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 ?

Recognition

• young age at onset

• family history

BC 42BCd31

BC60

BCd45

LuCd51

2

Recognition: Histology + IHC

Improving Recognition: Future

+ ?

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

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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)

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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)

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0.00

0.20

0.40

0.60

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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

Surveillance/FU:

MRI ?

Systemic Rx?

Benefit of PM after BC?

Incidence of CBC Proph mastectomy

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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

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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 ?

Knowledge is

power

Life is what happens

to you when you are

busy making other

plans

J. Lennon

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

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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

Effect of B(S)O

Primary BC

CBC

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

1. Gezonde vrouw

2. Status na borstkanker

3. Diagnose borstkanker

4. Status na ovariumcarcinoom

Distant disease-free Survival

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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