XV Congresso Nazionale SIGU
Carcinoma Gastrico Ereditario:
Strategie Terapeutiche
Maria Di Bartolomeo
Divisione di Oncologia Medica
INDICE
•
Epidemiologia e sopravvivenza
•
Terapia adiuvante
–
–
Chemioradioterapia
Chemioterapia adiuvante
–
Studio
–
Analisi biologica
ITACA-S
•
Approccio neoadiuvante e perioperatorio
•
Nuova classificazione molecolare
•
Terapia biologica
Gastric cancer: a global disease
•
•
•
•
•
4th most common malignant disease ~ 930,000
2nd most common cause of cancer-related death worldwide ~700,000
Falling incidence of distal gastric cancer
Increasing incidence of proximal gastric cancer
Wide geographical variation
Incidence (males)
20 / 100 000
10 - 20 / 100 000
<10 / 100 000
www.cancer.gov
Kamangar F et al. J Clin Oncol 2006;24:2137–50
EUROCARE-4: Sopravvivenza dei Pazienti con Carcinoma
Gastrico. Dal 1995-1999
European Journal of Cancer 45 (2009)
Incidenza in Italia:
tasso grezzo rapporto tra casi e popolazione
Sardegna
Sicilia
Puglia
Uomini
Donne
Campania
Calabria
Abruzzo
Lazio
Lombardia
Emilia Romagna
Toscana
M arche
Umbria
0
5
10
15
20
25
30
35
40
45
50
Stimati dal Reparto Epidemiologia dei Tumori di
Epidemiologia Sorveglianza e Promozione della Salute
dell’ISS
Which advice for patients with familial
predisposition?
 HP screening and eradication
 In Japan & Korea: gastroscopy every year in patients
with familial incidence
Genetic counseling
Search for Ecadherin in families with ≥ 2 (with diffuse type gastric
cancer), esp. at younger age
 Gastroscopy every 1-2 years (some specified after
age 40) in Ecadherin mutation carriers
Consider gastrectomy in selected patients with
Ecadherin mutation
Type of surgical procedure in resectable
gastric cancer
 Extent of resection
 partial vs total: depending on location, margins (> 5 cm) and
diffuse type/signet cells
 partial gastrectomy for distal cancer (antrum)
Diffuse type/ signet cells: total gastrectomy
histology:
Extent of resection: D2 preferred: better long term
outcome
 Splenectomy: not done, unless direct invasion
 laparoscopic resection: clinical trials
 Reconstructive techniques (pouch): better QOL
 Improved outcome in high volume centers - centralisation
Neo-adjuvant and adjuvant therapy
for gastric cancer: different strategies
Post-operative
Chemoradiotherapy
(trend to perioperative CT
in academic centers)
Peri-operative
Chemotherapy
(ECF- 5FU/cisplatin)
Postoperative CT
Post-operative
Chemotherapy
(S-1 or combination)
Chemioradioterapia adiuvante
8/1991-6/1998: 556 pz (275 trattamento perioperatorio,281 chirurgia)
Chirurgia radicale
R
FU/LV (1 ciclo)
FOLLOW UP
Radioterapia
FU/LV(2 cicli)
FU/LV (2 cicli)
(Macdonald, NEJM, 2001)
Bajetta,
Cascinu,
Di Costanzo,
De Vita,
Ann Oncol, 2002
JNCI, 2007
JNCI, 2008
Ann Oncol, 2007
Stage
T3-4/N+
T3-4/N+
T3-4/N+
I-IIIB
Pts
137/137
196/201
128/130
112/113
Experimental
Arm
EAPFU/LV
PELFwk
PELF
ELFE
Control arm
Follow-up
FU/LV
Follow-up
Follow-up
HR
0.93
0.95
0.90
0.91
5-y OS control arm 49%
50%
48.7%
43.5%
ITACA-S
“Adjuvant chemotherapy for gastric cancer
with S-1, an oral fluoropirimidine “
10/2001-12/2004: 1059 pz (529 CT, 530 follow-up)
Resezione gastrica
R
S-1 x 1 anno
Follow-up
S-1 : 80mg/m2 /die
(Sakuramoto, NEJM 2007)
Mono CT vs Controllo
(N=324 dai 2 studi): Curva di Kaplan-Meier
HR=0.60 (p=0.03; 95% CI:0.42,0.84)
5 anni OS : 54% versus 69% nel gruppo mono-CT
15
Comparison of a sequential treatment with
irinotecan (CPT-11) plus 5-fluorouracil (5FU)/folinic acid (LV) followed by docetaxel
and cisplatin versus a 5-FU/LV regimen as
postoperative treatment for radically resected
gastric cancer
E.Bajetta, I.Floriani, M.Di Bartolomeo, R.Labianca,
A. Santoro, R.Casaretti, E.Pasquini, F.Di Fabio, G.Pinotti,
P.Bidoli, G.Rosati, A.Mambrini, A.Ciarlo, S.Ricci,
L. Frassinetti, F.Di Costanzo, AM.Bochicchio
on behalf of ITACA-S group
PRESENTED BY MARIA DI BARTOLOMEO
Not for profit, multicenter, randomized, parallel arm, superiority trial
Adenocarcinoma
of the stomach or GEJ
Stratified for
center and lymph-nodal
involvement (N-/N+)
Experimental
Experimental
armarm
CPT-11 :180 mg/m2 die 1
5-FU: 400-600 mg/m2 die 1,2
LV :100 mg/m2 die 1,2
Q2wks, 4 administrations
Control arm
5-FU: 400-600 mg/m2 die1,2
LV: 100 mg/m2 die 1,2
Q2wks, 9 administrations
TXT:75 mg/m2 die 1
CDDP: 75 mg/m2 die 1
Q3 wks, 3 administrations
ITACA-S
1106 Randomized
541 control arm
565 experimental arm
6 pts excluded due to major
violations:
3 control arm
3 experimental arm
6 pts crossed group
1100 ITT population
538 control arm
562 experimental arm
28 pts never started treatment:
4 pts from control to
experimental
2 pts from experimental to
control
16 control arm
12 experimental arm
1072 Safety population
520 control arm
552 experimental arm
HR:0.98
95%CI: 0.83-1.16
p=0.83
Median DFS: 41.3 months
5-year DFS: 44.8%
ITACA-S
HR:1.0
95%CI: 0.83-1.20
p=0.986
Median OS: 69.8 months
5-year OS: 52.2%
ITACA-S
BIOLOGICAL STUDY: FLOW CHART
Pathological disease stage, node
involvement, histological type,
tumor site (distal or proximal),
history of H.pylori infection
Selected Patients
from 25 centers
Primary tumor tissue sample from
gastric surgery
Formalin-fixed paraffin-embedded (FFPE) tissue.
Pathological diagnosis
Immunohistochemical staining
COX-2, E-cadherin, ßcatenin and osteopontin
proteins
Fluorescence in situ
ibridization
HER-2
amplification
Mutational analysis
DNA extraction
PI3KCA, BRAF, KRAS
mutations, MSI
Giemsa stains on
normal mucosa
H. pylori
Disease-free
interval and
overall survival
Molecular mechanisms of ß-catenin
and E-cadherin in gastric cancers
• E-cadherin regulates
adesion, migration and
differentiation
• ß-catenin regulates
adhesion, migration and
nuclear transcription
Molecular mechanisms of osteopontin
(OPN) and COX-2 in gastrointestinal
cancers
• OPN signaling results in
various functions, including
prevention of apoptosis,
modulation of angiogenesis,
degradation of extracellular
matrix, activation of PI3KCA and
NG-κB pathways
• COX-2 is involved in
angiogenesis and inflammation
ASSOCIATION OF BIOMARKERS AND PATHOLOGICAL VARIABLES
• E-Cadherin was significantly associated with diffuse type and poorly differentiated
tumors (p=0.02)
• OPN was significantly associated with pTNM (p=0.02)
Biomarkers distribution
% of samples
Osteopontin score
• negative
• positive
54%
46%
Cox score
• low
• high
92%
8%
Beta-catenin
• Normal membranes
• Cytoplasmic / loss membranes
• Any nuclear
62%
28%
10%
E-cadherin
• Normal membranes
• Cytoplasmic / loss membranes
• Any nuclear
65%
28%
7%
Osteopontin
RELAPSE FREE SURVIVAL,
RFS
5-year RFS
(95% confidence interval)
OPN negative
49.2%
(41.2,58.8%)
OPN + / ++
32.6%
(25.1,42.2%)
Log-rank test p<0.001
Time, months
Nuclear ß-catenin/E-cadherin
5-year RFS
(95% confidence
interval)
43.2% (37.0,50.3%)
Nuclear expression
33.2% (21.4,51.7%)
RELAPSE FREE SURVIVAL,
RFS
All others
Log-rank test p=0.04
Time, months
Trattamento pre-operatorio perchè’?
•
potenziale beneficio di un trattamento pre-operatoro
• incremento chirurgia R0
• trattamento delle micrometastasi
• valutazione chemiosensibilità del tumore
“Perioperative Chemotherapy in Operable Gastric
Cancer. Final Results of Randomized Trial”
7/1994-4/2002: 530 pz (250 CSC, 253 S)
• chirurgia non standardizzata
R
ECF X 3
Chirurgia
• Probabilità di sopravvivenza 5 anni:
CSC : 36% (30%-43%)
S:
23% (17%- 29%)
Chirurgia
HR: 0.75
(95% CI:0.60-0.93 P=0.009)
ECF X3
Follow up
(Cunningham, NEJM, 2006)
Role of HER2 in Gastric Cancer
clinicaloptions.com/oncology
Molecular Targets: Esophagogastric
Cancer
 KRAS mutation: < 5% to 10%[1,2]
 BRAF mutation: < 5%[1,2]
 EGFR overexpression: ~ 50% to 80%[3,4]
– TKIs inactive[4]
– Cetuximab monotherapy inactive[5]
 EGFR mutation: very low[4,6]
 HER2 overexpression: 10% to 25%[7]
1. Lee SH, et al. Oncogene. 2003;22:6942-6945. 2. Kim IJ, et al. Hum Genet. 2003;114:118-120. 3. Galizia G,
et al. World J Surg. 2007;31:1458-1468. 4. Dragovich T, et al. J Clin Oncol. 2006;24:4922-4927. 5. Chan JA,
et al. Ann Oncol. 2011;[Epub ahead of print]. 6. Mammano E, et al. Anticancer Res. 2006;26:3547-3550.
7. Yano T, et al. Oncol Rep. 2006;15:65-71.
Role of HER2 in Gastric Cancer
clinicaloptions.com/oncology
HER2 Positivity Histological Type
Histological type
Localization
Subtype
HER2 Positivity (%)
P Value
Intestinal
Diffuse
Mixed
32.2
6.1
20.4
< .001
GEJ
Gastric
33.2
20.9
< .002
Histological subtype and tumor sublocalization are important factors
for HER2 expression/amplification in gastric cancer
Bang YJ, et al. ASCO 2009. Abstract 4556. Reprinted with permission
Role of HER2 in Gastric Cancer
clinicaloptions.com/oncology
Survival Probability
ToGA: OS in IHC 2+/FISH+ or IHC 3+
(Exploratory Analysis)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median
Events OS
HR
FC + T
FC
11.8
0
2
4
6
120
136
16.0
11.8
95% CI
0.65 0.51-0.83
16.0
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Mos
Pts at Risk, n
228 218 196 170 142 122 100 84
218 198 170 141 112 96 75 53
65
39
51
28
39
20
28
13
20
11
12
4
11
3
5
3
4
0
1
0
0
0
Reprinted from The Lancet, 376(9742), Bang YJ, et al., Trastuzumab in combination with chemotherapy versus chemotherapy
alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label,
randomised controlled trial. 687-697, Copyright 2010, with permission from Elsevier.
Role of HER2 in Gastric Cancer
clinicaloptions.com/oncology
Median OS Increased to > 1 Yr With
Trastuzumab-Based Therapy
BSC[1]
12 mos
FAMTX[2]
C + S1[3]
CF[4]
IF[5]
EOF[6]
DCF[4]
ECF[6]
ECX[6]
XP[7]
EOX[6]
Trastuzumab + XP/FP[8]
HER2 IHC 2+/FISH+ or IHC 3+
15
10
5
0
Median OS in Patients With Advanced Gastric Cancer (Mos)
1. Murad AM, et al. Cancer. 1993;72:37-41. 2. Vanhoefer U, et al. J Clin Oncol. 2000;18:2648-2657.
3. Ajani JA, et al. J Clin Oncol. 2010;28:1547-1553. 4. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.
5. Dank M, et al. Ann Oncol. 2008;19:1450-1457. 6. Cunningham D, et al. N Engl J Med. 2008;358:36-46.
7. Kang YK, et al. Ann Oncol. 2009;20:666-673. 8. Bang YJ, et al. Lancet. 2010;376:687-697.
Acknowledgments
A.O. C. Poma – Mantova (Dr Aitini
A.O. Parma – Parma (Dr ssa Pucci- Dr Camisa)
A.O. Padova- (Prof Nitti- Prof Rugge)
A.O. Santa Maria Nuova - Reggio Emilia (Dr Boni)
A.O. San Carlo - Potenza (Dr Rosati- Dr Bilancia)
A.O. S.Orsola-Malpighi - Bologna (Dr Martoni)
A.O. Universitaria Careggi- Firenze (Prof. Di Costanzo)
Azienda USL 6 - P.O. di Livorno - Livorno (Dr Cappuzzo)
Fondazione IRCCS Istituto Nazionale- Milano (Dr.ssa Di Bartolomeo- Dr Pellegrinelli)
Fondazione Poliambulanza- Brescia (Dr Zaniboni)
G.B. Morgagni-L. Pierantoni- Forlì (Prof Amadori)
I.E.O. - Milano (Dr Fazio- Dr.ssa Lombardi)
Istituto Clinico Humanitas - Rozzano (MI) (Dr Santoro- Dr ssa Rubino)
Ospedale Civile “Guglielmo Saliceto” –Piacenza (Dr Cavanna)
Ospedali Riuniti- Bergamo (Dr Labianca)
Ospedale Civico - Carrara (Dr Cantore)
Ospedale degli Infermi - Rimini (Dr Ravaioli)
P.O. Serbelloni - Gorgonzola (MI) (Dr Venezia)
Università di Sassari – Sassari (Prof Farris)
Dr Filippo Pietrantonio
Prof Giuseppe Pelosi
Dr Alessandro Pellegrinelli
Dr. Giovanni De Luca
Dr.ssa Irene Floriani
Dr. Davide Poli
Sig. Monica Cropolato
Dr.ssa Eliana Rulli
Anatomia Patologica INT
Istituto Mario Negri