Molecular classification of colorectal cancer Fred T Bosman - - PowerPoint PPT Presentation

Molecular classification of colorectal cancer

Fred T Bosman University Institute of Pathology Lausanne

Current WHO classification of carcinoma of the colorectum

Adenocarcinoma, NOS

• Cribriform comedo-type

adenocarcinoma

• Medullary carcinoma, NOS
• Micropapillary carcinoma
• Mucinous adenocarcinoma
• Serrated adenocarcinoma
• Signet ring cell carcinoma

Adenosquamous carcinoma Spindle cell carcinoma, NOS Squamous cell carcinoma, NOS Undifferentiated carcinoma

Can we use morphology for precision medicine?

• Morphotypes have a poor relationship with

molecular characteristics

– K/NRAS mutations not reflected in morphology – MSI-H is relatively site-specific (right) and often of mucinous/medullary morphotype

• Immunoscore is related to MS-status (MSI-H)
• Grade not related to molecular profile
• Budding?
• Vascular invasion?

Pathways in the development of colorectal cancer

• The chromosomal instability (CIN) pathway
• The microsatellite instability (MIN) pathway
• CpG Island Methylator Phenotype (CIMP)

pathway

• The dysplasia-carcinoma pathway in IBD

Aberrant crypt focus Low grade adenoma High grade adenoma Carcinoma Metastases

• P16
• APC

+ telomerase

• P53
• SMAD4

Normal mucosa +KRAS

The adenoma-carcinoma sequence in the CIN pathway (After Vogelstein)

By array–CGH copy number variation is much higher in CIN (MSS) than in MIN (MSI-H)

Xie T et al. 2012 PLoS One 2012;7:e42001

CNV heterogeneity: drivers and bystanders

Xie T et al. 2012 PLoS One 2012;7:e42001

Familial adenomatous polyposis: APC/Wnt pathway

Colon ascendens cancer in the context of Lynch syndrome

Microsatellite instability

• A. MLH1
• D. PMS2
• B. MSH2
• E. BAT26 (normal)
• C. MSH6
• F. BAT26 (MSI)

MMRd CRC hypermutate

TCGA Nature. 2012; 487: 330–337

Colorectal cancer 5y disease free survival

• f stage II + III patients by MSI Status

I would not use ‘molecular grade’ (confusing terminology) but simply call them MSI/MSS

Frequency Analysis

Stage II Stage III Stage IV MSI-H

22% (86/395) 12% (104/859) 3.5%

Is MSI a suppressor of lymph node and distant metastasis?

The CIMP pathway

The dysplasia-carcinoma sequence in inflammatory bowel disease

chronic inflammation low grade dysplasia high grade dysplasia adenocarcinoma 10 years ?

promoterhypermethylation microsatellite instability

• p53
• APC

+KRAS

• p27
• p16

+ gain of function mutation

• loss of function (through LOH, mutation
• r promotermethylation)

CRC colorectal carcinoma FAP familial adenomatous polyposis MP mutator phenotype CI chromosomal instability MSS microsatellite stable MSI microsatellite instable MYH MYH polyposis (After D Snover)

Pathways overlap

Patterns of SMAD-4 expression in colon cancer: (a) complete loss of expression in tumor glands as compared with normal crypts (arrow); (b) non-homogeneous expression: loss of expression in the lower part of the field contrasts with marked expression in the upper part (R.Fiocca et al. In preparation).

SMAD4 and prognosis (stage III)

(Yan P et al. Clin.Cancer Res. 2016)

0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 2 3 4 5 6 7 Years: Proportion disease free p=0.003 expression present no expression

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At risk: 819 709 602 535 488 417 42 2 145 114 85 74 66 61 7

no loss loss

MS- and SMAD4 status allow subtyping of CC

(Roth et al. J Clin Oncol. 2012;30:1288-95)

Recursive partitioning

Molecular markers differentiate T3N1 cases

Roth et al. 2012 JNCI

KRAS mutations are not prognostic in stage II/III colon cancer patients but BRAF mutations are!

(Roth et al. JCO 2010;28:466-74)

BRAF mutated CC express a common signature

BRAFm (blue) versus BRAFwt (yellow) Popovici et al. J Clin Oncol. 2012;30:1288-95

BRAFm signature as predictor of survival

Overall survival Survival after relapse

Will the BRAF signature be the companion test for BRAF inhibitor treatment?

(Popovici et al. J Clin Oncol. 2012;30:1288-95)

E.Missiaglia et al. Ann Oncol. 2014;25:1995-2001

Are left and right different?

Proximal and distal colon carcinomas have different biology

E.Missiaglia et al. Ann Oncol. 2014;25:1995-2001

Distal colon carcinomas progress faster after relapse

E.Missiaglia et al. Ann Oncol. 2014;25:1995-2001

WHO classification of carcinoma of the colorectum

Adenocarcinoma, NOS

• Cribriform comedo-type

adenocarcinoma

• Medullary carcinoma, NOS
• Micropapillary carcinoma
• Mucinous adenocarcinoma
• Serrated adenocarcinoma
• Signet ring cell carcinoma

Adenosquamous carcinoma Spindle cell carcinoma, NOS Squamous cell carcinoma, NOS Undifferentiated carcinoma Useful for patient stratification for treatment decisions?

Molecular subtypes of colon cancer

Budinska et al. J.Pathol.2013;231:63-76

With so many different approaches what do you do? Create a consensus molecular classification!

Dr.Steven Friend

Consensus molecular subtypes of CRC

Guinney et al. 2015 Nat.Med. Under revision CMS4 – Mesenchymal

23% SNCA high Stromal infiltration TGF-β β β β activation , Angiogenesis Worse relapse free and overall survival

CMS3 – Metabolic

13% Mixed MSI status , CIMP low SNCA low KRAS mutations Metabolic deregulation

CMS1 – MSI Immune

14% MSI, CIMP high Hypermutation BRAF mutations Immune infiltration and activation Worse survival after relapse

CMS2 – Canonical

37% SNCA high WNT activation MYC activation Better survival after relapse

Do molecular subtypes differ in survival?

CMS1 MSI immune CMS2 Canonical CMS3 Metabolic CMS4 Mesenchymal

Dienstman et al. Nature Reviews Cancer 2017;17:79-92

Consensus molecular subtypes: pathways involved

Molecular subtypes: host response pathways involved

Dienstman et al. Nature Reviews Cancer 2017;17:79-92

Can a panel of immunohistochemical markers equal CMS classification?

Anne Trinh et al. Clin Cancer Res 2017;23:387-398

BRAF mutated patients respond differently to targeted treatment. Are they different at molecular level?

Barras et al. Clin Cancer Res. 2017;23:104-115

Which gene modules are involved?

Barras et al. Clin Cancer Res. 2017;23:104-115

Prognostic significance

Barras et al. Clin Cancer Res. 2017;23:104-115

Potential impact on precision treatment

Barras et al. Clin Cancer Res. 2017;23:104-115

The nature of classifications

The paradigm shift

From ‘what does it look like’ to ‘which key molecular mechanisms are involved’

– ER, PR, Her2/neu and breast cancer – KRAS and colon, lung, head and neck ….. cancer – ALK, EGFR, ROS1 and lung cancer – MSI and colon cancer – Immune checkpoint status (PD-1/PD-L1; CSK4)

Advancing molecular technology

– almost anything can be done on FFPE tissues – fast and cheap NGS – disease/target dedicated platforms (Mammaprint, Coloprint etc.)

Conclusions

– For stratification of CRC TNM is not enough – A new layer of subgroups can be obtained with ‘classical’ molecular markers – New molecular technology reveals more heterogeneity (molecular and clinical) in CRC resulting in CMS classification – Understanding this heterogeneity will go along with the development of new molecular targets and accompanying predictive tests to be assessed in basket and umbrella trials – This requires large series of patients with detailed clinical data: large scale pooling of tumor genotypes based upon diagnostic testing

The PETACC3 consortium

IPA Lausanne

Pu Yan Edoardo Missiaglia

HUG Genève

Arnaud Roth

GI oncology/Genetics Leuven

Sabine Tejpar

Pathology Genova

Roberto Fiocca

SAKK Bern Dirk Klingbiel SIB Lausanne

Mauro Delorenzi David Barras Vlad Popovici (now in Brno) Eva Budinska (now in Brno)

Pfizer Oncology San Diego

Scott Weinrich Graeme Hodgson Mao Mao Xie Tao