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Eterogeneità tumorale: il punto di vista del clinico

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ETEROGENEITÀ TUMORALE:

IL PUNTO DI VISTA DEL CLINICO

LAURA PIZZUTI ONCOLOGIA MEDICA 2

IRCCS ISTITUTO NAZIONALE TUMORI REGINA ELENA

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DISCLOSURE

• I’m not a basic researcher (but just a simple clinician)

“The collaboration between clinicians and researchers is vital in an era requiring a deep understanding of the molecular biology

underlying the development of cancer. ESMO 2017 will be a truly integrated congress, bringing together researchers and clinicians to

help bridge the gap between innovation and clinical implementation.”

Fortunato Ciardiello, ESMO President

(3)

WHAT WE KNOW

Neoplasms evolve

This evolution has been recognized since 1976 and it explains the processes of both carcinogenesis and acquired therapeutic resistance

The evolution of neoplasms is shaped by the selective pressures of their micro environmental ecology

Between and within cancer types, tumors probably display differences in the dynamics of cancer evolution and ecology, including the rates at which new clones appear and go extinct, how different those clones are from one another and whether they appear in bursts or at a more regular pace

Many of the evolutionary and ecological properties of a neoplasm are clinically relevant, though this is

not always true and in most cases their clinical relevance has not yet been tested

(4)

UNANSWERED QUESTIONS THE GENOMIC LANDSCAPE OF METASTATIC BREAST CANCER IN THE CLINIC?

1. If some cancers are ‘born to be bad’…

• Can a ‘genomic signature’ be incorporated with other clinical/ pathological/ gene expression signatures to improve our ability to identify those cancers destined to relapse?

2. In the window between primary tumor diagnosis and the clinical diagnosis of metastasis a cancer’s genome changes substantially …

• Driver mutations at metastasis sample from a wider range of cancer genes than in primary tumors and so an even broader range of therapeutic strategies may be appropriate – how are we going to address this?

• Which genomic alterations to target - trunk’ versus ‘branch’? How can clinical trials address this?

3. How can we improve the rate at which patients within molecular screening initiatives

are fed into of clinical trials?

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INTER-TUMOR HETEROGENEITY

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PRECISION MEDICINE

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INTRATUMOR HETEROGENEITY

(8)

INTRATUMOR HETEROGENEITY

(9)

Intratumor heterogeneity

Stromal diversity

INTRATUMOR HETEROGENEITY

(10)

Intratumor heterogeneity

Epigenomic/state of differentiation diversity

INTRATUMOR HETEROGENEITY

(11)

TUMOR EVOLUTION

(12)

INTRATUMOR HETEROGENEITY: Leading to a

Sampling Bias?

(13)

SYSTEMATIC REVIEW OF DISCORDANCE RATE BETWEEN PRIMARY TUMOR AND DIFFERENT SITES OF METASTASIS

Yeung C et al. Cancer Metastasis Rev 2016

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SYSTEMATIC REVIEW OF DISCORDANCE RATE BETWEEN PRIMARY TUMOR AND DIFFERENT SITES OF METASTASIS

Yeung C et al. Cancer Metastasis Rev 2016

(15)

SYSTEMATIC REVIEW OF DISCORDANCE RATE BETWEEN PRIMARY TUMOR AND DIFFERENT SITES OF METASTASIS

ER CHANGES:

Frequency depends on metastatic site

Yeung C et al. Cancer Metastasis Rev 2016

(16)

TEMPORAL HETEROGENEITY: ESR1 MUTATION

AS AN EXAMPLE

(17)

HOW APPLICABLE ARE THESE FINDINGS TO

OTHER DATA SETS?

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TUMOR CHARACTERIZATION

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TUMOR CHARACTERIZATION

(20)

TUMOR CHARACTERIZATION

(21)

FUNCTIONAL ASSAYS

Functional assays

Patient-derived models

(22)

Tumoroids

Characterization and Functional Analysis Patient

Cancer Biology DNA Sequencing

Gene expression

Preclinical studies

Patient stratification Circulating

biomarkers

PDX

Epigenomics

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VAN DER VELDEN et al. LBA59_PR - Expanding the use of

approved drugs: The CPCT’s Drug Rediscovery Protocol (DRUP)

Patient with advanced cancer

Who has exhausted treatment options

If a tumor profiling test has been performed:

Via regular diagnostics or CPCT

Revealing an actionable target

For which targeted therapy is available

But not for patients’ tumor type

Submit to DRUP study team:

Actionable target present?

Matching drug available?

Evidence for potential efficacy?

If so:

Obtain informed consent

Screen patient

Obtain pre-treatment biopsy Start study

treatment

van der Velden et al. Amsterdam

Study flow chart

Since Sep 2016, ∼250 cases were

submitted for review and about 1/3 of these patients have started study

treatment

Clinical benefit was observed in 37%

(6% CR, 14% PR, 17% SD ≥ 16 weeks;

all CRs and 2/3 of PRs were ongoing at the time of writing and awaiting ≥30 days confirmation)

About 2/3 of case submissions were rejected, mainly due to a general protocol ineligibility (18%)

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GUPTA et al. 1628O - Development of the Manchester Cancer Research Centre Molecular Tumour Board for matching patients to clinical trials based on tumour and ctDNA genetic profiling

esmo.org

THE TARGET TRIAL

Tumour ChARacterisation to Guide Experimental Targeted Therapy

DNA extraction

MOLECULARTUMOUR BOARD

Targeted panel of 24 cancer genes

Illumina MiSeq NGS

20ng DNA input

Detects point mutations and indels to 5% MAF Tissue sample

(archival / fresh)

Blood sample (6-12ml plasma)

ctDNA isolation

Targeted panel of 653 cancer genes

NextSeq NGS

>5ng cfDNA input

Mutation and copy number evaluation

Detection level ≥2.5%

Tissue and blood results in a realistic time

frame (2-3 weeks)

Gupta et al. Manchester

(25)

Pernas Simon et al. 315TiP - AGATA molecular screening

program: Implementing precision medicine in patients with

advanced breast cancer in Spain

(26)
(27)

Rapid Autopsy Process

Preliminary Discussion Identification

Notification Formal

Autopsy Consent

Transport Research

Analysis

Diagnostic Autopsy Report

Walmsley et al. Boston

WALMSLEY et al. 1629O - A systematic rapid autopsy program tracks temporal and spatial heterogeneity of human tumors and identifies mechanisms of resistance to targeted therapies

Full analysis of 3 autopsy series revealed molecular alterations driving resistance to PI3K-alpha inhibitors, CDK4/6

inhibitors and FGFR inhibitors in patients with PIK3CA-altered metastatic breast cancer and FGFR2 fusion positive

cholangiocarcinoma

Rapid autopsies complement serially collected tissue and liquid biopsies,

providing invaluable samples for analysis of tumor heterogeneity, evolutionary dynamics and determination of

resistance mechanisms to targeted therapies

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TUMOR CHARACTERIZATION LEADS TO PRECISION THERAPY

Tumor characterization leads to precision therapy Challenges:

- Samples (quality, how representative, timing) - Bioinformatics

- More drugs and actionable targets (more research)

(29)

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