Breast Cancer Risk Assessment And Genetic Testing

Early detection is considered the most effective tool available to fight against breast cancer. Enhanced public awareness in recent years has contributed significantly to the detection of small carcinomas which are associated with a better prognosis. In addition, remarkable efforts have been made to detect risk factors that will help to identify those women most likely to develop breast cancer and the genes that contribute to these risks.

Among various factors studied, age and gender plays an important role. The incidence of breast cancer increases with age and the rate is higher in the developed western world, i.e. North America and Northern Europe. Other risk factors include a personal history of prior breast cancer, family history of bilateral, premenopausal or familial cancer syndrome and atypical ductal hyperplasia, particularly if associated with family history.

Breast cancer occurs in both sporadic and inherited forms. However, only 5-10 % of cases are due to inheritance of germ line mutations in predisposing genes. A breast cancer susceptibility gene named BRCA1 has recently been discovered. It is localized to the chromosomal region 17q¹²-q²¹ on the long arm of chromosome 17. Shortly after this discovery, researcher announced the discovery of a second breast cancer gene, BRCA2, on the short arm of chromosome 13. In contrast to BRCA1, which is also responsible for a large proportion (more than 75%) of inherited predisposition to ovarian cancers, mutations in BRCA2 are found in at least one third of cases of familial breast cancer. This suggests that BRCA2, may also be an important breast cancer gene.

The identification of susceptibility genes in high-risk families can assist in risk estimation for genetic counseling and also serve as a guide in choosing candidates for clinical trials of breast cancer screening and chemopresentation.

Difficulty, however, remains in fostering the appropriate use of genetic testing in high-risk women and in educating the public. Since the discovery of breast cancer genes BRCA1 and BRCA2, there has been an explosion in media coverage fostered by the current public interest. It appears that the tremendous media coverage has led the public to believe that almost all breast cancer cases are related to inherited susceptibility. This is an important issue, since it has been already mentioned that 90-95% of breast cancer cases are sporadic in nature are not genetically determined.

In addition, as interest in cancer risk assessment and genetic testing grows, many assume that breast cancer risk assessment involves only genetic testing. This is compounded by the active marketing of biotech companies who benefit financially if large number of population are genetically screened. A greater concern is the issue of "conflict of interest" when some of the most respected clinical researchers in this area own stock options in the companies which are marketing the genetic testing.

In clinical practice, genetic testing is only one of the tools used to assess breast cancer risk. Many individuals concerned about their breast cancer risk will not benefit from genetic testing. The most important step, however, is the provision of the education and counseling required to help individuals make informed and responsible decisions about their health care.

Breast cancer risk assessment and counseling requires a comprehensive family history to assemble information about all the family members and their cancers and includes obtaining confirming records on affected relatives. To assess cancer risk, two approaches are used. One is pedigree analysis which can be done with or without genetic testing. The other approach is assessment of risk based on epidemiologic studies.

Hereditary breast cancer typically presents in a younger age group. The classic signs of hereditory breast cancer include a history of cancer in two or more relatives, typically through two or more generations, an increased incidence of bilateral cancers, multiple primary tumors and an autosomal dominant pattern of inheritance.

In hereditary breast cancer, screening high-risk families can play a significant role in reducing the mortality from cancer. This is achieved by a realistic assessment of an individual's hereditary risk and by empowering them in their pursuit of health-promoting activities and a participation in cancer screening guidelines.

Patient education is an important component of any cancer assessment program. It is important to realize that most individuals with a family history of breast cancer will not have an increased hereditary risk of this disease. Many will, however, benefit from risk analysis and a better understanding of their risk, compliance with screening guidelines, and what genetic susceptibility testing can offer.

Currently, testing for increased hereditary risk of breast cancer is commercially available for mutation in the genes BRCA1 and BRCA2. Aside from breast, families with BRCA1 mutation have increased risk of development of cancer of the ovary, colon, and prostate. BRCA2 mutations are associated with an increased risk of cancers which include male and female breast, ovary, fallopian tube, prostate, colon, esophagus and pancreas (Table 1).

Table 1: Breast Cancer Genes and Their Associated Risk
Genetic Alteration	Sex	Breast Cancer Risk	Other Cancer Risks
BRAC1	F	87%	Bilateral breast, ovarian and colon cancer
BRAC1	M	Negligible	Colon and prostate cancer
BRAC2	F	87%	Ovarian cancer
BRAC2	M	6% by age 70	Not known

Different BRCA1 and BRCA2 mutations appear and produce different cancer risk, however, neither the lifetime risk nor the type(s) of cancers can be predicted. In addition, not all of these mutations can be detected and an increase in hereditary risk can be due to mutation in genes not yet identified. Thus negative genetic testing cannot exclude the possibility of a genetic predisposition.

For genetic testing, an affected family member should be first tested for the presence or absence of a specific mutation. If no mutation is found in the affected member, there is no need to offer genetic testing to these unaffected family members, since the test results will not be informative. If a mutation is detected in an affected individual, then it is advisable to test the close unaffected family members for the presence or absence of the same mutation. If no mutation is found, the unaffected relative's risk is not increased due to the genes carried by the affected relative. Although the chances are less than those of the mutation carriers, these unaffected relatives can still develop breast cancer later in life.

Genetic testing is expensive and subject to controversy. Issues surrounding genetic testing involves discrimination in terms of insurability, as well as employability. Legislation is definitely needed to protect high-risk individuals from both insurance and employer discrimination based on the genetic information.

Genetic testing should be considered only if the results significantly change the decision of a high risk individual as far as prophylactic interventions are concerned. Proper measures should also be taken to assure that the high-risk individual understands the uncertain nature of the predicted risks as well as the associated consequences.

It is important to provide pre-test and post-test counseling, including test result interpretation to the patient. Psychosocial factors and personal beliefs about causes and prognosis of the illness must also be taken into account to provide relevant information to the patient that is understood. These factors can affect comprehension and response to risk information and influence the management decision of an individual.

Individuals at increased risk for breast cancer are currently offered the options of increased surveillance or prophylactic surgery. These individuals are also suitable candidates for chemoprevention as part of an approved research protocol.

It is not yet clear that prophylactic mastectomy will indeed reduce breast cancer mortality in high-risk individuals. It appears that the presence of mutation in the residual breast tissue following mastectomy, may ultimately lead to the development of breast cancer. Similarly, prophylactic oophrectomy does not guarantee protection from ovarian carcinoma since tumors may arise spontaneously in the peritoneal reflection. Furthermore, individuals from high-risk breast cancer families are well aware that breast examination and mammography may not detect pre-malignant lesions.

Considering the complexity of the unresolved issues, the intensity of the anxiety faced by the women in families likely to harbor mutated breast cancer gene must not go unrecognized. This is particularly important when recommending the genetic testing. As more scientific information becomes available, it remains the responsibility of physicians to educate their patients and make sure that they benefit from new discoveries.

Currently, women at risk are advised to undergo clinical breast examination and mammography every 6-12 months beginning between ages 25 and 35 years. The rational behind this recommendation is the preliminary reports is based in the literature that BRCA1 related tumors may have a faster growth rate than sporadic tumors. The option of prophylactic mastectomy is only supported in selected informed women after extended counseling. For a young women with a documented BRCA1 mutation, it is recommended to have pelvic examination with transvaginal ultrasound every 6-12 months. Prophylactic oophrectomy at the completion of childbearing or at the time of menopause remains a serious consideration for a high-risk woman.

Breast cancer risk assessment and genetic testing is still in its infancy and more years of experience and research are needed to mature the concepts. Until then, like a bridge between the science and the public, we the physicians must protect the interest of our patients, understand their concerns, and share our knowledge with them generously. Physicians should also play an important role in educating the media on the proper interpretation of scientific information and how best to present scientific discoveries to the public. We must foster the dignity of science and protect it from premature commercialization.

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Breast Cancer Risk Assessment And Genetic Testing

March, 1998/ Jacksonville Medicine