department of oncology & neurosciences stefano iacobelli university “g. d’annunzio”...
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Department of Oncology & Neurosciences
Stefano IacobelliUniversity “G. d’Annunzio” Chieti-Pescara, ItalyConsorzio CINBO
Medical Management of Breast Cancer
(Early & Advanced)
Factors Influencing Selection of Systemic Therapy for Primary Breast Cancer
OptimalTreatment selection
Risk of recurrenceor death
Benefit from treatment
Tumor characteristics:ER, PR, HER-2
Comorbidities Toxicities
ADVANCED/METSTATIC DISEASE
MBC – Systemic therapy – Selection criteria
Trastuzumab +Endocrine therapy
Trastuzumab +Chemotherapy
Trastuzumab only
IHC 3+ FISH Pos
(15%)
All other cases(85%)
HER 2 status
Endocrine therapy
Long DFS
Age >35 years
Response to previous endocrine therapy
ER+ tumor
Slowly growing disease(soft tissues, skeleton)
Chemotherapy
Short DFS
Age <35 years
Failure to previous endocrine therapy
ER- tumor
Rapidly growing disease
Death from breast cancer in women 30-79 years
Year Death rate
1975: 48.31990: 49.72000: 38.0
Death rate decreased of 24% from 1990 to 2000
NEJM 353: 1784-92, 2005
But also because of the advent of new anticancer drugs, allowing more MBC patients to live longer
Overall survival from time of recurrence (Giordano, Cancer 2004)
Patients divided in 5 groups by year of recurrence
1950s: cyclophosphamide, methotrexate1960s: 5-FU, vinblastine, vincristine1970s: doxorubicin, mitomycin-C, tamoxifen1980s: mitoxantrone, etoposide, aminoglutethimide,
megestrol acetate, goserelin, leuprolide1990s: paclitaxel, docetaxel, vinorelbine, gemcitabine, trastuzumab,
capecitabine, epirubicin, anastrozole, letrozole, exemestane
Survival longer in the more recent groups
5-year OS: from 14% to 44%
New drugs approved by
FDA
TamoxifenAromatase inhibitors
- Inhibitors (anastrozole, letrozole) - Inactivators (exemestane)
Fulvestrant
Progestins
MBC – Endocrine active agents
Proposed Sequence of Endocrine TherapiesPremenopausal Women with ER-Positive Advanced
Breast Cancer
Ooph = oophorectomy; AI = aromatase inhibitor; AIA = aromatase inactivator; MA = megestrol acetate
First-line Tamoxifen + Ooph Ooph + AI/AIA
Second-line Fulvestrant AI/AIA Fulvestrant Tamoxifen
Fourth-line Tamoxifen MAMAMA
Third-line AI/AIA Fulvestrant MA Fulvestrant
EARLY DISEASEEndocrine therapy
Tamoxifen represents the first example of ‘’target therapy’’ for cancer!
EBCTCG, Lancet 2005
Tamoxifen began to be used in clinical trials for MBC in 1971 and has remained “the gold standard” for first-line endocrine therapy for almost 30 yrs.
Second-line drugs were mainly represented by progestins and the first-generation AIs, aminoglutethimide
Recently, new hormonal agents have been developed, particularly novel AIs
AIs
Aromatase Inhibitors
Aromatase
Adrenalglands
ANDROGENS OESTROGENS
(Testosterone, androstenedione)
(Oestradiol, oestrone)
tumourgrowth
Aromatase Inhibitors
ASCO Tech Assessment of Aromatase Inhibitor Adjuvant Therapy 2004
“Adjuvant therapy for postmenopusal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence”
Winer EP, J Clin Oncol 2005
“Treatment option include 5 years of AI or sequential therapy consisting of tamoxifen (for either 2 to 3 yrs) followed by aromatase inhibitors for 2 - 3, to 5 years”
Tamoxifen
Aromatase inhibitor
Control
Extended adjuvant therapy
Switching
Direct comparison (up-front)
ATAC, BIG-1 98
IES, ARNO-95, ITA
MA-17,ABCSG8
Aromatase Inhibitor adjuvant treatment strategies
R
R
R
Overall SurvivalATAC 0.97 (0.84, 1.11)BIG-1 98 0.91 (0.75, 1.11)
Disease-free SurvivalATAC 0.87 (0.78, 0.97)BIG-1 98 0.82 (0.71, 0.95)
Time to Distant RecurrenceATAC 0.86 (0.74, 0.99)BIG-1 98 0.81 (0.67, 0.98)
Favours 5 yrs AI Favours 5 yrs Tam0.70.5 1 1.5
Overall SurvivalABCSG8/ARNO 0.76 (0.51, 1.12)IES 0.85 (0.71, 1.02)ITA 0.56 (0.28, 1.13)
Disease-free SurvivalABCSG8/ARNO 0.60 (0.44, 0.81)IES 0.76 (0.66, 0.88)ITA 0.57 (0.38, 0.85)
0.50.2 2 5Favours AI switch Favours Tam alone1
Up-front
Switching
BIG 1-98: Primary Core Analysis26-Month Median Follow-Up
0 2 5 Years
Tamoxifen
Letrozole
Tamoxifen Letrozole
Letrozole Tamoxifen
A
B
C
D n=1540
n=1548
n=2463
n=2459
8010 pts
Primary core analysis compares letrozole vs tamoxifen monotherapy Tamoxifen: arms A and C Letrozole: arms B and D Excludes events and follow-up beyond switch for C and D Primary endpoint: DFS
Thürlimann et al. N Engl J Med. 2005;353:2747.
RANDOMI
ZE
Patient/Tumor CharacteristicsLetrozole Tamoxifen
Median age (y) 61 61Tumor size >2 cm (%) 36.5 37.7Node+ (%) 41.5 41.2CT given (%) 25.3 25.3ER+/PgR+ (%) 63.5 62.7ER+/PgR– (%) 20.2 20.5ER+/PgR unknown (%) 14.5 14.3
Receptor positivity was a study requirement:99.8% of patients had receptor-positive tumors
CT = chemotherapy. Thürlimann et al. N Engl J Med. 2005;353:2747.
BIG 1-98: DFS At 26 Months
Thürlimann et al. N Engl J Med. 2005;353:2747.
97.797.6
YearlyDFS (%)
95.193.4
90.589.0
86.884.6
84.081.4
No. at risk
38923896
29642926
12611238
892866
40034007
567544
N HR (95% CI) P Value
8010 0.81 (0.70-0.93) 0.003
LETTAM
% o
f p
ts a
live
an
d
dis
ease
-fre
e
Years from randomization
Absolute difference 2.6%
0
20
40
60
80
100
1 2 3 4 5
NPT 1/2.6 x100 = 38 pts!
ATAC Trial
Predefined Adverse Events
0.2 0.4 0.6 0.8 1.0 2.01.5
Hot flushes
Odds ratio (‘Arimidex’/tamoxifen)
In favour of Anastrozole In favour of tamoxifen
Joint disorders
Vaginal bleeding
Vaginal discharge
Endometrial cancer**
Fractures***
Ischaemic cerebrovascular event
Venous thromboembolic events
Deep venous thromboembolic events
*AEs on treatment or within 14 days of discontinuation
**Excludes patients with prior hysterectomy and includes on- and off-therapy AEs
***Fractures occurring at any time prior to recurrence (includes patients no longer receiving treatment) Lancet, 2005
Hadji P, The Breast 2007
Clinical fracture rates in adjuvant AI trials
QALYs: Quality adjusted life years; ICUR: Incremental cost-utility ratio
Both up-front and sequential AI options are cost-effective alternatives to TAM alone, but early switching to EXE appears to be the economically preferred option based on its more favourable cost-utility vs up-front ANA.
Breast Cancer Res Treat 2007
2005 costs/Canada/Markov model
*Drug cost+ FU+adverse events+relapse management
*
Arguments in favour of the switching strategy
First OS advantage demonstration vs tamoxifen*– ITT 15% (-2% – 29%) p = 0.08– ER+/Unknown 17% (0% – 31%) p = 0.05
To minimize the adverse risk of both agents
Limiting the costs of treatment with aromatase inhibitors
*(IES study)
Arguments in favour of the upfront strategy
Contraindication to TAM
Previous therapy with SERMs
Risk of early relapse (adverse prognostic
factors)
Biological rationale (PGR-, HER2+)
Where are we in 2008 with respect to adjuvant chemotherapy for breast
cancer?
Mortality from breast cancer: adjuvant chemotherapyEBCTGG, Lancet 1998
Adjuvant Treatment for Breast Cancer
The most important achievement of medical oncology in terms of lives saved
The ErbB Receptor Familyand Their Ligands
The ErbB Receptor Familyand Their Ligands
Heregulins
EGFTGF-
AmphiregulinBetacellulin
HB-EGF
NRG2NRG3
HeregulinsBetacellulin
ErbB-1 (EGFR) ErbB-2 (HER2/neu) ErbB-3 (HER3) ErbB-4 (HER4)Fernandes et al, 1999. Moghal et al, 1999.
Extracellular Ligand-binding Domain
Tyrosine Kinase Domain
What about patients with HER2+breast cancer?
Trastuzumab in early breast cancer: studies designs of the adjuvant trials
Baselga at al., The Oncologist, 2006
Trastuzumab Adjuvant Trials: Efficacy Results
Trial and arm
N° pts N° events 3-year DFS (%)
HR 95% CI
B31/N9831
AC-TH 1.672 133 87 0.48 0.39-0.59
AC-T 1.679 261 75
BCIRG 006
AC-DH 1.074 128 87 0.61 0.48-0.76
DCarboH 1.075 142 86 0.67 0.54-0.83
AC-D 1.073 192 81
HERA
H 1.703 218 81 0.64 0.54-0.76
Control 1.698 321 74
FinHer
CT+H 115 12 89 0.42 0.21-0.83
CT alone 116 27 78
Neoadjuvant (Primary) Therapy
Pre-clinicalResearch
5-10 yrs
Primary Chemotherapy(End-point = pCR)
3 – 4 months !
ClinicalTrials
3-5 yrs
End Points
(DFS, OS,..)
5-8 yrs
DRUG DEVELOPMENT: A LONG AND EVERMORE EXPENSIVE PROCESS
Adjuvant sytemic chemotherapy:Conclusions
• Highly effective in reducing annual odds of recurrence and death;
• Benefits persist for at least 20 years, probably indefinitely;
• Chemotherapy is administered blindly!! No validated method to predict benefit or efficacy for individual patients exists.
•Prognostic factors
•Predictive factors
Nodal status
Tumor size
Grade
ER/PgR
HER-2
Young age
LVI
ER/PgR
HER-2
(Grade)
Proliferative activity
“Current parameters do not allow us to adequately distinguish patients most likely to benefit from treatment”
a heterogeneous disease!
Breast Cancer
“Histological looks alike” - BCPz 39 a. pre-menopause
CDI 2.2 cm, N (-), G1 ER (±)/PR(+), HER-2 (-)
09/2000: QUART FEC100 x 6 LHRH-Tam
Pz 47 a. pre-menopause
CDI 2.4 cm, N (-), G1 ER (±)/PR(+), HER-2 (-)
12/2003: QUARTFEC100 x 6 LHRH-Tam
09/2005: NED 10/2004: Bone metastases
ERA of Molecular Biology
Only treat those who need treatment
Only treat those who will benefit from treatment
• “omics” technologies for discovery of new
prognostic and predictive markers
• Development of targeted therapies
Genomics
Proteomics
“Molecular signature of cancer”
Gene expression analysis
<1995: Northern Blotting, RNAse protection etc
1 Week: Analyse several genes on 10s of samples
>1995: DNA Microarrays
1 Week: Analyse whole genome on 10s of samples
Courtesy of JA Foekens
BREAST CANCER CLASSIFICATION BREAST CANCER CLASSIFICATION USING GENE EXPRESSION PROFILINGUSING GENE EXPRESSION PROFILING
Breast Cancer
=
At least 4 different diseases!!!
Sorlie T et al, PNAS 2001
Courtesy of Lisa CAREYCourtesy of Lisa CAREY
Basal-like
HER-2+/ER-
Luminal ALuminal B
Normal
The Amsterdam profile
van ‘t Veer et al, Nature 2002
gyui
Training set: 78 patients
Study design
78 breast tumorsPatients < 55 yearsTumor size <5 cmLymph node negative (LN0)No adjuvant therapy
Prognosis reporter genes
Distant metastasis< 5 years (n=34)
NO distant metastasisin 5 years (n=44)
70-gene signature Validation: NEJM / JNCI
50
100
0
25
75
BC – Using the usual selection criteria (St. Gallen)
(100 N-, pre-menopausal pts receiving CT at 5 yrs FU)
83 will be alive even w/o CT
14 will die despite CT
3 will be alive thanks to CT
Using the 70-gene signature
Only 27% of pts will be overtreated
Dutch 70-gene prognosis profile (Agendia)
76-gene signature Veridex / Erasmus MC
- All lymph node-negative patients: untreated and also ER+ patients treated with adjuvant tamoxifen
- Based on global gene expression, frozen tissues
Three major expression profiles70-gene signature Agendia: MammaPrint®
- Lymph node-negative patients <60 years: untreated
- Based on global gene expression, frozen tissues
21-gene signature Genomic Health Inc: OncoType DXTM
- HR+ lymph node-negative patients treated with adjuvant tamoxifen: paraffin-embedded tissues
- Based on 16 candidate genes + 5 control genes: RT-PCR
Commercially available
70-gene signature Agendia: MammaPrint®
~$ 200021-gene signature Genomic Health Inc: OncoType DXTM
~$ 3400
Question: Who is going to pay for such a high-tech test?
Challenge:
How to justify the health economic value for an expensive test that has not been prospectively validated?
EORTC – TransBig Mindact trial
Discordant: 35% Randomized decision making
Both high risk: 55% Both low risk: 10%
6,000 lymph node-negative breast cancer patients
Clinical risk (Adjuvant ! online) and genomic risk (Mammaprint®)
CT No CT
Use clinical risk Use genomic risk
High Low High Low
TAILORx study design
10,000 ER+ / HER2- lymph node-negative breast cancer patients
OncoType DX assayTM
Primary Study Group RS 11-25: ~44%
Secondary Study Group 1 RS < 11: ~29%
Secondary Study Group 2 RS > 25: ~27%
HT alone CT + HT
RANDOMIZE Stratification factors: tumor size, menopausal status, planned
chemo, planned radiation
Hahn & Weinberg, 2002
A Subway Map of Cancer Pathways
BC: targets we want to direct therapy toward
Agent VEGF VEGFR PDGFR EGFR HER-2 c-KIT MAPtau TopoII mTOR
Bevacizumab X
Sunitinib X X X
Lapatinib X X Trastuzumab X
mTOR inhibitors x
Anthracyclines X X
Taxanes X
- E7389 (synthetic analogue of halichondrin B that inhibits the polymerization of tubulin and the assembly of microtubules)
- Trabectedin (tetrahydroisoquinoline alkaloid)
- Tipifarnib (farnesyl-transferase inhibitor)
- RAD001 (mTOR inhibitor)
- XRP9881 (taxane derivatives)
- Vorinostat (histone deacetylase inhibitor)
- BZL101 (aqueous extract of the Scutellaria barbata)
- Dasatinib (dual SRC/ABL kinase inhibitor)
- Ispinesib (Kinesin Spindle Protein Inhibitor)
- Pazopanib (multi-tyrosine kinase inhibitor)
- Ertumaxomab (anti-CD3 x anti-HER-2-neu monoclonal antibody)
- BIBW 2992 (dual, irreversible EGFR- and HER2-inhibitor)
And many more……!!
New biological targeted drugs in BC• Some wonderful successes! (i.e. Trastuzumab);
• Data are still limited, although clinicians are racing ahead of the science;
• Mechanisms of resistance just as important as success;
• Cost of new drugs not affordable in the future;
• Imperative to develop & validate diagnostic tests to predict response in individual patients;
• A pletora of new agents: Imperative to pool data across studies, across disease subtypes, across agents;
• Consensus conference to agree on trial design/endpoints, assessment of biomarkers.
Drug costs (6 courses) in BC
Anthracycline-based regimens (EC, FEC) € 1.400
Anthracycline-based regimens + taxanes € 9.000
Trastuzumab (6 wks) € 2.500
CMF i.v. € 180
Lyposomal anthracyclines + taxanes + Trastuzumab € 12.600
Lyposomal anthracyclines € 7.200
Anticancer therapy is expensive!
Bevacizumab + capecitabine € 21.600Bevacizumab + paclitaxel ± Trastuzumab € 39.600
Thank you for your attention!