Perspectives in advanced colorectal cancer
Chris Verslype, MD PhD Eric Van Cutsem, MD, PhD
University Hospital Gasthuisberg Leuven, Belgium
Barcelona, June 16, 2005
Metastatic Colorectal Cancer
- Progress
has been made in the management:
“one drug” disease five active drugs - Most patient still die - Important challenges:
1. optimal selection of patients: implement the increasing
knowledge on molecular markers and pharmacogenomics in clinical practice 2. define the specific molecular targets of the novel agents 3. develop a treatment strategy for different lines
4. strategies to increase CR and cure rate: multimodal R/
What are molecular markers for?
• Prognostic markers for risk-adapted therapy – Stage II and Stage III colon cancer: adjuvant chemotherapy – Stage II and III rectal cancer: adjuvant chemoradiation • Predictive markers for tailored/individualized therapy – Adjuvant regimens – Advanced-disease regimens
Molecular determinants of outcome in colorectal cancer
• Microsatellite instability, allelic deletions • Oncogenes and suppressor genes (c-myc, Ki-Ras, p53, p21, Topo I, Topo II, Fos,
hMLH1, Bcl-2/Bax and MDR1)
• MDR-related proteins (Pgp, MRP and LRP)
• Genomic polymorphisms (XPD, ERCC1, GSTP1 and TS 3´-UTR) • COX-2 • Ki-67 • …
TS, TP and DPD vs. survival
Estimated Probability of Surviving
1.00
0.90
0.80
0.70
0.60 0.50
TS<=4,TP<=18, and DPD<=2.5 (n=12) TS>4, or TP>18, or DPD>2.5 (n=21)
p<0.0001 (Logrank)
6 12 18 24 30 36
0.40
0.30 0.20
0.10
0.00 0
Months since start of chemotherapy
Salonga D et al. Clinical Cancer Research 2000; 6: 1322-1327
MSI phenotype and 5-FU based adjuvant chemotherapy
Elsaleh et al. Lancet 2000; 355: 1745-1749
low ERCC1 n=40
Low ERCC1 (N=40)
High ERCC1 (N=10) high ERCC1 n=10
p=0.001
p<0,001
N=50
From the irinotecan metabolism to toxicity prediction Polymorphism of promotor of UGT1A1
Ando et al. Cancer Research, 2000; 60: 6921
100% 80% 60% 40% 20% 0% -/- UGT1A1*28 -/+ UGT1A1*28 +/+ UGT1A1*28 no toxicity
Leucopenia+ diarrhea grade III +IV
The emerging Integrated Circuit of the Cell
Hanahan & Weinberg, Cell 2000;
The emerging Integrated Circuit of the Cell
Human genome : 518 kinases (90 Tyrosin kinases)
Hanahan & Weinberg, Cell 2000; G. Manning, Science, 2002
Correlation of rash and survival after treatment with cetuximab
16 Survival (months) 14 12
10 8 6
4 2 0
CRC
Study:
9923
CRC
0141
CRC
BOND
CRC
Van Cutsem (2004)4
Pancreatic
Xiong (2004)5
SCCHN
Kies (2002)6
Saltz (2001)1
Saltz (2004)2 Cunningham (2004)3
No reaction
Grade 1
Grade 2
Grade 3
1. Saltz et al. Proc ASCO 2001. 2. Saltz et al. J Clin Oncol 2004. 3. Cunningham D…Van Cutsem E. N Engl J Med 2004. 4. Van Cutsem et al. EORTC/NCI Geneva 2004. 5. Xiong H et al. J Clin Oncol 2004. 6. Kies et al. Proc ASCO 2002.
Can we find other parameters to predict response to EGFR inhibitors?
SKIN
1 2
Biomarker Assays
Grb2 Sos Shc Grb2
TUMOR
pEGFR
K
Shc K
pEGFR
PI3K
Sos
Ras
pMAPK
PTEN
Akt
Raf
pMAPK
GSK-3 mTOR
FKHR
Bad p27
MEK1/2
Survival
MAPK
pAkt
D1 Cyclin Cell cycle progression
Proliferation
p27
p27
Mutations in TK-domain in lung cancer
N = 120, heterozygous mutations in exons 18-21 (codons 746-759) † Resp vs. non-response 8/9 vs. 0/7 NSCLC Other tumours 2/25 0/95
N = 119, heterozygous somatic mutations in codons 746-759 ‡ Female vs. male Adeno vs. others Japan vs. others Non- vs. smokers Resp vs. non-response 20 vs. 9% 21 vs. 2% 26 vs. 2% 54 vs.11% 5/5 vs. 0/4
† Lynch, NEJM 2004; 350: 21 ‡ Gullermo-Paez, Science 2004; 304: 1497
Molecular tumour characteristics and response to Avastin plus IFL in metastatic CRC: predictive hazard ratios for risk of death according to biomarker status and treatment subgroup
Placebo plus IFL Biomarker All subjects Total n 267 78 152 10 217 88 125 139 66 191 75 57 130 n 120 34 67 3 97 37 57 63 31 92 28 28 55 Median (months) 17.45 13.6 17.64 7.95 17.45 13.6 21.72 21.72 16.36 17.45 16.26 18.66 17.64 n 147 26.35 44 19.91 85 27.7 7 15.93 120 26.35 51 19.91 68 27.7 76 27.7 35 NR 99 26.35 47 25.07 29 NR 75 27.7 Avastin plus IFL Median (months) HR 0.57 0.69 0.58 0.11 0.53 0.67 0.57 0.54 0.67 0.70 0.32 0.47 0.37 (95% CI) (0.39–0.85) (0.37–1.31) (0.34–0.99) (0.01–1.06) (0.34–0.82) (0.37–1.20) (0.31–1.06) (0.30–0.95) (0.32–1.42) (0.45–1.10) (0.15–0.70) (0.18–1.19) (0.20–0.69)
0.2 0.5 1 2 5
HR favouring, Avastin Placebo
k-ras sequencing Mutant Wild type
b-raf sequencing Mutant Wild type
K-ras and b-raf sequencing Mutant Wild type
p53 sequencing Mutant Wild type p53 immunohistochemistry Positive Negative VEGF-A in situ Hybr. Score = 3 Score <3
Koeppen H, et al. Eur J Cancer Suppl 2004;2:48 (Abstract 150)
Individualisation of treatment in metastatic CRC
…..
TS TP
P53 Tumor
MSI Topo I
EGFR, VEGF, Cox-2, IGF…
Patient
Individual personal treatment
Pharmacogenetics : cytotoxic metabolism