www.excemed.org

IMPROVING THE PATIENT’S LIFE THROUGH

MEDICAL EDUCATION

Masterclass for masters ‘See beyond’: An oncology brainstorming

15-16 September 2016

Ghent, Belgium

Samra Turajlic

CRUK Clinician Scientist, Francis Crick Institute

Consultant Medical Oncologist, Royal Marsden Hospital

Debate: Is tumor heterogeneity a new hallmark of cancer?

• What type of tumour heterogeneity?

• What makes a hallmark of cancer?

Burrell, Mcgranahan, Bartek and Swanton Nature 2013

Intercellular Heterogeneity Intertumour Heterogeneity

What do we mean by tumour heterogeneity?

Intratumour Heterogeneity

Absent from normal cells

Common to all or almost all

cancers (generic)

Enable tumour growth and

metastatic dissemination

What are the criteria for a “hallmark of cancer”?

Hanahan and Weinberg, 2000, 2011

Is heterogeneity unique to tumours? Intrinsic error rate of DNA replication somatic mosaicism

Contributes to cellular diversity and normal development and function

(e.g. hypermutation and cells of the adaptive immune system)

. What is the rate of somatic mosaicism? Theoretical: 100-1000 mutations per cell during the first 15 years of life Increases with age and environmental exposure?

Do these linegaes expand under selective pressure?

Is heterogeneity unique to tumours?

2-6 mutations per Mb per cell

Positive selection for mutations in cancer genes in 30%

Mixture of clonal expansions

Martincorena et al. Science 2015

Intertumour heterogeniety is ubiqitous

Fisher et al. 2014 Genome Biology

ClearcellLowgrade

Sarcomatoiddifferen a on

ClearcellHighgrade

Is Intratumour heterogeniety ubiqitous?

R1

R4 R2

R3 R5

A,B

F

D

D,E

GL

R5

R2

R4

R3C

Renal Cell Cancer

Gerlinger et al. Nat Gen 2014

GBM

Wang et al. Nat Gen, 2016

Ovarian Cancer

Zhao et al. PNAS 2016

NSCLC

De Bruin et al. Science 2015

Murugaesu et al.

Cancer Disc 2015

Oesophageal Ca Breast cancer

Yates et al.

Nat Med 2015

Prostate ca

Gundem et al.

Nature 2015

Pancreatic cancer

Yachida et al. Nature 2010

Is Intratumour heterogeniety ubiqitous?

Heterogeneity enables hallmarks of cancer

Heterogeneity is essential for metastases

Obenauf, Trends Cancer 2015

Metastatic bottleneck

Heterogeneity is essential for metastases

Turajlic and Swanton, Science 2016

Shain and Bastian, Nat Rev Cancer, 2016; Shain et al NEJM, 2015

Heterogeneity is essential for invasion and metastases

Is the heterogeneity random?

Venkatesan, Birbek and Swanton, in preparation

Tumour heterogeneity is a hallmark of cancer and has therapeutic implications

Hanahan and Weinberg 2011

Distant metastasis clone

Local recurrence clone

Treatment-resistance clone

EGFR T790M

KRAS MT

NRAS MT

BRAF-mutant melanoma EGFRi sensitive CRC EGFR-mutant NSCLC

Intratumour heterogeneity and treatment resistance

McGranahan, Furness, Rosenthal et al. Science 2016

Implications of intratumour heterogenity for immunotherapy

Sub-clonal neoantigens do not drive equally effective anti-tumor immunity

• It is a pervasive feature of cancers

• It enables other hallmarks of cancer

• It has a profound effect on therapy

• It is not unique to tumour tissue

Is tumor heterogeneity a new hallmark of cancer?

Intratumour heterogeneity

Microenvironment Immune system