Molecular Pathology of Breast Cancer · 2018-12-06 · breast cancer –Intrinsic Subtypes Prat et...
Transcript of Molecular Pathology of Breast Cancer · 2018-12-06 · breast cancer –Intrinsic Subtypes Prat et...
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Molecular Pathology of Breast Cancer
Elena Provenzano
Lead Breast Pathologist
Addenbrookes Hospital
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Biology of breast cancer• Breast cancer is not a single disease but a collection of
diseases with different molecular characteristics and clinical outcomes
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Why do we need molecular characterisation of breast cancer
• To identify patients whose prognosis is so good that adjuvant therapy after local surgery would not be beneficial
• To identify patients whose prognosis is so poor that a more aggressive adjuvant approach would be warranted
• To identify patients likely to be responsive or resistant to particular forms of therapy ( = predictive factors)
• => Individualised patient management
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Traditional classification of breast cancer
• Assessment of the extent to which the appearance of a carcinoma resembles normal breast glandular tissue
• Tumour type
• Histological Grade
• ER and HER2 status
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Newer classification systems for invasive breast cancer – Intrinsic Subtypes
• Gene expression patterns of breast carcinomas distinguish tumour subclasses with clinical implications
• ‘Intrinsic subtypes’• Sørlie, Perou et al.
• PNAS, 2001; 98(19 ):10869–74
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Newer classification systems for invasive breast cancer – Intrinsic Subtypes
• Immunohistochemical correlates
• ER positive - Luminal breast cancers
• type A – PgR +, HER2 -, low proliferation
• type B – PgR +/-, HER2 +/-, high proliferation
• ER negative
• HER2 positive
• Basal breast cancers – ER/PgR/HER2 -, CK5/ CK14 / EGFR +
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Newer classification systems for invasive breast cancer – Intrinsic Subtypes
• Intrinsic subtypes are reproducible across platforms,
however assignment of individual cancers to a molecular
subtype shows only moderate reproducibility
• Dependent upon platform used, expression thresholds, and
composition of the population
• Basal-like group most reproducible, luminal B and HER2
enriched least reproducible
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Newer classification systems for invasive breast cancer – Intrinsic Subtypes
• Concordance between gene expression and IHC defined
subtypes modest at best
• Luminal A versus Luminal B – Ki67 cut point of 14% [Cheang
et al., JNCI 2009]. Sensitivity 72%, specificity 77%
• Follow up study looking at 2 large clinical series [Prat et al.,
JCO 2013]:
• 81-85% of luminal A correctly identified
• 35-52% of luminal B misclassified as Luminal A
• Improvement if include PR with cut off of 20%
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Newer classification systems for invasive breast cancer – Intrinsic Subtypes
Prat A and Perou C, Mol Oncol 2011
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Newer classification systems for invasive breast cancer – Intrinsic Subtypes
Prat et al., JNCI 2014;106(8).
• Heterogeneity within HER2 positive disease, largely driven by ER status
• Clinically HER2 + and – tumours within each intrinsic subtype differ only in expression of genes in or near the HER2 amplicon on 17q
• Highest levels of HER2 pathway activation in cHER2+ HER2 enriched tumours
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Newer classification systems for invasive breast cancer – Intrinsic Subtypes
• Retrospective analysis of NOAH study looking at PAM50 subtypes
• Only 55% of HER2+ tumours HER2-E subtype; 21% luminal, 7% basal-like, 18% normal-like
• Better pCR rates in HER2-E vs luminal HER2+ tumours (53% v 29%) with larger improvement in EFS with addition of Trastuzumab
Prat et al., Clin Cancer Res 2014;20(2):511-21.
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Pereira et al., Nature Comms 2016.
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A new molecular taxonomy of breast cancer
0.0
0.3
0.5
0.8
1.0
0 5 10 15
Luminal A (2202/430)
Luminal B (1253/450)
HER2 (538/215)
Basal (825/273)
Normal-like (404/92)
Subtype (subjects/events)
PAM50
0.0
0.3
0.5
0.8
1.0
0 5 10 15
IntClust 1 (400/134)
IntClust 2 (167/69)
IntClust 3 (959/198)
IntClust 4 (938/229)
IntClust 5 (455/189)
IntClust 6 (189/69)
IntClust 7 (497/103)
IntClust 8 (709/168)
IntClust 9 (376/139)
IntClust 10 (548/168)
Subtype (subjects/events)
IntClust
Surv
ival
Follow-up (years)
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Integrative clustersIntClust Molecular Features Prognosis
1 Amp 17q23, mut GATA3, High instability Intermed
2 Amp cyclin D1.High instability
Poor
3 Mut PIK3CA and CDH1, low instability Good
4 Low instability, immune upregulation Good
5 HER2 Amp Poor
6 Amp ZNF703, high instability Intermed
7 16p gain, 16q loss, amp 8q Good
8 1q gain, 16q loss Good
9 8q gain, 20q amp, high instability Intermed
10 TNBC; high instability, DNA damage repair Poor
Mukherjee et al., NPJ Breast Ca 2018
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Integrative clusters
Mukherjee et al., NPJ Breast Ca 2018
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Integrative clusters
Mukherjee et al., NPJ Breast Ca 2018
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Different clinical behaviour0
20
40
60
80
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0
Bas
al
HER2
Nor
mal
Lum
inal
B
Lum
inal
A
020
40
60
80
10
0
IntC
lust 1
0
IntC
lust 5
IntC
lust 4
IntC
lust 1
IntC
lust 9
IntC
lust 6
IntC
lust 3
IntC
lust 7
IntC
lust 8
IntC
lust 2
Pe
rce
nt
No pCR pCR
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ILC - Molecular• Distinct morphology but genetic heterogeneity
• Gene expression profiling and copy number analysis reveals two subgroups
• Immune related –immune signalling and cytokine pathways, with upregulation of immune response inhibitors
• 78% have moderate to severe lym infiltrate
• Hormone related –ESR1 and PGR, cell cycle and ER target genes
Michaut et al., Nature Scientific Reports
Jan 2016.
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ILC - Molecular
• Mutations:
• CDH1 – 43-63%
• PIK3CA – 35-48%
• TP53 – 5-27%
• PTEN – 14% (more common than NST – 3%)
• GATA 3 – 3-5% (less common than NST –20%)
• ERBB2 – 4-18%
• Remainder low frequency
Ciriello et al., Cell 2015;163:506-19.
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Case 1
• 63 y.o. female
• Presented clinically with a lump in the left UOQ
• Core biopsy – grade 3 invasive cancer, mixed NST and micropapillary; ER/ PR 8, HER2 borderline/ FISH non-amp
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Case 1
• Proceeded to WLE and SLNB
• Final histology:
• 19 mm grade 3 invasive ca, mixed NST and micropapillary
• Clear of margins
• SLN – 0/2
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Case 1
10 year chemotherapy benefit
= 4.5% -> discuss
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Gene based prognostic tests
• Gene expression profiling
• cDNA arrray or RT-PCR based
• Several gene signatures have been proposed
• 21 gene – Oncotype Dx® - TAILORx
• 70 gene – Mammaprint® - MINDACT
• PAM50 – uses intrinsic subtypes
• 12 gene - EndoPredict
• Little overlap in specific genes that make up the signatures, but all include genes involved in proliferation and ER signalling
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Oncotype DX
ER GROUP
ER PgR
Bcl2 SCUBE2
INVASION GROUP
Cathepsin L2
Stromelysin 3
PROLIFERATION
GROUP
KI67
STK-15
SURVIVIN
CYCLIN B1
MYBL2
REF GROUP
Beta-actin GAPDH
RPLPO GUS
TFRC
HER2 GROUP
HER2 GRB7
Combine results in an algorithm to get the recurrence score:
<18 6.8%
18-30 14.3% 10yr distant recurrence rate
>30 30.5%
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Case 1
Recurrence score = 12 – low risk
Endocrine therapy and RT only
WGS as part of PBCP – validated PIK3CA mutation
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TNBC –Genomic Subtypes
• Gene expression array analysis of TNBC identified 6 subtypes, now refined to 4 (immunomodulatory group reflects TILs and MSL reflects stromal contamination)
• Basal like 1 – elevated cell cycle and damage response genes
• Basal like 2 – growth factor signalling and myoepithelial genes
• Mesenchymal – epithelial-mesenchymaltransition and growth factor pathways
• Luminal Androgen Receptor • luminal gene expression driven by AR
• lower grade
• higher incidence of lymph node and bone metastasis
• high incidence PIK3CA mutations (40%)
Lehmann et al. J Clin Inv 2011;121(7):2750-67.
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TNBC – response to NACT
• Masuda et al., Clin Ca Res 2013;19(19):5533-40
• Different rates of pCRbetween subtypes
• No difference in OS – LAR group had low pCR rate but best survival at 3 years
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Basal Breast Cancers
• ‘Triple negative’ – ER, PgR and HER2 negative
• Express basal cytokeratins – CK 5/6, CK14
• Express EGFR
• Distinct morphology – high grade, central acellular zones, necrosis, high mitotic count
• Heterogeneous group – medullary-like, metaplastic, adenoid cystic carcinoma
• Associated with BRCA1 mutations in young women
• Associated with worse prognosis and distant metastasis, particularly visceral metastases
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Basal Breast Cancers
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Basal Breast Cancers
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Carcinoma with medullary features• Circumscribed tumour with
pushing rather than infiltrating margin
• Interconnecting sheets of large, bizarre and pleomorphic carcinoma cells forming a syncytial network
• Prominent lymphocytic inflammatory cell infiltrate
• Usually ER/ HER2 negative
• Association with BRCA1 mutations
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TNBC – LAR Subtype
• Luminal Androgen Receptor
• luminal gene expression driven by AR
• lower grade, higher incidence of lymph node and bone metastasis
• high incidence PIK3CA mutations (40%)
• Molecular Apocrine Subtype
• Farmer et al., Oncogene2005
• 3 groups; luminal (ER+), basal and an ‘intermediate’ group -> ER- but with a luminal keratin expression pattern
• 50% HER2 positive
• Androgen receptor positive with expression of metabolism related signatures and increased androgen signalling
• Review of histology – apocrine features but not classical apocrine carcinomas
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Carcinoma with Apocrine Features• Large cells with abundant
granular eosinophilic cytoplasm
• Round nuclei with prominent nucleoli
• Pure apocrine carcinoma incidence 1-5%
• Older women
• AR and GCDFP15 positive
• ER/ PR negative
• 10-60% HER2 positive
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Androgen Receptor
• AR is the most commonly expressed hormone receptor in breast cancer
• Up to 90% of breast cancers are positive depending upon methods and cut offs used (literature 60-90%)
• ER + - 85-95% AR+ (LumA – 91%, LumB – 68%)
• ER - - 15-70% AR+ depending on series
• ER-/ HER2+ - 50-66% AR+
• TNBC – 32% AR+ (20-55%)
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Apocrine Carcinoma and AR
TNBCAR+
BC
Apocrine
Ca
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Future Classification
• Hypermutated tumour
• Associated with increased expression of neoantigens -> host immune response with TILS
• BASKET OF BASKETS trial – eligible for immune therapy
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Case
• 49 year old female presented with a painful right breast lump
• Core biopsy – grade 3 invasive carcinoma NST, ER/ PR/ HER2 negative
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Case• Enrolled into PARTNER trial using platinum based chemotherapy
with a novel targeted agent, olaparib.
• The patient also consented to WGS in the Personalised Breast Cancer Program
• No germline mutations including BRCA1/2
• Cosmic signature 3 – defective double stranded DNA break repair by homologous recombination
• Likely to respond well to trial therapy with platinum and targeted DNA damage repair agent
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Case
• Complete radiological response on midtreatment MRI
• Final histology: pCR following neoadjuvant chemotherapy
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Personalised Breast Cancer Programme – whole genome sequencing looking for mutations and copy number alterations
Actionable mutations:
Highly Actionable (Tier 1) - Robust evidence
- Genomic alteration validated in clinical trials
– Clinical evidence of association with response to therapy
Potentially Actionable (Tier 2)
- Evidence mutation is activating (oncogene) or non-activating (tumour suppressor gene) in models
- Pre clinical evidence of association with response to treatment but clinical evidence lacking/ insufficient
Dr Jean Abraham and Prof Carlos Caldas
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Future Classification
• Whole genome sequencing -> mutational signatures
• Cosmic signatures – distinct patterns of mutations are associated with different mechanisms of DNA damage
• Signature 1 = age related
• Signature 2 = APOBEC family of cytosine deaminases; C>T
• Signature 3 = double stranded DNA damage repair; BRCA1 and 2 mutation carriers
• Concept of Basket studies – eligibility for trial dependent upon mutational profile or presence of specific mutations rather than tissue type