The Link Between Breast and Ovarian Cancer: The Ovarian P erspective

The Link Between Breast and Ovarian Cancer:The Ovarian Perspective

Janiel M. Cragun, MDAssistant Professor

Department of OB/GYN

Educational Series-Promoting Good Health

All Faculty, CME Planning Committee Members, and the CME Office Reviewer

have disclosed that they have no financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Disclosure

1. Identify individuals who should be referred for genetic risk evaluation of Breast and Ovarian Cancer Syndrome.

2. Identify interventions which decrease the risk of ovarian cancer in high risk populations.

3. Describe risks and benefits of prophylactic oophorectomy in patients at risk for breast and ovarian cancer.

Educational Objectives

2013 Estimated US Cancer Cases**Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.

Women805,500

• 29% Breast• 14% Lung & bronchus• 9% Colon & rectum• 6% Uterine corpus • 6% Thyroid • 4% Non-Hodgkin

lymphoma• 4% Melanoma of skin• 3% Kidney & renal pelvis • 3% Ovary• 3% Pancreas

2013 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.

Women273,430

• 26% Lung & bronchus• 14% Breast• 9% Colon & rectum• 7% Pancreas• 5% Ovary• 4% Leukemia• 3% Non-Hodgkin

lymphoma• 3% Uterine corpus• 2% Liver & bile duct• 2% Brain/ONS

Breast OvarianIncidence per 100,000 123.8 12.5

Cases per year 232,340 22,240

Median age 61 63

Lifetime risk 12.29%1 in 8

1.37%1 in 73

Deaths per 100,000 22.6 8.1

Deaths per year 39,620 14,030

Breast and Ovarian Cancer

http://seer.cancer.gov/statfacts/html/breast.htmlhttp://seer.cancer.gov/statfacts/html/ovary.html

http://seer.cancer.gov/statfacts/html/breast.html

http://seer.cancer.gov/statfacts/html/breast.html

http://seer.cancer.gov/statfacts/html/ovary.html

Risk Factor Breast Cancer Ovarian CancerAge Average age 61 Average age 63

Parity Protective, increasing Protective, increasing

Breastfeeding Protective Protective

Early Menarche, Late Menopause

Increased Increased

Birth control Increased Protective

Tubal ligation/hysterectomy Protective

Fertility drugs, Infertility Possible, Yes

Estrogen Possibly protective Yes, prolonged periods

Estrogen and Progesterone Increased Unclear

Family History 5-10% 10%

Breast Cancer Yes Possible

Diet Unclear Protective, low fat

Smoking Evidence limited Mucinous type

Alcohol Increased No

Obesity Increased, maybe Increased, premenopausal

Risk Factors

Risk Factor Breast Cancer Ovarian CancerAge Average age 61 Average age 63

Parity Protective, increasing Protective, increasing

Breastfeeding Protective Protective

Early Menarche, Late Menopause

Increased Increased

Birth control Increased Protective

Tubal ligation/hysterectomy Protective

Fertility drugs, Infertility Possible, Yes

Estrogen Possibly protective Yes, prolonged periods

Estrogen and Progesterone Increased Unclear

Family History 5-10% 10%

Breast Cancer Yes Possible

Diet Unclear Protective, low fat

Smoking Evidence limited Mucinous type

Alcohol Increased No

Obesity Increased, maybe Increased, premenopausal

Risk Factors

• Mutations in BRCA 1 and BRCA 2 are 95% of hereditary ovarian and breast cancers• 5%-10% of breast cancer • 4-11% of ovarian cancer • Tumor suppressor genes:

• Involved with DNA repair:• Two hit hypothesis

• Patient inherits one mutated gene• The other gets knocked out

Breast and Ovarian Cancer Syndrome

Pruthi, S., B.S. Gostout, and N.M. Lindor, Identification and Management of Women With BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer. Mayo Clin Proc, 2010. 85(12): p. 1111-20.American College of, O., et al., ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol, 2009. 113(4): p. 957-66.Berek, J.S., et al., Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer. Obstet Gynecol, 2010. 116(3): p. 733-43.http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional

http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional

• BRCA carriers: 0.13 – 0.3% total population• 2% in the Ashkenazi Jewish heritage• Founder mutations

• Ashkenazi Jews• Eastern European Jews

• Poland• French Canadians• Icelanders• Netherlandic• Swedish• Dutch• Greek

BRCA Gene Mutation

Pruthi, S., B.S. Gostout, and N.M. Lindor, Identification and Management of Women With BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer. Mayo Clin Proc, 2010. 85(12): p. 1111-20.American College of, O., et al., ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol, 2009. 113(4): p. 957-66.Berek, J.S., et al., Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer. Obstet Gynecol, 2010. 116(3): p. 733-43.

BRCA 1 BRCA 2

Chromosome 17 13

Mutations 1200 1300

Risk of ovarian cancer 39-46% (25-65%) 12-20% (15-20%)

Risk of breast cancer 65-74% (40-85%) 65-74% (40-85%)

Risk of breast then ovary

12.7% 6.8%

Onset of ovarian cancer Increase by age 36-39y Increase by 44-46y

Onset of breast cancer Increased by age 40y Increased by age 45y

Other cancers Pancreatic, prostate, fallopian tube

Pancreatic, prostate, fallopian tubes, male breast

Breast and Ovarian Cancer Syndrome

American College of, O., et al., ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol, 2009. 113(4): p. 957-66.

• CHEK 2: checkpoint kinase 2• Breast, other cancers, not ovary• Czechoslovakian ancestry

• TP53, Li-Fraumeni• PTEN, Cowden’s• LKB1, Peutz-Jeghers

• Breast, uncommon ovarian • ATM, Ataxia-telangiectasia

• Breast, not ovary• PALB 2

•Breast, possibly ovarian•Russian and Polish ancestry

• MSH2, Muir-Torre Syndrome• RAD 51: Ovarian• MEN1: Ovarian• CDH1, E-cadherin

• Lobular breast, gastric, not ovary

• MRE11A/RAD50/NBN• Nijmegen Breakage Syndrome • Eastern Europe/Slavic ancestry• Breast, not ovary

• Genome wide association studies• 20 breast: FGFR 2, 6 ovarian:

BNC2• Both: BABAM1,TERT,Myc

• Multiplex testing• BARD1, BRIP1, MRE11A,

MUTYH, PMS2, STK11• Lynch Syndrome

• Ovarian, colon, uterine

What about the other 5%

Walsh, T., et al., Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA, 2006. 295(12): p. 1379-88.Bogdanova, N. and T. Dork, Molecular genetics of breast and ovarian cancer: recent advances and clinical implications. Balkan J Med Genet, 2012. 15(Suppl): p. 75-80.Domchek, S.M., et al., Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol, 2013. 31(10): p. 1267-70http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional



• Patients with greater than an approximate 20-25% chance of having an inherited predisposition to breast cancer and ovarian cancer and for whom genetic risk assessment is recommended:• Women with a personal history of both breast cancer and

ovarian cancer• Women with ovarian cancer and a close relative with ovarian

cancer or premenopausal breast cancer or both• Women with ovarian cancer who are of Ashkenazi Jewish

ancestry• Women with breast cancer at age 50 years or younger and a

close relative with ovarian cancer or male breast cancer at any age

• Women of Ashkenazi Jewish ancestry in whom breast cancer was diagnosed at age 40 years or younger

• Women with a close relative with a known BRCA1 or BRCA2 mutation.

When to Refer


• Patients with greater than an approximate 5-10% chance of having an inherited predisposition to breast cancer and ovarian cancer and for whom genetic risk assessment may be helpful:•Women with breast cancer at age 40 years or younger•Women with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer of high grade, serous histology at any age•Women with bilateral breast cancer (particularly if the first case of breast cancer was diagnosed at age 50 years or younger)•Women with breast cancer at age 50 years or younger and a close relative with breast cancer at age 50 years or younger•Women of Ashkenazi Jewish ancestry with breast cancer at age 50 years or younger•Women with breast cancer at any age and two or more close relatives with breast cancer at any age (particularly if at least one case of breast cancer was diagnosed at age 50 years or younger)

•Unaffected women with a close relative that meets one of the previous criteria.

When to Refer(Continued…)


• In the setting of high grade serous ovarian, primary peritoneal or fallopian tube cancer (not mucinous or borderline):• Patients without family history of breast or

ovarian cancer:• 16-21% will have germline BRCA1

mutation• 9% will have a germline BRCA2 mutation.

When to Refer (Continued…)

• Both paternal and maternal lines• Adoption • Hysterectomy/oophorectomy at young age • Few female relatives• Testing less than 21 is discouraged.

Remember


• Mutation is in family, but patient did not inherit

• Undetectable mutation in BRCA or other gene• unknown if patient shares the

predisposition• No inherited predisposition in the family.

No Deleterious Mutation

• Population based study in Sweden• In women with both breast and ovarian cancer.• 19% carried BRCA1 gene mutations.• None carried BRCA2 gene mutations.• Limitations:

• 4 BRCA1 mutations, 1 BRCA2 mutation. • (75% of mutations in their clinic)

Breast and Ovarian Cancer

Einbeigi, Z., et al., Occurrence of both breast and ovarian cancer in a woman is a marker for the BRCA gene mutations: a population-based study from western Sweden. Fam Cancer, 2007. 6(1): p. 35-41.

• Risk of ovarian cancer in patients with family history of breast cancer

• United Kingdom population study, 895 families• BRCA2: 17 times more likely to have ovarian

cancer • BRCA1: 50 times more likely to have ovarian

cancer• BRCA1/2 negative: only 1 case observed• BRCA unknown: risk equal to the general

population

When the BRCA is Positive

Ingham, S.L., et al., Ovarian cancer among 8,005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2. J Med Genet, 2013. 50(6): p. 368-72.

• Strategies • Surveillance• Chemoprevention

• Oral contraceptives for 3-6 years.May increase the risk of breast cancer.

• Surgery: removal of fallopian tubes and ovaries• Screening

• No evidence of improved survival or mortality• Ca125 and TVUS

• starting age 30-35 or • 5-10 years earlier than earliest age of first

diagnosis

Risk Reduction- Ovary


• Removal of fallopian tubes and ovaries by age 40

• Decreased risk of ovarian cancer, fallopian tube cancer and peritoneal cancer by 85-90%

• Decreased overall death rate in women with BRCA1 or BRCA2 mutations

Surgery


• Surveillance• Clinical breast exam semiannually• Annual mammogram• Annual MRI at 25

• Chemoprevention• Tamoxifen reduces breast cancer risk by 62% in BRCA2

carriers.• Tamoxifen does not decrease the risk in BRCA1 carriers

• Surgery• Removal of breast tissue (bilateral mastectomy)

• reduces risk of breast cancer by 90-95%• Removal of fallopian tubes and ovaries

• reduces risk of breast cancer by 40-70%

Risk Reduction, Breast


• Prospective Cohort Study• 2482 BRCA1 or BRCA2 mutation carriers.

• Risk reducing mastectomy:•Decreased risk of breast cancer

• Risk reducing removal of tubes and ovaries• Lower risk of ovarian cancer

• Lower risk of first diagnosis breast cancer in BRCA1/2 mutation carriers

• Lower all-cause mortality (death)• Lower breast cancer specific death• Lower ovarian cancer-specific death

Risk Reducing Surgery

Domchek, S.M., et al., Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA, 2010. 304(9): p. 967-75.

• Multicenter, prospective study• 1,079 BRCA1 or BRCA2 mutation carriers• Patients older than 30• 85% risk reduction BRCA1 associated gynecologic

cancer 72% risk reduction BRCA2 associated breast cancer

• Risk reduction of BRCA1 breast cancer and BRCA2 associated gynecologic cancer not significant.

• Conclusion: Risk reduction may differ by mutation.

Risk Reducing Surgery

Kauff, N.D., et al., Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol, 2008. 26(8): p. 1331-7.

• Meta-analysis• 10 studies, risk reducing removal of tubes and

ovaries• Breast Cancer

• BRCA 1/2: 51% reduction• BRCA 1: 53% reduction• BRCA 2: 53% reduction

• Ovarian/Fallopian tube cancer• BRCA 1/2: 79% reduction• Separate estimate of BRCA mutations not

possible.

Risk Reduction

Rebbeck, T.R., N.D. Kauff, and S.M. Domchek, Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst, 2009. 101(2): p. 80-7.

• If BRCA is negative, manage based on family history

• If only breast cancer, but no ovarian• unknown risk for ovarian• may not be able predict risk

When the BRCA is Negative


• Population based study, San Francisco• 2935 female first-degree relatives• Looked at BRCA1 and BRCA 2 for breast• Looked at BRCA1 for ovary• For families negative for BRCA, risk only elevated for the

cancer site

When the BRCA is Negative (Cont…)

BRCA negative or untested BRCA positive

Family history Breast Cancer

Ovarian Cancer

Breast Cancer

Ovarian Cancer

Breast Cancer

1.5CI 1.2-1.8*

1.1CI 0.8-1.6

10.6CI 1.2-53.0

3.3CI 1.4-7.3

Ovarian Cancer

0.9CI 0.5-1.4

1.9CI 1.0-4.0

7.9CI 1.2-53.0

11.3CI 3.6-35.9

Lee, J.S., et al., Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations. Cancer Epidemiol Biomarkers Prev, 2006. 15(2): p. 359-63.

* Higher if diagnosed before 40

• “The health benefits of this surgery (cancer prevention) should outweigh the costs of the procedure in terms of quality of life and long term health.” Finch et al.

• Quality of life is menopause-specific (see next slide)• PLCO trial showed risks of unnecessary surgery

• Randomized controlled trial• Screening Intervention

• Annual screening with Ca125 for 6 years• Transvaginal Ultrasound for 4 years.

• No change in mortality• Complications from surgical interventions (15%)

Risks of Surgical Menopause

Buys, S.S., et al., Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA, 2011. 305(22): p. 2295-303.Finch, A., et al., The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation. Gynecol Oncol, 2011. 121(1): p. 163-8.

• Frequency of symptoms post surgery• Change in libido (50%)• Change in sex life (43.9%)• Vaginal dryness (52.1%)• Hot flashes (42.9%)• Sleep disturbances (46.9%)• Weight gain (40.8%)• Depression (21.4%)• Mood swings (23.5)• Change in body image (31.6%)

Surgical Menopause: Quality of Life

Campfield Bonadies, D., A. Moyer, and E.T. Matloff, What I wish I'd known before surgery: BRCA carriers' perspectives after bilateral salipingo-oophorectomy. Fam Cancer, 2011. 10(1): p. 79-85

• Norwegian controlled observational study• Risk reducing salpingo-oophorectomy• 325 women with Hereditary Breast and Ovarian Cancer• Association with metabolic syndrome

• Norwegian population based study• Risk reducing salpingo-oophorectomy, less than age 50• Higher risk of type 2 diabetes and cardiovascular disease.

• Danish nurse cohort study• Early menopause (less than 40-45) • Increased risk of ischemic heart disease• More pronounced with early oophorectomy• Hormone replacement

• May decrease risk in early oophorectomy• Does not decreased risk in early natural menopause

Effect of Early Surgical Menopause

Michelsen, T.M., et al., Metabolic syndrome after risk-reducing salpingo-oophorectomy in women at high risk for hereditary breast ovarian cancer: a controlled observational study. Eur J Cancer, 2009. 45(1): p. 82-9.Dorum, A., et al., Bilateral oophorectomy before 50 years of age is significantly associated with the metabolic syndrome and Framingham risk score: a controlled, population-based study (HUNT-2). Gynecol Oncol, 2008. 109(3): p. 377-83.Lokkegaard, E., et al., The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy. Maturitas, 2006. 53(2): p. 226-33.

• Cohort study, Mayo clinic• Removal of ovaries before menopause (< age 45)

Effect of Early Surgical Menopause

Rocca, W.A., et al., Long-term risk of depressive and anxiety symptoms after early bilateral oophorectomy. Menopause, 2008. 15(6): p. 1050-9.Rocca, W.A., et al., Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol, 2006. 7(10): p. 821-8.Rivera, C.M., et al., Increased cardiovascular mortality after early bilateral oophorectomy. Menopause, 2009. 16(1): p. 15-23.Rocca, W.A., et al., Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology, 2007. 69(11): p. 1074-83.Rocca, W.A., et al., Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology, 2008. 70(3): p. 200-9.Rivera, C.M., et al., Increased mortality for neurological and mental diseases following early bilateral oophorectomy. Neuroepidemiology, 2009. 33(1): p. 32-40.

USO BSO Reference HR CommentsMortality, cardiovascular 1274 1091 2,383 1.44 Unilateral protective with HR 0.82

With estrogen HR 0.65Without estrogen HR 1.84

Dementia 813 676 1472 1.46 Association greater with young age

Parkinson’s 1242 1075 2368 1.68

Mortality, Neurologic 1274 1091 2383 5.24

Depression --- 666 673 1.54 Association greater with young age

Anxiety --- 666 673 2.29 Association greater with young age

Mortality 1293 1097 2390 1.67 Mostly in those without estrogen

USO: removal one tube and ovaryBSO: removal two tubes and ovaries

• Prospective observational study

• Nurses’ Health Study• 29,380 patients

• 16,345 hysterectomy• 13,035 hysterectomy with

ovarian conservation• 24 years follow-up• Oophorectomy vs. conservation

Oophorectomy and MortalityHazard Ratio

95% CI

Overall Mortality

1.12 1.03-1.21

Coronary Heart disease

1.17 1.02-1.35

Stroke 1.14 0.98-1.33

Breast Cancer 0.75 0.68-0.84

Ovarian Cancer 0.04 1.01-0.09

Total Cancers 0.90 0.84-0.96

Lung cancer 1.26 1.02-1.56

Total cancer mortality

1.17 1.04-1.32

Parker, W.H., et al., Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study. Obstet Gynecol, 2009. 113(5): p. 1027-37.

• Prospective observational study, California Teachers Study • 42,004: natural menopause • 3,785: surgical menopause • Age < 45, No hormone replacement • 10 year follow-up

Mortality and Early Menopause

Menopause < 45 Menopause > 45Relative risk 95% CI Relative risk 95% CI

Overall Mortality 0.86 0.74-1.00 0.87 0.80-0.94

Coronary Heart disease

0.85 0.66-1.11 0.83 0.71-0.96

Total cancer mortality 0.92 0.67-1.23 0.84 0.72-0.98

Duan, L., et al., Bilateral oophorectomy is not associated with increased mortality: the California Teachers Study. Fertil Steril, 2012. 97(1): p. 111-7.

• Breast cancer is the most common of female malignancies and is the second highest cause of cancer death in women

• Ovarian cancer is rare in women, but is the most deadly of gynecologic cancers

• About 10% of breast and ovarian cancers are inherited• BRCA1 and BRCA2 mutations put patients at risk for breast and

ovarian cancer• BRCA1 and BRCA 2 mutation are responsible for 95% of inherited

breast and ovarian cancer• Other genes may put patients at risk for breast and ovarian cancer,

but we do not know as much about them.• Patients with a personal and family history concerning for BRCA

mutations should be seen by a genetic counselor/specialist

Summary

• Although a personal history of breast cancer may increase risk of ovarian cancer, this is not the case in all individuals.

• In high risk patients, the only known intervention to decrease risk of death from ovarian cancer is removal of the ovaries.

• In high risk patients, bilateral mastectomy reduces risk of breast cancer

• In high risk patients, removal of ovaries also decreases risk of breast cancer

• Tamoxifen reduces risk of breast cancer in BRCA2 carriers.• Other options to reduce risk of ovarian cancer include use of oral

contraceptives, but this may increase risk of breast cancer in BRCA mutation carriers.

• The decision for removal of ovaries is not straight forward and requires counseling. The benefit must outweigh the risk.

Summary

References1. Rocca, W.A., et al., Long-term risk of depressive and anxiety symptoms after early

bilateral oophorectomy. Menopause, 2008. 15(6): p. 1050-9.2. Pruthi, S., B.S. Gostout, and N.M. Lindor, Identification and Management of Women

With BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer. Mayo Clin Proc, 2010. 85(12): p. 1111-20.

3. Einbeigi, Z., et al., Occurrence of both breast and ovarian cancer in a woman is a marker for the BRCA gene mutations: a population-based study from western Sweden. Fam Cancer, 2007. 6(1): p. 35-41.

4. Lee, J.S., et al., Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations. Cancer Epidemiol Biomarkers Prev, 2006. 15(2): p. 359-63.

5. Ingham, S.L., et al., Ovarian cancer among 8,005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2. J Med Genet, 2013. 50(6): p. 368-72.

6. Parker, W.H., et al., Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study. Obstet Gynecol, 2009. 113(5): p. 1027-37.

7. Rivera, C.M., et al., Increased cardiovascular mortality after early bilateral oophorectomy. Menopause, 2009. 16(1): p. 15-23.

8. Rocca, W.A., et al., Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology, 2007. 69(11): p. 1074-83.

References9. Rocca, W.A., et al., Increased risk of parkinsonism in women who underwent

oophorectomy before menopause. Neurology, 2008. 70(3): p. 200-9.10. Duan, L., et al., Bilateral oophorectomy is not associated with increased mortality: the

California Teachers Study. Fertil Steril, 2012. 97(1): p. 111-7.11. Rivera, C.M., et al., Increased mortality for neurological and mental diseases

following early bilateral oophorectomy. Neuroepidemiology, 2009. 33(1): p. 32-40.12. Rocca, W.A., et al., Survival patterns after oophorectomy in premenopausal women: a

population-based cohort study. Lancet Oncol, 2006. 7(10): p. 821-8.13. Kauff, N.D., et al., Risk-reducing salpingo-oophorectomy for the prevention of

BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol, 2008. 26(8): p. 1331-7.

14. Rebbeck, T.R., N.D. Kauff, and S.M. Domchek, Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst, 2009. 101(2): p. 80-7.

15. Bogdanova, N. and T. Dork, Molecular genetics of breast and ovarian cancer: recent advances and clinical implications. Balkan J Med Genet, 2012. 15(Suppl): p. 75-80.

16. American College of, O., et al., ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol, 2009. 113(4): p. 957-66.

References17. Domchek, S.M., et al., Multiplex genetic testing for cancer susceptibility: out on the

high wire without a net? J Clin Oncol, 2013. 31(10): p. 1267-70.18. Walsh, T., et al., Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in

families at high risk of breast cancer. JAMA, 2006. 295(12): p. 1379-88.19. Buys, S.S., et al., Effect of screening on ovarian cancer mortality: the Prostate,

Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA, 2011. 305(22): p. 2295-303.

20. Zhou, B., et al., Hormone replacement therapy and ovarian cancer risk: a meta-analysis. Gynecol Oncol, 2008. 108(3): p. 641-51.

21. Domchek, S.M., et al., Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA, 2010. 304(9): p. 967-75.

22. Phung, T.K., et al., Hysterectomy, oophorectomy and risk of dementia: a nationwide historical cohort study. Dement Geriatr Cogn Disord, 2010. 30(1): p. 43-50.

23. Berek, J.S., et al., Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer. Obstet Gynecol, 2010. 116(3): p. 733-43.

24. Campfield Bonadies, D., A. Moyer, and E.T. Matloff, What I wish I'd known before surgery: BRCA carriers' perspectives after bilateral salipingo-oophorectomy. Fam Cancer, 2011. 10(1): p. 79-85.

References25. Michelsen, T.M., et al., Metabolic syndrome after risk-reducing salpingo-

oophorectomy in women at high risk for hereditary breast ovarian cancer: a controlled observational study. Eur J Cancer, 2009. 45(1): p. 82-9.

26. Dorum, A., et al., Bilateral oophorectomy before 50 years of age is significantly associated with the metabolic syndrome and Framingham risk score: a controlled, population-based study (HUNT-2). Gynecol Oncol, 2008. 109(3): p. 377-83.

27. Lokkegaard, E., et al., The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy. Maturitas, 2006. 53(2): p. 226-33.

28. Finch, A., et al., The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation. Gynecol Oncol, 2011. 121(1): p. 163-8.

29. http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-risk-factors30. http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-risk-

factors31. http://seer.cancer.gov/statfacts/html/breast.html32. http://seer.cancer.gov/statfacts/html/ovary.html

References33. http://www.cancerresearchuk.org/cancer-help/type/ovarian-cancer/about/ovarian-cancer-risks-and-causes#cancer34.American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.35. http://seer.cancer.gov/statfacts/html/breast.html

36. http://seer.cancer.gov/statfacts/html/ovary.html37. http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional38. Gammon, M.D. and W.D. Thompson, Infertility and breast cancer: a population-based case-control study. Am J Epidemiol, 1990. 132(4): p. 708-16.

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The Link Between Breast and Ovarian Cancer: The Ovarian P erspective