Grazie per aver scelto di utilizzare a
scopo didattico questo materiale
delle Guidelines 2011 libra.
Le ricordiamo che questo materiale è
di proprietà dell’autore e fornito
come supporto didattico per uso
personale.
Importance of phenotyping
(and genotyping) breast and
lung cancer
Modena, march 1st 2011
PierFranco Conte
Department of Oncology, Hematology and Respiratory
Diseases - University of Modena and Reggio Emilia
• Dec 1971, National Cancer Act by Richard Nixon
Conquest of Cancer is a National Crusade
One tumor is smarter than 100 brilliant cancer scientists
O. Brawley, American Cancer Society
We fought cancer ....and cancer won
(Newsweek, september 6, 2008)
• 1971 to 2008: 200 billion $ (US budget for cancer research)
• 1971 to 2005: overall cancer mortality from has fallen 7.5%
• 1971 to 2005: mortality for cardiovascular disease has fallen 70%
Molecular characterization of human tumors:
the dawn of a new beginning
• A successful story from the past….
• Lessons from a successful story….
• From size to biology:
- achievements
- opportunities
- challenges
Adjuvant Rx of EBC - Decision-making Algorithm
Prognostic
factors
Predictive
Factors
Risk
assessment
Proportional
benefit
Absolute
benefit
Toxicities
(short & long term)
Patient
Characteristics
and preference
Adjuvant medical treatments
Annual cancer mortality / 100,000 women, ages
35–69*
Cancer Mortality in women - Italy
ITALY
Breast
70
1951–2001
Stomach
60
Uterus
50
Lung
Screening
Adj HT
70
60
Adj ChemoRx
50
40
40
30
30
20
20
10
10
0
0
1950
1960
*Mean of annual rates in the
component 6-year age groups
1970
1980
1990
2000
2010
Source: WHO mortality and
UN population estimates
Molecular characterization of human tumors:
the dawn of a new beginning
• A successful story from the past….
• Lessons from a successful story….
• From size to biology:
- achievements
- opportunities
- challenges
A nice story….
M.R. 62y old - May 2005
Left radical mastectomy + ALND
ILC, pT2 (2.3cm), N2 (14/44 N+),
ER 90%, PgR 80%,
HER2 1+, Ki 67 10%
May-September 2005
dd chemoRx AC x 4 -> Paclitaxel x 4
RT on chest wall and axylla
anastrozole for 5y
A sad story….
C.B. 44 y old - April 2009
SE quadrantectomy + SN
IDC, pT1c (1.7cm), N0,
ER <1%, PgR 0%,
HER2 0, Ki 67 60%
May-September 2009
ChemoRx TAC x 6
RT on the breast
December 2009: lung mets
December 2010: NED
This tumor is big and lazy
This tumor is small and busy
Molecular characterization of human tumors:
the dawn of a new beginning
• A successful story from the past….
• Lessons from a successful story:
lesson # 1: biology can be more important than size
• From size to biology:
- achievements
- opportunities
- challenges
Number of patients with EBC needed to treat with
Adjuvant Therapy to prevent ONE recurrence
Comparison
Absolute Risk Reduction
%
NNT
11.8
8
Aromatase Inhibitors vs TAM*
3- 5.3
19 - 33
Aromatase Inhibitors vs Nil°
 16
6
Polychemo vs. Nil ( < 50)^
12.3
8
Polychemo vs. Nil ( 50+)^
4.2
23
Anthra vs CMF^
4.0
25
Taxanes vs. Anthra§
5
20
3rd gen taxane regimen vs Nil°
 23
4
ChemoRx + Trastuzumab vs ChemoRx
6.3 - 18
6 - 15
ChemoRx + Trastuzumab vs Nil+
13 - 35
2-3
Tamoxifen vs. Nil ^
Molecular characterization of human tumors:
the dawn of a new beginning
• A successful story from the past….
• Lessons from a successful story:
lesson # 1: biology can be more important than size
lesson # 2: we treat many patients to benefit one
• From size to biology:
- achievements
- opportunities
- challenges
60 yrs, pT1cN+, ER-, HER2+
non cancer death (4%)
20%
cured by locoregional
therapy (43%)
relapses
12%
CMF
Anthracyclines
6%
IIIrd generation regimens
Trastuzumab
6%
9%
ChemoRx + Trastuzumab is recommended based on level 1 scientific evidence;
however, this treatment is applied to 4% of the patients who will die for other reasons,
43% who will never relapse, 9% cured by CMF, 6% cured by anthra, 6% cured by taxanes.
Eventually, 12% of the patients will actually benefit from trastuzumab
Molecular characterization of human tumors:
the dawn of a new beginning
• A successful story from the past….
• Lessons from a successful story:
lesson # 1: biology can be more important than size
lesson # 2: many patients are treated to benefit one
lesson # 3: the “best” Rx is applied to all the patients as we are unable
to predict individual treatment sensitivity
• From size to biology:
- achievements
- opportunities
- challenges
Molecular characterization of human tumors:
the dawn of the new beginning
• A successful story from the past….
• Lessons from a successful story….
• From size to biology:
- achievements
- opportunities
- challenges
Hallmarks of Malignancy
Independence
from growth
signaling
Insensitivity to
growth inhibitory
signals
No limit on
proliferation
Cancer
cell
Invasion
and
metastasis
Evasion of
apoptosis
Development
of angiogenic
ability
Hanahan D, et al. Cell. 2000;100:57-70.
HER2/neu in breast cancer
Shortened median survival
HER2 overexpressing 3 years
HER2 normal
6–7 years
Abnormal high
amplification
Slamon et al. Science 1987
Trastuzumab:
humanised anti-HER2 monoclonal antibody
• Targets HER2 oncoprotein
• High affinity (Kd=0.1nM)
and specificity
• 95% human, 5% murine
– decreased potential for
immunogenicity
– increased potential for
recruiting immune-effector
mechanisms
B31/N9831- Disease-Free Survival
87%
85%
75 %
67 %
AC T
AC TH
N
Events
1679 261
1672 134
HR=0.48,
2P=3x10-12
BAC EGFR mut+: Response to TKI
12-00
12-02
INTACT 1: Gefitinib in combination with chemotherapy
Proportion
event
free
Median survival, months
1-year survival rate, %
Log rank vs placebo
1.0
0.8
0.6
9.92
43
0.7759
(p=0.4377)
9.86
41
1.0290
(p=0.3034)
11.07
45
Gefitinib 500 mg/day
Gefitinib 250 mg/day
Placebo
WE DIDN’T KNOW ABOUT
EGFR MUTATION
0.4
0.2
0.0
At risk
0
4
1093
898
8
12
16
Survival time (months)
20
641
11
463
152
24
EGFR mutations in NSCLC
• EGFR mutations are overrepresented in responders to
EGFR inhibitors
• Mutations that confer
sensitivity to EGFR-TKIs include:
– exon 19 small
in-frame deletions (50%)
– exon 21 point mutations (40%)
e.g. 40% EGFR L858R
Extracellular
ligand-binding
domain
Deletions
(vIII) ~ 1%
TM
Exon 18
19
• Mutations known to cause
resistance to first-generation
EGFR-TKIs include:
– exon 20 in-frame insertions
– exon 20 point mutations (e.g.
T790M)
– Role of cMET amplification
Sharma et al. Nature Rev Cancer 2007;7;169
Ji et al. Proc Natl Acad Sci USA 2006;103;7817
Stephens et al. Nature 2004;431:525
20
21
22
23
24
Tyrosine
kinase
domain
K Kobayashi et al, P ASCO 2009
Activity of Crizotinib in EML-ALK4 Fusion
Non-Small Cell Lung Cancer
Maximum change in tumor size (%)
60
Progressive disease
Stable disease
40
Confirmed partial response
Confirmed complete response
20
0
–20
–30%
–40
–60
–80
–100
Bang et al ASCO 2010
Molecular characterization of human tumors:
opportunities and challenges
•
•
•
•
•
Accelerated clinical translation
Biological complexity
Cancers as rare diseases
High through-put technologies
Costs of cancer treatments
Rate of success in drug development
Cost of bringing a new
cancer drug to clinical
practice is >€1 Billion!
Likelihood of success
20
15
11%
10
5%
5
0
CNS
Arthritis
Cardiovascular
Oncology
Metabolic
Women’s
Infectious
Opthal- disease
health
diseases
mology
Urology
All
Kola Nat Rev Drug Discovery 2004
Accelerated Clinical Translation
BRAF-mutated melanoma
BRAF
mutations
identified
2002
Phase II
positive
(BRIM2)
Phase I
initiated
2004
2006
Synthesis
PLX4032
2009
2010
2011
Phase I
presented
at ASCO
Phase III
positive
(BRIM3)
Phase III
launched
Phase III
results
expected
EML-ALK4 lung cancer
EML-ALK4
translocation
identified
2007
2008
Phase I amended
2009
2010
Phase I
presented
at ASCO
2012
Different Models Emerge
• Tumors with real “oncogene addiction”[1]
–
–
–
–
–
–
–
HER2+ BC
EGFR-mutated NSCLC
EML-ALK4 NSCLC
GIST
CML
BRAF mut+ MM
HIF/VEGF RCC
• Tumors with a more complex genetic make-up
– Deciphering relative importance of one pathway vs others
– Importance of drug combinations
1. Weinstein IB. Science. 2002;297:63-64.
The Erb-B signalling network
Lung and Breast Cancer Diseases – 201…
Lung Cancers
Breast Cancers
PI3Kmut
10%
SCLC 15%
HER3+
SCC 30%
ER+
65-75%
ADENO 40%
LCC 15 %
Somatic Mutations in
Adenocarcinoma
Breast Cancer
K-ras
EGFR
B-raf
Her2
PIK3CA
ALK
MET
Other
EML-ALK4 3-5%
EGFR 10-15%
HER2+
15-20%
Triple
negative
15%
IGFR1+
p95
4-8%
P53mut
30-40%
FGFR1
Ampl 8%
PTENloss
30-50%
BRCAMut
8%
30
High throughput technologies
Shifting paradigms
Prognostic and predictive factors are identified at
molecular level
CHERLOB – Gene expression and pCR
pCR
32
The Challenge of Personalized Oncology
“If it were not for the
great variability among
individuals, medicine
might have well been a
science and not an art”
― Sir William Osler, 1892
Challenging the “classic” paradigms
• Reinforce the “no tumor no drug” policy (BioBanks)
• Establish a new Pharma-Academia partnership
• Allow for joint development of NMEs from different
Pharma companies
• Project Zero Delay: A Process for Accelerating the
Activation of Cancer Clinical Trials (R. Kurzrock,
JCO, e-pub august 3, 2009)
• Improve the scientific advice process with regulatory
authorities
• Implement and govern post-launch studies
an only answer….
The questhas
for personalized
cancer medicine..
The Right Dose of
The Right Drug for
The Right Indication for
The Right Patient at
The Right Time
molecular characterization of human
tumors