Quale ruolo per la biopsia liquida?

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Quale ruolo per la biopsia liquida?

A.O.U.P. "P. Giaccone" University Hospital DIPARTIMENTO DI DISCIPLINE CHIRURGICHE,

ONCOLOGICHE E STOMATOLOGICHE

MEDICAL ONCOLOGY UNIT

(Dir.: Prof. Antonio Russo)

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Dichiarazione conflitto di interessi

Tutti i rapporti finanziari intercorsi negli ultimi due anni devono essere dichiarati.

X Non ho rapporti (finanziari o di altro tipo) con le Aziende del farmaco

Ho / ho avuto rapporti (finanziari o di altro tipo) con le Aziende del farmaco

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0 1000 2000 3000 4000 5000 6000 7000

8000 Liquid biopsy in cancer

2006 2016

Liquid Biopsy

The extent of the problem

- Andreyev HJ, […], Russo A, […]: Mutant K-ras2 in serum. Gut. 2003

- Bazan V,[…], Russo A: TP53 and Ki-Ras in plasma of pts with CRC... Ann Oncol 2006 - Gargano G., […], Russo A: Mammaglobin in the blood of BC pts… Ann Oncol 2006

< 50

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Components

 Circulating Tumor Cells (CTC)

 Circulating nucleic acids (ctDNA, cfDNA, ctRNA, miRNAs)

 Exosomes

Release mechanisms

 Secretion

 Necrosis

 Apoptosis

Liquid biopsy

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Liquid biopsy

Open questions in BRCApos OC

- Quali meccanismi di resistenza ai PARPi?

- L’utilizzo di CT a base di platino o di PARPi può influenzare la comparsa di mutazioni di reversione?

- Quando ricercare la mutazione di reversione?

- Come potrebbe cambiare il management delle pts

affette da OC?

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Not HRD

BRCA1 Germline

8% BRCA2 Germline 6%

BRCA1 SOMATIC BRCA2 SOMATIC

BRCA1 Methylation 11%

EMSY Amplification 6%

PTEN Loss 6%

Other HRD 5%

CCNE1 Amplification RB1 Loss 14%

4%

MMR Germline 2%

Other 31%

Review literature 2017

4%

3%

HRD High grade serous OC

Potential benefit of PARP inhibition in 50%

- BRCA1/2 GERMLINE mutations 14%

- BRCA1/2 SOMATIC mutation 7%

Total 21%

Not only germline mutation Not only BRCA mutation

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BRCA1/2 reversion muts

(18-30%) 53BP1

regulation Replication on

fork dynamics Exploiting altered

cell cycle regulation

Drug efflux:

p-glycoproteins

Signal trasduction (MET/HGFR, PI3K/AKT)

miRNA

environment PARP

expression

PARPi in BRCAmut

Acquired resistance mechanism

(8)

LOH or somatic mutation

BRCA

Germinal mutation

Platinum

Cell death

Resistant neoplastic

cells

Secondary mutation

Secondary mutation Open Reading or Frame restoring

PARPi

Russo et al. "Back to a false normality": new intriguing mechanisms of resistance to PARPi. Oncotarget, 2017

PARPi + BRCA: Acquired resistance mechanism

Reversion of BRCA1/2 Germline mutation

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Pt 57 years HG serous OC

(Stage IV) February 2014

Cytoreductive surgery

Analysis of BRCA germline mutation BRCA2: c.4588A>T

p. K1530X

Platinum based CT

July 2015 Radiological PD

Maintainace with olaparib Nov 2015

Olaparib start

Other treatments

ctDNA results:

BRCA2 reversion variant c.4588 A>C p. K1530N

DNA binding BRC repeat s

0 500 1000 1500 2000 2500 3000 3417

0 500 1000 1500

Prot eina t ronca

DN A binding

2000 2500 3000 3417

0 500 1000

Nov 2017 Radiologic PD

ctDNA NGS analysis

Liquid biopsy: real time monitoring of the disease

Detect PARP inhibitors resistance

(10)

- Quali meccanismi di resistenza ai PARPi?

- L’utilizzo di CT a base di platino o di PARPi può influenzare la comparsa di mutazioni di reversione?

- Quando ricercare la mutazione di reversione?

- Come potrebbe cambiare il management delle pts affette da OC?

Liquid biopsy

Open questions in BRCApos OC

(11)

Liquid biopsy: Real Time monitoring of the tumor

Reversion of BRCA1/2 Germline muts in ctDNA from HG Serous OC pts

30 pts HGSOC Germline BRCA 1/2 POS

14 pts

Control cohort Primary debulking

surgery

Tumor samples

At primary surgery

Reading frame restoring

No

reversion mutations

16 pts

Recurrent cohort Recurrent OC cohort

Liquid biopsy

At OC recurrence

Tumor samples

At OC recurrence

5/16 (31%)

reversion mutations

4/16 (25%)

reversion mutations

Liquid biopsy

At primary surgery

Elizabeth L. Christie et Al, JCO 2017

Resistant to Platin-based

CT or PARPi

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- Quali meccanismi di resistenza ai PARPi?

- L’utilizzo di CT a base di platino o di PARPi può

influenzare la comparsa di mutazioni di reversione?

- Quando ricercare la mutazione di reversione?

- Come potrebbe cambiare il management delle pts affette da OC?

Liquid biopsy

Open questions in BRCApos OC

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ARIEL 2

Phase 2, Open-Label Study:

Rucaparib in pts with Platinum-Sensitive, Relapsed,

HG OC, Fallopian Tube, or Primary Peritoneal

Cancer

PART 2

Evaluation of HRD status and rucaparib efficacy:

pts received ≥ 3 prior CT regimens

PART 1

Evaluation of HRD status and rucaparib efficacy:

pts received ≥ 1 prior platinum-based regimen with platinum-sensitive disease

Lin KK et Al: BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov. 2018

Liquid biopsy: Real Time monitoring of the tumor

BRCA1/2 reversion muts in ctDNA from HG Serous OC pts:

Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib

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cfDNA in BLOOD PLASMA SAMPLES

COLLECTION

Before treatment with PARPi

Progression after treatment with PARPi

Liquid biopsy: Real Time monitoring of the tumor

BRCA1/2 reversion muts in ctDNA from HG Serous OC pts:

Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib

Primary Resistance

Acquirend Resistance

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97 pts HGSOC BRCA 1/2 POS

97 pts Before treatment

with PARPi

78 pts

Progression after treatment with PARPi

Primary Resistence Aim Aim

Acquirend Resistence

18% (2/11) platinum- refractory

2% (1/48) platinum-

sensitive

13% (5/38) platinum- resistant

BRCA reversion mutations

14% (1/7) platinum- refractory

8% (2/26) platinum-

sensitive

17% (5/30) platinum- resistant

Liquid biopsy: Real Time monitoring of the tumor

BRCA1/2 reversion muts in ctDNA from HG Serous OC pts:

Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib

BRCA reversion mutations

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Lin KK et Al: BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov. 2018

Liquid biopsy: Real Time monitoring of the tumor

BRCA1/2 reversion muts in ctDNA from HG Serous OC pts:

Monitoring during PARPi

BRCA reversion mutations in platinum- resistant or -refractory

HGSOC pts

clinical benefit from Rucaparib

treatment

(17)

- Quali meccanismi di resistenza ai PARPi?

- L’utilizzo di CT a base di platino o di PARPi può

influenzare la comparsa di mutazioni di reversione?

- Quando ricercare la mutazione di reversione?

- Come potrebbe cambiare il management delle pts affette da OC?

Liquid biopsy

Open questions in BRCApos OC

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Oncogenetic Counseling

Somatic

BRCA 1/2

Negative

Somatic

BRCA 1/2 +

Germline BRCA 1/2

Positive

Germline BRCA 1/2

Negative

Mini Counseling

Liquid biopsy: Real Time monitoring of the tumor Detecting resistance to PARP-inhibitors

(Not mucinous/not borderline) OC Ca fallopian tubes Ca primitive peritoneum

PARPi

Platinum-based CT

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