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Individual prognosis and predic1ve biomarkers.
Pr Frédérique PENAULT LLORCA, France
Prognosis
T N M
Classical prognosis and predic2ve factors
• Age • Grade • Histological subtypes • ER/PR and HER2 status • Ki67 +/-‐ mito2c index • Vascular invasion • Tumor margins
Oldies but
goldies
Grade I
Grade II
Grade III 8,9
SBR grade modified by Elston and Ellis
• Standardiza2on of tumor grading
• France 2011: Gr I 25%, Gr II 50%, Gr III 25%
• Lack of reproducibility
Group 3 - Average prognosis Medullary, classical lobular, lobular mixed
Group 1 -‐ Excellent prognosis: Tubular, invasive cribriform, mucinous
Group 2 -‐ Good prognosis Tubular mixed, mixed ductal NST and special type like adenoid cys1c, secretory
Group 4 - Poor prognosis Ductal NST, solid lobular, mixed ductal NST and lobular, micropapillary
18 Histological types : morphology maOers!
18 Histological types in breast cancer and only 4 molecular groups!
RE neg RE pos
C Perou & T Sorlie
Towards a simplified taxonomy of breast cancer? « defini2on of intrinsic subtypes has proven efficient in defining prognosis for breast cancer
pa2ents »
Intrinsic classifica2on easily translated by IHC
HER2 +
Basal Triple nega1ve
ER&PgR -‐, HER 2 -‐
ER /PgR+ HER2 -, Ki 67 <
ER /PgR + HER2 -, Ki 67 >
Luminal A Luminal B
15 %
15 %
60 %
CK 8, 18, 19
CK 5/6, 14, 17 EGFR, P53, ckit Pcad
Normal like
EE 2-3
EE 3
EE 1-2-3
HER2+ ER/ PgR+
Claudin Low
Predic1on
Surrogate defini2on of intrinsic subtypes of breast cancer
«basal-‐like» • ER and PgR absent • HER2 nega2ve • Approximately 80% overlap between « triple nega2ve » and intrinsic « basal-‐like »
• But « triple nega2ve » also include good prognosis special types such as medullary and adenoid cys2c carcinoma
• Staining for basal kera2n is considered insufficiently reproducible for general use
T N M
Classical prognosis and predic2ve factors
• Age • Grade • Histological subtypes • ER/PR and HER2 status • Ki67 +/-‐ mito2c index • Vascular invasion • Tumor margins
Oldies but
goldies
HER2
Nega1ve predic1ve value
(<5% chance to respond to anti-estrogens or trastuzumab)
HIGH 95%
Posi1ve predic1ve value
30-‐50%
Breast Cancer
ER/PGR
What is the level of predic2on accuracy clinically useful?
Ki67 why?
• Defini2on of luminal A and B
• Decision of CT for ER+, Grade II tumors
• At present, the enormous varia2on in analy2cal prac2ce markedly limits the value of Ki67
• An interna2onal panel of inves2gators with substan2al exper2se in the assessment of Ki67 and in the development of biomarker guidelines was convened to consider evidence for poten2al applica2ons.
MOLECULAR SIGNATURES
T N M
Yes , we have molecular biology !
• Age • Grade • Histological subtypes • ER/PR and HER2 status • Vascular invasion
• Tumor margins
Centralized tests
MammaPrint (Agendia, NL)
HR+ ET HR - / HER2- , T < 5cm, N ≤ 3
Fresh frozen=> FFPE DNA array
70 GENES CELL CYCLE/ PROLIFERATION
SIGNAL TRANSDUCTION INVASION, METASTASIS, ANGIOGENESIS
« CENTRALIZED » TEST
RECENTLY ADAPTATED TO FFPE
Group of genes (« signatures »)
EARLY RECURRENCE (Dg < 5 ans) PROGNOSTIC
GOOD SIGNATURE : LOW RISK
POOR SIGNATURE : HIGH RISK
HR+& HR-‐
MammaPrint – RESULTATS
UNE BONNE SEPARATION GLOBALE A BAS/HAUT RISQUE MAIS SANS CAPACITE DE RECONNAÎTRE
LES TUMEURS DE TRES BON OU DE TRES MAUVAIS PRONOSTIC
attendre les résultats de l’étude MindAct (MicroArray in Node-Negative Disease May Avoid ChemoTherapy)
80 genes
56 GENES
70 GENES
Where are the proofs
Formalin fixed, paraffin included samples Redundant genes? Valida2on of blue, target et theraprint?
?
OncotypeDX (Genomic Health, USA)
HR+ / HER2- , T1-3, N-/N+ FFPE specimens
qRT-PCR 21 GENES
PROLIFERATION, OESTROGENE, HER2, INVASION (16 GENES) + REFS (5 GENES)
« CENTRALIZED » TEST
(recurrence score) RS Late recurrence (10 years)
Benefit from adjuvant TT PROGNOSTIC AND PREDICTIVE
LOW RISK :
+ HORMONOTHERAPY / - CHEMOTHERAPY
INTERMEDIATE RISK : DISCUSSION
LOW RISK : + HORMONOTHERAPY / + CHEMOTHERAPY
Decentralized tests
EndoPredict (Sividon, GE)
HR+ / HER2- , T1-2, N0
FFPE qRT-PCR
7 GENES SIGNATURE PROLIFERATION, OESTROGENES
« LOCAL » TEST (SPECIAL EQUIPMENT IS REQUIRED)
SCORE OF RECURRENCE EP SCORE
LATE AND EARLY RECURRENCES (5 & 10 YEARS) PROGNOSIS
LOW RISK
HIGH RISK
UBE2C BIRC5 DHCR7
STC2 AZGP1 IL65T
RBBP8 MGP
Prosigna (PAM50) (NanoString Technology, USA )
IDENTIFICATION OF « MOLECULAR3 SUBTYPES » (LumA, LumB, HER2-enrichi, Basal)
FFPE
DNA ARRAY WITH BARCODES (1 gene = 1 barcode)
50 GENES
« LOCAL » TEST (SPECIAL EQUIPMENT IS REQUIRED)
LATE AND EARLY RECURRENCES (5 & 10 YEARS) PROGNOSIS
LOW RISK (ROR)
Intermediate risk
HIGH RISK (ROR)
Conclusion • Accurate pathology tes2ng is essen2al for individual
pa2ent selec2on and treatment design (subtypes / IHC based intrinsic classifica2on/grading)
• Tissue prepara2on is the KEY for accurate biomarkers evalua2on
• Gene signatures may provide increased confidence for treatment decision – Oncotype Dx® is recommended by St Gallen’s Panel of experts (also by ASCO, NCCN)
– The other signatures are either recommended to a lesser extend or very promizing
• However, even using gene signatures, there will be cases for which treatment decision will not be straighjorward
Conclusion
• For the 2me being pathology cannot be safely replaced by molecular assays
• Advantages of combining two approaches should be discussed – The target popula2on will be the ER+, HER2-‐, N-‐ (Luminal Breast Cancer) and not grade 3
• Predic2ve tests are awaited!
Source: Weigelt, Reis-‐Filho & Swanton, Ann. Oncol. 2012;Suppl 10:x211
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