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Preventing BRCA-related cancers: The case for oophorectomy

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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.


 

References

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 cancer3,4

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

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