the her superfamily of receptors and related pathways in gastroesophageal cancers
DESCRIPTION
The HER Superfamily of Receptors and Related Pathways in Gastroesophageal Cancers. AKA: ToGA: The starting point. Jordan Berlin, M.D. Ingram Associate Professor of Medicine Vanderbilt-Ingram Cancer Center. Disclosures. For this talk Advisory board and research support: Roche/Genentech - PowerPoint PPT PresentationTRANSCRIPT
The HER Superfamily of Receptors and Related
Pathways in Gastroesophageal Cancers
Jordan Berlin, M.D.
Ingram Associate Professor of Medicine
Vanderbilt-Ingram Cancer Center
AKA: ToGA: The starting point
Disclosures
For this talk
– Advisory board and research support: Roche/Genentech
– Advisory Board and research support: Amgen
– Research Support: Lilly/Imclone
I have a lot of relationships, but no others relevant
ToGA trial design
HER2-positiveadvanced GC
(n=584)
5-FU or capecitabinea + cisplatin(n=290)
R
aChosen at investigator’s discretion GEJ, gastroesophageal junction
5-FU or capecitabinea + cisplatin
+ trastuzumab(n=294) Stratification factors
− advanced vs metastatic − GC vs GEJ− measurable vs non-measurable− ECOG PS 0-1 vs 2− capecitabine vs 5-FU
Phase III, randomized, open-label, international, multicenter study
1Bang et al; Abstract 4556, ASCO 2009
3807 patients screened1
810 HER2-positive (22.1%)
Rationale for trastuzumab in HER2-positive GC
There is no universal standard treatment, but– fluoropyrimidine (capecitabine / 5-FU) / platinum
(cisplatin / oxaliplatin)-based chemotherapy considered as reference regimen
• epirubicin or docetaxel sometimes added• biologicals are under investigation
Unmet need for new treatment options in advanced gastric cancer
Some gastric adenocarcinomas are HER2 positive Trastuzumab is effective against HER2-overexpressing
GC cell lines in vitro and in vivo
Fujimoto-Ouchi et al 2007; Gravalos & Jimeno 2008
Primary end point: OS
Time (months)
294290
277266
246223
209185
173143
147117
11390
9064
7147
5632
4324
3016
2114
137
126
65
40
10
00
No. at risk
11.1 13.8
0.00.10.20.30.40.50.60.70.80.91.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Event
FC + TFC
Events
167182
HR
0.74
95% CI
0.60, 0.91
p value
0.0046
MedianOS
13.811.1
T, trastuzumab
Secondary end point: PFS
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Event
294290
258238
201182
14199
9562
6033
4117
287
215
133
93
82
62
61
61
40
20
00
5.5 6.7
No. at risk
0.00.10.20.30.40.50.60.70.80.91.0
Time (months)
FC + TFC
Events
226235
HR
0.71
95% CI
0.59, 0.85
p value
0.0002
MedianPFS
6.75.5
113
OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)
1.0
0.8
0.6
0.4
0.2
0.0
363432302826242220181614121086420
Time (months)
11.8 16.0
FC + T
FC
Events
120136
HR
0.65
95% CI
0.51, 0.83
MedianOS
16.011.8
Event
0.1
0.3
0.5
0.7
0.9
218 198
40
53
124
2011
228 218
196 170
170 141
142 112
12296
10075
8453
6539
5128
10
00
No. at risk
3920
2813
CALGB 80403 / ECOG E1206: Schema
Stratification:ECOG 0-1 vs 2ADC vs. SCC
ARM A: (ECF + cetuximab); 1 cycle = 21 days
Cetuximab 400 250mg/m2 IV, weeklyEpirubicin 50 mg/m2 IV, day 1Cisplatin 60mg/m2 IV, day 1Fluorouracil 200mg/m2/day, days 1-21
ARM B: (IC + cetuximab); 1 cycle = 21 days
Cetuximab 400 250mg/m2 IV, weeklyCisplatin 30 mg/m2 IV, days 1 and 8Irinotecan 65 mg/m2 IV, days 1 and 8
ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days
Cetuximab 400 250mg/m2 IV, weeklyOxaliplatin 85 mg/m2 IV, day 1Leucovorin 400 mg/m2, day 1Fluorouracil 400 mg/m2 IV bolus, day 1Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)
Enzinger PC and Burtness B, et al. ASCO 2010
• Cetuximab: chimerized monoclonal antibody - EGFR (oropharyngeal cancer , NSCLC, and colorectal cancer)
• EGFR expression – 3/4 of ADC and SCC 1-5
• EGFR expression correlates with prognosis in esophagogastric ADC and SCC 1-5
• KRAS mutations occur in approx. 2% of esophageal cancers6
CALGB 80403 / ECOG E1206: Background
1-5 Mukaida. Cancer 1991; Itakura. Cancer 1994; Yacoub. Mod Pathol 1997; Torzewski. Anticancer Res 1997; Koyama. J Cancer Res Clin Oncol 1999; 6 Lea. Carcinogenesis 2007
ECF-C IC-C FOLFOX-C Total N=67 N=71 N=72 N=210
Mos 95% c.i. Mos 95% c.i. Mos 95% c.i. Mos 95% c.i. OS median 11.5 (8.1,12.5) 8.9 (6.2,13.1) 12.4 (8.8,13.9) 11.0 (8.8,12.3) # dead 51 52 51 154 PFS median 5.9 (4.5,8.3) 5.0 (3.9,6.0) 6.7 (5.5,7.4) 5.8 (5.1,6.8) # dead/pd 57 64 63 184 TTF median 5.5 (3.9,7.2) 4.5 (3.6,5.6) 6.7 (4.8,7.2) 5.5 (4.5,5.9)
#dead/pd/ off forAE 58 66 64 188
CALGB 80403/ECOG 1206: Survival
So what happened? ToGA worked and there is no real signal
from ECOG/CALGB trial
– Is this a failure of the “science?”
– Does HER 2 overexpression mean something different than HER 1 (EGFR)?
Data from breast, colon and lung cancer don’t suggest they are the same. Her 2 is a driver, but HER 1 is not in most cases
– Am I reading too much into CALGB/ECOG trial?
Authors of REAL3 and EXPAND hope so
Next Steps
TOGA identified that for a small subset of GE patients, trastuzamab helps improve survival but not miraculously
We need to identify further targets, optimization of identified targets and how to combine targeted therapies
How do we select?
HER family HER 1, 2, 4 transmembrane protein with
extracellular ligand binding domains and intracellular tyrosine kinase domain
HER 3 membrane bound with ligand binding domain (neuregulin, for example) but no kinase domain
– HER 3 heterodimerization may be key effector of HER2 activation
Activation by ligand results in homo- or heter-dimerizaiton and activation of PI3k and/or MAP K pathways
www.cellsignal.com/reference/pathway/ErbB_HER.html
www.cellsignal.com/reference/pathway/ErbB_HER.html
Underlying etiology
Find a driver of cell growth such as Her 2
One place to start is with the start of the cancer
Helicobacter Pylori– Increasing evidence that CagA + H. Pylori
stimulates malignant transformation– Some data exists on methods by which H.
Pylori stimulates this process
H Pylori
CAG A + H. Pylori binds to CD 74 receptor
– This results in IL-8 production (other cytokines) through NF-kappa B activation
– Induces CD 74 expression
– MEK inhibition may decrease the IL-8 production
Beswick EJ, et al J Immunol 2005;175;171-176Sekiguchi H, et al Biosci Biotechnol Biochem. 2010;74:1018-24
What can CAG-A induce?
It has been associated with activation of – EGFR (red because it appears to come
up with all the below)MAP kinase
AKT
ERK
PI3 kinase
Nagy TA, et al J Infect Dis 2009; 199:641–5Tabassam FH, et al Cellular Micro 2009:11, 70–82Chen Y-C, et al W J Gastro 2006; 12: 5972-5977
Underlying etiology as a target
Based on this evidence, EGFR should be a key target
– Also, Ras mutations are rare (<2%)
H. Pylori is not the only etiology of gastric cancer and not the cause of esophageal cancer
– Likely more important in distal gastric cancer– ECOG/CALGB studied esophagus and GE junction
Is it possible EGFR inhibition is more relevant in H. Pylori associated disease?
Is it possible that if EGFR is an inciting event, by the time we find the cancer, it is too late to block EGFR and make a difference?
Target differences by location: Not a new concept
HER 2 overexpression by location
– GE junction: 24-32%
– Corpus/antrum: 10-18%
HER 2 overexpression by histology
– Diffuse: 2-7%
– Intestinal: 16-34%
Is it possible that activation of a kinase may have different effects in different cells?
Colon cancer and EGFR as an example:– EGFR inhibitors don’t work (and in some settings
may harm) if Ras is mutatedIs PI3 kinase irrelevant in this setting?Or is it that unbalanced stimulation of PI3K by EGFR
results in harm in some cases when Ras is also activated?
To butcher Orwell,– “All pathways are equally relevant but some are
more equally relevant than others”, but which pathway is more equally relevant varies
MET activation results in activation of beta catenin pathwasy, PI3kinase pathway, STAT pathway and NOTCH pathwayMET appears to prolong Ras induction and Ras mediates MET activation
Every protein and its brother stimulates PI3K and MAPkinase pathways
C-MET I get to talk about it because they said I should talk
about all the proteins that interact with the HER family and C-MET does
Overexpressed in both gastric and esophageal cancers
– In esophageal cancer, expression increases in the pathway from metaplasia to adenocarcinoma
Can confer poor prognosis Preclinical studies show some cell lines
susceptible to MET inhibition C-MET can activate HER signaling through cross-
talk with HER family receptorsAnderson MR, et al Clin Cancer Res 2006;12:5936-5943 Arkenau H-T J Cancer Res Clin Oncol 2009;135:855–866
C-MET inhibitionC-Met inhibition has worked in
both gastric and esophageal cell lines– C-Met inhibition in esophageal cancer
In at least one cell line (Flo-1), MET increased PI3K/AKT and PI3K inhibition mimicked the effects of MET inhibition
That means that in Flo-1 cells, PI 3 kinase mediates MET activity
Annotating the cell lines may help us better understand what works and when
Watson GA, et al Neoplasia . 2006, 8:949 – 955
C-MET Inhibition
Clinically, minimal data, but not impressive– Can the lab tell us why? One example:
Took C-MET addicted cell lines and made them resistant to inhibition
– Displayed C-MET gene amplification
– Progressively developed Wt Kras amplification
– Cells became resistant to C-Met inhibition but dependent on K-Ras
– Too bad we can’t inhibit Ras
Cepero V, et al Cancer Res 2010; 70; 7580–90.
Further complexity Src: a non-receptor tyrosine kinase
– Commonly activated in gastric cancer– Induces activation of ERK and AKT– In cell lines sensitive to Src inhibition, this results in
decreased phosphorylation of ERK and AKT and increased apoptosis
In a study of 16 gastric cancer cell lines, 14 with activated Src
– Dasatinib inhibited Src activated cell lines as long as MET was not activated
– MET inhibition inhibited Src resistant cell lines with Src activation
– Neither method inhibited cell lines without Src activation
Okamoto W, et al. Mol Cancer Ther 2010;9:1188-1197
HER and MET
Studies have now shown that activation of HER family receptors confers resistance to MET inhibition
– Activation of EGFR by providing ligand or by adding mutated, constitutively activated EGFR led to AKT and MAPK activation and resistance to MET inhibition
– HER 2/HER3 upregulation conferred secondary resistance to CMET inhibition
– MET independent activation of HER family receptors reactivates MAPK and AKT phosphorylation
Bachleitner-Hoffman, et al Mol Cancer Ther 2008;7:3499–508Corso et al. Molecular Cancer 2010, 9:121
What can we learn from the limited C-MET story I’ve shown?
C-Met, like HER family has complex interactions with other signaling pathways
Upregulation of C-MET doesn’t always mean C-MET sensitivity
There are many mechanisms of resistance to C-MET
– Mutations in another pathway, – Upregulation of pathway proteins– Gene overexpression – Stimulation by ligand of another, complimentary (HER)
pathway In turn, C-MET activation can confer resistance to
inhibition of another pathway
Bringing it Back to HER
Why is trastuzamab good, but no miracle?
– Cross-talk between pathways is clearly important
– Genetic variations in the interacting pathways occur (eg AKT, PTEN, PI3kinase)
– Mutations in interacting pathways occur (Ras 2%, AKT 2%, PI3K 16%)
– All of the above can confer either primary or secondary resistance
Hildebrandt MAT, et al J Clin Oncol 2009;27:857-871.Barbi et al. Journal of Experimental & Clinical Cancer Research 2010, 29:32Soung YH, et al Oncology 2006;70:285–289
HER is at the top of the cascade, why not go to the bottom?
www.cellsignal.com/reference/pathway/ErbB_HER.html
www.cellsignal.com/reference/pathway/ErbB_HER.html
The bottom (or close to it)
Yoon, et al showed that different co-mutations led to differential responsiveness of lung cancer lines to MEK inhibition
In HER activated, MET resistant cell lines, MAPK and AKT inhibition were both required to inhibit cell growth
PI3K mutations confer resistance to MEK inhibitors, especially in presence of Ras mutation
And the list goes on
Yoon Y-K, et al MOLECULAR CARCINOGENESIS 49:353–362 (2010)
Bachleitner-Hoffman, et al Mol Cancer Ther 2008;7:3499–508Wee S, et al Cancer Res 2009;69:4286-4293
Conclusions I Cancer is “driven” to grow
The HER superfamily and its downstream effectors are drivers of many gastroesophageal cancers (and other cancers too)
Targeting this superfamily will likely yield results
But to truly win, we have to get smarter
Gettin’ Smarter Characterize our cell lines Determine which variables predict for
sensitivity to which inhibitors Test our patients for these variables
and treat based on these variables Determine mechanisms of resistance
so we are ready to adjust It’s time to split, not lump
– Challenge will be in trial design