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Tratamientos dirigidos a tumores con defectos en los mecanismos de reparación homóloga del ADN

JM Piulats

Consultant or Advisory Role: BMS, MSD, Pfizer, Roche Genentech, Janssen, Astellas, Astra Zeneca, Clovis, BeiGene.

Research Funding: BMS, MSD, Pfizer, Merck-Serono, Roche Genentech, Janssen, BeiGene.

Disclosure Information

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DNA Repair Mechanisms

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Synthetic Lethality

PARPi

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PARP-inhibitors: Where are we now…

Ova

rian

Can

cer

Pro

stat

e C

ance

r

Pan

crea

tic

Can

cer

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PARP-inhibitors: Where are we now…

…are we ready for a Tumor Agnostic approach to Treat Patients with

BRCA1/2mut

BRCAness

HRDness

PARPness

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PARP-inhibitors: Differences with other Targeted Therapies

Oncogenic Addiction

Oncogene Biomarker AntiOncogene

Redundancy Biomarker?

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PARP-inhibitors: Biomarker HR gene mutations B

RC

A1

/2m

ut

No

n-B

RC

A D

NA

Dam

age

Rep

air

Alt

erat

ion

s

#SEOM20

PARP-inhibitors: Biomarker HR gene mutations

No

n-B

RC

A D

NA

Dam

age

Rep

air

Alt

erat

ion

s

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PARP-inhibitors: Biomarker HRD phenotype

DNA “scars”

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BRCAmut are Unreliable Tissue-Agnostic Biomarkers for PARPi

Individuals with germline BRCA1/2mut can develop other types of cancer. Somatic BRCA1/2mut are also found in other diverse cancers.

17,152 cancer patients 55 cancer types

2.7% (n=462) germline pathogenic BRCA1/2 allele

5.4% (n=919) somatic mutation in BRCA1/2 59% missense of uncertain importance 307 patients (1.8%) with LoF mutation in BRCA1/2

4.9%

53

%

Ovarian cancer Breast cancer Prostate cancer Pancreatic cancer

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BRCAmut are Unreliable Tissue-Agnostic Biomarkers for PARPi

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BRCAmut are Unreliable Tissue-Agnostic Biomarkers for PARPi

LOH

LOH

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BRCAmut are Unreliable Tissue-Agnostic Biomarkers for PARPi

Lineage variation in selection for BRCA1/2 biallelic inactivation:

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BRCAmut are Unreliable Tissue-Agnostic Biomarkers for PARPi

BRCA phenotypes are tumor lineage and zygosity-dependent:

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BRCAmut are Unreliable Tissue-Agnostic Biomarkers for PARPi

Most somatic heterozygous BRCA1/2 mutations in non-BRCA-assciated cancers are neutral passenger mutations. BRCA1/2 may be a consequence rather tan the cause of tumorigenesis.

BRCA phenotypes are tumor lineage and zygosity-dependent:

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BRCAmut are Unreliable Tissue-Agnostic Biomarkers for PARPi

Context-specific therapeutical sensitivity of BRCA1/2-mutant:

Uterine Sarcoma Homozygous BRCA2 deletion 6.5%

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Is HRDness a Tissue-Agnostic Biomarkers for PARPi?

DNA “scars”

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Is HRDness a Tissue-Agnostic Biomarkers for PARPi?

But, are there many patients out of BRCA-associated tumors?

• List of genes involved in HR is far from complete (CHD1 in prostate cancer). • HRD can also be induced. • Sequencing panels of HR-related genes will likely miss a subset of HRD cases.

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Conclusions

…are we ready for a Tumor Agnostic approach to Treat Patients with

BRCA1/2mut

BRCAness

HRDness

PARPness ?

PARPi will only be active in tumors where HRD generates genetic instability, probably as a founding event This might be seen only in BRCA-related diseases (+ uterine sarcomas?)