A clinician faces a problem in how best to counsel the woman with a family history of breast or ovarian cancer about her options for pregnancy prevention. The physician must guide her as she makes new and complex decisions. Recent data strongly support an amplified effect of the estrogens in oral contraceptives for the woman with a genetic risk for breast cancer. Nonetheless, a woman's immediate need to prevent pregnancy may be much more important to her than worrying about the long-term risk of breast cancer. Another factor is that oral contraceptives prevent ovarian cancer, so the physician may wish to prescribe them to protect her from ovarian cancer. In some genetic backgrounds, however, oral contraceptives not only do not prevent ovarian cancer, but they may raise the risk of breast cancer so significantly that they should not be taken. With other genetic backgrounds, oral contraceptives will protect the woman from ovarian cancer without much effect on her breast cancer risk.

When does each of these cancer risks or benefits become significant? The clinician can provide an important benefit to a woman who must prevent pregnancy yet worries about her cancer risk. The physician can help her evaluate the evidence, with its gaps and uncertainties, in the context of her own preferences. To assist in this evaluation, this decision aid provides base-line estimates of the cancer risk that accompanies each of a woman's options. In some cases, genetic testing is likely to provide valuable information as she makes choices about contraception and the risks vs. benefits of different alternatives available to her.

Recent research results suggest that oral contraceptives may be especially likely to precipitate breast cancer in a woman with a family history of breast or ovarian cancer. Modern lower-dose oral contraceptives may be safer than older, higher-dose forms, but the data are limited and incomplete.^[1,2]

The increase in the risk of breast cancer appears to be substantial for a woman with a family history of breast or ovarian cancer if she took the oral contraceptives that were in use before 1975. If her mother or her sister had contracted breast cancer,^[1] the pre-1975 pill increases her risk of breast cancer more than 3-fold (13 cancers in 426 families representing 2533 person years). If 3 first-degree relatives had breast or ovarian cancers, pre-1975 contraceptives raise her risk of breast cancer by 4.6 times (10 cancers in 132 families representing 733 person years). If there were 5 or more cases of breast or ovarian cancer in the family, the woman's risk goes up 11.4-fold (6 cancers in 35 families representing 326 person years).^[1]

Although oral contraceptives appear to increase the risk of breast cancer in women with a family history of breast cancer, there is strong evidence that they reduce ovarian cancer risk.^[3-5] In 1982, the Centers for Disease Control and Prevention (CDC) estimated that oral contraceptives could prevent about half of all cases of ovarian (and endometrial) cancer in the United States.^[6] With about 25,000 cases of ovarian cancer diagnosed per year, the CDC estimate meant that each year oral contraceptives could protect a total of 12,500 women from the disease.

Perhaps 90% of the 25,000 yearly ovarian cancer victims (22,500 women) have no hereditary risk factors for breast cancer. Oral contraceptives will not cause many cases of breast cancer among this majority of the women who do not have a hereditary predisposition. There would only be about 1 excess breast cancer diagnosed among 22,500 users aged 16-19 years between the time they start the pill and up to 10 years after they stop.^[2] Because cancer incidence rises rapidly with age, 22,500 users between the ages of 40 and 44 years would have about 72 excess cases of breast cancer due to pill use. The increased risk of breast cancer does not persist for those without hereditary breast cancer predisposition and normally drifts down over time until it is close to the risk of never users 10 years after stopping.^[2]

In contrast, the protection that oral contraceptives give against ovarian cancer appears to persist for 10-15 years after oral contraceptives have been discontinued. Presumably, the reason oral contraceptives protect against ovarian cancer is that they suppress ovulation and thereby reduce the chance that DNA damaged cells within ovaries will multiply.

Although ovarian cancer is less common than breast cancer, ovarian cancer is still the overall leading cause of gynecologic deaths from malignancies. More than two thirds of patients with ovarian cancer have widespread metastatic disease at initial diagnosis. Their outlook remains poor, with a 5-year survival rate of no more than 10%.^[7]

Most Ovarian Cancer Is Sporadic

The majority of ovarian cancers occur in the absence of a family history, with only 5% to 10% of cases linked to a family history of the disease.^[7-10] Women who have no family members with ovarian cancer have a lifetime risk of about 1 in 70 (1.4%). Among 25,000 of these women, pill use would prevent about half the 350 cases (175 cases) of ovarian cancer expected each year in women younger than 50 years. On the other hand, pill use would cause only about 1 breast cancer for 25,000 users aged 16-19 years and about 80 excess breast cancers for 25,000 users aged 40-44 years.^[2]

Women with 1 first-degree relative with ovarian cancer have about 5% risk by age 50 years; women with 2 or 3 first-degree relatives afflicted have a 6.4% risk.^[8] Many families with 2 or more cases of ovarian cancer do not have a known inherited ovarian cancer syndrome and would be eligible for protection by oral contraceptives.

Hereditary Ovarian Cancer Syndromes

Breast-ovarian cancer syndrome is responsible for about 90% of all cases of hereditary ovarian cancer and almost always arises because of mutations in BRCA1 or BRCA2 genes. Two other hereditary causes of ovarian cancer are familial site-specific ovarian cancer syndrome, and breast-endometrial-ovarian-colorectal cancer syndrome (Lynch Syndrome II or hereditary nonpolyposis colon cancer [HNPCC]).^[7,9-12]

Women from cancer-prone families are often counseled to take oral contraceptives to reduce their ovarian cancer risk.^[1,3-5] Narod and colleagues^[5] measured protection from the ovarian cancer caused by mutations in BRCA1 or BRCA2 genes. Depending on how long they were used, oral contraceptives reduced the risk of ovarian cancer by 30% to 60%. The authors did not notice any increase in breast cancer.^[5] Overall, if 5% of 25,000 or 1250 annual ovarian cancers are due to deleterious BRCA gene mutations, then a 30% to 60% reduction means that oral contraceptives might prevent 375-750 ovarian cancers per year in high-risk women. Unfortunately, for these women, the pill would multiply their already high lifetime breast cancer risks of 45% to 87% by as much as 3- to 11-fold. Virtually all of the 1250 women would get breast cancer.

The increased risk found for precipitating breast cancer in high-risk families (pre-1975 pills) warns high-risk women to avoid oral contraceptives and to abandon the strategy of using them for protection from ovarian cancer.^[13] Moreover, if the woman has a founder mutation in BRCA genes, then oral contraceptives will not change her ovarian cancer risk.^[14]

All past and current oral contraceptives are chemical derivatives of natural estrogen or progesterone, so there is no fundamental difference between the basic chemical makeup of past and present oral contraceptives. The high-dose forms of the pill in use before 1975 increased the risk of breast cancer in women with a family history of the disease,^[1] but no one uses these pills anymore. The daily dose of synthetic estrogens^[1,15] has dropped from 150 mcg of mestranol in 1960 to <= 50 mcg of ethinylestradiol. Progestins have fallen from 9.85 mg of norethyndrel to <= 1 mg of several progestins.

There is adequate data on the breast cancer risk of modern oral contraceptives for women who were not selected for a family history of breast cancer. A 1996 study^[2] reviewed data from large numbers of these women and found a 1.24-fold increase in breast cancer risk for current users but no significant difference in the relative risks associated with a particular estrogen and progestin. For this "normal" population, there was no significant dose effect when preparations in 3 broad dosage categories (< 50 mcg, 50 mcg, and > 50 mcg) were compared.^[2] This result further suggests the importance of a positive family history in increasing the breast cancer risk of oral contraceptives. A small study of Ashkenazi Jewish women suggested that current oral contraceptives increase the risk of breast cancer more in carriers of BRCA1 and BRCA2 mutations than in noncarriers.^[16] However numerous other studies of women with a family history of cancer who take low-dose oral contraceptives have yielded conflicting estimates^[1] of effects on breast cancer risk.

Recently, the National Toxicology Program of the National Institutes of Environmental Health Sciences examined toxicology data for several female steroid hormones and a few derivatives that are currently used in oral contraceptives. As a result of their study, they classified these compounds as "reasonably anticipated to be human carcinogens."^[17] This encourages physicians to discuss risks as well as benefits.

In the absence of hereditary breast cancer risk, oral contraceptives represent a convenient method to protect against ovarian cancer, but they are not the only option. In comparison to not giving birth, having a child reduces both breast and ovarian cancer risk 2- to 3-fold.^[7] Parity protected even women with BRCA founder mutations.^[14] For normal women, breast-feeding is associated with a moderate reduction in ovarian cancer risk, reducing the odds by about 20%.^[7] Oophorectomy carries a surgical risk, then a life-long commitment to estrogen replacement therapy and gives a gain in life expectancy of less than 2 years.^[18] Tying the Fallopian tubes reduces risk by 15% to 33%.^[7,18] Women should weigh the surgical risk and that the operation should be considered permanent. Similarly, hysterectomy is a weaker protective measure, reducing the odds by about 15%.^[7] A low-fat diet may also be protective, and avoiding talcum powder on the perineum is also advised.^[18] A history of fertility drugs that were used unsuccessfully is a controversial risk factor for ovarian cancer, but the use of gonadotrophins may be safer.^[7,18]

The information provided by a personal genetic test may be of real value in identifying the woman whose risk for breast cancer or other cancers is likely to be amplified by oral contraceptives. Depending on the mutation, oral contraceptives can increase the risk of breast cancer and may also fail to protect against ovarian cancer. Thus, a positive test for certain genetic mutations means that the strategy of using oral contraceptives to reduce the risk of ovarian cancer should be abandoned.^[13] In contrast, a woman worried about ovarian cancer who does not have one of these hereditary contraindications could then take oral contraceptives without danger of precipitating a known hereditary breast cancer.

There are specific screening criteria to identify women who may benefit from genetic testing (discussed later). In general, the number of affected relatives, the closeness of their biologic relationship, and the age at onset of their disease are important. Between 5% and 20% of all women have a family history of breast cancer. Many of these women will not have a family history that suggests a highly penetrant susceptibility gene.^[22,23] Only a small subset of these women will come from families where there is a high incidence of breast cancer and other cancers.

Genetic Testing Can Lead to Interventions to Detect Breast Cancer Earlier or to Prevent It

Against a positive genetic test result, there are a limited but growing number of options for preventing breast cancer or for earlier detection. For breast cancer, more frequent screening by physical breast examination is a minimal recommendation. Options like more frequent mammography may place a strain on a genetically defective DNA damage response^[24] if the woman has a BRCA or MSH2/MLH1 gene mutation (discussed below). For this high-risk woman, mammograms should at least be done with a modern machine that is known to emit the minimum radiation required for the radiograph. Other body parts should be shielded. It also seems prudent to consider substituting magnetic resonance imaging^[24] and adding ductoscopy and breast ductal lavage.^[25]

Hartmann and colleagues^[26] conducted a retrospective study of 639 women with a family history of breast cancer who had prophylactic mastectomy at the Mayo Clinic between 1960 and 1983. Prophylactic mastectomy produced over a 90% reduction in the number of breast cancers in high-risk women and BRCA mutation carriers.^[26,27] Chemoprevention with tamoxifen or other agents is another option. The goal is to make chemoprevention as effective as prophylactic mastectomy.

The Presence of Hazardous BRCA Gene Mutations May Preclude the Use of Oral Contraceptives

Women with inherited mutations in both copies of the BRCA1 and BRCA2 genes face a lifetime risk of breast cancer as high as 87% by age 70 years. Of perhaps greater clinical significance is that mutations in BRCA1 and BRCA2 may greatly increase the risk of breast cancer at an early age. A woman's chance of developing breast carcinoma before age 50 is normally only about 2%, but some mutations in BRCA1 or BRCA2 raise this risk to 33% to 50%.^[12] If breast cancer develops in carriers of some BRCA1/2 mutations, the risk of subsequent ovarian cancer goes up ten times.^[12]

BRCA genes are needed for repairing double strand breaks in DNA, for repairing other DNA damage, for chromatin remodeling, and for suppressing genome instability.^[28-31] Estrogenic stimulation activates the BRCA1 gene and causes a burst in the activity of DNA repair enzymes.^[32] Ordinarily, activation of normal BRCA1 by estrogens may help maintain genetic stability via repair or by inducing differentiation or apoptosis. A woman with impaired BRCA gene function would have difficulty repairing or removing cells containing DNA damaged by oxidized products of estrogens and oral contraceptives. Then oral contraceptives would act as tumor promoters by stimulating these damaged (initiated) cells. The pill could also cause further gene damage to initiated cells so that they progress to malignancy.

Risk Factors for BRCA Gene Mutations in Figure 1

The presence of a major risk factor (Table 1) has been proposed as a criterion for testing for a BRCA1 or BRCA2 mutation.^[37] Many BRCA gene mutations occur in women who do not have these major risk factors, so additional criteria are proposed (Figure 1, Table 1).^[38,39] "BRCAPro," a computer program to calculate probabilities of a BRCA gene mutation, is available on the Internet at: http://biosun01.biostat.jhsph.edu/~gparmigi/brcapro.html

Figure 1. Decision aid for genetic testing. Figure 1 contains a proposed flow chart to help decide whether genetic testing is likely to yield valuable information. It is assumed that the medical history and blood pressure measurement^[36] do not preclude the use of hormonal contraception. Criteria to decide whether to test for BRCA gene mutations are given in Table 1. Table 1 also lists additional criteria to assess the risk of colon cancer (HNPCC) mutations.^[37-42] Colon cancer mutations are included because they also predispose to breast cancer that might be stimulated by oral contraceptives.

Testing for hMSH2/hMLH1 Mutations May Identify More Women at Increased Risk of Breast and Ovarian Cancer

HNPCC, formerly known as Lynch II Syndrome, is the most common hereditary colon cancer syndrome. HNPCC is associated with a 50% risk of colorectal cancer. Breast cancer occurs in about 25% of female carriers with 68 years as the median age at breast cancer diagnosis.^[23]

HNPCC has been associated with germ-line mutations in 1 of 6 DNA mismatch repair genes, most commonly hMSH2 and hMLH1. This has led to the suggestion that the condition be renamed as "hereditary mismatch repair disease (HMRD)." In contrast, MSH2 and MLH1 mutate only occasionally in sporadic breast tumors (5% and 2%, respectively) in Japanese women.^[40,41]

These potentially adverse mental health problems must be weighed against important gains in surveillance and in the relief given by a negative test result. With adequate screening, it is possible to identify pathogenic mutations in a significant subset of families. This identification can have marked clinical importance. Despite the limitations of genetic testing, it is important to remember that today there are people alive who would have died without genetic tests that alerted physicians to problems.^[45]

Using genetic testing to aid in contraceptive decisions for high-risk women ensures that oral contraceptive decisions are made while aware of known genetic risk factors. In some cases, genetic testing can enable a clinician to reassure a woman that their joint decision to protect her from ovarian cancer with oral contraceptives will not substantially increase her risk of breast cancer. In other cases, they may prevent oral contraceptives from promoting or initiating hereditary breast cancer. Testing Ashkenazi Jewish women for 3 founder mutations now permits clear health directives.^[14,46] This illustrates the promise of the method.

The BRCA1 Gene is Well Studied and Provides Examples of Current Technical Limitations of Genetic Testing

Both BRCA1 and BRCA2 genes are quite large, and their analysis can be technically demanding. More than 1700 mutations or polymorphisms have been identified in the coding regions of BRCA1 and BRCA2.^[47] As recently as December of 1997, 30% to 40% of disease-associated mutations were not identified in a Dutch population.^[48] Virtually all methods in current use are based on polymerase chain reaction and use primers that are closely flanked by exons. This means that if a deletion or rearrangement is heterozygous, it will be missed.

Almost all the data thus far are derived from white women. This raises the question of how valid it is to extrapolate results to women who are not classified as white.

Another major source of error in genetic tests for BRCA1 is the relative inability to discriminate between disease-causing mutations and genetic polymorphisms. The effect on function is not known for many of the almost 900 BRCA1 mutations, polymorphisms, and sequence variants and the incidence of cancer is undefined for many BRCA1 and BRCA2 gene mutations. There is also no method of measuring mutations in promoter or control regions of the gene. Although functional assays have been used to identify some disease-associated BRCA1 missense mutations, more extensive functional evaluations are needed. This raises the specter of a 30% to 40% error in counseling patients and requires the clinician to be aware of the limitations of the method.

Heterozygous ATM Mutations

Ataxia telangiectasia (AT) is a complex autosomal recessive gene disorder that causes progressive childhood ataxia, numerous chromosome breaks, and radiation sensitivity. Cancer develops in affected homozygotes at a rate about 100 times higher than in unaffected age-matched controls.^[49] About 1.4% to 2% of the population carries 1 inactive ATM allele.

There is some evidence that ATM carriers have an increased breast cancer risk.^[23] Recent models^[50-54] of how ATM and BRCA1/2 participate in the DNA damage response are consistent with this evidence. According to these models, ATM protein signals BRCA1 protein that DNA damage has occurred and that the cell should be stopped from dividing. Women who lose both ATM alleles in some cells thus lose this DNA damage signal. Oral contraceptives might act as tumor promoters or initiators by stimulating or initiating the cells that have lost their DNA damage signal. However, ATM mutations were not found in numerous breast tumors^[50] so the issue is not settled.

Genes For Which We Cannot Yet Test

DNA damage activates the DNA damage response - a vast network of biochemical events.^[51,52] Early on within this DNA damage response network, checkpoint pathways arrest the cell cycle so that damaged cells will stop growing and will not divide and replicate the damage. Other pathways in the DNA damage response network activate DNA repair, transcription, cell suicide (apoptosis), or they inhibit blood vessel development (angiogenesis).^[51-54]

There are at least 130 proteins involved in DNA repair alone and many more involved in other pathways within the DNA damage response. A mutation anywhere in this vast network could prevent an adequate response to DNA damage and enhance tumor growth. Because oral contraceptives may cause DNA damage (tumor initiators) and stimulate division of damaged cells (tumor promoters), a woman with a defect in her DNA damage response network may be more likely to develop cancer while taking oral contraceptives.

The redundancy of the network helps explain why cancer is a multistep process.^{[46,51,52,55]} Unfortunately, tests for most of the proteins in the DNA damage response network do not yet exist and there are as yet no hereditary cancers that correspond to an inherited deficiency of many member proteins. Nonetheless, further knowledge of the DNA damage response network promises better risk assessment.

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