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Dr. Steven A. Narod MD, FRCPCCanada Research Chair in Breast CancerDirector, Familial Breast Cancer Research Unit, Women’s College HospitalProfessor, University of Toronto

The North American Menopause SocietyCaesar’s Palace, Las Vegas, NVOctober 1st 2015

� 1977 Familial Association of Cancer of the Breast and Ovary- Lynch

� 1990 King paper linked breast cancer on chromosome 17

� 1991 Ovarian cancer and BRCA1

� 1994 BRCA1 discovered

� 1995 BRCA2 discovered

� 2002 CHEK2 discovered

� 2007 PALB2discovered

� 2007 First GWAS study

� 2013 Introduction of gene panels

� Mastectomy decreases breast cancer incidence

� Mastectomy and breast cancer mortality?

� Oophorectomy prevents ovarian cancer

� Oophorectomy prevents breast cancer

� Oophorectomy as adjuvant treatment for breast cancer

� HRT and breast cancer risk?

� MRI and breast cancer staging

� MRI and breast cancer mortality?

� Tamoxifen and contralateral breast cancer

� Tamoxifen and primary breast cancer?

� Chemotherapy for all carriers

� Cisplatinum?

� Olaparib?

� Ovarian cancer patients

� Breast cancer patients◦ Triple negative ◦ Under age 40◦ Jewish◦ Family history

� Unaffected women◦ Strong family history!

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BRCA1BRCA1BRCA1BRCA1 BRCA2BRCA2BRCA2BRCA2

Breast Ovarian Breast Ovarian

70% 40% 70% 20%

Age Age distribution distribution of ovarian cancers among of ovarian cancers among BRCA1/2 carriersBRCA1/2 carriers

� Prevention of ovarian cancer

� Prevention of breast cancer

� Prevention of all-cause mortality

NNNN CancersCancersCancersCancers %%%%

Oophorectomy 3513 32 0.9%

No oophorectomy 2270 108 4.8%

Odds ratio 0.20 (95% CI 0.13-0.39, p=0.0001)

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Occult Ovarian, Fallopian Tube and Peritoneal Cancers Occult Ovarian, Fallopian Tube and Peritoneal Cancers Found at Preventive SurgeryFound at Preventive Surgery

BRCA1BRCA1BRCA1BRCA1 BRCA2BRCA2BRCA2BRCA2

Age of Oophorectomy (Years)

No. of Cancers

No. ofPatients

Prevalence of Cancer

No. of Cancers

No. ofPatients

Prevalence of Cancers

35-39 2 160 1.25% 0 31 0%

40-44 10 261 3.83% 0 55 0%

45-49 9 241 3.73% 0 85 0%

50-54 12 172 6.98% 0 57 0%

55+ 10 181 5.5% 2 96 2.1%

BRCA1N=376

BRCA2N=224

MRI 176 46.8% 134 59.8%

Preventive Mastectomy 153 40.7% 93 41.5%

Preventive Oophorectomy 284 75.5% 154 68.8%

Tamoxifen chemoprevention 38 10.1% 30 13.4%

Preventive measures among BRCA1 and BRCA2 Preventive measures among BRCA1 and BRCA2 Mutation Carriers in the USA with no history of Mutation Carriers in the USA with no history of

cancercancer

Ages 30Ages 30--6565

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� 10,832 BRCA1 carriers

� No breast cancer proper to menopause

� No bilateral mastectomy

� Menopause reached

� Cases ◦ 550 post-menopausal breast cancers

� Controls ◦ No breast cancer ◦ Post menopausal

� Matching◦ Year of birth ◦ Country◦ Age of menopause◦ Type of menopause

VariablesVariablesVariablesVariables ControlsControlsControlsControls N=432N=432N=432N=432 CasesCasesCasesCases N=432N=432N=432N=432 PPPP

Age 58.3 (32-87) 58.0 (34-83) 0.60

Age at diagnosis NA 53.0 (6.9)

Age menopause

NaturalSurgical

47.5

49.0

43.0

47.0

48.5

42.5

0.14

0.10

0.50

Menopause type NaturalSurgical

327 (75.7%)

105 (24.3%)Matched

HRT use

No Yes

341 (75.7%)91 (21.3%)

352 (81.5%)80 (18.5%) 0.31

OC use NoYes

265 (61.3%)167 (38.7%)

264 (61.4)166 (38.6) 0.93

Parityb

Mean parity for subjects with

parity (SD)2.5 (1.5) 2.4 (1.6) 0.65

HRT and Breast CancerHRT and Breast CancerComparison Comparison of case and controlsof case and controls

Mutation and type of Mutation and type of Mutation and type of Mutation and type of MenopauseMenopauseMenopauseMenopause

ControlControlControlControl CasesCasesCasesCases Univariate Univariate Univariate Univariate OR (95%CI) POR (95%CI) POR (95%CI) POR (95%CI) P

Multivariate*Multivariate*Multivariate*Multivariate*OR (95%CI) POR (95%CI) POR (95%CI) POR (95%CI) P

All (432 pairs)All (432 pairs)All (432 pairs)All (432 pairs)No HRTHad HRT

Surgical (105 pairs)Surgical (105 pairs)Surgical (105 pairs)Surgical (105 pairs)No HRTHad HRT

Natural (327 pairs)Natural (327 pairs)Natural (327 pairs)Natural (327 pairs)No HRTHad HRT

34191

6441

27750

35280

6441

28839

10.84 (0.59-1.19) 0.32

11.00 (0.57-1.74)1.00

10.74 (0.46-1.17)0.21

10.80 (0.55-1.16) 0.24

1.06 (0.58-1.96) 0.85

0.72 (0.44-1.18) 0.20

Risk of HRT/breast cancer Risk of HRT/breast cancer ((subjects divided by type of menopause)subjects divided by type of menopause)

* adjusted by OC (yes/no), parity (0, 1, 2, >=3) and country of residence (Canada, USA, Israel, Poland, and Other).

Type of menopauseType of menopauseType of menopauseType of menopause ControlControlControlControl CasesCasesCasesCases Univariate Univariate Univariate Univariate

OR (95%CI) POR (95%CI) POR (95%CI) POR (95%CI) P

MultivariateMultivariateMultivariateMultivariateaaaa

OR (95%CI) POR (95%CI) POR (95%CI) POR (95%CI) PAll BRCA1 All BRCA1 All BRCA1 All BRCA1 ((((432pairs432pairs432pairs432pairs))))No HrtHrt<=3 yrs3<Hrt

34152

39

3525030

10.93 (0.60-1.43) 0.73

0.71 (0.42-1.22) 0.22

10.89 (0.57-1.37) 0.59

0.67 (0.38-1.19) 0.17

Surgical (105 Surgical (105 Surgical (105 Surgical (105 pairs)pairs)pairs)pairs)No HrtHrt<=3 yrs

3<Hrt

6424

17

642417

11.00 (0.51-1.97) 1.00

1.00 (0.43-2.32) 1.00

11.06 (0.52-2.18) 0.871.06 (0.41-2.71) 0.91

Natural (327 pairs)Natural (327 pairs)Natural (327 pairs)Natural (327 pairs)No HrtHrt<=3 yrs3<Hrt

2772822

2882613

10.88 (0.50-1.54) 0.66

0.56 (0.28-1.15) 0.11

10.86 (0.48-1.54) 0.620.52 (0.24-1.13) 0.10

Risk Risk of breast cancer by duration of HRT use of breast cancer by duration of HRT use

a: adjusted by OC (yes/no), parity (0, 1, 2, >=3), and country of residence (Canada, USA, Israel, Poland, and Other).

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DrugDrugDrugDrug Controls Controls Controls Controls CasesCasesCasesCases OR (95%CI) pOR (95%CI) pOR (95%CI) pOR (95%CI) pUnadjustedUnadjustedUnadjustedUnadjusted MultivariateMultivariateMultivariateMultivariateaaaa

BRCA1BRCA1BRCA1BRCA1(N=432)(N=432)(N=432)(N=432)NeverNeverNeverNever 341 352 1 1

EEEE 42 46 1.06(0.66-1.69)0.82 1.00(0.62-1.62)0.99

EPEPEPEP 41 28 0.67(0.40-1.12)0.12 0.65(0.38-1.11)0.11

Risk of breast cancer by type of HRTRisk of breast cancer by type of HRT

a: Adjusted by parity form 0, 1, 2, >= 3, OC (yes/no), and country of residence (Canada, Israel, other Europe, Poland, and USA.

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Univariate RR (95%CI) P

MultivariateRR (95%CI) P

All subjects 0.47 (0.29-0.76) 0.002 0.46 (0.27-0.79) 0.005

BRCA1 onlyBRCA2 only

0.36 (0.19-0.68) 0.0020.70 (0.32-1.52) 0.36

0.38 (0.19-0.77) 0.0070.57 (0.23-1.43) 0.23

Age of diagnosis<50≥ 50

0.47 (0.28-0.79) 0.0040.53 (0.15-1.83) 0.32

0.48 (0.27-0.88) 0.020.29 (0.15-2.03) 0.29

ChemotherapyYesNo

0.38 (0.21-0.70) 0.0020.67 (0.29-1.53) 0.34

0.38 (0.19-0.76) 0.0060.52 (0.20-1.36) 0.18

StageIII

0.42 (0.18-0.97) 0.040.50 (0.28-0.90) 0.02

0.32 (0.12-0.83) 0.020.51 (0.27-0.99) 0.05

ER-statusNegativePositive

0.06 (0.01-0.41) 0.0050.71 (0.36-1.39) 0.31

0.07 (0.01-0.51) 0.0090.76 (0.32-1.78) 0.53

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UnivariateRR (95% CI) P

Multivariate a

RR (95%CI) P

Chemotherapy 0.97 (0.67-1.38) 0.84 0.72 (0.46-1.14) 0.16

Oophorectomyb 0.62 (0.42-0.90) 0.01 0.66 (0.42-1.02) 0.06

Ipsilateral Mastectomy (versus lumpectomy)

0.76 (0.54-1.08) 0.13 0.92 (0.67-1.26) 0.59

Contralateral Mastectomyb 0.56 (0.34-0.87) 0.009 0.57 (0.36-0.92) 0.02

North American North American StudyStudy

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Variables Univariate

RR (95%CI)P

Multivariate

RR (95%CI)P

Year of diagnosis

Age of diagnosis

<40 years

40+

1.43(0.72-2.86)0.31

1

2.26(1.01-5.08)0.05

1

Size (cm)

0-1.0

1.1-2.0

2.1-2.9

3.0+

1

1.57(0.79-3.13)0.20

2.23(1.13-4.40)0.02

3.93(1.97-7.87)0.0001

1

1.30(0.62-2.74)0.48

1.85(0.88-3.89)0.11

2.52(1.19-5.36)0.02

Nodes

Negative

Positive

1

3.17(2.06-4.86)<0.0001

1

2.99(1.82-4.92)<0.0001

Oophorectomy**

No

Yes

1

0.40(0.24-0.65)0.0003

1

0.41(0.24-0.69)0.0008

Chemotherapy

No

platinum/platinumAC

other

1

0.63(0.21-1.90)0.42

1.01(0.44-2.33)0.98

1

0.66(0.20-2.19)0.50

0.40(0.16-1.01)0.05

All cause survival after breast cancer: All cause survival after breast cancer: BRCA1 BRCA1 carrierscarriers

Predictors of Survival in BRCA1-Positive Breast Cancer Patients in Poland

Huzarski T,1 Byrski T,1 Gronwald J,1 Cybulski C,1 Oszurek O,1 Szwiec M,3 Gugała K,4 Stawicka M,5 Morawiec Z,6

Mierzwa T,7 Falco M, Janiszewska H,8 Kilar E,9 Marczyk E,10 Kozak-Klonowska B,11 Siołek M,11 Surdyka D,12

Wiśniowski R,13 Posmyk R,14 Domagała P,2 Sun P,15 Lubiński J,1 Narod SA15 and the Polish Breast Cancer Consortium

Breast Breast cancer specific survival: BRCA1 carrierscancer specific survival: BRCA1 carriers

Variables Univariate

RR (95%CI)P

Multivariate

RR (95%CI)P

Year of Birth (trend) 0.98 (0.95-1.01) 0.24 0.96(0.92-1.00)0.05

Age of diagnosis

<40 years

40+

1.55(0.66-3.60)0.31

1

1.93(0.73-5.10)0.19

1

Size (cm)

0-1.0

1.1-2.0

2.1-2.9

3.0+

1

2.06(0.87-4.91)0.10

2.55(1.07-6.12)0.04

5.06(2.11-12.1)0.0003

1

1.56(0.62-3.90)0.35

1.81(0.71-4.62)0.21

2.68(1.05-6.83)0.04

Nodes

Negative

Positive

1

3.87(2.29-6.55)<0.0001

1

3.41(1.90-6.13)<0.0001

Oophorectomy**

No

Yes

1

0.55(0.31-0.96)0.04

1

0.60(0.33-1.07)0.08

Chemotherapy

No

Platinum/platinumAC

Other

1

0.40(0.09-1.77)0.23

1.15(0.42-3.18)0.78

1

0.34(0.07-1.67)0.18

0.42(0.14-1.28)0.13

� Oophorectomy prevents ovarian cancer and breast cancer

� Oophorectomy is adjunct treatment for breast cancer

� Combination of cis-platinum and oophorectomy?

� HRT safe for unaffected carriers

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EUROPE:� Jan Klijn

� SiranoushManoukian

� Dominique Stoppa-Lyonnet

� Barbara Pasini

� Christian Singer

� Catharina Anne Speiss

� Pal Moller

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UNITED STATES:� Fergus Couch� Mary Daly� Susan Domchek• Charis Eng• Judy Garber• Claudine Isaacs• Beth Karlan • Henry Lynch• Wendy McKinnon• Susan Neuhausen• Ken Offit• FunmiOlopade• Mark Robson• Howard Saal• Nadine Tung• Jeffrey Weitzel• Marie Wood• Dana Zakalik• Kevin Sweet• LeighaSenter• Carrie Snyder• Tuya Pal

CANADA:

� Peter Ainsworth• Ab Chudley• Andrea Eisen• William Foulkes• ParvizGhadirian• Donna Gilchrist• Ed Lemire• Barry Rosen• Joanne Kotsopoulos• Kelly Metcalfe• Ping Sun• Susan Armel• Louise Bordeleau• Ophira Ginsburg• Seema Panchal• Aletta Poll• Wendy Meschino• Gillian Mitchell

POLAND: • Jacek Gronwald

• Jan Lubinski

• Cezary Cybulski

• Tomasz Huzarski

• Tomasz Byrski