4a
1991 Cell. catalytic subunit (p34PSK- in human breast cancer, Bate Sso,r t1 a9lp9h4a bOetniccalolygene.
8C0%SF-inducible G1 J
C3e/llc.d k4), Matsushime, 1992 Buckley, 1993 Oncogene. in cancer
cyclin, Matsushime,
710%991 Cell.
60%
50%
CycD Deletions of CDK4 inhibitor
40% gene in multiple human
CDK4 or CDK6 cancers, Nobori, 1994
30% Nature.
A new regulatory motif
2A0% novel cyclin encoded by a causing specific inhibition
bc1-linked candidate oncogene, of cyclin D/CDK4, Serrano,
1M0%otokura, Nature 1991. 1993 Nature.
0%
Cancer type
Mutation data + + + + + + + + + + + + + + + + + - + + + + + +
CNA data + + + + + + + + + + + + + - + + + + + + + + + +
Mutation Deletion Amplification Multiple alterations
* 126 studies (% altered samples < 36%) out of 150 have been filtered out.
cBioPortal (http://cbioportal.or g) Version 1.5.1 | MSKCC (http://www.mskcc.org/mskcc/html/44.cfm) | TCGA (http://cancergenome.nih.gov/)
Questions and feedback:
The RB-pathway and functional interactions
1992 1996-2001
1995
CDK4/6 and Functions of
Mutual Exclusivity
RB Phosphorylation the RB-Pathway
in Cancer
1992 1994 1996 1998 2000
Retinoblastoma-protein-
Direct binding of Phosphorylation inactivates RB: dependent cell-cycle Canonical CDK4/6-pathway
cyclin D to the Livingston, Harlow, Weinberg, inhibition by the tumor
retinoblastoma Mittnacht, Knudsen, Bartek, suppressor p16, Lukas, Mitogens
p
prRobd puhcto s(pRhbo)r yalnadti on Rubin, etc. 1995 Nature. p16INK4A Oncogenes
by CDK4, Kato, 1993 CycD
Genes Dev. CDK4 or CDK6
Co-repressors
Mutual exclusivity in
cancers, Bartek, 1995 RB
International Journal of
Cancer. E2F RB
Functional interactions P
of the retinoblastoma
p
cyrcoltienisn, Ewwitehn D, 1-t9y9p3e EN2eFv ins sa, Kcraietilcina,l Dtaeragne,t L oivfi nRgBs:t on, Rthoelera opfe cuytcicli nta Drg1e at,s E2F Proliferation
Cell. RB� Lukas, Farnham, Kouzarides, etc. Yu, 2001 Nature.
CDK-inhibitors: Start to present
1992 2004 2005-2014 2015
First CDK First Specific CDK4/6 Inhibitor Effectiveness Shown
Inhibitors CDK4/6 Inhibitor Development in Breast Cancer
2002 2010 Present
Growth inhibition with Specific inhibition of cyclin- Treatment of growing CDK4/6 Inhibitors
reversible cell cycle dependent kinase 4/6 by PD teratoma syndrome.
arrest of carcinoma cells 0332991. Fry, 2004 Mol Vaughn, 2009 N Engl J Improve PFS in
by flavone L86-8275. Cancer Ther. Med.
Kaur, 1992 J Natl Cancer Phase I study of PD 0332991, a HR+/HER2- breast
Inst. cyclin-dependent kinase inhibitor.
cancer
Schwartz, 2011 Br J Cancer.

Phase I, dose-escalation trial of the oral
cyclin-dependent kinase 4/6 inhibitor PD
0332991. Flaherty, 2012 Clin Cancer Res.

PALOMA 2
PALOMA 3

MONALEESA 2

Turner, 2015 N Engl J Med.