Tratamientos dirigidos a tumores con defectos en los ......Tratamientos dirigidos a tumores con...
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#SEOM20 Tratamientos dirigidos a tumores con defectos en los mecanismos de reparación homóloga del ADN JM Piulats
Transcript of Tratamientos dirigidos a tumores con defectos en los ......Tratamientos dirigidos a tumores con...
#SEOM20
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
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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?)
