Molecular Subtypes: Ready for Prime Time Wells Messersmith, MD, FACP Professor Director,...
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Molecular Subtypes: Ready for Prime Time Wells Messersmith, MD, FACP Professor Director, Gastrointestinal Medical Oncology Program Co-Head, Division of
Molecular Subtypes: Ready for Prime Time Wells Messersmith, MD,
FACP Professor Director, Gastrointestinal Medical Oncology Program
Co-Head, Division of Medical Oncology Program co-Leader,
Developmental Therapeutics March 2014
Slide 2
Conflict of Interest: 1.No employment, speakers bureaus, stock
ownership, royalties, patents, etc 2.Data Safety Monitoring Board
for OncoMed 3. PI or Local PI of clinical trials by
Genentech/Roche, GSK, Pfizer, Millenium, Bayer, Onconova, and
NIH/CTEP.
Slide 3
Outline/Objectives: 1.Introduction 2.Molecular subtypes already
in use 1.KRAS/NRAS (added wrinkle: L v R?) 2.BRAF/MSI (L v R)
3.Risk Stratification in Adjuvant Setting 4.PI3K Molecular
Subtypes
Slide 4
Colorectal Diagnostics: What Was State of Art in 2008? CEA
recommended for staging, post-operative, monitoring response DNA
ploidy or proliferation assays not recommended p53, TS, DPD, TP
insufficient data Ras insufficient data MSI not recommended 18q- or
DCC - not recommended FDA approved tests for colorectal cancer (not
widely used): - EGFR Immunohistochemistry (Dakocytomation PharmDx)
- UGT1A1 Invader Assay (irinotecan glucuronidation) - toxicity -
Circulating tumor cells (CellSearch test) - prognosis Copyright
2009 ASCO
Slide 5
Where have we gone wrong with predictive molecular tests in
past? -EGFR staining and EGFR-targeting mAbs -Used to be REQUIRED
for insurance approval -Predictive tests for 5-FU efficacy
-Thymidylate Synthase (TS) expression and polymorphisms
-Methylenetetrahydrofolate reductase (MTHFR) polymorphisms
-Dihydropyrimidine Dehydrogenase (DPD) Deficiency (*2A variants)
-Topoisomerase, ercc1 (studies pending), UGT1A1.
Slide 6
Tests for Cytotoxics: Irinotecan UDP-glucuronosyltransferase
(UGT) 1A1 - Irinotecans active metabolite, SN-38, is eliminated via
glucuronidation by UDP-glucuronosyltransferase 1A1 (UGT1A1). -
Patients homozygous for *28 allele (7 vs 6 TA repeats) have 70%
reduction in UGT1A1 activity - According to U.S. FDA, patients
homozygous for *28 should be considered for dose reduction based on
small retrospective studies (increased diarrhea in some,
neutropenia in others) - large studies (FOCUS, N9741, PETACC3) have
failed to confirm clinical usefulness
http://www.fda.gov/cdrh/pdf5/k051824.pdf
Slide 7
Outline/Objectives: 1.Introduction 2.Molecular subtypes already
in use 1.KRAS/NRAS (added wrinkle: L v R?) 2.BRAF/MSI (L v R)
3.Risk Stratification in Adjuvant Setting 4.PI3K Molecular
Subtypes
Slide 8
Distinct Biology of R v. L CRC BRAF mut MSI KRAS PIK3CA
Mucinous differentiation Right Left 18q loss 20q Gain EREG
expression EGFR gain HER2 gain Poor Prognosis Sensitive to
Cetuximab Good Prognosis High mutation Frequency Analysis of
PETACC-3 samples (n=2849) Missiaglia, ASCO 2013
Slide 9
N0147 Trial: Testing Adjuvant Cetux Stage 3 ColonCancer (N =
3768) PREREGISTER RANDOMIZE Centralized K-ras analysis K-ras WT
K-ras Mut REGISTER Arm G Arm G Adjuvant therapy per primary
oncologistAdjuvant therapy per primary oncologist Report therapy
givenReport therapy given Annual status through year 8Annual status
through year 8 Arm A mFOLFOX6 Arm D mFOLFOX6 + Cetuximab Note: in
analysis, segregated proximal versus distal with splenic flexure as
cut-off Alberts, JAMA 2012
Slide 10
Negative Adjuvant Trial: N0147 Alberts, JAMA 2012 - No
difference in DFS with the addition of cetuximab; detrimental
effect for patients >70, even in KRAS WT group. - However, trial
should yield other useful information
Slide 11
N0147: KRAS and BRAF worse For stage IIII CRC, magnitude of
detrimental effect of KRAS and BRAF mutation is lower than other
analyses. KRAS MT (HR=1.45, p
Popovic, ASCO 2013 PETACC-3 (5-FU vs. FOLFIRI): Worse OS (and
RFS) for BRAF Mutants: L>R - independent of MSI status,
left-sided tumors do worse. leftright
Slide 14
BRAF/MSI Biology: TCGA The Cancer Genome Atlas Network Nature
487, 330-337 (2012) doi:10.1038/nature11252 BRAF mutation
associated with hypermutated (MSI-H) tumors.
Slide 15
Ogino, Clin Can Res 2012 - BRAF mutation analyzed in 506 colon
cancer patients from CALGB 89803 (n=75 BRAF mutated patients) -
Worse overall survival in BRAF mutated patients (HR=1.66); mainly
in microsatellite stable (MSS) patients - Trend to improvement with
irinotecan added to 5-FU/LV (HR=0.52) in BRAF MT patients, albeit
low numbers.
Slide 16
Ogino, Clin Can Res 2012 - Due to confounding effect of MSI
status in BRAF MT patients, Ogino proposed this strategy for
classification. Must split, rather than lump, BRAF MT patients
Slide 17
What about dMMR and FOLFOX? What about dMMR and FOLFOX?
Although n
PI3K Mutations (Samuels, Science 2004) - Colorectal and gastric
cancers frequently harbor mutations. - Not found in 76 polyps
(except two >5cm tubulovillous adenomas) - Co-existent with KRAS
and BRAF mutations (distinct pathway) Functionally important: -
Nontruncating - Nonsynonymous - Conserved residues - Higher PI3K
activity 2004 www.sciencemag.org
Slide 29
How strong is PI3K data? Report Drugs Findings Lievre C 7% with
PI3K mutn Can Res 2006, n=30 (97% chemo) no effect Sartore-Bianchi
C and P 13.6% with PI3K mutn Can Res 2009, n=110 (67% chemo) lower
RR, survival Perrone C 13% with PI3K mutn Ann Oncol 2009, n=32
(100% chemo) lower RR, survival De Roock (#1896) C and P 12% with
PI3K mutn AACR 2009, n=200 no effect Di Nicolantonio C and P 13%
with PI3K mutn AACR 2009, n=132 lower RR, survival Retrospective
clinical cases; conflicting.
Slide 30
PI3K as a predictive marker Prenen, Clinic Can Res 2009, n=200,
12% PIK3CA MT - Used sequenome MALDI-TOF MassArray system - No
relationship between PIK3CA and KRAS - No relationship between
PIK3CA and response, survival Exon 9 - 20 Note: PIK3CA mutations
have been associated with resistance to trastuzumab in breast
cancer (possible increased dependence on her2/her3 dimerization).
Burns, Cancer Cell 2007 2009 American Association for Cancer
Research
Slide 31
Additive Prediction DeRoock, Lancet Oncol 2010 Response rate
increase as markers are added (retrospective database)
Slide 32
PIK3CA mutations and aspirin Liao X et al. N Engl J Med
2012;367:1596-1606 Mutant = aspirin benefit wildtype
Slide 33
Possible Mechanism? Di Popolo et al, Oncogene 2000 PI3K signal
transduction pathways regulate COX-2 expression and PGE2 synthesis.
PD = PD098059 (MAPK inhibitor) LY = LY294002 (PI3K inhibitor) COX2
expression PGE2
Slide 34
Conclusions -The revolution of genetic information on tumors
over the last 5 years has greatly increased understanding of tumor
biology. -But this has not yet translated into the clinic, since
most anti-cancer drugs are used empirically. -Ignorance (lack of
research) is costly and deadly; without knowledge of KRAS, for
instance, we would be spending $700,000,000 per year harming
patients in the U.S. -Knowledge of relevant biomarkers is critical
in caring for colorectal cancer patients; however, important to use
markers that have been validated/qualified across multiple
studies.