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DNA repair deficiencies and PARP inhibitors in Triple Negative Breast Cancer
Andrew TuttDirector
Breakthrough Breast Cancer Research CentreLondon
Overview
• Evidence for targetable DNA damage defect in TNBC
• Is platinum a probe for Homologous Recombination Deficiency?
• What are the special “+ve” populations – gBRCA / “BRCAness”
• Biomarkers of Homologous Recombination Deficiency (HRD)
Focus on Genomic Scars as biomarkers
• Potential novel combinations including targeting S-Phase Stress
Breast Cancer have variable genome
complexity reflecting DNA repair competence
Palm Baobab TreeChestnut
Risk of treatment failure ?Lee and Swanton (2011) Cancer Research; Yap and Swanton Sci Trans Med (2012)
Alexandrov et al Nature 2013
BRCA1 BRCA2 Mutation
associated
APOBEC associated
Alexandrov et al Nature 2013
Stable genome- low instability
Unstable genome- high instability
TNBCs have highly variable
Chromosome structural instability
BRCA1 BRCA2 Mutation
associated
APOBEC associated
Genomic Instability generates high tumour
heterogeneity and few recurrent targetable mutations
MYH3
LAMB3 MYH4
ITGA6
LAMB4COL7A1
ITGA8
COL11A1
LAMB2
MYOC
MYH11P53
PI3KCA
The mutator phenotypes that define the
Baobab’s shape may be “actionable” targets
BRCA1 is a genome stability “caretaker” and
is mutated in ≈15% of patients with TNBC
Roy et al Nat Rev Cancer 2012 Walsh and King Cancer Cell 2007
BRCA1 and BRCA2 share function in the DNA DSB and replication fork damage response
*
*
**
*
*
*
*
Roy et al Nat Rev Cancer 2012 Walsh and King Cancer Cell 2007
BRCA1 and BRCA2 share function in the DNA DSB and replication fork damage response
*
*
**
*
*
*
*
HR deficiency implicated
In Sporadic TNBC
Methylation
Somatic mutation
Other epigenetic mechanisms
Roy et al Nat Rev Cancer 2012
When HR fails other DNA repair processes (NHEJ) take over driving a mutator phenotype
Roy et al Nat Rev Cancer 2012
When HR fails other DNA repair processes (NHEJ) take over driving a mutator phenotype
The pattern of
rearrangements across the
genome may act as a
diagnostic tattoo for HR failure
This presentation is the intellectual property of the author/presenter. Contact them at andrew.tutt@icr.ac.uk for permission to reprint and/or distribute
San Antonio Breast Cancer Symposium December 9-13, 2014
DSB at DNA crosslinkpt
pt
DNA crosslink unhooked by
XPF/ERCC1 and RPA
Moynahan et al Mol Cell 2000 Tutt et al EMBO J 2001
XPFERCC1
XPFERCC1
FancJ
BRCA1
Hueng et al Nat Rev Mol Cell Biol 2012
BRCA1 / BRCA2 and HR are involved in repair of DNA platinum adducts
This presentation is the intellectual property of the author/presenter. Contact them at andrew.tutt@icr.ac.uk for permission to reprint and/or distribute
San Antonio Breast Cancer Symposium December 9-13, 2014
Search for homologous sequence
on identical sister chromatid
Original sequence is restored
DSB at DNA crosslinkpt
BRCA2Rad51
X-link excision and DNA resynthesis
pt
DNA crosslink unhooked by
XPF/ERCC1 and RPA
Moynahan et al Mol Cell 2000 Tutt et al EMBO J 2001
XPFERCC1
XPFERCC1
FancJ
BRCA1
Hueng et al Nat Rev Mol Cell Biol 2012
BRCA1 / BRCA2 and HR are involved in repair of DNA platinum adducts
Zander, S. A.L. et al. Cancer Res 2010;70:1700-1710
Models of BRCA1 mutated basal-likebreast cancer have specific chemo-sensitivities
BRCA1
Mutation
Carriers with
Tumors >2cm
Clinical and
Pathological
Response
Platinum for Neoadjuvant Therapy in BRCA1 Mutation Carriers
.
CISPLATIN
75mg/m2
q 3wks IV x 12
wks
•N = 25
•median age: 46
•28% with clinically positive lymph nodes
•22 pts completed 4 cycles of Cisplatin
Pathological Response 72%
Gronwald et al ASCO 2009
Copyright © American Society of Clinical OncologySilver, D. P. et al. J Clin Oncol; 28:1145-1153 2010
Biomarkers of neoadjuvant
cisplatin response in TNBC
Breast Cancer Res 2014:16,211
Birkbak et al., Cancer Discov. 2012 Apr;2(4):366-75
Breast Cancer Res 2014:16,211
Birkbak et al., Cancer Discov. 2012 Apr;2(4):366-75
Numerical and Structural Chromosomal Instability associated
with BRCA1/2 inactivation and Cisplatin Sensitivity
Popova et al., Cancer Research. 2012 Aug 72:5454-5462. Abkevich et al., Br J Cancer. 2012 Nov 6;107(10):1776-82.
High Grade Serous
Ovarian Cancer
No: LoH
> 15Mb
Basal Like Breast Cancers
& BRCA1/2 mutations
No: adjacent
> 10Mb CNA
Large State Transition
BRCA1/2 mutant
BRCA1/2 intact
Numerical and Structural Chromosomal Instability associated
with BRCA1/2 inactivation and Cisplatin Sensitivity
Popova et al., Cancer Research. 2012 Aug 72:5454-5462. Abkevich et al., Br J Cancer. 2012 Nov 6;107(10):1776-82.
High Grade Serous
Ovarian Cancer
No: LoH
> 15Mb
Basal Like Breast Cancers
& BRCA1/2 mutations
No: adjacent
> 10Mb CNA
Large State Transition
BRCA1/2 mutant
BRCA1/2 intact
Platinum as a probe for HR deficiency
in metastatic TNBC?
• Very few TNBC specific trials -> mostly subsets
• Often platinum assessed in combination
• Many cross study comparisons of subgroups
• Various “triple-negative” definitions
• BRCA1/2 mutation rarely characterised
• Mostly no correction for differences in disease free interval
• Randomized data comparing platinum to standard of care
chemotherapy in first or second line
Platinum in metastatic TNBC
Unselected and gBRCAmRegimen N ORR (%) PFS
(mths)
Prior Adj
Chemo (%)
Iniparib Trials
Gem / Carbo1
1st line
2nd/3rd line
258
148
110
30% 4.1
4.6
2.9
90%
Ph II gBRCA1m2
1st line
2nd line
20
11
9
80% (TTP)
12
65%
TBCRC009
Carbo / Cis3
86
11
gBRCAm
26%
55% gBRCAm
20% gBRCAwt
2.9 86%
1. O’Shaughnessy J, et al. ASCO 2011 (abstract) 2. Byrski et al Breast Cancer Res 2012 14:R110
3. Isakoff S, et al. ASCO 2014 (abstract)
TBCRC 009 Tested Two HRD deficiency “scar”
Fingerprints in tumour DNA
Popova et al., Cancer Research. 2012 Aug 72:5454-5462. Abkevich et al., Br J Cancer. 2012 Nov 6;107(10):1776-82.
Telli et al ASCO 2013
Developed in HGSOC
Tested in PrECOG 0105
No: LoH
> 15Mb
Basal Like Breast Cancers
& BRCA1/2 mutations
No: adjacent
> 10Mb CNA
Large State Transition
BRCA1/2 mutant
BRCA1/2 intact
Platinum sensitivity is associated with higher HRD scores
Presented By Steven Isakoff at 2014 ASCO Annual Meeting
TNT Trial design20
RANDOMISE
(1:1)
Docetaxel (D)
100mg/m2 q3w, 6 cycles
Carboplatin (C)
AUC 6 q3w, 6 cycles
ER-, PgR-/unknown & HER2- or known BRCA1/2
Metastatic or recurrent locally advanced
Exclusions include:
• Adjuvant taxane in ≤12 months
• Previous platinum treatment
• Non-anthracyclines for MBC
A Priori subgroup analyses:
• BRCA1/2 mutation
• Basal-like subgroups (PAM50 and IHC)
• Biomarkers of HRD
On progression,
crossover if appropriateOn progression,
crossover if appropriate
Carboplatin (C)
AUC 6 q3w, 6 cyclesDocetaxel (D)
100mg/m2 q3w, 6 cycles
59/188 (31.4%)
67/188(35.6%)
0 20 40 60 80 100
Carboplatin
Docetaxel
% with OR at cycle 3 or 6 (95% CI)
Objective response21
Absolute difference (C-D)
-4.2% (95% CI -13.7 to 5.3)
Exact p = 0.44
Randomised
treatment - all
patients (N=376)
21/92*(22.8%)
23/90*(25.6%)
0 20 40 60 80 100
Carboplatin (Crossover=Docetaxel)
Docetaxel (Crossover=Carboplatin)
% with OR at cycle 3 or 6 (95% CI)
Absolute difference (D-C)
-2.8% (95% CI -15.2 to 9.6)
Exact p = 0.73
Crossover
treatment - all
patients (N=182)
*Denominator excludes those with no first progression and
those not starting crossover treatment
17/25(68.0%)
6/18(33.3%)
0 20 40 60 80 100
Carboplatin
Docetaxel
Percentage with OR at cycle 3 or 6 (95% CI)
Objective response – BRCA 1/2 status22
Absolute difference (C-D)
34.7% (95% CI 6.3 to 63.1)
Exact p = 0.03
Germline BRCA 1/2
Mutation (n=43)
Interaction: randomised treatment & BRCA 1/2 status: p = 0.01
0 20 40 60 80 100
Carboplatin
Docetaxel
Percentage with OR at cycle 3 or 6 (95% CI)
No Germline
BRCA 1/2
Mutation (n=273)
Absolute difference (C-D)
-8.5% (95% CI -19.6 to 2.6)
Exact p = 0.16
36/128
(28.1%)
53/145
(36.6%)
Bimodality
Breast & Ovarian Ca
BRCA1/2 mutation
BRCA1 methylation
Score ≥ 42 HRD High
Timms et al. Breast Cancer Res 2014, 16:475
MYRIAD Composite HRD biomarker analysis
23
Bimodality
Breast & Ovarian Ca
BRCA1/2 mutation
BRCA1 methylation
Score ≥ 42 HRD High
Timms et al. Breast Cancer Res 2014, 16:475
MYRIAD Composite HRD biomarker analysis
23
HRD score
*excluded from analyses
Tested: 220
HRD high (≥42): 81
HRD low (<42): 114
Test failed: 25*
376 patients recruited
Positive
LN143 patients
Primary
tumour309 patients
Blood
288 patients
Negative
LN112 patients
Recurrent
tumour102 patients
HRD score by BRCA 1/2 mutation25
Carboplatin Docetaxel
0
10
20
30
40
50
60
70
80
90
100
Germline BRCA1
Germline BRCA2
No Mutation
Somatic
Tumour mutation (germline unknown)
High HRD
Score ≥ 42
Low HRD
Score < 42
Myriad cut-point
19/65(29.2%)
17/49(34.7%)
0 20 40 60 80 100
Carboplatin
Docetaxel
Percentage with OR at cycle 3 or 6 (95% CI)
13/34(38.2%)
20/47(42.6%)
0 20 40 60 80 100
Carboplatin
Docetaxel
Percentage with OR at cycle 3 or 6 (95% CI)
Objective response – HRD score26
Absolute difference (C-D)
-4.4% (95% CI -26.0 to 17.2)
Exact p = 0.82
High HRD score
(n=81)
Low HRD score
(n=114)
Absolute difference (C-D)
-5.4% (95% CI -22.7 to 11.9)
Exact p = 0.55
Interaction: randomised treatment & dichotomised HRD score: p = 0.91
HR repair can be regained by the
evolutionary pressure of chemotherapy
Reversion of BRCA1 mutations Loss of 53BP1
Swisher et al Cancer Res 2008 vol. 68 (8) pp. 2581-6
Aly A , Ganesan S J Mol Cell Biol 2011;3:66-74
Tumours may regain
HR repair “fitness” to survive
chemotherapy S-phase stress
Adapted from Nik-Zainal et al Cell 2012
Tumours may regain
HR repair “fitness” to survive
chemotherapy S-phase stress
Adapted from Nik-Zainal et al Cell 2012
Early TNBC
Tumours may regain
HR repair “fitness” to survive
chemotherapy S-phase stress
Adapted from Nik-Zainal et al Cell 2012
Early TNBCAdvanced
TNBC
Tumours may regain
HR repair “fitness” to survive
chemotherapy S-phase stress
Adapted from Nik-Zainal et al Cell 2012
Is an old HRD “tattoo”
a good marker of
current repair
competence?
A biker can become a
Priest but can’t lose his
old “Hells Angel”
tattoos Early TNBCAdvanced
TNBC
Tumours may regain
HR repair “fitness” to survive
chemotherapy S-phase stress
Adapted from Nik-Zainal et al Cell 2012
Is an old HRD “tattoo”
a good marker of
current repair
competence?
A biker can become a
Priest but can’t lose his
old “Hells Angel”
tattoos Early TNBCAdvanced
TNBCHRD = Diagnostic filter
for Early HRD
May need measures of
current repair capability
for metastatic clones
Perhaps the HRD Scar biomarker is not sophisticated enough
• Have minimum and maximum size thresholds
• Take account of CNP and regions of LOH in the germline
• Exclude effect of very localised Chromothripsis events
• Allow better differentiation of genome instability mechanisms
Pro
po
rtio
n
S AbCNA
S AiCNA
S CnLOH
0.2
0.4
0.6
0.8
1.0
no scar
B
C
D
KCL METABRIC TCGA TNBC cell lines
0.2
P < 0.05
S AbCNA
S CnLOH
KCL TNBCs
0.4
NtAI
SCNA
SAI
SCnLOH
SAiCNA
SAbCNA
NtA
I
SCNA
SAI
SCnL
OH
SAiC
NA
0.4 0.5 0.5 0.8 0.4 0.2
0.2 0.6 0.8 0.6 0.3
0.7 0.3 0.7 0.6
0.6 0.8 0.6
0.6 0.3
0.5
0.6 0.8
0.0
Fre
qu
ency
1
Spearman’s rank correlation coefficient
non-significant P
0 20 40 60
0.00
0.01
0.02
0.03
0.04
0.05
0 20 40 60 80
0 20 40 60 80
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Fre
qu
en
cy
0.00
0.01
0.02
0.03
0.04
0.05S AiCNA
PrECOG
BRCA1/2: mutated
0
10
20
30
40
50
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wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
P = 0.0036
P = 0.083
mutated wildtype wildtype mutated
SA
i
PrECOG TNBCsG
TCGA HGSCs
P = 0.00499
S Ai
0.00
0.01
0.02
0.03
0.04
0 20 40 60 80 100
Fre
qu
en
cy
Fre
que
ncy
SLO
H
0.20.70.50.70.50.1
0.10.80.80.50.3
0.50.50.60.5
0.80.70.5
0.70.2
0.5
METABRIC TNBCs
NtA
I
SCNA
SAI
SCnL
OH
SAiC
NA
KCLTNBCs
P = 0.0019
P = 0.1
P = 0.00529
Platinum
non-responders
Platinum
responders
BRCA1/2:
Figure 2. TNBCs differ in the extent and variety of genomic scarring they exhibit
Score Score
Score Score
Allelic ImbalancedCopy Number
Aberration
SAiCNA
Copy Neutral Loss of
Heterozygosity
SCnLOH
●
●● ●
Allelic Balanced Copy Number
Aberration
SAbCNA
●●
A
0
5
10
15
20
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nL
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A
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SC
nL
OH
SA
i
mutated wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
BRCA1/2:
P = 0.528
P = 0.271
P = 0.362
P = 0.0265
P = 0.378
P = 0.0339
mutated wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
BRCA1/2:
P = 0.0082
P = 0.161
P = 0..00356
P = 0.0181
P = 0.175
P = 0.0391
mutated wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
BRCA1/2:
mutated wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
BRCA1/2:
PrECOG TNBCsE
TCGA HGSCs
PrECOG TNBCsF
TCGA HGSCs
SLO
H
Pro
po
rtio
nS AbCNA
S AiCNA
S CnLOH
0.2
0.4
0.6
0.8
1.0
no scar
B
C
D
KCL METABRIC TCGA TNBC cell lines
0.2
P < 0.05
S AbCNA
S CnLOH
KCL TNBCs
0.4
NtAI
SCNA
SAI
SCnLOH
SAiCNA
SAbCNA
NtA
I
SCNA
SAI
SCnL
OH
SAiC
NA
0.4 0.5 0.5 0.8 0.4 0.2
0.2 0.6 0.8 0.6 0.3
0.7 0.3 0.7 0.6
0.6 0.8 0.6
0.6 0.3
0.5
0.6 0.8
0.0
Fre
qu
ency
1
Spearman’s rank correlation coefficient
non-significant P
0 20 40 60
0.00
0.01
0.02
0.03
0.04
0.05
0 20 40 60 80
0 20 40 60 80
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Fre
qu
en
cy
0.00
0.01
0.02
0.03
0.04
0.05S AiCNA
PrECOG
BRCA1/2: mutated
0
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wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
P = 0.0036
P = 0.083
mutated wildtype wildtype mutated
SA
i
PrECOG TNBCsG
TCGA HGSCs
P = 0.00499
S Ai
0.00
0.01
0.02
0.03
0.04
0 20 40 60 80 100
Fre
qu
en
cy
Fre
que
ncy
SLO
H
0.20.70.50.70.50.1
0.10.80.80.50.3
0.50.50.60.5
0.80.70.5
0.70.2
0.5
METABRIC TNBCs
NtA
I
SCNA
SAI
SCnL
OH
SAiC
NA
KCLTNBCs
P = 0.0019
P = 0.1
P = 0.00529
Platinum
non-responders
Platinum
responders
BRCA1/2:
Figure 2. TNBCs differ in the extent and variety of genomic scarring they exhibit
Score Score
Score Score
Allelic ImbalancedCopy Number
Aberration
SAiCNA
Copy Neutral Loss of
Heterozygosity
SCnLOH
●
●● ●
Allelic Balanced Copy Number
Aberration
SAbCNA
●●
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SC
nL
OH
SA
i
mutated wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
BRCA1/2:
P = 0.528
P = 0.271
P = 0.362
P = 0.0265
P = 0.378
P = 0.0339
mutated wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
BRCA1/2:
P = 0.0082
P = 0.161
P = 0..00356
P = 0.0181
P = 0.175
P = 0.0391
mutated wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
BRCA1/2:
mutated wildtype wildtype mutated
Platinum
non-responders
Platinum
responders
BRCA1/2:
PrECOG TNBCsE
TCGA HGSCs
PrECOG TNBCsF
TCGA HGSCs
SLO
H
NHEJ / SSA Non-Conservative HR by GC Genome duplication
S AbCNA
S AiCNA
S CnLOH
no scar
A B
C
0.2
P < 0.05
KCL TNBCs
0.4
NtAI
SAI
SCnLOH
SAiCNA
SAbCNA
NtA
I
SAI
SCnL
OH
SAiC
NA
0.4 0.5 0.5 0.4 0.2
0.2 0.6 0.6 0.3
0.7 0.7 0.6
0.8 0.6
0.5
0.6 0.8 1
Spearman’s rank correlation coefficient
non-significant P
SLOH
0.20.70.50.50.1
0.10.80.50.3
0.50.60.5
0.70.5
0.5METABRIC TNBCs
NtA
ISA
I
S CnL
OH
SAiC
NA
KCLTNBCs
Figure 1 (A-C). The extent and nature of allelic imbalance genomic scarring differentially
associate with platinum-based chemotherapy sensitivity in TNBC and HGSC
SLOH
0
20
40
60
80
Sco
re
KCL METABRIC TCGA TNBC cell lines
S AbCNA
S CnLOH
Fre
qu
en
cy
0 20 40 60
0.00
0.01
0.02
0.03
0.04
0.05
0 20 40 60 80
0 20 40 60 80
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Fre
qu
ency
0.00
0.01
0.02
0.03
0.04
0.05S AiCNA
PrECOG
S Ai
0.00
0.01
0.02
0.03
0.04
0 20 40 60 80 100
Fre
qu
ency
Fre
que
ncy
Score Score
Score Score
ER+ cell lines
1
2
3
4
5
6
9
8
7
10
11
12
13141516171819
2021
22
X
Scores of Chromosome Instability Scarring(SCINS)
Johnathan
Watkins
Anita
Grigioradis
S AbCNA
S AiCNA
S CnLOH
no scar
A B
C
0.2
P < 0.05
KCL TNBCs
0.4
NtAI
SAI
SCnLOH
SAiCNA
SAbCNA
NtA
I
SAI
SCnL
OH
SAiC
NA
0.4 0.5 0.5 0.4 0.2
0.2 0.6 0.6 0.3
0.7 0.7 0.6
0.8 0.6
0.5
0.6 0.8 1
Spearman’s rank correlation coefficient
non-significant P
SLOH
0.20.70.50.50.1
0.10.80.50.3
0.50.60.5
0.70.5
0.5METABRIC TNBCs
NtA
ISA
I
S CnL
OH
SAiC
NA
KCLTNBCs
Figure 1 (A-C). The extent and nature of allelic imbalance genomic scarring differentially
associate with platinum-based chemotherapy sensitivity in TNBC and HGSC
SLOH
0
20
40
60
80
Sco
re
KCL METABRIC TCGA TNBC cell lines
S AbCNA
S CnLOH
Fre
qu
en
cy
0 20 40 60
0.00
0.01
0.02
0.03
0.04
0.05
0 20 40 60 80
0 20 40 60 80
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Fre
qu
ency
0.00
0.01
0.02
0.03
0.04
0.05S AiCNA
PrECOG
S Ai
0.00
0.01
0.02
0.03
0.04
0 20 40 60 80 100
Fre
qu
ency
Fre
que
ncy
Score Score
Score Score
ER+ cell lines
1
2
3
4
5
6
9
8
7
10
11
12
13141516171819
2021
22
X
Scores of Chromosome Instability Scarring(SCINS)
Johnathan
Watkins
Anita
Grigioradis
Suggestions for PARPifrom gBRCA+ platinum data
• A BRCA1 or BRCA2 mutation is associated with high pathological response to platinums in early disease
• This gBRCA+ effect persists in advanced disease and is specific to platinum rather than taxane chemotherapy
• Suggests metastatic clones of gBRCA+ BC remaining after adjuvant chemotherapy retain HR repair defect and might gain specific benefit from PARP inhibitors in advanced disease or adjuvant context
• Suggests that BRCA mutation testing of blood and possibly tumour be considered in an oncology as well as a genetics clinic in many with TNBC
Suggestions for PARPifrom gBRCA+ platinum data
• Raises Q of what standard of care comparitor regimen for PARP inhibitors should be in gBRCA+ advanced breast cancer trials
• Raises need to further assess design of trials of combination platinum and PARP inhibitor strategies particularly in gBRCA+ breast cancer
• Raises questions of trials of maintenance PARP inhibitors after platinum response in gBRCA+ mBC and platinum responsive mTNBC
• Supports trial designs of adjuvant PARP inhibitors in women with BRCA1 or BRCA2 mutations with breast cancer at high metastatic risk
• HR Deficiency or BRCAness present in early breast cancer but not associated with BRCA1 or BRCA2 mutation appears to exist
• … but this form of HR deficiency may have more reversible biological drivers such as methylation of BRCA1 that are no longer present in the metastatic clones surviving adjuvant chemotherapy
• These non-mutated HRD scar +ve tumours might be considered to be the “Biker Priests”
• in women with TNBC and no BRCA1 or BRCA2 mutation diagnostics for targetable BRCAness or HR Deficiency require further work especially in advanced recurrent breast cancer
Suggestions from the non gBRCA+ TNBC platinum data
Ramanathan et al Abst 29LBA ECCO 2013
BMN 673
PARP inhibitors in gBRCA mutated cancer
Breast
Niraparib
Ovary
Michie et al Abst 2513 ASCO 2013
Breast
PARPi monotherapy in sporadic TNBC
TNBC BRCA
TNBC non-BRCA
Non-TNBC BRCA
–100
–20
–40
–60
–80
0
20
100
80
60
40
120
Be
st
% c
ha
ng
e f
rom
ba
se
lin
e
23 treated patients with target lesions identified at baseline
22 had at least one follow-up assessment
1 patient had no follow-up tumour size assessment
– 1 due to missing / incomplete post-baseline assessments
BRCAness sufficient for
synthetic lethality uncommon in
advanced non-BRCA TNBC?
BRCA1 methylation present in
20% TNBCTimms et al Breast Cancer Res 2014, 16:475
K Gelmon et al Lancet Oncology 2011
PARP inhibition focused on gBRCA companion
diagnostic groupincluding those with TNBC
R
Potent PARP
inhibitor at MTD as
continuous
exposure
Physician Choice
within SOC options
Capecitabine
or
Vinorelbine
or
Eribulin
or
Gemcitabine
gBRCA1 / BRCA2
Carriers
Advanced
anthracycline taxane
resistant breast cancer
Primary
endpoint
PFS
Niraparib – EORTC / BIG BRAVO Trial
BMN 673 – EMBRACA - NCT01945775
OLYMPIAD – Olaparib - NCT02000622
Can we combine platinums with potent PARP inhibitors?
• Balmana et al tested 75mg/m2 cis with continuous olaparib
• Not tolerable but reduction of Cisplatin to 60mg/m2 with olaparib at 50mg BD D1-5 tolerable.
Balmana et al Ann Oncol (2014) doi: 10.1093/annonc/mdu187
• Another Phase I study found Carboplatin dose of AUC 5 Q21 could be delivered with Olaparib at 400mg BD for 14 days1
• Combination of carboplatin with paclitaxel (175 mg/m2) required lowering the doses of carboplatin (AUC 4) and olaparib (200 mg bid, days 1–10) but was then tolerable2
• Combinations with paclitaxel and carboplatin and veliparibhave been achieved in early3 and advanced4 breast cancer
• Differences in drug mechanisms of action on PARP trapping may be relevant
1. Lee et al J Clin Oncol 31, 2013 (suppl; abstr 2514)2. Oza A et al J Clin Oncol 30, 2012 (suppl abstr 5001)3. Rugo et al SABCS 2013 abst S5-024. Somlo et al ASCO 2014 (Abstr 1021)
Can we combine platinums with potent PARP inhibitors?
Can veliparib sensitized chemotherapy improve on a platinum directed chemotherapy approach?
NCT01506609
If combinations are challenging perhaps platinumsfollowed by PARP as maintenance?
R
Potent PARP
inhibitor at MTD as
continuous
maintenance
Continue
chemotherapy
while tolerable
Advanced
1. gBRCA1 / BRCA2
2. TNBC
Responding to Platinum
Regimen after 3 or 6
cycles
• Statistically significant
PFS improvement
(HR 0.35, P<0.00001)
• In gBRCA carriers
(HR=0.18 95% P<0.00001)
Ledermann J et al. N Engl J Med 2012;366:1382–1392
0
0.6
0.8
0.9
0
0.1
0.2
0.3
0.4
0.5
0.7
1.0
3 6 9 12 15 18
Pro
ba
bil
ity o
f
pro
gre
ss
ion
-fre
e s
urv
iva
l
Time from randomization (months)
Hazard ratio 0.35
(95% CI, 0.25–0.49)
P<0.00001
Randomized treatment
Placebo
Olaparib 400 mg bid monotherapy
olaparib placebo
Events: Patients (%)
60:136 (44%)
94:129 (73%)
Median (mo) 8.4 4.8
Maintenance therapy after platinum response
early in ovarian cancer management
Ledermann J et al. J Clin Oncol 2013;31(15S):abstr 5505
To avoid late resistance can we bring novel PARP inhibitor approaches in earlier in High Risk TNBC
New Diagnosis
Post-Rx residual disease
Neoadjuvant Rx Second Adjuvant
Investigational Drug Rx
Relapse
Vs
No Relapse
Definitive Surgery
TNBC
Cisplatin with or without rucaparib after preoperative
chemotherapy in patients with triple-negative breast cancer
(TNBC): Hoosier Cancer Research Network BRE09-146
Abstract 1019Sujaata Dwadasi, Yan Tong, Tom Walsh, Michael A. Danso, Cynthia X. Ma, Paula
Silverman, Mary-Claire King, Susan M. Perkins, Sunil S. Badve, Kathy Miller
Presented by: Steven Isakoff - Discussant
R
a
n
d
o
m
i
z
e
Cisplatin
X 4 cycle
Cisplatin +
Rucaparib
30mg IVx3d
X 4 cycle
Rucaparib
100mg PO q wk
X 24 weeks
• Eligibility
– TNBC (or BRCA+)
– Residual disease (RCB 2/3, M-P 0-2, node +)
– No prior cisplatin (carboallowed)
– 128 patients
– 65 cisplatin
– 63 cis/rucaparib
Median RCB 2.6 v 2.7
1 Year DFS
C 83% v C/R 83%
22/128 patients BRCA
mutation
DFS C 85% v C/R 100%
Randomise 1:1
Double blind
N=1320
IDF
S
Dis
tant D
FS
; OS
Post neoadjuvant gBRCA
TNBC,
Non-PathCR pts
Post adjuvant gBRCA
TNBC
T2 or N+
Olaparib
300 mg bd
12 month
duration
Placebo
12 month
duration
Restricted to Germline
Mutation carriers
PIK3CA pathway and PARPi synergy
Juvekar A et al. Cancer Discovery 2012;2:1048-1063
Ibrahim Y H et al. Cancer Discovery 2012;2:1036-1047
Rehman F L et al. Cancer Discovery 2012;2:982-984
PIK3CA Mutation / PTEN or INPP4 loss
PIK3CA blockade of overactive pathway
Activation of ERK
Suppression of BRCA1/2 and reduced HR
Susceptibility to a PARP inhibitor
Control
Olaparib
BKM120
BKM+Olap
Matulonis et al Abstract 2510 ASCO 2014
G1 S G2 M
Cyclin BCdk1
DNA Damage
Targeting Mutant TP53 with Platinum and
ATR inhibition
p53 ATM
G1 S G2 M
Cyclin BCdk1
DNA Damage
Wee1
Stalled DNA
replication forks
Replication
stress
(c-MYC)
Platinum adducts
Replication Inhibitors
PARPi?
Targeting Mutant TP53 with Platinum and
ATR inhibition
ATR
Chk-1
G1 S G2 M
Normal
MitosisCyclin BCdk1
DNA Damage
Wee1
Stalled DNA
replication forks
Replication
stress
(c-MYC)
Platinum adducts
Replication Inhibitors
PARPi?
Targeting Mutant TP53 with Platinum and
ATR inhibition
ATR
Chk-1
G1 S G2 M
Normal
MitosisCyclin BCdk1
DNA Damage
Wee1
Stalled DNA
replication forks
Replication
stress
(c-MYC)
Platinum adducts
Replication Inhibitors
PARPi?
Targeting Mutant TP53 with Platinum and
ATR inhibition
G1 S G2 M
Normal
MitosisCyclin BCdk1
DNA Damage
Stalled DNA
replication forks
Replication
stress
(c-MYC)
Platinum adducts
Replication Inhibitors
PARPi?
Targeting Mutant TP53 with Platinum and
ATR inhibition
G1 S G2 M
Normal
MitosisCyclin BCdk1
DNA Damage
Stalled DNA
replication forks
Replication
stress
(c-MYC)
Platinum adducts
Replication Inhibitors
PARPi?
Targeting Mutant TP53 with Platinum and
ATR inhibition
G1 S G2 M
Normal
MitosisCyclin BCdk1
DNA Damage
Stalled DNA
replication forks
Replication
stress
(c-MYC)
Platinum adducts
Replication Inhibitors
PARPi?
Targeting Mutant TP53 with Platinum and
ATR inhibition
Premature
Chromatin
Condensation
Forced Early
Mitotic Entry
Targeting p53 loss with ATR inhibition in
combination with platinum therapy
Reaper Nat. Chem. Biol. 2011
51
0.0 0.2 0.3 0.6 1.3 2.5 5.0
10
.0
20
.0
20
.0
10
.0
5.0
2.5
1.3
0.6
0.3
0.0
-50510
15202530
35404550
5560
Synergy/Antagonism
VE-821
(M)
Cisplatin
(M)
0.0 0.2 0.3 0.6 1.3 2.5 5.0
10
.0
20
.0
20
.0
10
.0
5.0
2.5
1.3
0.6
0.3
0.0
-5
0
5
10
15
20
25
30
35
40
45
50
55
60
Synergy/Antagonism
VE-821
(M)
Cisplatin
(M)
Conclusions
• Significant evidence BRCA1 and BRCA2 mutation carriers have systemic therapy clinical trial and standard of care options distinct from others
• Identification of BRCA1/2 mutation is currently the clearest diagnostic of an HRD defect that is targeted by platinum chemotherapies and PARP inhibitors
• BRCA1 and BRCA2 mutation in germline and tumour should be reported in trials testing these agents and new HRD diagnostics
• The development of tumour based diagnostics for DNA repair deficiencies to inform choice of treatment for metastatic sites of disease outside the context of BRCA1/2 mutation remains a work in progress
• Trials specific to women with uncommon but important genetic forms of DNA repair deficient BC are possible and should be conducted
Acknowledgments
Fraser Symmans
Steven Isakoff
TNT Trial TMG
BRAVO Trial Steering Group
OlympiA Trial Steering Group
Breakthrough Breast Cancer
Cancer Research UK
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