Examining large groups of cancer patients to identify ways of predicting which therapies cancers might respond to.

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2 Stratified Medicine Examining large groups of cancer patients to identify ways of predicting which therapies cancers might respond to. Looking in detail at cancer cells and their genetic make up. Permit targeted therapies directed to particular gene abnormalities Personalised medicine utilise genetic and other information to improve diagnosis and management of disease.

3 Clinical Centre Genetic Technology Centre Stratified Medicine Programme clinical/ 3 technology centres 9000 patients Blood (control DNA) and tumour tissue Breast, colorectal, prostate, lung, ovarian, melanoma

4 Problems with CNS tumours (independent of origin) Rare and symptoms non-specific no clear correlation between tumour type and presentation Location of tumour can have profound impact on symptoms small brainstem tumour v large cortical tumour Primary brain tumours infiltrate widely complete surgical excision impossible in most cases Risk in surgical management balance of excision v preservation of function risk of biopsy Skull is a rigid box. symptoms if intracranial pressure rises Tumours can transform low-grade tumours can transform to high-grade tumours

5 In The Beginning (1978) All High Grade Gliomas were The same

6 Primary tumours of CNS International standardised classification system Tumours graded from I to IV Light microscopy based (WORLD Health Organisation) Regularly updated and revised UK exam for neuropathologists twice/ year

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8 WHO Classification of tumours of the CNS (2007) Astrocytic Tumours well-circumscribed Diffuse astrocytoma Anaplastic astrocytoma Glioblastoma WHO Grade I II III IV Oligodendroglial Tumours Oligodendroglioma Anaplastic oligodendroglioma II III Mixed Gliomas Oligoastrocytoma Anaplastic oligoastrocytoma Glioblastoma with an oligodendroglial component II III IV Grades I & II= low grade Grades III & IV = high grade

9 73M seizure- right temporal lobe lesion

10 Response Grade n Score Astrocytoma +/- diffuse/ fibrillary/ II 32 2 low grade Oligoastrocytoma II 10 2 Ganglioglioma I (5)/ II (3) 8 0 PML/ virus 2 0 DNET I 2 0 Abnormal brain tissue 1 0 Oligodendroglioma II 1 0

11 42M Headache. Left frontal tumour

12 Response Grade n Score Oligodendroglioma II 53 2 Oligodendroglioma I 1 1 Oligoastrocytoma II 2 0

13 48F Right temporal SOL

14 Response Grade n Score Glioblastoma +/- small cell/ IV 52 2 oligo. component High-grade mixed glioma IV 1 0/1 (anaplastic astrocytoma/ anaplastic oligodendroglioma/ glioblastoma) Anaplastic (rhabdoid) meningioma III 1 0 Anaplastic oligodendroglioma III 2 0

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16 49F frontal Co-deletion 1p19q 60F temp/parietal 1p = red 1q =green 1p 1p

17 1p19q co-deletion

18 P<0.0002

19 Oligodendroglial tumours WHO 2007 Oligodendroglioma Oligoastrocytoma II III II III In reality Oligodendroglial (any) II III co-deletion1p19q no co-deletion 1p19q

20 TEMOZOLOMIDE: Alkylating (methylating) cytotoxic chemotherapy agent

21 TEMOZOLOMIDE: Alkylating (methylating) cytotoxic chemotherapy agent MGMT N N dr CH 3 O N N NH 2 HS CH 2 NH CH CO NH 2 COOH Active MGMT Guanine methylated by Temozolomide repair by MGMT NH 2 N N dr O N NH NH 2 NH S CH CH 2 Inactive MGMT CO COOH Normal Guanine Irreversible inactivation

22 MGMT MGMT UM UM M

23 MGMT gene silencing and benefit from Temozolomide in glioblastoma Hegi, M.E et al (for EORTC), NEJM, 2005

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25 MGMT methylation status and outcome: Glasgow cohort U M Survivor MEDIAN SURVIVAL: Methylated (n=30) = Unmethylated (n=42) = p = Times Months

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27 IDH mutation (H09 ICC) and outcome: Glasgow cohort 1 0 Survivor MEDIAN SURVIVAL H09 positive (n=7) = H09 negative (n= 83) = P = Times Months

28 Glasgow High Grade Glioma Protocol Oligo component High grade glioma IDH1 stain MGMT molecular negative positive methylated unmethylated 1p19q Report to MDT Management A Management B Management C Management?

29 Scottish Cancer Taskforce National Cancer Quality Steering Group Brain and Central Nervous System Cancer Clinical Quality Performance Indicators QPI 2 Molecular Analysis QPI Title: Description: Rationale Evidence: and Patients with biopsied or resected gliomas should have molecular analysis performed on the tumour tissue to inform treatment decision making/prognostic treatment. Proportion of patients with brain/cns cancer who undergo relevant molecular analysis of tumour tissue. This QPI measures 2 distinct elements: (i): Patients with gliomas with an oligodendroglial component who have the tumour tested for combined loss of 1p/19q; and (ii): Patients with glioblastomas who have the tumour tested for MGMT promoter methylation status. (i) Combined loss of 1p/19q in gliomas with a significant oligodendroglial 1 component is associated with a more favourable response to therapy (chemotherapy or radiotherapy) and is associated with considerably better prognosis when compared to tumours with intact 1p/19q 3. As such, where indicated, 1p/19q analysis should be carried out to help determine treatment and provide information on predicted tumour response to therapy and prognosis. (ii) Determination of MGMT promoter methylation status predicts response to therapy (chemotherapy or concomitant chemoradiotherapy) in glioblastomas 2 and assists in determination of prognosis (Rivera et al, 2012; Alberta Health Services, 2010a). As such, where indicated, MGMT promotor methylation analysis should be carried out to help determine treatment and provide information on predicted tumour response to therapy and prognosis. All patients with an oligodendroglial component should have access to 1p19q analysis All patients with glioblastoma should have access to MGMT analysis Specification (i): Numerator: Number of patients with glioma with an oligodendroglial 1 component where tissue sample is tested for 1p/19q. Target: 90% Denominator: All patients with glioma with an oligodendroglial 1 component. Exclusions: Cases in which there is insufficient viable tissue for molecular analysis. Specification (ii): Numerator: Number of patients with glioblastomas 2 where tissue sample is assessed for MGMT promoter hypermethylation status. Target: 90% Denominator: All patients with glioblastoma 2. Exclusions: Cases in which there is insufficient viable tissue for molecular analysis.

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