Transcript Diapositiva 1

AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA
Evoluzione del trattamento del tumore
mammario: dalla ricerca alla clinica
Nonantola, 18 Novembre, 2011
PierFranco Conte
Dipartimento di Oncologia, Ematologia e Malattie dell’ Apparato Respiratorio
Università di Modena e Reggio Emilia
The Conquest of Breast Cancer:
a few more steps ahead….
– Where we are now
– How we got here
– Standard of Care for EBC
– Remaining questions
– The Challenges ahead
TRENDS IN MORTALITY FROM BREAST CANCER IN SELECTED
COUNTRIES: AGE-STANDARDISED RATE (W) PER 100,000
http://globocan.iarc.fr/factsheets/cancers/breast.asp
The Conquest of Breast Cancer:
a few more steps ahead….
– Where we are now
– How we got here
– Standard of Care for EBC
– Remaining questions
– The Challenges ahead
Breast cancer mortality in neighbouring European countries with different
levels of screening but similar access to treatment: trend analysis of WHO
mortality database
• Breast cancer mortality in three pairs of countries (North Ireland vs Rep. of
Ireland, the Netherlands vs Belgium and Sweden vs Norway) from 1989 to 2006
• Countries in each pair had similar healthcare services, but differing
implementation of mammography screening, with a gap of about 10-15 years
• No correlation between the introduction of screeening and reduction in breast
cancer mortality
• The steepest fall in mortality observed was among the women under 50 who
had not been invited for screening
• Screening did not play a direct role in the reductions of breast cancer mortality
• Improvements in adjuvant treatment may be a more plausible explanation.
P Autier et al; BMJ 2011
Annual cancer mortality / 100,000
women, ages 35–69*
Cancer Mortality in women - Italy
70
60
50
ITALY
Breast
1951–2001
Stomach
Uterus
Adj HT
Screening
AdjChemoRx
70
60
50
Lung
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
EBCTCG META-ANALYSIS
Adjuvant chemotherapy versus no treatment
< 50 N-
< 50 N+
5-y absolute DFS gain with
polychemotherapy:
-
14.6% in N+ pt under 50 y
9.9% in N- pt under 50 y
5.9% in N+ pt aged 50-69 y
5.3% in N- pt aged 50-69 y
50-69 N-
50-69 N+
Lancet 365: 1687, 2005
EBCTCG META-ANALYSIS
ER + EBC: Tamoxifen for 5y
At 15 yrs, Tamoxifen increases DFS by 13.2% and OS by 9.2%
EBCCTG, Lancet 2011
The Conquest of Breast Cancer:
a few more steps ahead….
– Where we are now
– How we got here
– Standard of Care for EBC
– Remaining questions
– The Challenges ahead
Adjuvant Treatment of EBC:
Refinement of Standard of Care
1990 on: increasing use of anthracyclines
2000 on: increasing use of taxanes
increasing use of aromatase inhibitors
2005 on: increasing use of trastuzumab
Anthra-based ChemoRx vs no ChemoRx
10 y Breast Cancer Mortality
Patients
#
N+
10y gain
RR
p
all
8575
82%
6.5
0.79
<0.00001
< 55 y
2808
70%
5.6
0.81
0.004
55-69 y
5373
88%
6.5
0.79
<0.00001
ER-poor
2076
73%
7.1
0.80
0.003
ER +
5433
86%
6.4
0.77
<0.00001
ER+& <55 y
1582
77%
5.6
0.83
0.05
ER+ & 55-69 y
3578
90%
6.0
0.78
0.0002
EBCTCG 2011 in press
EBCTCG Meta-analysis
Anthra + Taxane vs non Taxane ChemoRx
(33,084 pts; 82% N+)
5y
RR
gain
p
recurrence
0.86
2.9
<0.00001
BC mortality
0.88
1.4
0.0001
EBCTCG 2011 in press
Adjuvant Chemotherapy for EBC
• Regimens of proven efficacy:
– 1st generation: CMF, AC
– 2nd generation: FAC, FEC, DC, AC/P
– 3rd generation: FEC/D, AC/wP, ddAC/P,TAC
• Evidence and Recommendations:
– Anthracycline/taxane based regimens provide meaningful DFS
and OS benefit
– Sequential anthracycline/taxane are NOT inferior and more
tolerable than combined regimens
– The most effective schedules are 3-weekly docetaxel and weekly
paclitaxel
– TC x 4 is superior to AC x 4 (this is NOT one of the most active
regimen and should be considered only when anthracyclines are
contraindicated)
Adjuvant Treatment of EBC:
Refinement of Standard of Care
1990 on: increasing use of anthracyclines
2000 on: increasing use of taxanes
increasing use of aromatase inhibitors
2005 on: increasing use of trastuzumab
Meta- Analysis of adjuvant trials of AIs vs Tamoxifen
UP-FRONT :
• two trials (ATAC, BIG 01-98)
• 9,856 patients
• 8 y gain = 3.9 % in DFS, 0.5 % in OS
M Dowsett et al, JCO 2010
Meta- Analysis of adjuvant trials of AIs vs Tamoxifen
SWITCH :
• four trials (ARNO, IES, ITA, ABCSG VIII)
• 9,015 patients
• 6 y gain = 3.6 % in DFS, 1.7 % in OS
M Dowsett et al, JCO 2010
Predictors of Early Distant Metastasis
• Patients treated with tamoxifen at greatest risk for
distant metastasis, within the first 2.5 years
–
–
–
–
–
–
Age 75 years
Tumors 2 cm
Grade 2
1 node involved
Lymphovascular invasion
Not screen detected
Mansell J et al. Breast Cancer Res Treat 2008; Dec 27 [Epub ahead of print].
Adjuvant Endocrine Therapy for HR+ EBC
• Treatments of proven efficacy:
– Pre-menopause: Tamoxifen for 5y; LHRH agonists for 2-5y; Tam+LHRH
– Post-menopause: AI for 5y; either sequence of Tam/AI for 5y
– Extended adjuvant AI after 5y tamoxifen
• Evidence and Recommendations:
–
–
–
–
AIs provide a better DFS (OS gain ?) than Tamoxifen
Either sequence of Tam/Letrozole is not inferior to upfront Letrozole
Upfront AIs may be superior to sequential therapy in high risk pts
Extended adjuvant AIs may provide a DFS and OS gain in high risk pts
Adjuvant Treatment of EBC:
Refinement of Standard of Care
1990 on: increasing use of anthracyclines
2000 on: increasing use of taxanes
increasing use of aromatase inhibitors
2005 on: increasing use of trastuzumab
HER2+ Early Breast Cancer
Median follow-up (HR)
HERA
1 year (0.54)
HERA
2 years (0.64)
N9831 AC-T-H
1.5 years (0.87)
Combined analysis
2 years (0.48)
BCIRG 006 ACDH
2 years (0.61)
2 years (0.67)
BCIRG 006 DCarboH
3 years (0.42)
FinHER VH / DH
4 years (0.86)
PACS 04
0
Favours
Herceptin
1
Favours no
Herceptin
2
HR
Piccart-Gebhart NEJM 2005; Romond NEJM 2005; Slamon SABCS 2006; Smith, Lancet 2007; Perez ASCO 2005; Joensuu NEJM 2006; Spielmann SABCS 2007
N9831- Sequential vs Concurrent Trastuzumab
E Perez et al, JCO 2011
Slamon D et al. N Engl J Med 2011;365:1273-1283
BCIRG 006 - outcomes
DFS
Survival
Arm
Events #
HR
Events #
HR
AC-T
257
1
141
1
AC-TH
186
TCH
214
0.64
p< 0.001
0.75
p= 0.04
94
113
0.63
p< 0.001
0.77
p=0.04
Slamon D et al. N Engl J Med 2011;365:1273-1283
Adjuvant Trastuzumab for HER2+ EBC
• Treatments of proven efficacy:
– Any chemotherapy followed by trastuzumab for 1y
– AC-TH followed by trastuzumab up to 1y
– TCH followed by trastuzumab up to 1y
• Evidence and Recommendations:
– Trastuzumab for 1y reduces the risk of relapse by 25-50%
– Trastuzumab administered concomitantly to chemotherapy and up to 1y
is superior to sequential administration alone
– TCH is less cardiotoxic than AC-TH (is it also equally effective?)
The Conquest of Breast Cancer:
a few more steps ahead….
– Where we are now
– How we got here
– Standard of Care for EBC
– Remaining questions
– The Challenges ahead
Adjuvant treatments of EBC
Remaining questions
– Genomic assays to predict outcome and chemosensitivity of HR+ tumors
– Trastuzumab for small, N-ve HER2+ tumors
Genomic assays to predict clinical outcome
C Sotiriou & L Pusztai
Benefit of Tamoxifen or Chemotherapy by RS
NSABP B-20
NSABP B-14
1.0
0.8
DRFS
0.6
Low Risk (RS<18)
0.4
0.2
Placebo
Tamoxifen
0.0
0
2
4
6
8
10
12
14
16
Years
1.0
0.8
DRFS
0.6
Int Risk (RS 18-30)
0.4
0.2
Placebo
Tamolxifen
0.0
0
2
4
6
8
10
12
14
16
Years
1.0
0.8
DRFS
0.6
High Risk (RS≥31)
0.4
0.2
Placebo
Tamoxifen
0.0
0
2
4
6
8
Years
10
12
14
16
Genomic Health Web Site (november 2011)
• OncotypeDx testing requests:
- more than 10,000 doctors
- 55 countries
- 175,000 patients
Meta-analysis: overall impact of RS on treatment
decisions
Treatment plan prior to
Oncotype DX®
Treatment plan
after RS
Treatment plan
after RS
33% change
4% change
CT + HT
HT
Overall, the RS led to a 37% change in treatment decisions
•
•
33% from CT+HT HT
4% from HT  CT+HT
Hornberger J, et al. SABCS 2010. Poster P2-09-06.
IHC4 score vs GHI-RS
Predicted TTDR for a
13.9%
>65ys patient with node13.4%
neg, 1-2cm poorly
differentiated tumor
9.2%
receiving anastrozole.
7.6%
Kaplan Meyer curves for
either the 25° or 75°
percentile of each score .
Predicted 9-year distant recurrence
probabilities for 25° and 75° percentiles
of the IHC4 and GHI-RS scores for
different G, Nodal status for a woman
>65yrs with a 1-2cm tumor receiving
Cuzick J et al, JCO 2011
anastrozole.
Adjuvant treatments of EBC
Remaining questions
– Genomic assays to predict outcome and chemosensitivity of HR+ tumors
– Trastuzumab for small, N-ve HER2+ tumors
High Risk of Recurrence for Patients with HER2+,
Node-negative Tumors 1 cm or Smaller
•
•
•
•
•
N=965, 10% HER2+ tumors
More T1a than T1b were HER2+ (32.3 vs 43.9%)
No patient got chemo or trastuzumab
All tissues were reviewed and re-measured
Median follow up: 6.2 yrs
95.8%
93.7%
86.4%
77.1%
p<0.0001
RFS
p<0.0001
DRFS
Gonzalez-Angulo et al. J Clin Oncol 2009
BCIRG 006 – Subset analysis
Supplement to: Slamon et al., NEJM 2011; 365:1273-83
HER2+ EBC patients
Adjuvant trastuzumab trials vs Modena Cancer Registry
(B31/N9831/HERA/FinHer/BCIRG006/PACS04)
Modena Cancer
Registry
Age (median)
49
59
> 60 y %
~ 16
43.9
T1 %
44.5
71.9
N0 %
21
57.9
T1N0 %
~2
48.7
Characteristic
Adjuvant trastuzumab trials
Piccart N Engl J Med 2005; Romond N Engl J Med 2005; Joensuu N Engl J Med 2006; Slamon D, SABCS 2006;
Spielmann M et al, SABCS 2007; Federico M, RTM 1998-2007
Adjuvant Trastuzumab for T1 N0 HER2+ EBC
• Prognosis of small, N0, HER2+ tumors is poorer
• Trastuzumab has shown efficacy in these patients
• Small, node negative tumors as well as elderly patients, are
underepresented in clinical trials
• Cardiac safety and cardiac recovery in elderly patients treated with
trastuzumab are basically unknown
• In these patients, competitive deaths are prevalent, and the decision to
treat should be based on a careful evaluation of the risk/benefit ratio
• Trials designed for frail and low risk patients are warranted
The Conquest of Breast Cancer:
a few more steps ahead….
– Where we are now
– How we got here
– Standard of Care for EBC
– Remaining questions
– The Challenges ahead
Breast Cancer Diseases – 2011
ER+
65-75%
All Breast Cancers
HER2+
15-20%
Triple
negative
15%
Breast Cancer Diseases – 201…
ER+
65-75%
PI3Kmut
10%
HER3+
IGFR1+
All Breast Cancers
HER2+
15-20%
p95+
4%
P53mut
30-40 %
Triple
negative
15%
BRCAMut
8%
FGFR1
Ampl 8%
PTENloss
30-50%
Clinical Genomics: The Next Frontier
Stratton, Campbell and Futreal Nature 2009
PhRMA Report 2011, Medicines in development for cancer
New agents for the breast cancer molecular subtypes
ER+
65-75%
HER2+
15- 20 %
Triple negative
15%
mTOR inhibitors
PI3K inhibitors
Lapatinib
Neratinib
Pertuzumab
TDM-1
AntiHER2 combinations
Trastuzumab + mTORi
New cytotoxics (eribulin, ixabepilone, vinflunine)
Platinum salts
Bevacizumab
PARP inhibitors
AntiEGFR (Cetuximab, erlotinib)
Anti androgens
Neo-Adjuvant: A Faster Approach
Number of Patients
Efficacy Endpoint
Primary analysis
Adjuvant
Neo-adjuvant
thousands
hundreds
DFS
pCR
years after end of
recruitment
months after end of
recruitment
Biological Window
No
Yes
Functional Imaging
No
Yes
Sample Collection
baseline
multiple time points
+++++
++
Cost
HER2+ EBC
RCTs of PCT + dual antiHER2 blockade
Trial
pts #
Regimen
pCR %
(breast & N)
Neo-ALLTO1
455
wPac+T/L/TL
20 /27.6/46.9*
NeoSphere2
417
DT/DTP/TP/DP
21.5/39.3*/11.2/17.7
CherLob3
121
T = trastuzumab
L = Lapatinib
P = Pertuzumab
wP-FECT/L/TL
25.7/27.8/43.1*
* p value < 0.05
1Baselga
J et al, SABCS 2010; 2Gianni L et al, SABCS 2010; 3Guarneri V et al, ASCO 2011
43
ALTTO study design: use of lapatinib in adjuvant setting
for ErbB2-positive breast cancer1
Trastuzumab
Surgery
Completion
of all (neo)
adjuvant
anthracyclinebased
chemotherapy
(≥4 cycles)
No taxane
Design 2
Concomitant
paclitaxel
Randomisation
Design 1
Lapatinib
Trastuzumab
Wash
out
Lapatinib
12 wks
6 wks
34 wks
(12 wks)
Lapatinib + trastuzumab
52 wks
N = 8000 (2000 patients per treatment arm)
1. www.clinicaltrial.gov NCT00490139
The Conquest of Breast Cancer:
from Evidence Based to Personalized Medicine
• Breast Cancer mortality is declining because of earlier diagnosis
and effective adjuvant treatments
• Randomized clinical trials have allowed to define the appropriate
therapy for the average patient population
• The backbone of adjuvant treatments is based on the molecular
characterization of the disease:
•
•
•
HR+  Endocrine therapy
HER2+  AntiHER2 therapy
Triple negative  Chemotherapy
• Clinical genomics will allow to move forward personalized cancer
medicine:
•
•
•
More refined prognosticators  to spare unecessary therapy
More reliable predictors of sensitivity  to administer individualized therapy
More reliable predictors of resistance  to develop innovative therapies