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Risk of Breast and Ovarian Cancer in Women With Strong Family Histories

Risk of Breast and Ovarian Cancer in Women With Strong Family Histories

Assessing genetic risk for women with strong family histories of breast and ovarian cancers is becoming increasingly important in oncology and medical genetics as our understanding of the molecular basis of these cancers improves. Dr. Srivastava and coauthors outline some of the major features of genetic counseling for these malignancies. Many of these principles apply to genetic counseling in general and are not unique to women with an increased risk of breast and ovarian cancer. We encourage all physicians to inquire about family history on both the maternal and paternal sides and to refer any patient (woman or man) whom they suspect may be part of a familial syndrome for more specialized counseling.

Family History Issues

Defining what constitutes a strong family history is difficult, because many people today are members of small nuclear families or may not be in contact with relatives. Paternal transmission is often ignored in breast cancer risk assessments, but can be relevant in cases of paternal transmission where there may be no first-degree relative with breast or ovarian cancer. Therefore, the strongest indicator of a heritable syndrome of breast and ovarian cancers may be the presence of early-onset disease or multiple primary tumors within an individual.

Although the likelihood of finding a deleterious mutation in a susceptibility gene increases with the number of affected individuals in a family, mutations have been reported in patients who do not report any family history of breast or ovarian cancers. This may be due to numerous factors, including patients being unaware of family members’ medical conditions, as well as the presence of low-penetrance alleles of cancer susceptibility genes.

Translating Complex Data for Patients

Clinical encounters with patients seeking genetic testing are challenging in that a tremendous amount of sophisticated information must be conveyed in simple language to patients who are often anxious and may have limited previous education in genetics. Discussions with patients are based on the most complete and accurate family history that is attainable and include education in the major heritable predisposition syndromes, lifetime risk assessment, likelihood of finding a deleterious mutation, and an outline of risk-reducing options.

Obtaining the most accurate and complete family history is the key to risk assessment. All disease states or associated conditions should be noted and pathology reports should be used to substantiate cancer diagnoses. This latter recommendation is tedious, but exceedingly important since the family tree is used to decide the likelihood of a genetic predisposition as well as which individuals would be expected to be the most informative for genetic testing. Diagnoses in generations older than the patient seeking risk assessment tend to be the most vague, and confirmation is critical.

Multiple visits with numerous family members may be necessary to adequately explain the issues of chromosomal inheritance, predisposition genes, and subtleties within the field, such as the distinction between polymorphisms and mutations. Patients are often asked to reiterate what has been outlined for them, in an effort to ensure understanding. Patients may need to discuss these issues with their cancer care specialist, who should be knowledgeable about the complexities of genetic testing.

Flaws in Risk Hierarchy

Numerous hereditary syndromes, inherited in an autosomal dominant fashion predispose to the development of breast and ovarian cancers, and the responsible genes are known in most cases: breast/ovarian cancer syndrome (BRCA1/BRCA2); Cowden’s syndrome (PTEN); Peutz-Jeghers syndrome (LKB1/STK11); Muir-Torre syndrome (MSH2/MLH1); and Li-Fraumeni syndrome (TP53). Srivastava et al divide these syndromes into three categories (high, moderate, and low) based on the likelihood that the patient with that syndrome will develop breast or ovarian cancer. This simple categorization is misleading, however.

Mutations in genes such as PTEN confer a high risk but are variably penetrant, probably based on other modifying genes.[1] Therefore, to place these syndromes in such a hierarchy implies that patients with Cowden’s syndrome, for example, are at a lower risk for the development of breast cancer, compared to a woman with a BRCA2 mutation. However, depending on the specific mutation present within a family and the accompanying modifying genes within an individual, this may not be true. Therefore, hereditary syndromes that confer an increased risk of breast and ovarian cancer should be considered equally within families.

On the other hand, there are probably other genes with low-penetrant alleles that contribute to increased breast cancer risk in families. However, such genes should probably not be classified as "low-risk" genes. Assessment of risk should be made on an individual basis. One of the limitations of genetic testing at the present time is that we are only offering testing for coding region mutations in BRCA1 and BRCA2.

Limitations of Genetic Testing

Individual risk assessment for breast and ovarian cancers is a complex issue. Risk can be estimated in two ways. First, computer models exist to approximate the likelihood of a patient developing breast or ovarian cancer within her lifetime and to calculate the likelihood of a patient having a BRCA1 or BRCA2 mutation. Second, genetic testing can be performed to determine whether an individual carries a deleterious mutation in one of the genes known to predispose to breast and ovarian cancer.

The lifetime risk of a patient developing breast or ovarian cancer can be approximated using the Gail or Claus models, each of which is useful but has limitations (Figure 1).[2,3] The Gail model considers the following risk factors: age of onset of menarche, age at first birth, the number of first-degree relatives with breast cancer, and the number and outcomes of breast biopsies. The Gail model does not take into account ages at cancer diagnosis or relatives beyond the first degree (thereby almost assuredly neglecting paternal transmission of a mutation).

In contrast, the Claus model considers breast cancer cases within first- and second-degree relatives as well as ages at diagnosis, but may overestimate risk in nonmutation carriers. Figure 1 demonstrates an example in which the Gail and Claus models yield significantly different risk estimates. In clinical practice, both estimates can be helpful in counseling and should be calculated.

The likelihood that a patient carries a mutation in BRCA1 or BRCA2 can be estimated using the BRCAPRO[4,5] or Myriad models.[6] Variables considered in the BRCAPRO calculation include first- and second-degree relatives with breast/ovarian cancers, cancers in males vs females, ages at diagnosis, ethnicity, and family size. The Myriad model considers the extended family history, ages at diagnosis, and ethnicity. In general, these two models generate similar estimates and may be helpful in identifying patients who are likely to benefit from BRCA1/BRCA2 genetic testing, which now costs over $2,600.

Taken together, these two types of risk assessments are very important when counseling patients. Patients with strong family histories generally overestimate their risks of developing breast or ovarian cancers.[7] Providing these risk approximations for patients can significantly ease anxiety, may affect a patient’s decision to undergo testing for BRCA1/BRCA2 mutations, and/or may alter a patient’s perspectives on risk-reduction strategies. The most common reason patients are referred to our cancer risk clinic at the University of Chicago is to discuss options for risk reduction, especially as they approach menopause and have to decide on hormone replacement therapy.

Reducing the Risk for Breast and Ovarian Cancers

Options to decrease a patient’s risk of developing breast or ovarian cancer fall into three general categories: increased surveillance, chemoprevention, and prophylactic surgery. The first entails encouraging patients to perform a monthly breast self-examination and to undergo twice-yearly medical examinations and yearly mammography. In patients with strong family histories, screening mammography should begin 5 to 10 years prior to the age at which the youngest woman in the family was diagnosed with cancer, but probably not before age 25. Newer techniques for breast imaging, such as digital mammography, breast ultrasound, and magnetic resonance imaging, are modalities that are likely to become more frequently used in the coming years.[8]

Screening for ovarian cancer is more controversial, and therefore, when appropriate, patients should be encouraged to participate in clinical trials. For women known to carry a mutation in BRCA1 or BRCA2, a semiannual pelvic examination with transvaginal ultrasound is recommended. Some advise following a patient’s CA-125 level semiannually as well.

Women with strong family histories of breast cancer are candidates for chemoprevention. The use of oral contraception agents has been shown to be an effective prevention strategy in protecting women against ovarian cancer.[9-11] Tamoxifen (Nolvadex) reduces the risk of developing breast cancer in high-risk women by close to 50%, but the effect in BRCA carriers is unknown.[12] In addition, women who carry BRCA1 or BRCA2 mutations and have had breast cancer can decrease their risk of developing cancer in the contralateral breast by about 50% with 5 years of tamoxifen therapy.[13] Whether other selective estrogen-receptor modifying drugs will have similar effects is currently being tested. The Study of Tamoxifen and Raloxifene (STAR) is randomizing 22,000 high-risk postmenopausal women to either tamoxifen or raloxifene (Evista) and will follow them to determine which drug is more effective at preventing breast cancer.

Because patients with strong family histories tend to overestimate their risk of developing breast or ovarian cancers, they also tend to refuse estrogen-replacement therapy after menopause. However, the morbidity associated with estrogen depletion in postmenopausal women far outweighs the small increased cancer risk associated with hormone replacement therapy. Therefore, patients who are not considered at high risk after careful risk assessment should be encouraged to adopt effective strategies to reduce their risk of osteoporosis and cardiovascular disease because cardiovascular disease remains the leading cause of death for women after menopause.

Prophylactic surgery is the most radical option for women at increased risk due to strong family histories of breast and ovarian cancers. Most women who carry BRCA1 or BRCA2 mutations do not choose to undergo bilateral mastectomies, but those who do remain content with their decisions several years later.[14] For women who have completed their families, prophylactic oophrectomy almost entirely relieves them of the risk of ovarian cancer and significantly decreases their risk of breast cancer.[15]

Women who seek surgical consultations without having had comprehensive genetic counseling may benefit from hearing of their risks and options prior to undergoing surgery for many of the reasons outlined above. Before a woman undergoes prophylactic surgeries (without knowing the mutation status of her BRCA1 and BRCA2 genes), it is essential that she have a firm understanding of her quantitated risks.

Conclusions

Medicine today is becoming increasingly molecular in its diagnosis and treatment. Because of the numerous hereditary syndromes and known genes that predispose to the development of breast and ovarian cancers, women with strong family histories need to be identified and counseled by a multidisciplinary team. Their risks and options need to be outlined. Such women and families need to be encouraged to participate in clinical trials to evaluate the psychological implications of these diseases as well as our therapeutic interventions.

Genetic testing for cancer susceptibility is here to stay. Oncologists should now embrace the translation of these scientific advances to clinical care.

References

1. Lynch ED, Ostermeyer EA, Lee MK, et al: Inherited mutations in PTEN that are associated with breast cancer, Cowden’s disease, and juvenile polyposis. Am J Hum Genet 61:1254-1260, 1997.

2. Gail MH, Brinton LA, Byar DP, et al: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually [see comments]. J Natl Cancer Inst 81:1879-1886, 1989.

3. Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73:643-651, 1994.

4. Berry DA, Parmigiani G, Sanchez J, et al: Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst 89:227-238, 1997.

5. Parmigiani G, Berry D, Aguilar O: Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62:145-158, 1998.

6. Frank TS, Manley SA, Olopade OI, et al: Sequence analysis of BRCA1 and BRCA2: Correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 16:2417-2425, 1998.

7. Iglehart JD, Miron A, Rimer BK, et al: Overestimation of hereditary breast cancer risk. Ann Surg 228:375-384, 1998.

8. Kuhl CK, Schmutzler RK, Leutner CC, et al: Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: Preliminary results. Radiology 215:267-279, 2000.

9. Hankinson SE, Colditz GA, Hunter DJ, et al: A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstet Gynecol 80:708-714, 1992.

10. Gross TP, Schlesselman JJ: The estimated effect of oral contraceptive use on the cumulative risk of epithelial ovarian cancer. Obstet Gynecol 83:419-424, 1994.

11. Narod SA, Risch H, Moslehi R, et al: Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339:424-428, 1998.

12. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998.

13. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Hereditary Breast Cancer Clinical Study Group. [In process citation]. Lancet 356:1876-1881, 2000.

14. Schrag D, Kuntz KM, Garber JE, et al: Benefit of prophylactic mastectomy for women with BRCA1 or BRCA2 mutations. JAMA 283:3070-3072, 2000.

15. Rebbeck TR, Levin AM, Eisen A, et al: Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91:1475-1479, 1999.

 
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