1

What’s New in HereditaryBreast and Ovarian

Cancer?

Steven A. Narod, MDSteven A. Narod, MDCanada Research Chair in Breast Cancer

1968-20081968-2008

• Genetic basis of hereditary cancerGenetic basis of hereditary cancer

• Somatic mutations in cancer and cancer Somatic mutations in cancer and cancer progressionprogression

Genetic Basis of Hereditary CancerFamilial Associations

• Single site:-Prostate

• Multi-site:-retinoblastoma- osteosarcoma-breast-ovary-colon-endometrium-ovary-pancreas-melanoma-breast/sarcoma/adrenocortical

Genetic basis for cancer - Somatic mutations

• General chromosome instability

• Specific chromosomal abnormalities-translocations-deletions-amplifications

• Point mutations-oncogene activation

• Tumour suppressor genes-two hit theory: retinoblastoma-1985-1995 loss of heterozygosity: e.g. DCC

• Microsatellite instability-mismatch repair phenotype-HNPCC spectrum

• Microdeletions/ fusion proteins: e.g. TMPRSS-ERG prostate cancer fusion

For a genetic test to reach the clinic:• Disease must be relatively common

• Personal concern regarding risk

• Reasonable proportion of positive tests (>5%)

• Physician awareness

• Prevention or screening available

Currently: breast, ovary, colon, melanoma

Breast Cancer Genes:

1990: P53 <1% of hereditary bc1994: BRCA1 20% of hereditary bc1995: BRCA2 20% of hereditary bc1997: PTEN <1% of bc1998: ATM <1% of bc2002: Chek2 1% of bc2007: BRIP1 0.7% of hereditary bc2007: PALB2 1.1% of hereditary bc2007: eCADHERIN 1 of 23 familial lobular

cancers2007: FGFR2 OR=1.6 freq.=0.14

(homo)

Nature Genetics 2007 June 28;447:1087-93Nature Genetics 2007 June 28;447:1087-93

Hereditary Breast Cancer Syndromes

• Breast/ovarian cancer Syndrome

• Cowden Syndrome

• Li-Fraumeni Syndrome

Who to test for BRCA1 and BRCA2 mutations?

• All triple-negative breast cancers under age 40

• All familial breast cancers• All male breast cancers• Multiple primary breast and ovary cancers• All Jewish women with breast cancers• All French-Canadian women with breast

cancers• All invasive ovarian cancers• At risk relatives!

Approach to the BRCA Population

• Identify unaffected carriers• Prevent breast and ovarian cancer• If not, then find cancers at an early stage• Treat cancers appropriately

Mutation Positives in WCHMutation Positives in WCH2004 - 20082004 - 2008

Total UNAFFECTED

AFFECTED % UNAFFECTED

2008 (until end of year)

34 33 1 97%

2007 28 22 6 79 %

2006 14 11 3 79 %

2005 8 6 2 75%

2004 19 12 7 63%

TOTAL 103 84 19 82%

Topics to Discuss

• Update on screening

• Update on prevention

• Update on treatment

MRI and Breast Cancer Detection MRI and Breast Cancer Detection in BRCA Carriers - Sensitivityin BRCA Carriers - Sensitivity

N with mutations

Invasive cancers

% by MRI% by

mammogram

Warner(2004)

236 16 81% 31%

Kriege(2004)

358 20 80% 33%

MARIBS (2005)

120 12 92% 23%

TOTAL 714 48 83% 30%

Odds Ratio for Advanced Breast Cancer

OR = 0.30 (0.12 – 0.72)

P = 0.007

Carrier Database 2008

• No cancer 3806• Breast cancer 4097• Ovarian cancer 1262• Both 401• Other cancer 826

• BRCA1 6838• BRCA2 2092• Both mutations 33

N=9043

Risks of Cancer to Age 70 Among Carriers of BRCA1 or BRCA2 Mutations

Breast Ovarian Cancer Cancer

BRCA1 80% 25 - 50%

BRCA2 80% 10 - 25%

Prevention of Breast Cancer

Weight Gain Breast feeding Mastectomy Coffee

Oophorectomy Tamoxifen Pregnancy Oral Contraceptives Hormone

Replacement Therapy

Factors to consider:

Prophylactic Mastectomy

Preventive removal of both breasts prior to thedevelopment of breast cancerApproximately 95% risk reduction (Hartmann,1999)2 types:

Total mastectomy Subcutaneous mastectomy

Prophylactic Mastectomy and Breast Cancer

Average four years of follow-up

Prophylactic Number of Number of Mastectomy Subjects New Breast

Cancers

Yes 174 0

No 1134 76

expected—9.5p=0.00005

Prophylactic Mastectomy by Country

ALLAUSTRI

ACANADA FRANCE

ISRAEL

ITALY NORWAYPOLAN

DUSA

Number of Number of womenwomen

1086

24 349 4 78 16 133 205 277

ProphylactiProphylactic c mastectommastectomyy

18% 21% 22% 25% 4% 13% 5% 4% 35%

The Risk of Contralateral Breast Cancer in BRCA Mutation Carriers

Contralateral Mastectomy by Country

ALL AUSTRIA CANADA FRANCE ISRAEL ITALY NORWAY POLAND USA

Number of Number of womenwomen

927 19 318 20 52 17 15 184 302

ContralaterContralateralalMastectomMastectomyy

27% 16% 28% 10% 2% 6% 0% 4% 49%

Association Between Age at Oophorectomy and Breast Cancer

(BRCA1)Case-Control Study

Age At Oophorectomy

Number With Oophorectomy

Unadjusted Adjusted

Case Control ORP-value (95%

CI)OR

P-value (95% CI)

No oophorectomy

1021 1320 1.0 1.0

< 40 17 50 .36 0.0004 (.2 -.63) .36 .0005 (.20 - .64)

[41-50] 16 34 .49 .02 (.27 - .91) .50 .02 (.27 - .92)

51+ 5 7 .67 .50 (.21 – 2.1) .66 .48 (.21 – 2.1)

*Adjusted for OC, parity

Prophylactic Oophorectomy by Country

ALL AUSTRIA CANADAFRANC

EISRAE

LITALY

NORWAY

POLAND USA

Number of Number of womenwomen

2142

46 682 31 126 36 176 395 650

Prophylactic Prophylactic oophorectomoophorectomyy

57%

54% 54% 71% 66% 50% 74% 34%

68%

Is HRT safe following prophylactic mastectomy?

Risk of Breast Cancer with HT use by type of menopause in BRCA carriers

Type ofMenopause

Control subjects, No.

Case patients, No.

Unadjusted P Multivariable P

Surgical (62 pairs)

No HT 28 39 1 1

HT 34 23 0.43 (0.18 to 0.96)

.04 0.48 (0.19 to 1.21)

.12

Natural (174 pairs)

No HT 140 150 1 1.0

HT 34 24 0.67 (0.38 to 1.17)

.16 0.68 (0.37 to 1.27)

.22

All (236 pairs)

No HT 168 189 1.0 1.0

HT 68 47 0.57 (0.39 to 0.91)

.02 0.58 (0.35 to 0.96)

0.03

Contralateral Breast Cancer Associated with Tamoxifen

OR 95% CI p-value

BRCA1 CARRIERSTamoxifen 0.31 0.00003 (0.18-0.54)

BRCA2 CARRIERSTamoxifen 0.33 0.006 (0.14-0.86)

EITHERTamoxifen 0.33 0.0000006 (0.21-0.51)

Tamoxifen by Country(unaffected carriers)

ALLAUSTRI

ACANADA FRANCE

ISRAEL

ITALY NORWAY POLAND USA

Number of Number of womenwomen

888 19 273 3 75 14 127 197 180

TamoxifenTamoxifen 8% 5% 10% 0% 12% 0% 0% 7% 13%

Why the Reluctance?

• Belief in effectiveness– Lack of data on primary cancer– ER-negative cancers

• Side effects

• Dependency on screening

Tamoxifen and the risk of primary breast cancer

998 12

975 35

No Tamoxifen Tamoxifen

Breast Cancer

No Breast Cancer

1973 47

OR = 0.32 p-value = 0.001

1010

1010

2020

Genes responsible for hereditary ovarian cancer

• BRCA1

• BRCA2

• MSH2

• MLH1

Frequency of BRCA1/BRCA2 Mutations Among Patients with Cancer in Ontario

• 1372 incident Cases of Ovarian Cancer

• Population-based Series

• Mixed ethnicities

• Invasive only

• PTT Performed on Exons 11 of BRCA1, 10 and 11 of BRCA2

• DGGE (BRCA1)

• DhPLC (BRCA2)

• Direct Sequencing

• 179 mutations identified

• 110 in BRCA1 (8%)

• 69 in BRCA2 (5%)

• 10 MLPA (6% of mutations, < 1% of cases)

• estimated frequency, incl. MLPA (13.0%)

Prevalence of Mutations in Patients with Ovarian Cancer by Age

Age N BRCA1 BRCA2 Total Pos % Pos

<29 13 0 0 0 0

30-39 82 9 0 9 11

40-49 290 48 16 64 22.1

50-59 396 31 19 50 12.6

60+ 571 16 30 46 8.1

Unknown 3 1 0 - _

Total 1355 105 65 169 12.5%

Prevalence of Mutations in Patients with Ovarian Cancer by Histology

Histology N BRCA1 BRCA2 Total Pos

% Pos

Clear Cell 91 1 2 3 3.3

Serous 719 74 49 123 17.1

Endometrioid

288 18 6 24 8.3

Mucinous 132 0 0 0 0

Other 124 12 8 20 16.1

North American Prospective North American Prospective Study of OophorectomyStudy of Oophorectomy

• 1828 carriers followed for 3.5 years• 50 cancers diagnosed

(fallopian/ovarian/peritoneal)

No oophorectomy: 32 cases1.0% per year

Oophorectomy: 7 cases0.2% per year

Risk Reduction= 80%

(HR=.20, 95% CI, 0.07-0.58, p=0.003)

Cancer of the Peritoneum Following Prophylactic Salpingo-oophorectomy (n=12)

Case Mutation

Age at Surgery

Age at diagnosis of PC

Time elapsed

(yrs)

Time since

diagnosis (yrs)

Vital Status

1 BRCA 1 56 58 2 1 Deceased

2 BRCA 2 46 49 2.5 2.7 Deceased

3 BRCA 1 36 39 2.2 0.4 Alive

4 BRCA 1 50 56 5.3 0.6 Alive

5 BRCA 1 55 57 2 0.1 Alive

6 BRCA 1 36 53 16 2.5 Alive

7 BRCA 1 51 56 5.7 2.8 Alive

8 BRCA 1 51 71 20 0.8 Alive

9 BRCA 2 56 61 5 4.5 Alive

10 BRCA 1 44 45 1 4 Alive

11 BRCA 1 38 43 5 1.5 Deceased

12 BRCA 1 52 60 8 0.5 Alive

47.6 54 5.4 42%

Odds Ratios for Reproductive Factors and Hereditary Ovarian Cancer: BRCA1

EXPOSUREODDS RATIOUNADJUSTED

P-VALUE

ODDS RATIOAJDUSTED

P-VALUE

PARITY

nulliparous 1.0 1.0

one 0.74 0.10 0.81 0.34

two 0.58 0.0005 0.66 0.04

three 0.47 <0.0001 0.54 0.004

four or more 0.42 <0.0001 0.49 0.004

BREASTFEEDING

never 1.0 1.0

less than one year 0.69 0.004 0.79 0.12

more than one year 0.56 0.001 0.64 0.01

ORAL CONTRACEPTIVES

never 1.0 1.0

0-1 year 0.65 0.007 0.69 0.02

1-3 years 0.64 0.01 0.67 0.03

3-5 years 0.43 <0.0001 0.41 <0.0001

5+ years 0.49 <0.0001 0.48 <0.0001

TUBAL LIGATION

no 1.0 1.0

yes 0.73 0.03 0.80 0.15

Odds Ratios for Reproductive Factors and Odds Ratios for Reproductive Factors and Hereditary Ovarian Cancer: BRCA2Hereditary Ovarian Cancer: BRCA2

EXPOSUREODDS RATIOUNADJUSTED

P-VALUEODDS RATIOADJUSTED

P-VALUE

PARITY

nulliparous 1.0 1.0

one 1.95 0.12 2.82 0.06

two 1.59 0.20 2.47 0.05

three 1.87 0.11 3.84 0.008

four or more 1.20 0.69 2.32 0.13

BREASTFEEDING

never 1.0 1.0

less than one year 0.98 0.95 0.84 0.58

more than one year 0.63 0.17 0.56 0.13

ORAL CONTRACEPTIVES

never 1.0 1.0

0-1 year 0.58 0.10 0.56 0.09

1-3 years 0.44 0.02 0.42 0.02

3-5 years 0.14 0.0006 0.14 0.001

5+ years 0.36 0.002 0.37 0.004

TUBAL LIGATION

no 1.0 1.0

yes 0.76 0.20 0.63 0.13

Recommendations

• Test all non-mucinous cancer patients

• Oral contraceptives 3 yrs (30-35)

• Oophorectomy 35 yrs old

• HRT 5 yrs

• Breast Feeding (BRCA1) 12 months

Uptake of clinical genetic testing for ovarian cancer in Ontario

• What proportion of women who are eligible for testing are actually offered testing?

• In 2001, genetic testing for BRCA1 and BRCA2 became freely available to all women in Ontario with a diagnosis of invasive ovarian cancer.

• Identified using the Ontario Cancer Registry

• Asked if they had been offered testing by doctors

• Asked if they wished to be tested.

Uptake of clinical genetic testing for ovarian cancer in Ontario

• 550 women contacted

• 80 women (19%) had undergone previous clinical genetic testing for BRCA1 and BRCA2.

• 24 mutations detected

• 491 requested genetic testing (89%)

• total of 41 mutations

• 17 of 41 mutations had been missed

Do carriers of BRCA1 mutations have a

different response to specific chemotherapy

agents compared to non-carriers?

• BRCA1 protein is a key component in the repair of double-strand DNA breaks (homologous recombination)

• BRCA1 mutation is associated with impaired DNA repair

• Agents that induce double strand breaks used as chemotherapy including mitomycin C, cis-platinum, radiotherapy

• Loss of heterozygosity renders cancer cells particularly sensitive

• Pre-clinical studies in cells with null BRCA1 show these cells are highly sensitive

• Synthetic lethality

Polish Study Neo-adjuvant Therapy in BRCA1

Carriers

• Database of 6903 women with breast cancer below 50 years

• Three founder mutations with BRCA 1• 400 mutation carriers • 102 were treated with neo-adjuvant

therapy• Endpoint: pathologic complete response

(PCR)

Numbers of patients treated with, and responding to different chemotherapy regimens

Regimen Number treated

Number of PCR

%PCR

CMF 14 1 7%

AC 23 5 22%

FAC 28 6 21%

AT 25 2 8%

Cis-platinum

Total

12

102

10

24

83%

24%C: cyclophosphamideM: methotrexateF: 5-flourouracilA: adriamycinT: docetaxelCMF category includes four patients with CMFP and two patients with CMFVP

Risk of breast cancer in women without a BRCA mutation

• 365 families identified• Proband negative for BRCA1 and BRCA2

– 2 breast cancers under age 50 or– 3 breast cancers any age

• 1492 women identified• Affected first degree relative

• Average follow-up 6.2 years• 65 cases observed• 15.2 cases expected• SIR = 4.3• Annual risk 1% per year

Future Directions, Non-carriers

Risk Model for non-carriers• Polygenic SNPs• Mammographic density• Vitamin D• Fasting insulin

Chemoprevention• Raxoxifene/tamoxifen

Screening• MRI

ContributorsContributors EUROPE:• Gareth Evans• Jacek Gronwald• Jan Klijn• Siranoush Manoukian• Hakan Olsson• Jan Lubinski• Dominique Stoppa-

Lyonnet• Pal Moller• Barbara Pasini• Paolo Radice• Teresa Wagner• Christian Singer• Catharina Anne

Speiss

UNITED STATES:• Fergus Couch• Mary Daly• Susan Domchek• Charis Eng• Judy Garber• Claudine Isaacs• Beth Karlan • Noah Kauff• Henry Lynch• Wendy McKinnon• Jane McLennan• Susan Neuhausen• Ken Offit• Funmi Olopade• Michael Osborne• Boris Pasche• Mark Robson• Howard Saal• Nadine Tung• Barbara Weber• Jeffrey Weitzel• Marie Wood• Dana Zakalik• Talia Donenberg• Kevin Sweet

CANADA: • Peter Ainsworth• Ab Chudley• Andrea Eisen• William Foulkes• Parviz Ghadirian• Donna Gilchrist• Doug Horsman• Charmaine Kim-

Sing• Ed Lemire• Ivo Olivotto• Barry Rosen• Amy Finch• Joanne Kotsopoulos• Kelly Metcalfe• Ping Sun• Christine Maugard• Susan Armel• Louise Bordeleau• Ophira Ginsberg• Seema Panchal• Aletta Poll• Wendy Messchino• Amber Trivedi ISRAEL:

• Eitan Friedman• Ruth Gershoni-

Baruch• Gad Rennert