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Future directions regarding Hereditary Breast Cancer. C. Seynaeve, ErasmusMC-Daniel den Hoed, Rotterdam BMM Brussels, October 13, 2006. HBC: Future Directions. Entities and Risk Assessment Recognition Outcome data: further delineation Clinical practice after a history of BC / OC - PowerPoint PPT Presentation
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Future directions regarding
Hereditary Breast Cancer
C. Seynaeve, ErasmusMC-Daniel den Hoed, RotterdamBMM Brussels, October 13, 2006
HBC: Future Directions
• Entities and Risk Assessment
• Recognition
• Outcome data: further delineation
• Clinical practice
• after a history of BC / OC
• at BC diagnosis
• Guidelines
• Systemic therapy ?
Chemoprevention
Advanced/M1 disease
Entities
BRCA1/2 mutation family CLTR 60-80%, CBC 30-50% 18-20% of the tested families
• mutations are being missed
Strongly increased BC risk (HB(O)C) CLTR 30-40%, CBC …?
• frequent occurrence of breast / ovarian cancer
• young age at diagnosis
Mildly increased BC risk (Familiar BC) CLTR 20-30%
• Occurrence of BC, more frequently than expected
• Varying ages at onset (> 50 yrs)
• Combinations with other malignancies in family
Risk Assessment Models
Limitations Future
• CLTR - Risk within following year(s)
• All type of mutations - Specified for separate mutations
• Only breast cancer - Incorporation of other types of
Ca
• No modifying factors - Modifying factors incorporated
• Cumulative effect of diff. types - Including the effect of preventive
of preventive measures and/or measures and/or systemic therapy
systemic therapy not yet incor-
porated
Hereditary Online ?
Tumour characteristics
BRCA2 BRCA1 non-BRCA1/2 Sporadicn=90 n=170 n=238 n=759
Age (yr) 44 (27-85) 42 (23-82) 47 (25-77) 43 (23-82)
N status (%)
N0 43 63 52 50N 4+ 27 10 18 24
Histologylobular 9% 4% 11% 10%medullary 2% 7% 1% 2%
Differentiation grade (%)I 3 1 8 8III 65 88 61 63
Receptor status positive (%)ER / PR 84 / 64 27 / 33 73 / 74 67 / 54
OvaCa (%/yr) 0.5% 0.7% 0.1% -
C. Brekelmans et al., in press* p-value significant (vs BRCA2)
Local Recurrence Rate after BCT
C
umul
ativ
e p
ropo
rtio
n
0 15
0.00
0.20
0.40
0.60
0.80
1.00
....
years At risk:
sporadic 410 289 142 53 17
BRCA1 76 42 27 12 4
BRCA2 33 16 9 4 2
non-BRCA1/2 111 66 38 18 4
Incidence of Contralateral Breast Cancer (CBC)
C
umul
ativ
e p
ropo
rtio
n
0 15
0.00
0.20
0.40
0.60
0.80
1.00
years At risk:
sporadic 756 486 236 92 31 BRCA1 161 82 36 15 7 BRCA2 87 39 22 14 5
non-BRCA1/2 228 134 66 33 14
% annually BRCA 3.1% vs. Non- 1% vs. Spor. 0.7%
Breast cancer-specific Survival (BCSS)
C
umul
ativ
e p
ropo
rtio
n
0 15
0.00
0.20
0.40
0.60
0.80
1.00
years At risk:
sporadic 759 507 245 98 36 BRCA1 170 97 48 22 9 BRCA2 89 52 31 17 10
non-BRCA1/2 238 143 71 37 18
Prognostic factors for BCSS
HBC cases HR (95% CI) p-value
T size T1 1.0
T2 1.81 (1.16-2.8) 0.009
T3/4 4.43 (2.3-8.43) < .001
Nodal status
negative 1.0
1-3 + 2.52 (1.3-4.9) 0.006
4 + 3.83 (1.89-7.7) < .001
Histological grade 1.73 (0.91-3.31) 0.09
ER (pos/neg) 0.49 (0.3-0.8) 0.006
Chemo (y/no) 0.45 (0.2-0.86) 0.02
PBSO (y/no) 0.32 (0.1-1.02) 0.061
Not signif.: Age at diagnosis, CBC, PBSO, Horm. therapy
Incidence of CBC Proph mastectomy
C
umul
ativ
e pe
rcen
tage
0 5 10 15
0
20
40
60
no PM
PM
Years At risk:
no PM 113 46 29 13 PM 2 10 8 4
Logrank P=.008
no PM 169 34 PM 50 0
N O
CBC after unilateral BRCA-BC
Metastases free Survival after unilateral BRCA-BCMetastasis free Proph mastectomy
C
umul
ativ
e pe
rcen
tage
0 5 10 15
0
25
50
75
100
no PM
PM
Years At risk:
no PM 113 56 38 14 PM 2 10 8 4
Logrank P=.53
no PM 169 32 PM 52 8
N O
16-10-2001
Risk CBCReconstruction after mast.and/or RT is more difficult
Considerations at BC diagnosis + Recognition heredity
• Tumor stage T/N• Tumorcharacteristics• Patientcharacteristics:knowledge, personality, ..
Accelerated genetic testing ?
• Referral to Oncological Centre: Geneticist + Oncologist
• Family Cancer TEAM: multidisciplinary approach
• surgeon / plastic surgeon, psychologist, ……..
Choice at BC diagnosis
BRCA mutation carrier, BC under surveillance n= 25
standard therapy: 7 28%PM (after lump/ablation) 14 56%BC confirmed at PM 4 16%
BC before genetic testing result n= 23
regular treatment: 8 35%PM (directly after lump/ablation) 15 65%
Dutch Guideline w.r.t. Follow-up after Breast cancer
BRCA mutation carrier + strongly increased BC risk
0-1 yr: every 3 months
2-5 yr: biannual physical, yearly imaging (+ MRI*)
5-10 yr:
< 50 yr: biannual physical, yearly imaging (+ MRI*)
> 50 yr: yearly exam, and imaging (+ MRI* < 60 yr)
Mildly increased risk
0-1 yr every 3 months
2-5 yr biannual physical, yearly imaging
>5-10 yr yearly visit, with imaging examination
> 10 yr
< / > 50 yr yearly control / population screening
* MRI for mutation carrier (and/or dens mammo)
Prevention ?
Randomized studies in premenopausal women
Zoladex + Tamoxifen versus no treatment
Zoladex + Aromatase Inhibitor versus no treatment
Zoladex +/- bisphosphonate versus no treatment
to be further investigated
Value of tamoxifen: unclear
value of aromatase inhibitors: IBIS2 study
Further ideas
EGFR ?? , other targeted therapies ?
Should BRCA mutant Breast Cancer
be treated differently
regarding systemic therapy ?
Tumour
No normal BRCA1/2
BRCA1/2 function impaired
Abnormal repair
Normal tissues
1 normal copy of BRCA1/2
retained BRCA1/2 function
Normal repair
Sensitivity of Brca2 null cells toplatinum agentsCarboplatin Sensitivity of
BRCA2 deficient V-C8 cells
0 50 100 150 200 250 30010 -5
10 -4
10 -3
10 -2
10 -1
10 0
VC8
VC8 BAC
Carboplatin Conc M.
BRCA2 null
BRCA2 Wt
Carboplatin (M)
Response to neo-adjuvant Anthracyclin-based chemotherapy in BRCA-mutation (n=11) and non-carriers (n=27)
Clinical Response cCR cPR p-value
- BRCA1/2 10 (93%) 1 -
- Non-carriers
Unmatched 8 (30%) 19 0.0009
Matched 2 (18%) 9 0.002
B pCR pPR p value
- BRCA1/2 carriers 4* (44%) 5 -
- Non-carriers
Unmatched 1 (4%) 26 0.009
Matched 0 9 0.08
* 2x BRCA1, 2x BRCA2
# matching for TN stage
Chappuis, J.Med. Genet., 2002
BRCA1/2 mutation carrier, first-line chemotherapy for M1 breast cancer
BRCA Trial I
Randomise2:1
CarboplatinAUC 6 q3w6 cycles
Response rateToxicityTime to progression
Docetaxel100mg/m2
6 cycles
Upon progression
CarboplatinAUC 6 q3w6 cycles
Response rateToxicityTime to progression
Docetaxel100mg/m2
6 cycles
Andrew Tutt, Max Parmar, James MacKay
Poly (ADP-ribose) polymerase (PARP)
Involved in DNA base-excision repair
Binds directly to DNA damage (SSBs)
Produces large branched chains of poly(ADP-ribose)
NN
OH
O
N
NN
O
F O
NN
N
FN
O
O
KU-0058684IC50 = 3.2nM
KU-0058948IC50 = 3.4nM
KU-0051529IC50 = 730nM
Fold Differences in SF50 Brca2-/- v Wildtype
133 1250 -
10 -9 10 -8 10 -7 10 -6 10 -5 10 -40-4
-3
-2
-1
0
conc (M)
10 -9 10 -8 10 -7 10 -6 10 -5 10 -40-4
-3
-2
-1
0
conc (M)
10 -9 10 -8 10 -7 10 -6 10 -5 10 -40-4
-3
-2
-1
0
conc (M)
Brca2-/-
Brca2+/-
Brca2+/+
Brca2-/-
Brca2+/-
Brca2+/+
Brca2-/-
Brca2+/-
Brca2+/+
Brca2-/- cells are Extremely Sensitive to PARP Inhibition
Experiments in miceBRCA2 xenograft
PARP1 inhibitor no therapy
Tumorgrowth inhibition no growth inhibition
no side effects !!!
In humans
• phase I study
• phase II study
• in combination with other cytotoxic drugs
16-10-2001
CONCLUSIONS
• Growing evidence for separate entities, and the importance of early identification
• Concentration of cases
• Complex problem, necessitating a Multidisciplinary approach: “ONCO-GENETIC ADVISE”
• Individualized local treatment and FU
• pipeline: chemoprevention ?
different systemic treatment ???
new agents ?
Sensitivity of Brca1-/- cells to PARP inhibition compared to cisplatin
0
10
20
30
40
50
60
100
300
500F
old
dif
fere
nc
e i
n S
F5
0
Genes involved in Hereditary Breast Cancer
BRCA1 17q > 500 mut. 25-65%
BRCA2 13q > 300 mut. ..- 55%
p53 17p ?
Cowden (PTEN) 10q ?
ATM 11q ?
CHEK2*1100delC 22q 2-fold
repair genes MSH, MLH ?
Unknown: BRCAx, …., Polygenic model
Gene Chromosome Risk BC
BRCA1 BRCA2
• DCIS: less frequent, …
• Type: more “medullary”
• Mitoses: high grade
• “Pushing” margins
• often “basal” phenotype
• ER/PR: negative
• her2neu: negative
• p53 mutations: frequent
• Mitoses / celproliferation: variable data
• “Pushing” margins
• Cyclin D overexpression
• ER/PR: as sporadic BC
• P53 mutaties: as sporad. BC
Recognition: Histology + IHC
Tumour characteristics BRCA1 / Sporadic (2)
BRCA1 BRCA1 Sporadic p-value
(late tested) (unselected) n=53 n=170 n=446
Histology (%) (%) (%) 0.001
Duct/NOS 79 86 88
Lobul ar 2 3 9
Medullary 13 7 2
Histologic grade (%) 0.002
I 2 1 5
II 6 7 17
III 43 55 45
Receptor status (%) < .001
ER neg/pos 49 / 15 45 / 17 24 / 48
PR neg/pos 31 / 9 38 / 18 19 / 35
C. Brekelmans, Ann Oncol 2005
Hazard Ratio (HR) of HBC vs sporadic BC
BRCA2 BRCA1 Non-
BRCA1/2
IBTR 0.85 0.84 1.43
CBC 6.09 5.83 1.67
DDFS 0.75 1.25 0.82
BCSS 0.84 1.21 0.99
Event-free Rate after therapy for primary BC
5 jr 10 jr
(%) BRCA2 BRCA1 Non- Spor. BRCA2 BRCA1 non-
Spor.
IBTR 17 12 12 12 17 16 15 21
CBC 17 13 5 3 20 25 6 5
DDFS 73 68 73 64 61 60 61 57
BCSS 80 73 87 78 68 62 70 59
Risk reduction by Preventive measures
Breast Cancer
Tamoxifen 40%
Prophylactic Ovariectomy (P(S)O) 50%
PO + TAM 70% (?)
Prophylactic Mastectomy 90-100%
Mortality
By Regular MRI + Mammo Screening 25 - 40% (?)
by PM: healty women / after unilateral BC ? / NS
by Systemic therapy ?
by BSO ?
Overall Survival after unilateral BRCA-BCOverall survival Proph mastectomy
C
umul
ativ
e pe
rcen
tage
0 5 10 15
0
25
50
75
100
no PM
PM
Years At risk:
no PM 113 62 42 15 PM 2 13 9 4
Logrank P=.67
no PM 169 23 PM 52 4
N O
Results PM vs Surveillance / Healthy womenParameter Cohort Updated
2001 2004
Number 139 139
Proph. Mastectomy/Surveillance 76 / 63 79 / 60
Median follow-up na PM 3.0 yrs 5.4 yrs
Diagnosis Breast Cancer
* tijdens surveillance 8 9
* na PM 0 1 (metast.)
5 year Incidence of BC/surveill. 17% 13%
Protective effect of PM on BC p= 0.003 p= 0.01
Adjusted for PO/menopause p= 0.01 p= 0.04
Surveillance gezonde vrouw
BRCA mutatiedraagstervanaf 25 j LO mammae a 6 mnd, beeldvorming jaarlijks (incl. MRI)60-75 j jaarlijks LO + beeldvormingvanaf 35 j jaarlijks gyn. Onderzoek, PBSO vanaf 40 jPM ja
Sterk verhoogd risico 35-50 j LO mammae a 6 mnd, jaarlijks beeldvorming50-60 j jaarlijks LO mammae + beeldvorming> 60-75 j bevolkingsonderzoek (alternatief op indicatie) Gyn. Controle: op indicatiePrev. Chirurgie: nee, tenzij …….
Matig 35-50 j jaarlijks LO mammae + mammografie50-75 j via bevolkingsonderzoek (< 60 j, alternatief op indicatie)
** bij mut.draagsters of i.g.v. dens klierweefsel: MRI
Distant disease-free Survival
C
umul
ativ
e p
ropo
rtio
n
0 15
0.00
0.20
0.40
0.60
0.80
1.00
years At risk:
sporadic 758 423 201 82 30 BRCA1 167 83 41 21 9 BRCA2 89 47 26 14 9
non-BRCA1/2 237 126 65 31 16
+ ……..
PATIENT
Oncologic Gynaecologist
Surgical-oncologist
Medical Oncologist
Geneticist
Radiologist
PathologistEpidemiologist
Radiotherapist
Nurse
Family Cancer TEAM
Psychologist/social worker
Hypotheses:• sensitivity of BRCA mutant carriers to Platinum salts?• tolerance of normal tissues in BRCA mutation carriers to Platinum salts?• therapeutic window for Platinum drugs in BRCA mutation carriers ?
Endpoints:primary: Response rate
secondary: TTP, safety
Stratification factors:mutation status, adj. Taxane Chemo, Liver / lung M1, Trastuzumab therapyJewish ancestry
BRCA Trial I