1 What’s New in Hereditary Breast and Ovarian Cancer? Steven A. Narod, MD Steven A. Narod, MD Canada Research Chair in Breast Cancer
Jan 24, 2016
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)
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%
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%
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%
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%
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
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