What’s my risk REALLY?

OBJECTIVES:
Our patients are knowledgeable and curious regarding their risk for breast and other hormone based cancers. Genetic risk is getting more and more public. We have an obligation to keep ourselves informed of all the recent trends and research in this area. We are not physicians and our obligation should be only in the area of informed discussion and referral to expert advice. I hope this article provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and ovarian cancer. This summary is intended to provide us with a framework for discussing genetic testing, screening, and risk modification options with individuals at risk for hereditary breast and ovarian cancer, as well as for making referrals to cancer risk counseling services. It does not provide formal guidelines or recommendations for making health care decisions.

What is Genetic Risk?
Among women, breast cancer is the most commonly diagnosed cancer after non-melanoma skin cancer, and is the second leading cause of cancer deaths after lung cancer. In 2007, an estimated 180,510 new cases will be diagnosed, and 40,910 deaths from breast cancer will occur. The incidence of breast cancer, particularly for estrogen receptor-positive cancers occurring after age 50 years, has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy following early reports from the Women’s Health Initiative. Ovarian cancer is the seventh most common cancer, with an estimated 22,430 new cases in 2007, but is the fourth most deadly, with an estimated 15,280 deaths in 2007. A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history and by the observation of rare families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with autosomal dominant inheritance of cancer susceptibility. Formal studies of families have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many cancer-prone families. Mutations in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.

Family History as a Risk Factor for Breast Cancer/Ovarian:
In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first or a second degree relative with breast cancer. The risk conferred by a family history of breast cancer has been assessed in both case-control and cohort studies, using volunteer and population-based samples, with generally consistent results. In a pooled analysis of 38 studies, the relative risk of breast cancer conferred by a first-degree relative with breast cancer was 2.1. Risk increases with the number of affected relatives and age at diagnosis. Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio (OR) of 3.1 for the risk of ovarian cancer associated with at least one first-degree relative with ovarian cancer.

Genetic Risk (Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition): Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:

• Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.
• Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition and shows no evidence of it can still pass the altered gene on to his sons and daughters.

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. Those most strongly associated with both cancers are BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 mutations; of Cowden syndrome due to PTEN mutations; and with mutations in CHEK2. Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia (AT) gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with Lynch Syndrome, basal cell nevus (Gorlin) syndrome (OMIM), and multiple endocrines. Mutations in each of these genes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.
The family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following:

• Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).
• Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast and ovarian cancer in the same individual).
• Cases of male breast cancer.
• Possible increased risk of other selected cancers and benign features for males and females.

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers with those occurring in none-carriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2/neu receptor-negative and have a basal phenotype. BRCA1-associated ovarian cancers are unlikely to be of mucinous or borderline histopathology.

Difficulties in Identifying a Family History of Breast and Ovarian Cancer Risk:
When using family history to assess risk, the accuracy and completeness of family history data must be taken into account. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain. When comparing self-reported information with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.

Are There Other Risk Factors for Breast Cancer?
Other risk factors for breast cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, alcohol intake, physical activity, anthropometric variables, and a history of benign breast disease. These factors are considered in more detail in numerous reviews, including among BRCA1/BRCA2 mutation carriers. Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer.

Age: Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years. In women with a genetic susceptibility, breast cancer, and to a lesser degree, ovarian cancer tends to occur at an earlier age than in sporadic cases.
Reproductive and menstrual history: Breast cancer risk increases with early menarche and late menopause, and is reduced by early first full-term pregnancy. Although results have been complex and may be gene dependent, several studies have suggested that the influence of these factors on risk in BRCA1/BRCA2 mutation carriers appear to be similar to non-carriers.

Oral contraceptives: Oral contraceptives may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with oral contraceptive use did not vary according to a family history of breast cancer. Oral contraceptives are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers, but studies of their effect on breast cancer risk have been inconsistent.

Hormone Replacement Therapy: Data exist from both observational and randomized clinical trials regarding the association between postmenopausal hormone replacement therapy (HRT) and breast cancer. A meta-analysis of data from 51 observational studies indicated a relative risk of breast cancer of 1.35 (95% CI, 1.21–1.49) for women who had used HRT for 5 or more years after menopause. The Women's Health Initiative (WHI), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined HRT or placebo, was halted early because health risks exceeded benefits. Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR = 1.24; 95% CI, 1.02–1.5, P <.001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women’s Study in the United Kingdom. The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR = 0.77; 95% CI, 0.59–1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk. The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors. The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk. The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has only been studied in the context of bilateral risk-reducing oophorectomy, where short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk. Radiation exposure: Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear. Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 and BRCA2 mutations, and in association with germ-line ATM and TP53 mutations. Since BRCA1/2 mutation carriers are heterozygotes, however, radiation sensitivity might occur only after a somatic mutation has damaged the normal copy of the gene. The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose carcinogenic risk. A cohort study of BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of mutation carriers. Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of mammography and chest x-ray exposure in BRCA1 and BRCA2 mutation carriers have had conflicting results.

Alcohol Intake: The risk of breast cancer increases by approximately 10% for each 10g of daily alcohol intake (approximately 1 drink or less) in the general population. One study of BRCA1/BRCA2 mutation carriers found no increased risk associated with alcohol consumption.
Physical Activity and Anthropometry: Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of pre-menopausal breast cancer. Sedentary lifestyle may also be a risk factor. These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing mutations, but one study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.
Benign breast disease and mammographic density: Benign breast disease is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer). There may also be an association between benign breast disease and family history of breast cancer. An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram, and breast density may have a genetic component to its etiology.

Other Factors: Other risk factors, including those that are only weakly associated with breast cancer and those that have been inconsistently associated with the disease in epidemiologic studies (e.g., cigarette smoking), may be important in subgroups of women defined according to genotype. For example, some studies have suggested that certain N-acetyl transferase may influence female smokers’ risk of developing breast cancer. One study found a reduced risk of breast cancer among BRCA1/2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.

CONCLUSIONS:
As we can plainly see, risk for developing breast cancer is a complicated and substantial subject. It is not as simple as seems. Genetic risks and markers for breast and ovarian cancers vary in type, severity and nature. The better we understand the subject the better equipped we are to advice and direct our ever curious patients.