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Preventing BRCA-related cancers: The case for oophorectomy

OBG Manag. 2004 April;16(4):56-67

The team that conducted the recent prospective trial of risk-reducing surgery versus surveillance reviews the evidence, plus surgical technique, psychosocial factors, use of estrogen after surgery, and insurance issues.

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References

1. Liber AM. Ovarian cancer in a mother and five daughters. Arch Pathol. 1950;49:280-290.

2. Knudson AG, Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68:820-823.

3. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998;62:676-689.

4. Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68:700-710.

5. Oddoux C, Struewing JP, Clayton CM, et al. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996;14:188-190.

6. Tonin P, Weber B, Offit K, et al. Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med. 1996;2:1179-1183.

7. Schinzinger A. Ueber Carcinoma Mammae. Verhandlungen der Deutschen Gesellschaft fur Chirurgie. 18th Kongress, Berlin, Apr 24–27, 1889. Berlin, Germany: Hirschwald; 1889:28[abstract].

8. Love RR, Philips J. Oophorectomy for breast cancer: history revisited. J Natl Cancer Inst. 2002;94:1433-1434.

9. Feinleib M. Breast cancer and artificial menopause: a cohort study. J Natl Cancer Inst. 1968;41:315-329.

10. Brinton LA, Schairer C, Hoover RN, Fraumeni JF, Jr. Menstrual factors and risk of breast cancer. Cancer Invest. 1988;6:245-254.

11. Tobacman JK, Greene MH, Tucker MA, Costa J, Kase R, Fraumeni JF, Jr. Intraabdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet. 1982;2:795-797.

12. Piver MS, Jishi MF, Tsukada Y, Nava G. Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer. 1993;71:2751-2755.

13. Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA. 1997;277:997-1003.

14. Schrag D, Kuntz KM, Garber JE, Weeks JC. Decision analysis—effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med. 1997;336:1465-1471.

15. Grann VR, Panageas KS, Whang W, Antman KH, Neugut AI. Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients. J Clin Oncol. 1998;16:979-985.

16. Rebbeck TR, Levin AM, Eisen A, et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst. 1999;91:1475-1479.

17. Eisen A, Rebbeck TR, Wood WC, Weber BL. Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer. J Clin Oncol. 2000;18:1980-1995.

18. Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346:1609-1615.

19. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346:1616-1622.

20. Rutter JL, Wacholder S, Chetrit A, et al. Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: an Israeli population-based case-control study. J Natl Cancer Inst. 2003;95:1072-1078.

21. Lu KH, Garber JE, Cramer DW, et al. Occult ovarian tumors in women with BRCA1 or BRCA2 mutations undergoing prophylactic oophorectomy. J Clin Oncol. 2000;18:2728-2732.

22. Lafferty HW, Angioli R, Rudolph J, Penalver MA. Ovarian remnant syndrome: experience at Jackson Memorial Hospital, University of Miami, 1985 through 1993. Am J Obstet Gynecol. 1996;174:641-645.

23. Schorge JO, Muto MG, Welch WR, et al. Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations. J Natl Cancer Inst. 1998;90:841-845.

24. Levine DA, Lin O, Barakat RR, et al. Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol. 2001;80:395-398.

25. Paley PJ, Swisher EM, Garcia RL, et al. Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol. 2001;80:176-180.

26. Aziz S, Kuperstein G, Rosen B, et al. A genetic epidemiological study of carcinoma of the fallopian tube. Gynecol Oncol. 2001;80:341-345.

27. Colgan TJ, Murphy J, Cole DE, Narod S, Rosen B. Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am J Surg Pathol. 2001;25:1283-1289.

28. Scheuer L, Kauff N, Robson M, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol. 2002;20:1260-1268.

29. Colgan TJ, Boerner SL, Murphy J, Cole DE, Narod S, Rosen B. Peritoneal lavage cytology: an assessment of its value during prophylactic oophorectomy. Gynecol Oncol. 2002;85:397-403.

30. Meiser B, Butow P, Barratt A, et al. Attitudes toward prophylactic oophorectomy and screening utilization in women at increased risk of developing hereditary breast/ovarian cancer. Gynecol Oncol. 1999;75:122-129.

31. Hurley KE, Miller SM, Costalas JW, Gillespie D, Daly MB. Anxiety/uncertainty reduction as a motivation for interest in prophylactic oophorectomy in women with a family history of ovarian cancer. J Womens Health Gend Based Med. 2001;10:189-199.

32. Robson M, Hensley M, Barakat R, et al. Quality of life in women at risk for ovarian cancer who have undergone risk-reducing oophorectomy. Gynecol Oncol. 2003;89:281-287.

33. Kuerer HM, Hwang ES, Anthony JP, et al. Current national health insurance coverage policies for breast and ovarian cancer prophylactic surgery. Ann Surg Oncol. 2000;7:325-332.

34. Kauff ND, Scheuer L, Robson ME, et al. Insurance reimbursement for risk-reducing mastectomy and oophorectomy in women with BRCA1 or BRCA2 mutations. Genet Med. 2001;3:422-425.

KEY POINTS

Mutations in BRCA1 and BRCA2 may be responsible for more than 90% of inherited predisposition to ovarian cancer.
BRCA1 and BRCA2 mutations are associated with a lifetime risk of breast cancer of up to 85% and a 15% to 45% lifetime risk of ovarian cancer.
The only prospective trial to date found risk-reducing salpingo-oophorectomy (RRSO) was associated with an 85% reduction in ovarian cancer and a 68% reduction in breast cancer.
Because microscopic cancer may be found in 2% to 4% of RRSO specimens upon careful pathologic review, the ovaries and fallopian tubes should be sectioned in their entirety and examined by an experienced gynecologic pathologist.

When A.M. Liber encountered a family of 5 sisters and their mother with histologically confirmed papillary adenocarcinoma of the ovary, he recommended frequent gynecologic cancer screening for all family members and suggested prophylactic oophorectomy as an option.¹ The year was 1950.

Flash forward half a century or so, and prophylactic oophorectomy has gained wider acceptance for the prevention of hereditary ovarian and breast cancer, with the only prospective trial to date confirming its overall efficacy for women with BRCA1 and BRCA2 mutations. These mutations are related to the vast majority of inherited ovarian cancers.

Using the evidence published thus far, including the recently published prospective trial, we discuss surgical technique, post-oophorectomy estrogens, psychosocial impact, insurance reimbursement, and other issues.

Three hereditary syndromes

The single biggest risk factor for ovarian cancer is a family history, although only about 10% of cases are believed to be due to an inherited predisposition. Three syndromes are associated with such a predisposition:

Hereditary breast-ovarian cancer syndrome, caused by mutations in BRCA1 and BRCA2, is thought to be responsible for more than 90% of inherited predisposition to ovarian cancer.
Hereditary nonpolyposis colon cancer (HNPCC) syndrome is associated with mutations in the mismatch repair genes and a greatly increased risk of cancers of the colon, endometrium, ovaries, and urinary tract. HNPCC accounts for about 2% of inherited ovarian cancers.
A syndrome of site-specific ovarian cancer also has been proposed, though we lack conclusive evidence that it exists as a separate entity at the genetic level.

How BRCA mutations lead to cancer

BRCA1 and BRCA2 are tumor suppressor genes that play a role in genomic stability and double-stranded DNA break repair. BRCA1 is located on chromosome 17; BRCA2 on chromosome 13. Both genes function as classic tumor suppressors, as described by Knudson.² Only a single working copy of each gene is needed for the genes to effectively suppress tumors.

In patients with no inherited mutation in these genes, carcinogenesis caused by dysfunction of this pathway can occur only if both working copies of the gene are lost. In contrast, women with an inherited mutation in BRCA1 or BRCA2 start out with only a single working copy of the gene. If any cell loses this single copy, DNA repair cannot occur via this pathway, and cancer can develop.

These repair pathways seem to be particularly important in dividing breast and ovarian cells. This explains why women with inherited mutations in these genes develop cancers more frequently and at an earlier age.

Quantifying the risk

Specific risks associated with BRCA1 and BRCA2 mutations include:

a lifetime risk of breast cancer of up to 85%, with half of these cancers occurring prior to age 50
a 15% to 45% lifetime risk of ovarian cancer^3,4

Mutations in these genes can be inherited from a mother or father. In the general population, between 1 in 385 and 1 in 800 individuals carry a deleterious mutation in either BRCA1 or BRCA2.

In certain populations, such as Icelandic, French Canadian, or Eastern European Jewish populations, founder effects can contribute to a greatly increased frequency of mutation. For example, the Eastern European Jewish population, from which approximately 90% of North American Jews are descended, has one of the highest known frequencies of BRCA1 and BRCA2 mutation: 1 in 40 individuals carries a deleterious mutation in 1 of these 2 genes.^5,6

Most evidence is historical or retrospective

Liber was not the first to suggest oophorectomy to impact the risk of breast or ovarian cancer: The procedure was initially proposed by Schinziner in 1889 as a treatment for breast cancer.⁷ However, the earliest evidence that oophorectomy was performed as adjuvant therapy did not appear until 7 years later, in 1896 (reviewed by Love and Philips).⁸

In 1968, Feinleib⁹ reported that premenopausal oophorectomy decreased the rate of subsequent breast cancer. Twenty years later, Brinton suggested that prophylactic oophorectomy might reduce breast cancer risk in women with a family history of the disease.¹⁰