promising future biomarkers for colorectal cancer: focus on targeted therapies
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Promising Future Biomarkers For Colorectal Cancer: Focus on Targeted Therapies. Lee M. Ellis, MD Depts of Surgical Oncology and Cancer Biology UT MD Anderson Cancer Center Houston, Texas USA. A Few Definitions A “marker” is not a “marker” is not a “marker”. Prognostic marker - PowerPoint PPT PresentationTRANSCRIPT
Promising Future Biomarkers For Colorectal Cancer:
Focus on Targeted Therapies
Lee M. Ellis, MD
Depts of Surgical Oncology and Cancer Biology
UT MD Anderson Cancer Center
Houston, Texas USA
• Prognostic marker– associated with clinical outcome, independent of specific treatment
• Predictive marker– identifies groups receiving different degrees of benefit
from a therapy – specific for a given treatment (i.e., Ras for EGFR MoABs in CRC, HER2
expression for trastuzumab)
• Surrogate / activity marker– modulated by treatment– may be on target tissue (tumor) or surrogate tissue
(i.e., lymphocytes, skin)– might or might not correlate with clinical activity
A Few DefinitionsA “marker” is not a “marker” is not a “marker”
CRYSAL TrialWe Need to Do Better!!
Van Cutsem et al. NEJM 2009
• EGFR– Downstream signaling pathways
• RAS (Lenz)
• Raf
• PTEN/PI3K
– AACR Presentations (including EGFR amplifications)
• VEGF– ?
Biomarkers for Targeted Therapies in CRC
I apologize in advance for some mixing and matching as some studies report more than one marker.
Survival (anti-apoptosis)
Gene transcriptionGene transcriptionCell-cycle progressionCell-cycle progression
Angiogenesis
Invasion andmetastasis
Chemotherapy /radiotherapy resistance
Proliferation
pY
Ligand
Antibodies to EGFRcetuximab, panitumumab
EGFR-TKpY
EGF Receptor:EGF Receptor: Its Role in CRC Therapy Its Role in CRC Therapy
Meyerhardt & Mayer, N Engl J Med 2005Venook, Oncologist 2005
RAS RAF
MEK
MAPK
PI3K
AKTSTAT
PTEN
pY
pY
“Bypass” Pathways and EGFR Resistance
Clin Ca Res, Jan 2005
Now that Mutated K-Ras is an Established Marker of Resistance,
the Next Advance will be in the identification of resistance markers
in K-Ras Wild-type tumors
CRC
K-Ras WTK-Ras MT
B-RafPI3KPTENEGFR copy #
EGFR MoAB?
Bypass Pathways and EGFR Resistance
Camp et al Clin Ca Res 2005
B-Raf and Resistance to EGFR MoABs
• Mutated in 3-15% CRC
• Ras and Raf mutations exclusive of each other
• Gain-of-function mutations– Inability to convert the active form to inactive confirmation
Schubbert et al. Nat Rev Ca, 2007
“We hypothesized that in K-ras wild-type patients, B-raf mutations could have prognostic/predictive value.”
• All pts had progressed on at least one line of therapy– ~50% received monotherapy
with EGFR MoAB– ~50 MoAB with chemotherapy
• In patients with tumors with Mut B-raf, there were NO objective responses
Nicolantonio et al. JCO 2008Wild-Type BRAF is Required for Response to..(EGFR MoABS)
Wild-type K-ras
All Patients
B-Raf Predicts for Benefit of Anti-EGFR Therapy in Patients with WT Ras and the Entire Cohort
PFS OS
Ras and PFS
Bypass Pathways and EGFR Resistance
Camp et al Clin Ca Res 2005
Planchon et. al., J Cell Sci, 2008
Classic PTEN Pathway: Inhibition of the Activation of AKT
• PTEN is a phosphatase that blocks activation of Akt / survival pathway– Loss of function of PTEN associated with an increase in cell
survival signaling
Planchon et. al., J Cell Sci, 2008
PTEN Pathway – Functions in the Cytoplasm and Nucleus
Nuclear PTEN plays a role in chromosome stability, DNA repair, cell cycle arrest and cellular stability.
44th ASCO Annual Meeting, 2008
“PTEN …. Intensity was scored according to a four-tier system: 0, no staining; 1, weak; 2, moderate; and 3, strong. We attributed one, two, or three additional points if the percentage of positive cells was less than 25%, 25% to 50%, or greater than 50%, respectively. Specimenswere defined as positive if the score was 4 or greater.”
Loupakis et al. JCO 2009
Logrank Test: p=0.005HR = 0,49 95% CI: 0.20-0.75
PTEN+
PTEN-
PTEN Expression and PFS
• Only PTEN in the metastasis was predictive of efficacy.– PTEN in the primary tumor was NOT predictive of efficacy.
• PTEN in the primary tumor and liver metastasis was concordant in only 60% of cases
• pAKT was NOT predictive of efficacy.
Loupakis et al. JCO 2009
•
Challenges with PTEN• Expression in primary tumors does not reflect
expression in metastases– Although it is not lost or mutated in CRC, its expression
can be regulated by methylation or miRNA
• It will be hard to standardize IHC in different labs
Supplemental Figure 1: Representative examples of PTEN positive (A, B) and negative (C, D) cases. The cases reported in A and C panels were evaluated atOspedale Niguarda Ca’ Granda (Milan, Italy) whereas those in B and D at the Institute of Pathology in Locarno (Switzerland).
Sartore-Bianchi et al. Cancer Res 2009.
Bypass Pathways and EGFR Resistance
Camp et al Clin Ca Res 2005
Point Mutations in PIK3CA Observed in Human Tumors
Bader et al., Nat Rev Cancer 2005
Hotspots
Exon 9
Exon 20
CRC
Prenen, H. et al. Clin Cancer Res 2009
Fig. 1
Cetuximab 16
Cetuximab/Irinotecan 184
Sartore-Bianchi, A. et al. Cancer Res 2009
PFS and PIK3CA Mutational Status in mCRC Patients Treated With Panitumumab and Cetuximab
Cetuximab 13%
Panitumumab 20%
Cetuximab/Irinotecan 67%
110 pts> 85% received at least 1 prior Rx
• EGFR– Downstream signaling pathways
• RAS (Lenz)
• Raf
• PTEN/PI3K
– AACR Presentations (including EGFR amplifications)
• VEGF– ?
Biomarkers for Targeted Therapies in CRC
CAIRO -2 STUDY
CAPOX + Bevacizumab +/- Cetuximab755 Pts
Tissue in 545
EGFR copy number 7% no difference in PFS
among arms
Loss PTEN 42% no difference in PFS
Tol et al. Proc AACR, 2009 Abstract 691
EGFR amplification and PTEN did NOT predict for response to chemo + cetuximab therapy
BRAF & EGFR Amplification in Metastatic
CRC with Wild-type K-Ras 173 Pts
Factor RR PFS OS
Raf +/- 8 vs 31 wks 7 vs 15 mos
EGFR Amp
+
PTEN loss - - 12 vs 16 mos
Ras Wt (116)
Ras Mut (57)
PTEN
Negative Positive
EGFRAmplification
Raf Mt
WT Kras/ WT BRAF/ EGFR Amp = 80% RR
Laurent-Puig et al,Proc AACR 2009, A1897
Cetuximab based therapy
Do Mutations / Aberrations in the Primary Tumor Reflect the
Metastasis?
Pathway Primary Tumor Metastasis
K-Ras Mut 16/37 15/37
B-Raf Mut 2/36 2/36
PTEN Loss 8/38 12/38
EGFR Amplification
25/36 29/36
Overall, mutations do not change between the primary and the metastasis.But….expression levels or gene amplification may change.
The Role of PREDICTIVE Markers for Efficacy of EGFR MoABs
The sure thing ProbablyYes
Maybe, jury is still out No
K-Ras B-Raf PI3K mutations EGFR by IHC
EGFR amplification
PTEN
Gene expression arrays
• Excluding patients from EGFR MoAB Rx by use of multiple predictive factors will greatly increase the efficacy of EGFR MoABS • It is imperative to PROSPECTIVELY include biomarkers and tissue procurement in clinical trials
− When possible, biomarkers in primary tumors and liver metastasis should be compared
• Mutational status gives you a “black and white” answer and is more likely to be reproducible relative to other biomarkers (IHC, etc)
• EGFR– Downstream signaling pathways
• RAS (Lenz)
• Raf
• PTEN/PI3K
– AACR Presentations (including EGFR amplifications)
• VEGF– ?
Biomarkers for Targeted Therapies in CRC
What Holds Promise in Anti-VEGF Therapy?
None currently identified in CRC!
Hahn, O. M. et al. J Clin Oncol; 2008
Kaplan-Meier estimates for progression-free survival (PFS) of patients with low and high baseline volume transfer constant of contrast agent (Ktrans) and blood plasma volume fraction (Vp)
Schneider, et al. J Clin Oncol; 2008
Kaplan-Meier curve for overall survival (OS) in experimental arm by genotype; (A) vascular endothelial growth factor (VEGF)-2578 C/A; (B) VEGF-1154 G/A
VEGF Polymorphisms and Predictive Value in ECOG-2100
(Pac +/- Bev Metastatic Breast Cancer)
Caveats: • Predictive for OS, but not PFS• Small numbers• Did not include Pac Rx alone group
• Prognostic marker– associated with clinical outcome, independent of specific treatment
• Predictive marker– identifies groups receiving different degrees of benefit
from a therapy – specific for a given treatment (i.e., Ras for EGFR MoABs in CRC, HER2
expression for trastuzumab)
• Surrogate / activity marker– modulated by treatment– may be on target tissue (tumor) or surrogate tissue
(i.e., lymphocytes, skin)– might or might not correlate with clinical activity
A Few DefinitionsA “marker” is not a “marker” is not a “marker”
The Harvest of a Decade of
Biomarker Studies for Anti-angiogenic
Therapy
George Sledge
Grade 3/4 Hypertension Is Associated With Improved Median OS in E2100
Median OS:
25.3 mo vs. 38.7 mop=0.002
Schneider et al; J Clin Oncol, 2008
Reference N Malignancy Treatment Main Findings
Scartozzi et al.
39;25;11
Colorectal cancer
5-FU, irinotecan + bevacizumab
20% grade 2-3 HT; response in patients with grade 2-3 HT: 75% (n = 8) versus 32% (n = 31), P = 0.04
Rixie et al. 40; 32 mRCC Sunitinib 22.5% grade 3 HT; response in patients with grade 3 HT: OR 5.69 (95% CI 2.51-12), P = 0.03
Rini et al. 52 Cytokine-resistant mRCC
Axitinib Overall survival in patients with DBP ≥90 mmHg: not reached (n = 32) versus 12.9 months (n = 20)
Rini et al. 62 Sorafenib-resistant mRCC
Axitinib Overall survival in patients with DBP ≥90 mmHg: not reached (n = 39) versus 8.4 months (n = 23)
Spano et al. 69 Pancreatic carcinoma
Gemcitabine + Axitinib
6% grade 3 HT, 22% all-grade HT; overall survival in patients with DBP ≥90 mmHG: 13.0 months (95% CI 8.5-16.6) versus 5.6 months (95% CI 4.8-7.2)
Friberg et al. 52 Pancreatic carcinoma
Gemcitabine + bevacizumab
19% grade 3 HT; overall survival in patients with early HT (<56 days of treatment): 13.7 months versus 8.7 months (P = 0.007)
Rini et al. 32 Melanoma Axitinib Overall survival in patients with DBP ≥90 mmHg: 13 months (n = 19) versus 6.4 months (n = 13)
Rini et al. 32 NSCLC Axitinib Overall survival in patients with DBP ≥90 mmHg: 15 months (n = 19) versus 11.6 months (n = 13)
Rini et al. 60 Thyroid cancer
Axitinib Overall survival in patients with DBP ≥90 mmHg: not reached (n = 39) versus 21.6 months (n = 21)
Schneider et al.
345 Breast cancer Paclitaxel + bevacizumab
Overall survival in patients with grade 3-4 HT (n = 52): 38.7 months versus 25.3 months (n = 293), P = 0.02
Mir et al. Ann Onc 2009
Relationship Between HTN and the Efficacy of Anti-VEGF Rx
Numerous Studies Testing Dose Escalation of VEGF Inhibitors
A Dose Escalation Study of Sorafenib (BAY 43-9006, NSC 724772) in Normotensive Patients with Advanced Malignancies-Michael Maitland, Univ of Chicago
Angiogenic Cytokines Are Increased Prior to Disease Progression In Metastatic Colorectal Cancer Patients Treated With Bevacizumab
Scott Kopetz, Paulo M. Hoff, Cathy Eng, Michael Overman, Katrina Y. Glover, David Z. Chang, Robert
A. Wolff, James L. Abbruzzese, Lee M. Ellis, John V. Heymach
The University of Texas, M.D. Anderson Cancer Center, Houston, TexasCentro de Oncologia, Hospital Sírio Libanês, Sao Paulo, Brazil
• Sample Collection Study Aim 1:
• Subsequent samples were obtained every two weeks• n=40 with evaluable samples at the selected time points
Study Methods
Bevacizumab
FOLFIRI
Bevacizumab
Cycle 1Day 1
Cycle 2Day 15
Cycle 3Day 29
After Bevacizumab After FOLFIRI + BevBaseline
Cycle 4+Day 43
Bevacizumab
FOLFIRI
Every 2 weeks
Cytokines Increased Prior to Progression
Conclusions: Future PREDICTIVE Biomarkers for Targeted Therapies in mCRC
• EGFR MoABs– K-Ras ---- current and validated!– B-Raf– Not ready for prime time
• PI3K mutations?• PTEN?• EGFR amplifications?• Gene arrays (under study)?
• VEGF MoAB– Wide open– Can we learn from other disease sites?
• VEGF polymorphisms?
– I predict that imaging will be the answer
ASCO 2009…Tons of Colorectal CancerPredictive Biomarker Abstracts
Type: General Poster SessionTime: Sunday May 31, 8:00 AM to 12:00 PMLocation: Level 2, West Hall C
Type: Poster DiscussionTime: Monday June 1, 8:00 AM to 12:00 PMLocation: Level 2, W240ADiscussion: Monday June 1, 11:00 AM to 12:00 PMLocation: Level 2, West Hall E1