Morphological and Molecular Typing of breast Cancer

Transcription

1 Morphological and Molecular Typing of breast Cancer Ian Ellis Molecular Medical Sciences, University of Nottingham Department of Histopathology, Nottingham University Hospitals NHS Trust

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5 Histological Type Survival (%) Histological type Long term survivors n = 119 Consecutive series n = 1050 Short term survivors n = 200 Tubular Tubular variant Lobular Cribriform Papillary Mucinous Medullary Ductal NST Dixon et al, Br J Surg 1985; 72:

6 Tubular carcinoma is known to have a favourable prognosis, but does this subtype represents a distinct type of breast carcinoma and does it behave like other low-grade luminal A type breast carcinomas? Rakha et al. J Clin Oncol 28:99-104

7 Assessed the clinicopathologic and molecular features and prognostic value of TC compared with grade 1 ductal carcinomas of the breast. Large well-characterized series of breast cancers 2,608 invasive carcinoma, unselected consecutive cases 212 Grade 1 ductal carcinomas 102 Tubular carcinomas Rakha et al. J Clin Oncol 28:99-104

8 TC more likely to be detected on mammographic screening, had smaller median size, and less frequently showed lymphovascular invasion. Compared with grade 1 ductal carcinoma, TC was associated with longer disease-free survival (213.25, P 0.001) and breast cancer specific survival (28.8, P 0.003). None of the patients with TC developed distant metastasis or died from the disease without an intervening recurrence as invasive carcinoma of different histologic type Rakha et al. J Clin Oncol 28:99-104

9 Conclusion The biologic behaviour of TC is excellent and is more favourable than that of grade 1 ductal carcinoma. Patients with TC may be at risk of developing second primary carcinomas in the contralateral breast, which may be of higher grade and poorer potential prognostic outcome. Patients with TC have a close to normal life expectancy, and as a consequence, adjuvant systemic therapy may not be justified in their routine management. Rakha et al. J Clin Oncol 28:99-104

10 Allele Loss in Breast Carcinoma 1p 1q 3p 6q 7q 8p 11p 11q 13q 16q 17p 17q 18q

11 Allele Loss in Tubular Carcinoma High LOH: 3p 11q 13q 16q FHIT ATM? Man et al Cancer Research 1996, 56: 5484

12 E Cadherin Lobular Carcinoma?Common Precursor LOH 16q Low Grade Carcinoma C-erbB-2 & p53 High Grade Carcinoma Other candidates: BRCA 1 17q Medullary BRCA 2 13q Tub & Lob 1q 3p 11q 13q 17q Tubular

13 ?Common Precursor E Cadherin LOH 16q Lobular Carcinoma Lobular Ductal Low Grade Carcinoma C-erbB-2 & p53 High Grade Carcinoma

14 E Cadherin Lobular Carcinoma?Common Precursor 16q LOH 16q Low Grade Carcinoma C-erbB-2 & p53 High Grade Carcinoma 17q

15 Class 1?Common Precursor E Cadherin 16q LOH 16q Lobular Carcinoma Low Grade Carcinoma Class 2 C-erbB-2 & p53 17q High Grade Carcinoma

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20 Genome plots of the previous case FEA Cyclin D1 DCIS Cyclin D1 Cyclin D1 LN

21 Conclusion Luminal Type A lesions Luminal ck ER rich HER2 neg 16q del CCLs ADH/ Low Grade DCIS ALH/ LCIS LOW GRADE NEOPLASIA FAMILY Cribriform TUBULAR G1 IDC TUBULOLOBULAR ILC

22 ER neg ER pos Sorlie, et al. PNAS 2001

23 N=113 (11 special types of breast cancer) Operon arrays 24,650 genes TMAs 22 markers

24 Special types of breast cancer are more homogeneous at the transcriptome level Luminal Basal-like Mol apocrine Mucinous A Classic ILC/ Tubular Mucinous B Neuroendocrine Micropapillary Adenoid cystic Medullary Metaplastic Pleomorphic ILC Apocrine Weigelt et al. J Pathol 2008

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26 The integrative subgroups have distinct clinical outcomes

27 IntClust 3 Low genetic instability Luminal A predominant Good prognoses types (tubular, lobular)

28 IntClust 2 ER positive, poor prognosis 11q13/14 cis-acting tumours CCND1 (11q13.3), EMSY (11q113.5), PAK1 (11q14.1), RSF1 (11q14.1) 11q13/14 amplicon(s)

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32 Nottingham Prognostic Index Grade + LN Stage + (0.2 x Size) cm

33 Cum. Survival N P I EPG GPG MPG I.4 MPG II.2 0 Chi-Square DF P-Value <.0001 PPG Time

34 ER neg ER pos Sorlie, et al. PNAS 2001

35 A signature to rule them all? Weigelt, Baehner, Reis-Filho J Pathol 2010; 220:

36 Oncotype DX 21-Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 CD68 BAG1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC RS = x HER2 Group Score x ER Group Score x Proliferation Group Score x Invasion Group Score x CD x GSTM x BAG1 Category RS (0-100) Low risk RS <18 Int risk RS 18 and <31 High risk RS 31 Paik et al. N Engl J Med. 2004;351:

37 Distant Recurrence at 10 Years Oncotype DX Clinical Validation: RS as Continuous Predictor 40% 35% Low-Risk Group Intermediate- Risk Group High-Risk Group 30% 25% My RS is 30. What is the chance of recurrence within 10 years? 20% 15% 10% 5% 0% 95% CI Recurrence Score

38 Proliferation Proliferation Meta-Analysis Gene signatures Blue dots: good prognosis Red dots: poor prognosis Wirapati et al. Breast Cancer Res 2008;10:R65

39 Take home message Prognostic gene signatures Correlate with proliferation (and grade!) Ki-67? Good discriminatory power ER positive disease Limited value for ER negative disease Cannot be readily applied to FFPE samples Complementary to histopathology

40 MIB1 growth fraction in breast cancer

41 Propability of Survival Propability of Distant Metastasis Kaplan-Meier survival plot for luminal BC using Ki67LI and Mitotic Index (A) Breast cancer specific survival (BCSS) at 10 and 70% Ki67LI (B) Metastasis-free survival at 10 and 70% Ki67LI (C) & (D) BCSS and DMFS for mitosis frequency scores. 1.0 A 1.0 B p< p< BCSS in Months Time taken to distant metastasis 240 C D

42 Proliferation in the luminal class Significant differences between MS (1, 2 & 3) and outcome BCSS (p<0.001, HR=2.302, 95%CI= ) DMFS (p<0.001, HR=1.958, 95%CI= ). Ki67LI at 10% and 70% cut-offs, luminal BC were subdivided into low, moderate and high proliferative subclasses with significant differences BCSS (LR = , p<0.001, HR=2.705, 95%CI= ) DMFS (LR=90.870, p<0.001, HR=2.258, 95%CI= ) (Figure 2). Multivariate Cox proportional hazard analysis showed that both MS and Ki67LI are independent prognostic factors in luminal BC (p<0.001). However, Ki67LI ability in predicting BCSS and DMFS surpassed that of MS

43 Prognostic Value of a Combined ER, PgR, Ki67, HER2 Immunohistochemical Score (IHC4) and Comparison with the GHI Recurrence Score in postmenopausal breast cancer patients treated with anastrozole or tamoxifen A TransATAC study Jack Cuzick Mitch Dowsett, Chris Wale, Janine Salter, Emma Quinn, Lila Zabaglo, Elizabeth Mallon, Anthony Howell, Aman Buzdar, John Forbes on behalf of the ATAC/LATTE Trialists Group

44 IHC tests performed ER 10 3 x 600u cores, 6F11 antibody, H-score/30 PgR 10 3 full sections, clone 16, % positive cells/10 HER2 3 cores, HercepTest with FISH+ (ratio >2) on 2+ cases, +/- Ki-67 3 cores, SP6 antibody (Abcam), log ( x % positive cells)

45 Distant recurrence - predicted values KM curves to 9 yrs with shrinkage adjustment for IHC4 ( 6.8%) and inflation of GHI-RS (12.2%) Follow-up time (years) IHC4 p25 GHI RS p25 IHC4 p75 GHI RS p75 Node neg, Poor/undifferentiated, Size 2cm, Age 65y, anastrozole

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