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Ataxia-Telangiectasia A-T is an autosomal recessive condition that results in cerebellar ataxia, immune defects, telangiectasias, radiosensitivity, and a predisposition to malignancy, especially leukemia and lymphoma [ 37 ]. A-T is caused by mutations in the ATM gene, which is involved in maintaining genome stability [ 38 ]. Studies of obligate heterozygote carrier females have revealed a greater relative risk, of between five and seven times, for breast cancer. New breast cancer susceptibility genes are being reported that confer smaller breast cancer risks than those associated with mutations in BRCA1 and BRCA2.

A specific deletion in CHEK2 , delC, has been reported recently to result in a low-penetrance susceptibility to breast cancer and has also been identified in some families with both hereditary breast and colon cancer susceptibilities [ 44 — 46 ]. Vahteristo et al. From these data, Meijers-Heijboer et al. Offit et al. The carrier frequencies in both the healthy volunteers and the breast cancer cases were lower than those previously reported, 0.

The key to identifying women who are at risk for a hereditary predisposition to breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. It is imperative to ask about both the maternal and paternal family histories of cancer, given that most hereditary breast cancer predispositions are inherited in an autosomal dominant fashion and occur through both male and female transmission. Essential information includes the age at cancer diagnosis, type of cancer, age at death, relationship of the affected individual to the patient, and information about unaffected family members.

Family history is ever changing and should be updated often. Features suggestive of a hereditary predisposition to breast cancer. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus. Both models were generated from large population-based data sets and provide estimates of absolute lifetime breast cancer risk [ 52 , 53 ].

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The Gail model incorporates personal reproductive history, breast biopsy history, history of atypical hyperplasia, and the number of first-degree relatives mothers, sisters, or daughters diagnosed with breast cancer. The Gail model may underestimate the breast cancer risks for a woman from a hereditary breast cancer family and for a woman with a paternal family history of breast cancer.

The Claus model is based on family history and places emphasis on the age at breast cancer diagnosis. The model incorporates either a maternal or paternal family history first- and second-degree relatives. Unlike the Gail model, the Claus model cannot be used for a woman without a family history of breast cancer. The Gail model was used to determine eligibility for the Breast Cancer Prevention Trial BCPT [ 54 ] and is currently used to identify women who may benefit from chemoprevention with tamoxifen.

A more comprehensive review of these models has been published [ 12 ]. Women considering genetic testing for BRCA1 and BRCA2 mutations can be assessed using various published risk models that generate a pretest probability that an individual or family carries a deleterious mutation in either gene. Each model has strengths and weaknesses, but it is not within the scope of this paper to review each in detail.

The reader is referred to Domchek et al. Genetic testing is available at selected laboratories for each of the hereditary syndromes described herein. It generally consists of gene sequencing, but testing for ATM heterozygosity is not routinely done in the absence of a family history of A-T.

The ASCO recognizes that clinicians must be informed of the range of issues involved in genetic testing for cancer risk and believes that physicians who offer genetic testing should be aware of the benefits and limits of current testing procedures and the range of prevention and treatment options available to patients and their families. ASCO principles for genetic risk assessment [ 59 , 60 ].

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Whenever predisposition testing is done, pre- and posttest counseling should discuss possible risks and benefits of cancer early detection and prevention modalities, which have presumed, but unproven, benefits for individuals at the highest hereditary risk for cancer. All individuals at hereditary risk for cancer should have access to appropriate genetic testing and associated medical care, which should be covered by public and private third-party payers.

There should also be continued support of patient-oriented research to analyze the psychological impact of genetic testing of at-risk populations. Pretest and posttest counseling, including informed consent, are considered critical elements of the testing process [ 59 ]. Patients pursuing genetic testing are informed that choosing to be tested is a very personal decision that has the potential to change the way they think about themselves and the way they interact with their families.

It is important to encourage patients to think about how the information may affect them and to ask them to consider how they wish to use the information once it is available.


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Testing an individual who has been diagnosed with cancer provides the most information because not all hereditary breast cancer is accounted for by the genes presently known and because current technology is not able to detect all gene mutations. Patients should be informed of the benefits, limitations, and costs of genetic testing.

How are genetic conditions treated or managed? - Genetics Home Reference - NIH

There are three possible test outcomes that are described below by focusing on testing for BRCA1 and BRCA2 mutations, given that this testing is now the most common in clinical practice. This result confirms a greater risk for developing breast or ovarian cancer and may allow the patient, together with her physicians, to develop a medical management plan that is best suited to her needs.

A positive result also has implications for other family members. Members of the affected branch of the family have varying risks of carrying the familial mutation, which depend upon their relationship to the affected individual. Patients receiving a positive test result are strongly encouraged to share their test results with their extended family, in the event that other family members wish to be tested.

Testing for a known familial mutation is much less expensive than full gene sequencing, and the results are easily interpreted. A negative result indicates that no deleterious mutations were identified in either BRCA1 or BRCA2 , but the interpretation of a negative test result is dependent upon the specific case scenario, as described below. If a genetic mutation has been identified previously within the family, and the patient receives a negative result, the result is considered a true negative, meaning that the patient did not inherit the known familial mutation.

Due to limitations in current technology, the result does not exclude the possibility that a mutation still exists in the gene, nor does the result exclude the possibility of a mutation in a different cancer susceptibility gene [ 2 ]. The level of residual risk faced by the patient is dependent upon the strength of her personal and family histories of cancer. For those women who have family histories of cancer that reflect an autosomal dominant predisposition family history of breast and ovarian cancer , the negative result could mean that their cancer occurred sporadically.

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Without the identification of a mutation in another affected family member, however, the negative test result does not rule out the possibility of a hereditary predisposition. Thus, the woman may still be at significant risk to develop another breast cancer and perhaps ovarian cancer. For a woman whose family history of cancer is less striking few affected females with no ovarian cancer history , the majority of the risk for a hereditary breast cancer predisposition is excluded through the testing, and her risk for another breast cancer or ovarian cancer would be similar to that of other women with the disease.

Those unaffected women who test negative for a BRCA1 or BRCA2 genetic mutation have ruled out the majority of their risk for harboring a genetic mutation, but the meaning of this result cannot be interpreted completely in the absence of a known family mutation.

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Clarification of the results might be possible if an affected family member was tested and found to carry a deleterious mutation. This may be a good situation in which to use the Claus model for breast cancer risk assessment [ 52 ]. This result usually refers to a missense mutation that is a substitution of one amino acid for another. Missense mutations do not result in the truncation of the protein product, they may or may not occur in the coding regions of the gene, and they may or may not affect the function of the gene product. Without a functional assay to determine the implication of each gene change, the interpretation of the variant result is dependent upon clinical observation.

If the variant does not track with the cancer in the family or if it has been inherited from the side of the family without a history of cancer, it may be of less concern clinically.


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If the BRCA1 variant was previously identified in conjunction with a known deleterious BRCA1 mutation, then the variant is less likely to be of clinical significance, based on an animal model suggesting that BRCA1 deficiency is lethal at the embryo stage [ 61 ]. BRCA2 homozygosity has been reported to cause Fanconi anemia, therefore a BRCA2 variant that has been previously identified in conjunction with a known deleterious BRCA2 mutation is less likely to be the cause of the breast cancer history [ 62 ].

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Unfortunately, the meaning of a variant result is frequently unclear, which makes it difficult to comment on its contribution to cancer risk. A variant result is frustrating to both the patient and the health care provider, and genetic testing for the variant in other unaffected family members is generally not recommended, as the results are not of use in guiding medical management. Each option is considered separately below. Hartmann and her colleagues conducted a retrospective study of all women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at the Mayo Clinic between and [ 63 ].

The women were divided into two groups on the basis of family history: those women considered to be at high risk and those at moderate risk. A control study of the sisters of the high-risk probands and the Gail model were used to predict the number of breast cancers expected in these two groups in the absence of prophylactic mastectomy. Among these families, there were women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy: at high risk and at moderate risk.

What is genetic counseling and how do I know if I need it?

The median length of follow-up was 14 years, and the median age at prophylactic mastectomy was 42 years. According to the Gail model, The investigators of that study also compared the number of breast cancers among the high-risk probands with the number among their sisters who had not undergone prophylactic mastectomy. Of the sisters, By contrast, breast cancer was diagnosed in 1. A smaller study, which examined the benefit of prophylactic mastectomy in carriers of genetic mutations that predispose women to develop invasive breast cancer, also showed benefit, but the number of individuals studied was small and the median follow-up time was only 3 years [ 64 ].

Based on these studies, women with greater risks for breast cancer may be offered prophylactic mastectomy as a validated management option. Adequate consideration of the physical and psychological consequences must be provided through presurgical counseling. The finding of a lower contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention.

All endometrial cancers in the tamoxifen group were stage I localized disease ; no endometrial cancer deaths have occurred in this group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were higher in the tamoxifen group. Despite these side effects, using tamoxifen as a preventive agent is appropriate in many women with greater risks for the disease, especially those women with a history of lobular carcinoma in situ or atypical ductal or lobular hyperplasia.

In particular, the absolute risks from tamoxifen of endometrial cancer, stroke, pulmonary embolism, and deep vein thrombosis increase with age, as does the protective effect of tamoxifen on fractures. Tamoxifen is most beneficial for younger women with an elevated risk of breast cancer.