Post on 06-Dec-2018
“Manejo Actual del Cáncer de Colon y Recto”
P. García Alfonso Sr. Oncología Médica
HGU Gregorio Marañón de Madrid
Tasas de mortalidad USA 1975-2008 57.100 en 2003 vs 51690 en 2012
Fundamento actual del tratamiento del CCR
Soporte
5 FUbolo
5-FUIC
Com
bina
cion
IRIN
OTEC
AN
Com
bina
ción
OXAL
IPLA
TINO
Xeloda = 5 FU IC Bevacizumab
YCetuximab
SUPERVIVENCIA
1960 1980 1990 1999 2005
6
10-12
14-15
16 - 21
21 –25 ++Cirugía de metástasis
Panitu
mumab
K-ras
Nuevos Fármacos Cirugía de metástasis
Tratamiento Individualizado
La era de la Quimioterapia
5-FU es la base de la quimioterapia en el tratamiento del CCR
• 5-FLUOROURACILO
– 1957 (1): primera experiencia en el tto de CCR. Limitada eficacia
– 1989 (2): biomodulación con leucovorín (Clínica Mayo)
– 1990-95 (3): infusión continua prolongada de 5FU (Lokich)
– 1997 (4): infusión continua intermitente (de Gramont)
(1) Heidelberger. Nature 1957
(2) Poon. J Clin Oncol 1989
(3) Díaz-Rubio Eur J Cancer 1990
(4) De Gramont. J Clin Oncol 1997
Tournigand C, et al. J Clin Oncol. 2004;22:229-237.
Conclusion: no survival advantage to starting either FOLFIRI or FOLFOX6
Median OS (Mos)
10 20 30 40 50
0.25
0.50
0.75
1.00
Pro
bab
ility
FOLFIRI/FOLFOX6 FOLFOX6/FOLFIRI
P = .99
FOLFIRI and FOLFOX6 sequencing trial in advanced CRC: Survival
Tournigand C, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229-37. Reprinted with permission from the American Society of Clinical Oncology.
0 0
Access to Chemotherapy Improves Survival
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
22
20
18
16
14
12
Me
dia
n O
S (M
os)
0 20 40 60 80
Patients With 3 Drugs (%)
LV5FU2
Bolus 5-FU/LV
Infusional 5-FU/LV + irinotecan
Infusional 5-FU/LV + oxaliplatin
Bolus 5-FU/LV + irinotecan
Irinotecan + oxaliplatin
First-line therapy
La era de los Biológicos
Various therapeutic strategies targeting VEGF have been explored Approaches to VEGF inhibition include:1
– Anti-VEGF antibodies
– Anti-VEGFR antibodies
– Soluble VEGFR – Small-molecule
TKIs
Precise inhibition of VEGF-mediated pathways avoids „off target‟ pathways affected by receptor- targeting agents2–7
VEGFR
Antibodies inhibiting VEGF
Soluble VEGFRs (VEGF-TRAP)
Angiogenesis
Small molecules inhibiting VEGFRs (TKIs)
1. Hicklin & Ellis. JCO 2005; 2. Baka et al. Expert Opin Ther Targets 2006 3. Presta et al. Cancer Res 1997; 4. Jain et al. Nat Clin Pract Oncol 2006
5. Morabito et al. Oncologist 2006; 6. Kerbel. Science 2006; 7. Verheul & Pinedo. Nat Rev Cancer 2007
Angio
Persistent activation of the EGFR pathway is a frequent event in mCRC
From Ciardiello F & Tortora G. N Engl J Med 2008;358:1160–1174. Copyright © (2008) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
Mutación de ras
En el cáncer colorrectal ocurre en el 35-45% de los pacientes
>95% de las mutaciones ocurren en el exon 2 de K-ras
– codón 12 (>90%) – codón 13 – codón 62
Impiden la hidrólisis del GTP (RAS permanentemente “on”), y causan transformación celular
GDP
GTP
inactive
active *
Clasificación del CCRm
KRAS wild-type KRAS mutant
Anti-VEGF or anti-EGFR antibodies
No anti-EGFR antibodies.
Si anti-VEGF
versus
versus
Therapeutic implications
Bevacizumab targets VEGF
Avastin binds all known isoforms of VEGF, preventing – interaction with its
receptors – activation of downstream
signalling pathways
This ultimately leads to vascular regression, leaving the tumour dormant
Avastin
–P –P
P– P–
VEGF
X
Growth Proliferation
Migration Survival
X
First-Line Irinotecan/5-FU/LV + Bevacizumab
Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.
HR: 0.66; P < .001
OS
(%)
Months 0 10 20 30 40
IFL/bevacizumab (n = 402) IFL/placebo (n = 411) 20.3 15.6
10.6
100
80
60
40
20
0 0 10 20 30
PFS
(%)
Months
6.2 HR: 0.54; P < .001
100
80
60
40
20
0
Copyright © 2004 Massachusetts Medical Society. All rights reserved.
Adding bevacizumab to FOLFOX4 significantly improved OS and PFS in the 2nd-line setting...
Giantonio BJ et al. J Clin Oncol 2007;25:1539–44.
All patients had received prior chemotherapyfor advanced CRC with irinotecan + a fluoropyrimidine
10,8
4,7
12.9*
7.3†
0
2
4
6
8
10
12
14
Overall survival Progression-freesurvival
Med
ian
surv
ival
(mon
ths)
FOLFOX4 (n=291)
FOLFOX4+ bevacizumab (n=286)
Adding bevacizumab also improved the
overall response rate:22.7% vs 8.6%
(p<0.0001)
*p=0.0011 vs FOLFOX4.†p<0.0001 vs FOLFOX4.
Estudio TRIBE: Fase III Avastin + FOLFOXIRI vs Avastin + FOLFIRI (# 336)
Objetivo ppal: SLP
Objetivos secundarios: response rate, duration of response, secondary R0 surgery rates of metastases, overall survival, biomarker evaluation
Loupakis, et al. Abstract 336 (presented Saturday January 26, 14.00‒15.30)FOLFIRI = irinotecan 180mg/m2, LV 200mg/m2, bolus 5-FU 400mg/m2, infusional 5-FU 2,400mg/m2 over 48 hours q2w; FOLFOXIRI = irinotecan 165mg/m2, oxaliplatin 85mg/m2, LV 200mg/m2, bolus 5-FU 200mg/m2, infusional 5-FU 3,200 mg/m2 over 48 hours q2w
Previously untreated,
unresectablemCRC
(n=508)
Avastin 5 mg/kg q2w + FOLFOXIRI
(up to 12 cycles)
Avastin 5 mg/kg q2w + FOLFIRI
(up to 12 cycles)
R
Avastin + 5-FU
Avastin + 5-FU
PD
PD
Estudio TRIBE: 1L FOLFOXIRI + Avastin alcanzasuperior SLP que FOLFIRI + Avastin
Median follow-up: 26.6 monthsLoupakis, et al. Abstract 336 (presented Saturday January 26, 14.00‒15.30)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54
Time (months)
PF
S e
sti
ma
te
Avastin + FOLFOXIRI
(n=252)
Avastin + FOLFIRI (n=256)
Median PFS (months) 12.2 9.7
Unstratified HR (95% CI, p value)
0.73(0.60‒0.88, p=0.0012)
Stratified HR (95% CI, p value)
0.71(0.59‒0.86, p=0.0006)
FOLFOXIRI + Avastin (n=252)FOLFIRI + Avastin (n=256)
9.7 12.2
FOLFOXIRI + Avastin alcanza superior SLP que FOLFIRI + AvastinTambien alcanza incremento significativo en TR: 65% vs 53% (p=0.006)
Tripletes más Bevacizumab
Estudio fase III AVEX: 1L Xeloda + Avastin incrementasignificativamente la SLP en pacientes ≥70 años
La SLP muestra beneficio similar en todos los subgruposanalizados, incluyendo los ≥75 años
Cunningham, et al. Abstract 337 (presented Saturday January 26, 14.00‒15.30)
Xeloda + Avastin (n=140)
Xeloda (n=140)
Median PFS (months) 9.1 5.1
HR (95% CI, p value) 0.53(0.41‒0.69, p<0.001)
PF
S e
sti
mate
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Time (months)
Xeloda + Avastin (n=140) Xeloda (n=140)
5.1 9.1
Estudio fase III AVEX: OS and ORRtambién incrementos en los objetivos secundarios
Cunningham, et al. Abstract 337 (presented Saturday January 26, 14.00‒15.30)
Xeloda + Avastin (n=140)
Xeloda (n=140) HR (95% CI, p value)
Response rate (%) 19.3 10.0 NR (p=0.042)Median OS (months) 20.7 16.8 0.79
(0.57‒1.09, p=0.182)
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46
OS
esti
mate
Time (months)
16.8 20.7
Xeloda + Avastin (n=140) Xeloda (n=140)
Capecitabina más Bevacizumab es eficaz en los ancianos
¿Cual es la duración idonea del bevacizumab?
Continuous VEGF inhibition with bevacizumab until PD is a rational approach
Folkman. In: Cancer: Principles and Practice of Oncology 2005; Relf, et al. Cancer Res 1997 Hanrahan, et al. J Pathol 2003; Fontanini, et al. Clin Cancer Res 1997
VEGF VEGF bFGF
TGFb-1 VEGF bFGF
TGFb-1 PIGF
VEGF bFGF
TGFb-1 PIGF
PD-ECGF
VEGF bFGF
TGFb-1 PIGF
PD-ECGF Pleiotrophin
Bevacizumab After First Progression: BRiTE
0 5 10 15 20 25 30 35
Months
Esti
mat
ed
Ove
rall
Surv
ival
, %
Pat
ien
ts
No treatment
No bevacizumab
Bevacizumab
Postprogression therapy
12.6 19.9 31.8
Grothey A, et al. ASCO 2007. Abstract 4036.
n = 253 n = 531 n = 642
1.0
0.6
0.4
0.8
0.2
0
BEV + standard first-line CT (either
oxaliplatin or irinotecan-based)
(n=820)
Randomise 1:1
Standard second-line CT (oxaliplatin or irinotecan-
based) until PD
BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-
based) until PD
PD
ML18147 study design (phase III)
CT switch: Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin
Study conducted in 220 centres in Europe and Saudi Arabia
Primary endpoint • Overall survival (OS) from randomisation
Secondary endpoints included
• Progression-free survival (PFS) • Best overall response rate • Safety
Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based) • First-line PFS (≤9 months, >9 months) • Time from last BEV dose (≤42 days, >42 days) • ECOG PS at baseline (0/1, 2)
OS
0 6 12 18 24 30 36 42 48
OS
estim
ate
Time (months)
1.0
0.8
0.6
0.4
0.2
0
No. at risk CT 410 293 162 51 24 7 3 2 0 BEV + CT 409 328 188 64 29 13 4 1 0
9.8 11.2
HR: 0.81 (95% CI: 0.69–0.94) p=0.0062 (log-rank test)
PFS
PFS
estim
ate
Time (months)
1.0
0.8
0.6
0.4
0.2
0
410 119 20 6 4 0 0 0 409 189 45 12 5 2 2 0
4.1 5.7
CT (n=410) BEV + CT (n=409)
HR: 0.68 (95% CI: 0.59–0.78) p<0.0001 (log-rank test)
0 6 12 18 24 30 36 42
OS and PFS in the overall population
Lancet Oncol 2013 Jan;14(1):29-37.
Cetuximab (ERBITUX®) Mechanism of action
Cetuximab (Erbitux™)
• IgG1 monoclonal antibody• Binds to EGFR with high
specificity & affinity• Blocks receptor dimerization,
autophosphorylation and signal transduction• Promotes receptor internalization • May elicit ADCC response • Promising pre-clinical activity
Cetuximab has shown activity alone and in combination with irinotecan in EGFR-expressing tumours (1)
8,6
4,1
6,9
1,5
0,0
2,0
4,0
6,0
8,0
10,0
12,0
Overall survival* Time-to-progression
Med
ian
(mon
ths)
Cetuximab + irinotecan (n=218)Cetuximab alone (n=111)
Cunningham D et al. N Engl J Med 2004;351:337–45.*50% of patients in the monotherapy group received additional irinotecan after disease progression.
Patients had received at least one prior treatment regimen,including an irinotecan-based regimen
Overall response rate (primary endpoint) was 22.9% vs 10.8% for combination therapy vs cetuximab monotherapy (p=0.007)
COIN: Improved response but no survival benefit for cetuximab + mFOLFOX/XELOX
Arm A mFOLFOX/
XELOX
(KRAS wt, n=367)
Arm B mFOLFOX/
XELOX + cetuximab
(KRAS wt, n=362)
Odds ratio/
Hazard ratio
p-value
ORR, % 57 64 OR=1.35 0.049
Median PFS, months 8.6 8.6 HR=0.96 0.60
Median OS, months 17.9 17.0 HR=1.04 0.67
Reprinted from The Lancet, 377, Maughan TS, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer:
results of the randomised phase 3 MRC COIN trial., 2103–2114, 2011 with permission from Elsevier
OS & PFS for (C) KRAS wild-type,
NORDIC VII Study
J Clin Oncol 30:1755-
1762
NORDIC VII: phase III study of FLOX with or without cetuximab
Panitumumab
Panitumumab inhibe la unión de los ligandos al EGFR y la dimerización
Anticuerpo monoclonal IgG2 del EGFR completamente humano*
Gran afinidad, KD = 5 x 10-11 M Inhibe la fosforilación de la tirosina del
EGFR inducida por ligandos
Inhibición de la unión de EGF al
EGFR
Esto puede derivar en: Proliferación celular Supervivencia celular Angiogénesis Diseminación metastásica
* Que sea completamente humano no tiene correlación con su seguridad o eficacia
EGF, TGFα u otros ligandos que se unen al EGFR
Panitumumab monotherapy in WT Kras CRC
Amado R, et al. J Clin Oncol 2008;26:1626-1634
2 4 6 8 10 12 14 16 18
Median PFS:
7.3 weeks
Median PFS: 12.3 weeks
Prog
ress
ion
Free
Sur
viva
l (%
)
Weeks
0
10
20
30
40
50
60
70
80
90
100
0 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
HR: 0.45 (95% CI: 0.34-0.59) P < .0001
Panitumumab + BSC (n = 124) BSC (n = 119)
10 12 14 16 18 20
Douillard JY, et al. J Clin Oncol 2010;28:4697–4705 Reprinted with permission. © (2010)American Society of Clinical Oncology. All rights reserved; Douillard J-Y, et al. ASCO 2011 (Abstract No. 3510)
PRIME: Panitumumab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt)
Resp
onse
rate
(%)
01020304050
6070
FOLFOX Pani + FOLFOX
5748
p=0.018RR
Panitumumab +FOLFOX (n=325)FOLFOX (n=331)
HR=0.88 p=0.17
0.00 4 12 20 24 32 36
Time (months)8 16 28
0.2
0.4
0.6
0.8
1.019.7 23.9
Time (months)
0.00 2 4 6 8 22
HR=0.80 p=0.0098.6 10.0
PFS OS
0.2
0.4
0.6
0.8
1.0
PFS
estim
ate
OS
estim
ate
Panitumumab± FOLFIRI is also an option in chemorefractory KRAS wild-type patientsLike cetuximab, panitumumab is a monoclonal antibody that targets
EGFR and inhibits the growth of tumour cells1
1. Vectibix Prescribing Information: Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125147s0148lbl.pdf(Last accessed September 2012); 2. Peeters M et al. J Clin Oncol 2010;28:4706–13.
5,9
14,5
3,9
12,5
0,02,04,06,08,0
10,012,014,016,0
Progression-free survival Overall survival
Med
ian
surv
ival
(m
onth
s)
Panitumumab + FOLFIRI (n=303)FOLFIRI alone (n=294)
p=0.004
p=0.12
Adding panitumumab to FOLFIRI improved PFS compared with FOLFIRI alone in KRAS wild-type patients2
Response rate was improved to 35% vs 10% with the additionof panitumumab2
Primary endpoints • OS Secondary endpoints • RR, PFS, time to treatment failure • Duration of response
CALGB-C80405: Head-to-head study of cetuximab and/or bevacizumab + CT in 1st line mCRC
Patients with untreated KRAS wt mCRC
N=2234
Cetuximab + FOLFOX/FOLFIRI
Bevacizumab + FOLFOX/FOLFIRI
Open-label, randomized, multicenter Phase III
Available at clinicaltrials.gov/ct2/show/NCT00265850
Bevacizumab +cetuximab + FOLFOX/FOLFIRI*
R
*Arm closed to accrual as of 09/10/2009
Biological head-to-head study: PEAK
Primary endpoint
– Progression-free survival (PFS) Secondary endpoints
– Overall survival (OS), objective response (OR), duration of response (DoR), time to progression (TTP), time to response (TTR) and resection rate
Untreated
(unresectable) KRAS wt mCRC
n=285
Panitumumab + mFOLFOX6 (experimental arm)
Bevacizumab + mFOLFOX6 (comparator arm)
R
Schwartzberg LS et al., ASCO GI 2013 (abstract 446)
Pani + mFOLFOX6
PEAK: No significant difference in PFS or OS with panitumumab + CT vs BEV + CT
OS PFS
Schwartzberg LS et al., ASCO GI 2013 (abstract 446)
Pani + mFOLFOX6 (n=142) Bev + mFOLFOX6 (n=143)
Median PFS#, mos (95% CI) 10.1 (9.0‒12.6)
Median OS mos (95%CI) 25.4 (22.9‒29.5)
ORR#, n (% [95%CI])
Pts receiving subsequent therapy after tx phase – n (%) Anti-EGFR 17 (12) 44 (31) Anti-VEGF 43 (30) 32(22)
Abbreviation: NR, not reached. #Assessments based on investigator review per modified RECIST 1.0. Pts with measureable lesion were included in the ORR analysis.
100
80
60
40
20
0 0 4 8 12 16 20 24 28 32 36
Months
Prop
ortio
n ev
ent-f
ree
(%)
Bev + mFOLFOX6
10.9 100
80
60
40
20
0 0 4 8 12 16 20 24 28 32
Months
Prop
ortio
n ev
ent-f
ree
(%)
10.1 25.4 0.87 (0.65‒1.17) p=0.35
0.72 (0.47‒1.11) p=0.14
(CAIRO 2)
PACCE trial Hecht JR JCO 2009
Liver Metastases in Colorectal Cancer: Outcomes
Resectable 20% to 25%
Liver Metastases
Survival Benefit 30% to 40% at 5 years
15% at 10 years
Resectable 10% to 20%
Downsizing
Size
Location
Number Nonresectable
75% to 80%
Folprecht G, et al. Lancet Oncol 2010; 11: 38–47
All patients
ERBITUX + FOLFOX6
ERBITUX + FOLFIRI KRAS wt KRAS mt
n=106 n=53 n=53 n=67 n=27
CR/PR 62% 68% 57% 70% 41%
95% CI 52–72% 54–80% 42–70% 58–81% 22–61%
R0 resections 34% 38% 30% 33% 30%
95% CI 25–44% 25–52% 18–44% 22–45% 14–50%
Tumor response and R0 are higher in KRAS wild type
Chemotherapy ± Cetuximab for Patients With KRAS Wild-
Type Unresectable Colorectal Liver-Limited Metastases
Le-Chi Ye et al. J Clin Oncol 2013;31
Estudios II de bevacizumab en pacientes con sólo metástasis hepáticas Altas tasas de respuesta de mas del 70%
1. Masi, et al. Lancet Oncol 2010; 2. Gruenberger, et al. JCO 2008; 3. Wong, et al. Ann Oncol 2011
80% 73% 78%
OR
R (%
)
100
80
60
40
20
0 Bevacizumab + FOLFOXIRI
Bevacizumab + XELOX
Bevacizumab + XELOX
GONO1
(n=30) Gruenberger2 (n=56)
BOXER3 (n=45)
Tasas de Resecabilidad del 20-40%
Bevacizumab más quimioterapia incrementa las tasas de respuestas patológicas
Avastin mas quimioterapia incrementa significativamente las tasas de respuestas patológicas
Ribero, et al. Cancer 2007; Klinger, et al. Ann Surg Oncol 2010
Pat
ien
ts w
ith
<25
% r
esid
ual
viab
le t
um
ou
r ce
lls
(%)
5-FU + oxaliplatin
(n=43)
Avastin + 5-FU + oxaliplatin
(n=62)
45%
23%
p=0.02
0
20
30
40
50
10
22% absolute improvement in patients with <25% residual viable tumour cells (p=0.02)
Respuesta patológica: bevacizumab mas quimioterapiaIncremento significativo en la respuesta patológica mayor
Maj
or
pat
ho
log
ical
res
po
nse
(%
)
Chemotherapy(n=50)
Bevacizumab +chemotherapy
(n=50)
38%
10%
Klinger, et al. Ann Surg Oncol 2010
p<0.00140
35
30
25
20
15
10
5
0
Estudio OLIVIA Fase II RANDOMIZADO Beva + FOLFOXIRI vs Beva + FOLFOX
Objetivo ppal: Tasa de Resecabilidad
Objetivos secundarios: response rate, duration of response, secondary R0 surgery rates of metastases, overall survival, biomarker evaluation
Previously untreated,
unresectable mCRC
(solo Metas
Hepáticas) Avastin 5 mg/kg q2w
+ FOLFOXIRI evaluación cada 4 ciclos
Avastin 5 mg/kg q2w + FOLFOX
evaluación cada 4 ciclos)
R
Cirugía de Metás
+
QT adyuvante
Cirugía de Metas
+
QT adyuvante
Nuevos Fármacos
Aflibercept • Soluble fusion protein
• Consists of portion of extracellular domains of human VEGF receptors 1 and 2 fused to human IgG1 Fc portion
• Binds all VEGF-A isoforms, VEGF-B and PlGF
• High affinity: binds VEGF-A and PlGF more tightly than native receptors
• Half-life in humans ~17 days
Aflibercept
VEGFR-1
VEGFR-2 Fc
IgG
Van Cutsem et al. Ann Oncol. 2011;22(suppl 5). Abstract O-0024
Van Cutsem 2012
Regorafenib (BAY 73-4506), an oral multikinase inhibitor targeting multiple tumor pathways: CORRECT
Multicenter, randomized, double-blind, placebo-controlled, phase III – Stratification: prior anti-VEGF therapy, time from diagnosis of metastatic
disease, geographical region
Global trial: 16 countries, 114 centers
Recruitment: May 2010 to March 2011
2:1
Evaluation with CT scan of abdomen and chest every 8 weeks
Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final analysis)
2012 ESMO consensus guidelines
Schmoll HJ et al. Ann Oncol 2012;23:2479–516.
NCCN guidelines: http://www.nccn.org/index.asp date of access January 2013
Group 3 Patients with less aggressive disease or who are unable to tolerate standard CT regimens
Schmoll H-J, Sargent D. Lancet 2007;370:105–107 Expert discussion at ESMO/WCGIC June 2009, Barcelona
Group 1 Patients with potentially resectable metastases
Group 2 Patients with non-resectable metastases, high tumor burden, and tumor-related symptoms
Aggressive therapy Less aggressive therapy
CT=chemotherapy
2012 ESMO consensus guidelines – therapy should be guided by patient characteristics
Biomarcadores y Conocimiento Biológico
Bardelli and Siena, J Clin Oncl 2010;28:1254-1261
Otros Biomarcadores en el tramiento anti-EGFR en kras wt.
BRAF-mutant CRC: simply a “different” disease
Tran B et al. Cancer 2011;117:4623–32.
Perc
ent s
urvi
val
KRAS: 40% PIK3-CA: 14.5% BRAF: 4.7% NRAS: 2.6%
Rodriguez J et al. European Journal of Cancer 2012
Bevacizumab efficacy not affected by biomarker status
Survival benefit also independent of VEGF (plasma and tissue) and TSP-2
(0.45–1.10) (0.15–0.70)
0.70 0.32
26.35 25.07
99 47
17.45 16.26
92 28
191 75
p53 overexpression Positive Negative
(0.30–0.95) (0.32–1.42)
0.54 0.67
27.70 NR
76 35
21.72 16.36
63 31
139 66
p53 mutation status Mutant Wild-type
(0.37–1.20) (0.31–1.06)
0.67 0.57
19.91 27.70
51 68
13.60 21.72
37 57
88 125
KRAS and BRAF mutation status Mutant Wild-type
(0.01–1.06) (0.34–0.82)
0.11 0.53
15.93 26.35
7 120
7.95 17.45
3 97
10 217
BRAF mutation status Mutant Wild-type
(0.37–1.31) (0.34–0.99)
0.69 0.58
19.91 27.70
44 85
13.60 17.64
34 67
78 152
KRAS mutation status Mutant Wild-type
(0.39–0.85) 0.57 26.35 147 17.45 120 267 All subjects
(95% CI)
HR
Median (months)
n
Median (months)
n
N
Biomarker
Placebo + IFL
0.2 0.5 1 2 5
HR
Bev + IFL
Jubb, et al. JCO 2006; Ince, et al. JNCI 2005 Bev = bevacizumab; TSP-2 = thrombospondin-2
Tumour VEGF-A and neuropilin expression: PFS
Foernzler et al. ASCO GI 2010
All
First tertile
Second tertile
Third tertile
First tertile
Third tertile
First tertile
Second tertile
Third tertile
First tertile
Second tertile
Third tertile
First tertile
Second tertile
Third tertile
Category Subgroup
0.2 0.4 0.6 1 2 3 4 5 6
All
VEGF-A
HER2
EGFR
Neuropilin
VEGFR-1
247 0.70 (0.49–1.00)
80 0.91 (0.49–1.69)
83 0.74 (0.39–1.40)
78 0.57 (0.29–1.10)
158 0.60 (0.38–0.95)
77 0.90 (0.49–1.64)
88 0.64 (0.34–1.19)
73 0.67 (0.33–1.38)
79 0.72 (0.40–1.30)
81 0.46 (0.22–0.93)
84 0.61 (0.31–1.21)
79 0.99 (0.55–1.77)
76 0.73 (0.37–1.42)
79 0.61 (0.30–1.25)
75 0.73 (0.38–1.40)
n HR (95% CI)
Patients with higher levels of VEGF-A show increased benefit
Patients with lower levels of neuropilin show increased benefit
HR (95% CI)
NO16966mCRC
• In this study, data suggest that high tumour VEGF-A and low neuropilin expression are associated with improved PFS
Caracterización Molecular del CCR: Atlas Genómico
• The Recurrence Score result predicts recurrence risk in stage II and III colon cancer, revealing underlying biology to provide value beyond conventional measures.
• The Recurrence Score result enables better discrimination of absolute treatment benefit as a function of risk, with greatest clinical utility in T3 MMR-P stage II and stage IIIA/B patients.
• Incorporating the Recurrence Score result into the context of clinicopathologic variables may better inform adjuvant therapy decisions for patients with stage II and III colon cancer.
Oncotype DX® Colon Cancer Assay Incorporating the Recurrence Score® Result into Treatment
El intestino elimina habitualmente 0,6-1,2 ml de sangre al día
(Hb fecal < 2 mg por gramo de heces ). Mandel, NEJM 1993 Hardcastle, Lancet 1996 Kronborg, Lancet 1996
-30%
-18%-15%
-35%
-30%
-25%
-20%
-15%
-10%
-5%
0%
Minnesota (1) Nottingham (2) Funen (3)
Reducción de mortalidad por cáncer de colon
Screening
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