come sfruttare le conoscenze biologiche per ridurre le...

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Farmacogenetica: come sfruttare le conoscenze biologiche per ridurre le tossicità e incrementare il sinegismo terpeutico Dr Valentina Citi Dip. Medicina Clinica e Sperimentale Università di Pisa

Transcript of come sfruttare le conoscenze biologiche per ridurre le...

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Farmacogenetica:

come sfruttare le conoscenzebiologiche per ridurre

le tossicità e incrementareil sinegismo terpeutico

Dr Valentina Citi

Dip. Medicina Clinica e SperimentaleUniversità di Pisa

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Tipologie di marker molecolari

Identificazione di patologie (cromosoma Philadelphia in

CML)

Associazione con l’outcome clinico (BRAF V600E tumore del

colon)

Attività di terapie specifiche (HER-2 e trastuzumab)

Diagnostici

Prognostici

Predittivi

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Biomarker predittivi

Drug activity Drug toxicity

• EGFR - lung• ALK - lung• BRAF - melanoma• BCR-ABL - AML• HER-2 - breast

• DPD – 5-FU• UGT – irinotecan• TPMT – 6-MP• CDA – gemcitabine

Tipologie di marker molecolari PREDITTIVI

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Biomarker predittivi

Drug activity Drug toxicity

• EGFR - lung• ALK - lung• BRAF - melanoma• BCR-ABL - AML• HER-2 - breast

• DPD – 5-FU• UGT – irinotecan• TPMT – 6-MP• CDA – gemcitabine

Tipologie di marker molecolari PREDITTIVI

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Quesito

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Fluoropirimidine

• Farmaci antimetaboliti analoghi delle basi pirimidiniche

• Potenti inibitori della timidilato sintetasi

• Ampiamente utilizzati per il trattamento di molti tumori solidi,

tra cui tumore del colon, della mammella e testa-collo.

Capecitabine5-FU Tegafur

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DPD

5-FdUMP

TS

Tolerable

toxicity

5-FDHU

5-FdUMP

TS

Severe

toxicity

5-FU

Deficiency

5-FDHU

5-FU

Normal

• Evitare tossicità mortale a seguito del trattamento con 5-FU è un aspetto di

rilevanza clinica

L’inattivazione del 5-FU dipende principalmente dalla diidropirimidina deidrogenasi

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1998

Enzymatic

activity of DPD

in PBMC

Test dose of 5-FU 250

mg/sqm i.v. and

concentration measurements

DPD genotyping

Factors to be considered for the choice of methods:

1) Minimal assay variability

2) Easy procedure

3) Widespread availability

4) Affordable cost

2002 2011

Time Line: valutazione dell’attività della DPD e della tossicità da 5-FU presso il nostro dipartimento

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DPD deficiency e 5-FU toxicity

61C>T

62G>A

74A>G

85T>C

257C>T

295-298delTCAT

100delA

496A>G

601A>C

632A>G

703C>T

812delT

Introne

5’

Esone

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

3’

1003G>T

1039delTG

1108A>G

1156G>T

1475 C>T

1601G>A

1627A>G

1679T>G

1714C>G

1896T>C

1897delC

IVS14+1G>A

2194G>A

2657G>A

2846A>T

2933A>G

2983G>T

Del Re M et al. EPMA Journal 2011

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Clinical data: patient #1

DIARRHEA 4

NAUSEA/VOMITING 3

STOMATITIS 3

NEUTROPENIA 3

THROMBOCYTOPENIA 2

85T>C 496A>G

Intron

5’

Exon

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

3’

1601G>A

1627A>G

1801G>C

1896T>C

IVS14+1GA

2194G>A

1st cycle

OXALIPLATIN 85 mg/m²,

FOLINIC ACID 200 mg/m²

5-FU i.v. bolus 400 mg/m²

followed by a 44-h continuous

400 mg/m² i.v. infusion

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Clinical data: patient #2

DEATH

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Raccomandazioni cliniche

“La terapia con fluoropirimidine è controindicata nei pazienticon gene DPYD mutato in omozigosi per le varianti DPYD*2A,c.1679T>G e c.2846A>T, poiché esse annullano l’attivitàenzimatica DPD, mentre è necessario ridurre il dosaggio dellafluoropirimidina almeno del 50% nei pazienti portatori dellemutazioni DPYD*2A, c.1679T>G e c.2846A>T in eterozigosi. Lamodifica della dose dovrà, inoltre, considerare anche eventualitrattamenti concomitanti.”

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Risposta

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Biomarker predittivi

Drug activity Drug toxicity

Response Resistance

Tipologie di marker molecolari PREDITTIVI

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Biomarker predittivi

Drug activity Drug toxicity

Response ResistanceEvolving tumor

Tipologie di marker molecolari PREDITTIVI

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Quesito

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Zong Y, Goldstein AS. Nat Rev Urol. 2013;10(2):90-8

Due meccanismi, ma non mutualmente esclusivi

Adaptation

resistant cells

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Adaptation

Clonal selection

Zong Y, Goldstein AS. Nat Rev Urol. 2013;10(2):90-8resistant cells

resistant cells

Due meccanismi, ma non mutualmente esclusivi

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Scientific background

• NSCLC is an heterogeneous disease with distinct molecular characteristics

• Specific activating mutations in the tyrosine kinase domain of EGFR or ALK

translocations are associated with sensitivity to TKIs (N Engl J Med 2004;

Eur J Cancer 2012)

• Metastatic tumors often carry different genetic clones. Therefore, at tumor

progression, further analysis of molecular markers is warranted (Lung

Cancer 2013)

• It is well known that treatment acquired resistance to TKIs is associated

with the acquired of secondary EGFR mutation (i.e. p.T790M) or ALK point

mutations (i.e. p.L1196M) (N Engl J Med 2005; J Clin Oncol 2013)

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Mechanisms of EGFR-TKIs acquired resistance

J Clin Oncol. 2013 Nov 1;31(31):3987-96

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J Clin Oncol. 2013 Nov 1;31(31):3987-96

Mechanisms of ALK-TKIs acquired resistance

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What’s the matter?

Several factors limit the feasibility of a re-biopsy andmolecular analysis:

amount of material that can be recovered duringbronchial endoscopy

difficult access to some tumor sites

invasive nature of sampling methods

possible dissemination of tumor cells

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Molecular analysisof cell-free

circulat ing DNA for the

diagnosisof somatic mutations

associated with resistance to

tyrosine kinase inhibitors in

non-small-cell lung cancerExpert Rev. Mol. Diagn. Early online, 1–16 (2014)

Marzia Del Re1,

Enrico Vasile2,

Alf redo Falcone2,

Romano Danesi* 1 and

Iacopo Petrini2

1Department of Clinical and

Experimental Medicine, Clinical

Pharmacology Unit, Pisa University,

Pisa, Italy2Department of Translational Research

and New Technologies in Medicine and

Surgery, Medical Oncology Unit,

Pisa University, Pisa, Italy

Author for correspondence:

Tel.: +39 050 992 632

[email protected]

In non-small-cell lung cancer, the molecular diagnosis of somatic mutations is instrumental for

the choice of the most appropriate treatment. However, despite an initial response, resistance

to tyrosine kinase inhibitors occurs and thereafter tumors progress. For this reason, next

generation inhibitors able to overcome acquired resistances are currently in development.

Therefore, the identification of the molecular determinants of resistance is needed to adapt

treatment accordingly. The analysis of circulating cell-free tumor DNA represents a powerful

tool to monitor the somatic changes induced by treatment. This review focuses on the most

recent advantages in the diagnosis of acquired resistance in circulating cell-free tumor DNA

and underlines the strategies ready to be translated in the clinical practice.

KEYWORDS: acquired resistance • ALK • circulating cell-free tumor DNA • EGFR • non-small-cell lung cancer

• pharmacologic inhibitors

Non-small-cell lung cancer (NSCLC) is the

worldwide leading cause of death for neoplastic

diseases. Surgery isthemainstay of treatment in

stagesI and II (25–30% of new diagnosis) with

5-year survival rates of 60–80% and 40–50%,

respectively [1]. For advanced diseases, the only

option isasystemic treatment includingchemo-

therapy or molecularly targeted drugs. The his-

tology of the NSCLC (FIGURE 1A) (squamous cell

vs adenocarcinoma) and the presence of onco-

genic mutations determine the choice of treat-

ment. Indeed, different types of oncogenic

drivers seem to characterize tumors with differ-

ent histologies [2,3]. For adenocarcinomas, the

identification of mutations already influences

thestandard clinical care.

Mainly, two different approaches have been

adopted to study the mutations of NSCLC;

the first one attempts to identify mutations in

already defined cancer genes (proto-oncogenes

and tumor-suppressor genes); the second one

screens the entire genome for mutations using

next-generation sequencing and then tries to

define which mutations are relevant for the

cancer growth.

In adenocarcinomas, using a combination

of whole-genome and exome sequencing, the

median exomic mutation rate was one of the

highest observed to date (8.1 events/mega-

base) [2]. Therefore, ‘driver’ mutations, those

able to guide the tumor growth, are diluted

within a large number of ‘passenger’ muta-

tions. These ‘passenger’ mutations occur ran-

domly and, in highly replicative tumor cells,

are determined by the intrinsic error of the

DNA polymerase and by the defective DNA

repair mechanisms. The statistically recurrent

somatic mutationsare the candidatedriversof

tumor growth, and those identified using

exome sequencing are summarized in FIGURE 1B.

This list includes most of the genes that are

possibletargetsof therapy and geneswithout a

developed inhibitor known to be relevant for

adenocarcinomas’ biology including KRAS,

informahealthcare.com 10.1586/14737159.2014.908120 Ó 2014 Informa UK Ltd ISSN 1473-7159 1

Review

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Molecular analysisof cell-free

circulat ing DNA for the

diagnosis of somatic mutat ions

associated with resistance to

tyrosine kinase inhibitors in

non-small-cell lung cancerExpert Rev. Mol. Diagn. Early online, 1–16 (2014)

Marzia Del Re1,

Enrico Vasile2,

Alf redo Falcone2,

Romano Danesi* 1 and

Iacopo Petrini2

1Department of Clinical and

Experimental Medicine, Clinical

Pharmacology Unit, Pisa University,

Pisa, Italy2Department of Translational Research

and New Technologies in Medicine and

Surgery, Medical Oncology Unit,

Pisa University, Pisa, Italy

Author for correspondence:

Tel.: +39 050 992 632

[email protected]

In non-small-cell lung cancer, the molecular diagnosis of somatic mutations is instrumental for

the choice of the most appropriate treatment. However, despite an initial response, resistance

to tyrosine kinase inhibitors occurs and thereafter tumors progress. For this reason, next

generation inhibitors able to overcome acquired resistances are currently in development.

Therefore, the identification of the molecular determinants of resistance is needed to adapt

treatment accordingly. The analysis of circulating cell-free tumor DNA represents a powerful

tool to monitor the somatic changes induced by treatment. This review focuses on the most

recent advantages in the diagnosis of acquired resistance in circulating cell-free tumor DNA

and underlines the strategies ready to be translated in the clinical practice.

KEYWORDS: acquired resistance • ALK • circulating cell-free tumor DNA • EGFR • non-small-cell lung cancer

• pharmacologic inhibitors

Non-small-cell lung cancer (NSCLC) is the

worldwide leading cause of death for neoplastic

diseases. Surgery isthemainstay of treatment in

stages I and II (25–30% of new diagnosis) with

5-year survival rates of 60–80% and 40–50%,

respectively [1]. For advanced diseases, the only

option isasystemic treatment including chemo-

therapy or molecularly targeted drugs. The his-

tology of the NSCLC (FIGURE 1A) (squamous cell

vs adenocarcinoma) and the presence of onco-

genic mutations determine the choice of treat-

ment. Indeed, different types of oncogenic

drivers seem to characterize tumors with differ-

ent histologies [2,3]. For adenocarcinomas, the

identification of mutations already influences

thestandard clinical care.

Mainly, two different approaches have been

adopted to study the mutations of NSCLC;

the first one attempts to identify mutations in

already defined cancer genes (proto-oncogenes

and tumor-suppressor genes); the second one

screens the entire genome for mutations using

next-generation sequencing and then tries to

define which mutations are relevant for the

cancer growth.

In adenocarcinomas, using a combination

of whole-genome and exome sequencing, the

median exomic mutation rate was one of the

highest observed to date (8.1 events/mega-

base) [2]. Therefore, ‘driver’ mutations, those

able to guide the tumor growth, are diluted

within a large number of ‘passenger’ muta-

tions. These ‘passenger’ mutations occur ran-

domly and, in highly replicative tumor cells,

are determined by the intrinsic error of the

DNA polymerase and by the defective DNA

repair mechanisms. The statistically recurrent

somatic mutationsare the candidate driversof

tumor growth, and those identified using

exome sequencing are summarized in FIGURE 1B.

This list includes most of the genes that are

possible targetsof therapy and geneswithout a

developed inhibitor known to be relevant for

adenocarcinomas’ biology including KRAS,

informahealthcare.com 10.1586/14737159.2014.908120 Ó 2014 Informa UK Ltd ISSN 1473-7159 1

Review

Ex

pert

Rev

iew

of

Mo

lecu

lar

Dia

gno

stic

s D

ow

nlo

aded

fro

m i

nfo

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om

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.19

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.

Marzia Del Re, Enrico Vasile, Alfredo Falcone, Romano Danesi and Iacopo Petrini

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DNA circolante è quantificabile nel plasma

cftDNA

Dead cells

Viable cells

Blood

Perkins G, et al. PLoS ONE 7(11): e47020, 2012

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Aim of the study

• Acquired resistance determines tumor progression

• Metastatic tumors have different genetic clones

• One drug-therapy could not be suitable to treat an heterogenoustumor

Daily monitoring of patients during

pharmacological treatment for the detection of

acquired mutations in cftDNA.

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Study design, patients and methods

33 EGFR+ NSCLC patients

All patients receivedgefitinib/erlotinib and underwentdisease progression

44 NSCLC patients were included in this analysis

Blood samples were collected at tumor progression and cftDNA wasextracted by QIAamp circulating nucleic acid kit (Qiagen®)

cftDNA was analysed by the ddPCR (BioRad®) to evaluate theappearance of resistance acquired mutations (codon 12 KRAS,p.T790M EGFR, ALK point mutations)

11 ALK+ NSCLC patients

All patients received crizotinib and underwent disease progression

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EGFR+ patients

o p.T790M was detected in 11

subjects (33.3%) alone and in 13

patients (39.4%) with mutant

KRAS

o KRAS mutation at codon 12 alone

or in combination with p.T790M

was demonstrated in 3 (9.1%)

o Six patients (18.2%) were negative

for both KRAS and p.T790M

Results

ALK+ patients

o ALK point mutations (p.L1196M,

p.G1269A) were detected in 2

subjects (18,2%) in combination

with mutant KRAS

o KRAS mutation at codon 12

alone was demonstrated in 8

(72,7%) patients

o Three patients (27,2%) were

negative for both KRAS and ALK

point mutations

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Mutant allele amplification

Wild type allele amplification

Sample ID 36 - EGFR p.T790M at gefitinib progression

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Mutant allele amplification

Wild type allele amplification

Sample ID 36 - EGFR p.T790M in response to AZD9291

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Mutant allele amplification

Wild type allele amplification

Sample ID 42 - ALK p.L1196M at crizotinib progression

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Sample ID 42 – ALK p.L1196M in response to AP26113

Wild type allele amplification

Disappearance of mutant allele

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Risposta

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Conclusioni

Tossicità da fluoropirimidine

• Le varianti DPYD*2A, c.1679T>G, c.2846A>T potrebbero essere associate a gravi tossicità a seguito della somministrazione di fluoropirimidine

• L’analisi di questi polimorfismi pre-trattamento potrebbe evitare eventi di tossicità grave

• Il costo dell’analisi viene ammortizzata dal miglioramento dello stato di salute del paziente

Resistenza farmacologica

• L’analisi molecolare di biomarker predittivi di resistenza dovrebbe essere incorporata nella pratica clinica

• Incrementare l’utilizzo di nuove tecnologie dovrebbe essere discusso tra clinici e farmacologi

• Il costo dell’analisi molecolare viene abbattuto dal miglioramento dell’outcome clinico del paziente

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Grazie per l’attenzione

Lab staff:

Prof. Romano Danesi

Dr Marzia Del ReDr Valentina CitiDr Marta PalombiDr Francesca Belcari

Ringraziamenti

• Tiseo M, Bordi P, Ardizzoni A,• D’Incecco A, Cappuzzo F,• Petrini I, Lucchesi M, Vasile

E, Falcole A, Chella A• Camerini A, Amoroso A• Inno A, Gori S• Spada D, Testa E• Malpeli G, Scarpa A