“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

¡ Muchas Gracias!

pgarcaalfonso@gmail.com