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4/15/2013
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Prostate: Review of Molecular Pathology in Diagnosis and Therapy Dominique Trudel MD MSc FRCPC
Disclosure
• None
Objectives
• To understand the difficulties associated with prostate cancer molecular profiling
• To enumerate 3 molecular markers of prostate cancer and to understand their (potential) clinical significance
Prostate cancer
• (Physically) insignificant or dramatic
• As pathologists, what can we do to help patients?
• Prognosticators
• Predictors
Siegel et al, 2013
New targeted therapies
• In castrate-resistant prostate cancer
• Many targets
• Androgen-deprivation • CYP17A1 inhibitors: abiraterone acetate, orteronel, TOK-001
• Androgen receptor inhibition: enzalutamide (MDV3100)
• Growth Factors • IGF-1R: Cixutumumab
• VEGF: Ramucirumab
• Immunotherapy: • sipuleucel-t (PAP), PROSTVAC
• Other: • Angiogenesis (Tasquinomod); HSP-27 (OGX-427); vitamin D…
New targeted therapies
• In castrate-resistant prostate cancer
• Many targets
• Androgen-deprivation • CYP17A1 inhibitors: abiraterone acetate, orteronel, TOK-001
• Androgen receptor inhibition: enzalutamide
• Growth Factors • IGF-1R: Cixutumumab
• VEGF: Ramucirumab
• Immunotherapy: • sipuleucel-t (PAP), PROSTVAC
• Other: • Angiogenesis (Tasquinomod); HSP-27 (OGX-427); vitamin D…
Targeted therapies without any requirement for target assessment
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New targeted therapies
• In castrate-resistant prostate cancer
• Many targets
• Androgen-deprivation • CYP17A1 inhibitors: abiraterone acetate, orteronel, TOK-001
• Androgen receptor inhibition: enzalutamide
• Growth Factors • IGF-1R: Cixutumumab
• VEGF: Ramucirumab
• Immunotherapy: • sipuleucel-t (PAP), PROSTVAC
• Other: • Angiogenesis (Tasquinomod); HSP-27 (OGX-427); vitamin D…
The role of the pathologist is not yet at the predictive level
Overall
• Gains are modest compared to prostate cancer history
• 3-5 months median survival in phase III studies
• Resistance mechanisms under study
Castrate-resistant disease
Saraon et al, 2011
Prostate cancer multiclonality
SNVs CNAs
Prostate cancer heterogeneity 2012-12-03
Page 1 of 1
Dominique Trudel
Pathology # S01-12197, MRN: 2907362
Date of first mapping: 8/16/2011
Prostate
Gleason pattern 4
Gleason pattern 3A, B:
Patterns 3 and 4 Right superior Left superior (-) (-)
No tumor (-) (-) (-)
Not submitted Anterior
Not existent (-) (-)
Unavailable material:
Seminal vesicles
(-) (-)
Right base Left base
AU AV Posterior
(-) (-)
(-)
C D (-) (-)
(-)
<5%
Gross description (-) (-)
(-)
(-)
(-) (-)
(-)
Right inferior Left inferior
1A frozen section
1B capsule
1AU base of right seminal vesicle
1AV base of left seminal vesicle
1C junction of right seminal vesicle and
prostate
1D junction of left seminal vesicle and
prostate
1E right bladder neck margin […]
1F left bladder neck margin [...]
1G right apical margin [...]
1H left apical margin [...]
The rest of the prostate is sectionned into
quadrants and submitted in toto as
follows:
1I to 1P right anterior (superior to inferior)
1Q to 1Y right posterior (superior to
inferior)
1Z to 1AJ left anterior (superior to
inferior)
1AK to 1AT left posterior (superior to
inferior)
P3
P4
P5 P6
Superior
Inferior
R L
F0
Non-Syn Stop-Loss
Legend
Deletion Amplification
ERG -
ERG +
ERG -
ERG -
ERG +
ERG +
ERG + ERG -
DIAGNOSIS, PROGNOSIS AND FUTURE DIRECTIONS
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Molecular markers of prostate cancer • TMPRSS2:ERG fusion
• PTEN loss
• NKX3.1 expression and loss
TMPRSS2:ERG
Clark and Cooper, 2009
• Found in 50% of prostate cancers
TMRPSS2:ERG
FISH IHC
Clark and Cooper, 2009
Table 1 Comparison of the 9FY and EPR 3864 anti-ERG monoclonal antibodies
Rosen, P. et al. (2012) Clinical potential of the ERG oncoprotein in prostate cancer Nat. Rev. Urol. doi:10.1038/nrurol.2012.10
TMPRSS2:ERG and prognostic
Pettersson et al, 2012
Potential clinical uses of ERG Ab • Negative in benign glands, positive in ~50% of
cancers:
• Diagnostic tool: high positive predictive value
• PIN positivity?
• Prognostication: no
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TMPRSS2:ERG in the future • Methylation array
• Unsupervised analysis
• Clustering according to ERG status
• Includes TBX15
DFS
Kron et al, 2012, 2013
PTEN
Song et al, 2012
PTEN loss
• No regulation of the PI3K-AKT pathway
• Favors switch from mitochondrial oxidative phosphorylation to anaeorobic glycolysis
• Loss of cell polarity
• In fibroblasts, creates a tumor-permissive stroma
• Etc
• Etc
•
PTEN loss in prostate cancer
• Microdeletions, 10q23.3; point mutations or methylation
• 30-60% of prostate cancers
• ~ 20% HGPIN
• Association with TMPRSS2:ERG
Krohn et al, 2012
PTEN loss in prostate cancer
Krohn et al, 2012
Detection in prostate cancer
• FISH
• IHC
• Lotan et al (Cell signaling D4.3)
• Sensitivity: 82%
• Specificity: 55%
• Krohn et al (Abcam Ab31392)
• No relationship
Lotan T L et al. Clin Cancer Res 2011;17:6563-6573
©2011 by American Association for Cancer Research
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Potential clinical uses of PTEN detection • Positive in benign glands, negative in ~30-60% of
cancers:
• Diagnostic tool: high positive predictive value
• But Ab reliability issues
• PIN positivity?
• Prognostication: probably
• Predictive value: not yet
NKX3.1
• Transcription factor involved in prostatic development
• Expression induced by androgens
NKX3.1 in prostate cancer
• No mutation, no methylation
• Allelic loss in ~ 50%
• Decreased expression as stage and grade increase
NKX3.1
• In frozen biopsies from RT-treated men
• Intermediate-risk
• aCGH
NKX3.1 detection
• No optimal method yet
• Very few studies
• FISH? IHC?
Potential clinical uses of NKX3.1 detection • Diagnosis: useful in metastasis ID
• Prognostication: not yet, probably
• Predictive value: not yet
• Decreased expression by androgen-deprivation therapy
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Summary
• New targeted therapies in prostate cancer don’t require pathological work-up
• Difficulties in developing new therapies/prognosticators arise from prostate cancer heterogeneity
• Low vs high-risk, versus M+
• Intraprostatic
Summary
• 3 genetic alterations with potential clinical use
• TMPRSS2:ERG
• PTEN loss
• NKX3.1 loss
