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Hereditary breast and ovarian cancer
Hereditary Breast and Ovarian Cancer t has been estimated that 1% to 10% of all cancers arise in individuals carrying a germline mutation. Several cancer predisposing genes have been discovered, making it possible to identify high-risk subjects by means of specific genetic tests. Some of the hereditary cancer syndromes are of particular interest for the general population since they are associated with susceptibility to common cancer, such as breast and colon cancer. In particular, the recent discoveries of breast/ovarian cancer genes, has resulted in excellent experimental models for translation into the clinical practice setting in concert with molecular genetics, genetic counseling, and surveillance and management programs. On the other hand, the availability of commercial testing remarkably expanded the demand for genetic testing, requiring appropriate counseling to clarify potential benefits and limitations. The following hereditary syndromes have been detected involving female cancer: breast-ovarian cancer (HBOC) syndrome, in which breast and ovarian cancer (even in the same subject) occur in the family; site-specific breast cancer (HBC) syndrome, in which only (early-onset) breast cancer occurs; Lynch syndrome II or hereditary non-polyposis colon cancer (HNPCC), in which an excess of endometrial and ovarian cancer has been observed; site-specific ovarian cancer (HOC), in which only ovarian cancer occurs in the family.1 In 1990, Hall et al2 identified linkage of familial site-specific BC susceptibility to the D17S74 locus on chromosome 17q21. An international consortium studying linkage to HBOC subsequently reported that 45% of hereditary site-specific BC families3 and 92% of families with HBOC syndrome were linked to BRCA1.4 However, none of the families with male breast cancer was linked to BRCA1. The BRCA1 gene codes for a protein that appears to be involved in the regulation of gene expression,5 although the signals that influence BRCA1 activation and the downstream genes under the regulation of BRCA1 have not yet been identified. A second major breast cancer locus (BRCA2) was mapped to
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Curr Probl Cancer 2003;27:24-28. 0147-0272/2003/$35.00 ⫹ 0 56/1/120003 doi:10.1067/mcn.2003.120003
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Curr Probl Cancer, January/February 2003
TABLE 1. % Probability of detecting a BRCA1 mutation Families Average Age of BC ⬍35 35-39 40-49 50-59 ⬎59
BC only
BC & OC
BC ⴙ OC
Both
17 12 5-8 2-3 1
55 43 23-33 11-16 7
77 68 54-57 25-35 17
97 92 83-85 66-75 55
BC, breast cancer cases in the family; OC, ovarian cancer cases in the family; BC & OC, breast and ovarian cancer cases in the family; BC ⫹ OC, breast and ovarian cancer in the same family member; Both, both conditions above in the family.
TABLE 2. Risk for breast & ovarian cancer associated with BRCA1 and BRCA2 mutations Risk Estimate (by age 70) Neoplasm Breast Ovary (*)
Gene BRCA1 BRCA2 BRCA1 BRCA2
High-risk families
Pop. Studies
85% similar 44%(*) ⬍10%
69% 21% -
Mean value; Risk depending on the type of mutation.
chromosome 13q12-13 in 1994. Initial studies indicated that part of the families with evidence against linkage to the BRCA1 locus were linked to BRCA2. BRCA1 and BRCA2 mutations occur in only a limited proportion of all BC and OC, not exceeding 5% to 7%. The estimated low prevalence of cancer susceptibility germline mutations excludes the cost-effectiveness of a large-scale genetic screening. The probability of detecting a BRCA mutation depends on the age of disease onset, the bilaterality and/or multifocality of cancer (breast), the presence of OC in the pedigree, ranging from approximately 5% to 95% in BC ⫹/⫺ OC families (Table 1). The risk for BC and OC associated with a BRCA mutation is illustrated in Table 2. Different factors can contribute to variable penetrance: different mutations in the extent to which they predispose, other genetic loci may increase the penetrance, and gene environment interactions. Women who have inherited a germline mutation in BRCA1 or BRCA2 may explore options to reduce their cancer risk such as enhanced screening, chemoprevention, and prophylactic surgery. There is not yet evidence that highly targeted surveillance programs can significantly Curr Probl Cancer, January/February 2003
25
TABLE 3. BRCA families - suggested surveillance programme Monthly breast self-examination (from the age 18-20) Annual/semiannual clinical examination (from the age 25-30) Annual mammography (from the age 30-35) Annual/semiannual CA125 and TV sonography (⫹/⫺ color-doppler) (from the age 25-30) U.S. Cancer Gen. Studies Consortium, 1997
affect cancer incidence and survival. However, data are available on the effectiveness of mammographic screening in the general population aged ⬎50 years (with a delayed effect in the earlier age range, 40 to 50) and on the high level of specificity and positive predictive value of CA125 determination and transvaginal ultrasound (without, however, a sufficient cost/benefit ratio in a large-scale setting). Different surveillance studies are currently in progress in mutation carriers, and a suggested surveillance program is detailed in Table 3. Women with a BRCA mutation have a at least 20% lifetime risk of developing BC and/or OC, thus are suitable for a chemopreventative approach. The BC prevention trials on tamoxifen demonstrated a significant reduction of the incidence of invasive BC in all age and risk groups, including women with familial BC.6 More recently, a significant reduction of contralateral BC associated with tamoxifen use in BRCA1 and BRCA2 mutation carriers has been observed. Prophylactic surgery may be an option for women who are at increased BC and/or OC risk. Reductions of 45% and 20% in BC risk have been reported after bilateral prophylactic salpingo-oophorectomy (BPSO), respectively, before the age of 40 years7 and at the time of hysterectomy in premenopausal women.8 A 50% reduction in BC risk has been estimated after BPSO in women with BRCA1 mutations.9 Although the subsequent development of papillary serous carcinoma of peritoneum is possible, BPSO seems to ensure an approximately 95% protection against OC in this setting.10 Bilateral prophylactic mastectomy (BPM) is a mutilating surgery and should be performed only on medical grounds. The patient’s agreement is mandatory but at the same time is not a sufficiently strong reason for operating. Surgical techniques currently available do not completely eliminate the risk of subsequent cancer development (ranging from 1% to 20%) because they do not allow the complete removal of all breast tissue, especially if a subcutaneous mastectomy is performed. Proposed criteria for consideration of BPSO and BPM are listed in Tables 4 and 5. The use of oral contraceptives has been associated with decreased risk for OC not only in the general population but also in women with familial 26
Curr Probl Cancer, January/February 2003
TABLE 4. PBSO - proposed criteria for consideration -
Age ⱖ35 yrs BRCA1 (BRCA2) mutation carriers (ⱖ25% lifetime risk for OC) Life expectancy not significantly reduced by the presence of severe illness Surgical option discussed in a multidisciplinary setting (incl. psychological consultation) Information about incomplete protection from subsequent cancer development (PSCP) Laparoscopic approach recommended HRT proposed in premenopausal women (to age 50, then consider a SERM) Postsurgical psychological support offered
TABLE 5. Prophylactic mastectomy for individuals at genetic risk of BC - proposed criteria for consideration age ⬎30 years, ⬍50 years - BRCA1 or BRCA2 mutation carrier at high-risk of developing ovarian cancer (at least 50%, lifetime) - high levels of anxiety due to fear about impending breast cancer - woman’s life expectancy not significantly reduced by the presence of severe illness - although the definitive choice is strictly personal, the surgical option must be discussed in a multidisciplinary setting, including psychological and plastic surgery consultations - the candidate must be aware of the uncomplete protection from subsequent cancer development, and of possible complications, including sexual and psychological sideeffects - total bilateral mastectomy is the recommended technique with immediate plastic reconstruction - postsurgical appropriate psychological support is to be offered
OC and with ascertained BRCA1 or BRCA2 mutations.11-13 Although long-term hormone replacement therapy (HRT) is associated with an increased BC risk, recognizing that most BCs that occur in BRCA1 and BRCA2 mutation carriers are ER negative, we no longer strictly withhold HRT from well-informed women who have undergone BPSO, at least until the age of 50 years, after which a SERM should be considered.
Synopsis The role of genetics in virtually all forms of gynecologic cancer has received intense interest in both the research and clinical community during the past decade. This interest surged even further in light of the identification of the BRCA1 and BRCA2 genes and their ultimate cloning. Even though there is still a lack of well-designed populationbased studies able to define the actual incidence of BRCA-linked BC and OC, the possible identification of women at genetic high risk for BC/OC has represented an essential step toward a decrease in cancer mortality Curr Probl Cancer, January/February 2003
27
rates. There is a strong variability in penetrance and studies on genetic and environmental factors potentially affecting penetrance are in progress. To date, there is no clear evidence for a significant impact of any preventative strategy on cancer risk/mortality in this setting. Nevertheless, counseling on prevention measures is strongly requested by high-risk individuals, whereas data from controlled trials are expected to be available in the next few years. By now, it should be mandatory to treat such individuals at experienced counseling clinics, within IRB-supervised protocols. Increasing is the amount of data about chemoprevention and the inclusion of high-risk subjects in controlled trials should be encouraged. Prophylactic surgery has been shown to decrease cancer risk, but it is less than expected and should only be considered in specific conditions.
REFERENCES 1. 2. 3. 4. 5. 6.
7. 8. 9. 10.
11.
12. 13.
28
Lynch HT, Fitzsimmons ML, Conway TA, et al. Hereditary carcinoma of the ovary and associated cancers: a study of two families. Gynecol Oncol 1990;36:48. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset breast cancer to chromosome 17q21. Science 1990;250:1684. Easton DF, Bishop DT, Ford D, et al. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 1993;52:678. Narod SA, Ford D, Devilee P, et al. An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Am J Hum Genet 1995;56:254. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66. 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 1998;90:1371. Brinton LA, Schairer C, Hoover RN, et al. Menstrual factors and risk of ovarian cancer. Cancer Invest 1988;6:245. Parazzini F, Braga C, LaVecchia C, et al. Hysterectomy, oophorectomy and premenopause, and risk of breast cancer. Obstet Gynecol 1997;90:453. Tobacman JK. Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian cancer prone families. Lancet 1982;2:795. Rebbeck TR, Levin AM, Eisen A, et al. Reduction in breast cancer risk following bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst In press. Piver MS, Baker TR, Jishi MF, et al. Familial ovarian cancer: a report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991. Cancer 1993;71:582. Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339:424. Tavani A, Negri E, Franceschi S, et al. Risk factors for epithelial ovarian cancer in women under age 45. Eur J Cancer 1993;29A:1297.
Curr Probl Cancer, January/February 2003
I
Curr Probl Cancer 2003;27:24-28. 0147-0272/2003/$35.00 ⫹ 0 56/1/120003 doi:10.1067/mcn.2003.120003
24
Curr Probl Cancer, January/February 2003
TABLE 1. % Probability of detecting a BRCA1 mutation Families Average Age of BC ⬍35 35-39 40-49 50-59 ⬎59
BC only
BC & OC
BC ⴙ OC
Both
17 12 5-8 2-3 1
55 43 23-33 11-16 7
77 68 54-57 25-35 17
97 92 83-85 66-75 55
BC, breast cancer cases in the family; OC, ovarian cancer cases in the family; BC & OC, breast and ovarian cancer cases in the family; BC ⫹ OC, breast and ovarian cancer in the same family member; Both, both conditions above in the family.
TABLE 2. Risk for breast & ovarian cancer associated with BRCA1 and BRCA2 mutations Risk Estimate (by age 70) Neoplasm Breast Ovary (*)
Gene BRCA1 BRCA2 BRCA1 BRCA2
High-risk families
Pop. Studies
85% similar 44%(*) ⬍10%
69% 21% -
Mean value; Risk depending on the type of mutation.
chromosome 13q12-13 in 1994. Initial studies indicated that part of the families with evidence against linkage to the BRCA1 locus were linked to BRCA2. BRCA1 and BRCA2 mutations occur in only a limited proportion of all BC and OC, not exceeding 5% to 7%. The estimated low prevalence of cancer susceptibility germline mutations excludes the cost-effectiveness of a large-scale genetic screening. The probability of detecting a BRCA mutation depends on the age of disease onset, the bilaterality and/or multifocality of cancer (breast), the presence of OC in the pedigree, ranging from approximately 5% to 95% in BC ⫹/⫺ OC families (Table 1). The risk for BC and OC associated with a BRCA mutation is illustrated in Table 2. Different factors can contribute to variable penetrance: different mutations in the extent to which they predispose, other genetic loci may increase the penetrance, and gene environment interactions. Women who have inherited a germline mutation in BRCA1 or BRCA2 may explore options to reduce their cancer risk such as enhanced screening, chemoprevention, and prophylactic surgery. There is not yet evidence that highly targeted surveillance programs can significantly Curr Probl Cancer, January/February 2003
25
TABLE 3. BRCA families - suggested surveillance programme Monthly breast self-examination (from the age 18-20) Annual/semiannual clinical examination (from the age 25-30) Annual mammography (from the age 30-35) Annual/semiannual CA125 and TV sonography (⫹/⫺ color-doppler) (from the age 25-30) U.S. Cancer Gen. Studies Consortium, 1997
affect cancer incidence and survival. However, data are available on the effectiveness of mammographic screening in the general population aged ⬎50 years (with a delayed effect in the earlier age range, 40 to 50) and on the high level of specificity and positive predictive value of CA125 determination and transvaginal ultrasound (without, however, a sufficient cost/benefit ratio in a large-scale setting). Different surveillance studies are currently in progress in mutation carriers, and a suggested surveillance program is detailed in Table 3. Women with a BRCA mutation have a at least 20% lifetime risk of developing BC and/or OC, thus are suitable for a chemopreventative approach. The BC prevention trials on tamoxifen demonstrated a significant reduction of the incidence of invasive BC in all age and risk groups, including women with familial BC.6 More recently, a significant reduction of contralateral BC associated with tamoxifen use in BRCA1 and BRCA2 mutation carriers has been observed. Prophylactic surgery may be an option for women who are at increased BC and/or OC risk. Reductions of 45% and 20% in BC risk have been reported after bilateral prophylactic salpingo-oophorectomy (BPSO), respectively, before the age of 40 years7 and at the time of hysterectomy in premenopausal women.8 A 50% reduction in BC risk has been estimated after BPSO in women with BRCA1 mutations.9 Although the subsequent development of papillary serous carcinoma of peritoneum is possible, BPSO seems to ensure an approximately 95% protection against OC in this setting.10 Bilateral prophylactic mastectomy (BPM) is a mutilating surgery and should be performed only on medical grounds. The patient’s agreement is mandatory but at the same time is not a sufficiently strong reason for operating. Surgical techniques currently available do not completely eliminate the risk of subsequent cancer development (ranging from 1% to 20%) because they do not allow the complete removal of all breast tissue, especially if a subcutaneous mastectomy is performed. Proposed criteria for consideration of BPSO and BPM are listed in Tables 4 and 5. The use of oral contraceptives has been associated with decreased risk for OC not only in the general population but also in women with familial 26
Curr Probl Cancer, January/February 2003
TABLE 4. PBSO - proposed criteria for consideration -
Age ⱖ35 yrs BRCA1 (BRCA2) mutation carriers (ⱖ25% lifetime risk for OC) Life expectancy not significantly reduced by the presence of severe illness Surgical option discussed in a multidisciplinary setting (incl. psychological consultation) Information about incomplete protection from subsequent cancer development (PSCP) Laparoscopic approach recommended HRT proposed in premenopausal women (to age 50, then consider a SERM) Postsurgical psychological support offered
TABLE 5. Prophylactic mastectomy for individuals at genetic risk of BC - proposed criteria for consideration age ⬎30 years, ⬍50 years - BRCA1 or BRCA2 mutation carrier at high-risk of developing ovarian cancer (at least 50%, lifetime) - high levels of anxiety due to fear about impending breast cancer - woman’s life expectancy not significantly reduced by the presence of severe illness - although the definitive choice is strictly personal, the surgical option must be discussed in a multidisciplinary setting, including psychological and plastic surgery consultations - the candidate must be aware of the uncomplete protection from subsequent cancer development, and of possible complications, including sexual and psychological sideeffects - total bilateral mastectomy is the recommended technique with immediate plastic reconstruction - postsurgical appropriate psychological support is to be offered
OC and with ascertained BRCA1 or BRCA2 mutations.11-13 Although long-term hormone replacement therapy (HRT) is associated with an increased BC risk, recognizing that most BCs that occur in BRCA1 and BRCA2 mutation carriers are ER negative, we no longer strictly withhold HRT from well-informed women who have undergone BPSO, at least until the age of 50 years, after which a SERM should be considered.
Synopsis The role of genetics in virtually all forms of gynecologic cancer has received intense interest in both the research and clinical community during the past decade. This interest surged even further in light of the identification of the BRCA1 and BRCA2 genes and their ultimate cloning. Even though there is still a lack of well-designed populationbased studies able to define the actual incidence of BRCA-linked BC and OC, the possible identification of women at genetic high risk for BC/OC has represented an essential step toward a decrease in cancer mortality Curr Probl Cancer, January/February 2003
27
rates. There is a strong variability in penetrance and studies on genetic and environmental factors potentially affecting penetrance are in progress. To date, there is no clear evidence for a significant impact of any preventative strategy on cancer risk/mortality in this setting. Nevertheless, counseling on prevention measures is strongly requested by high-risk individuals, whereas data from controlled trials are expected to be available in the next few years. By now, it should be mandatory to treat such individuals at experienced counseling clinics, within IRB-supervised protocols. Increasing is the amount of data about chemoprevention and the inclusion of high-risk subjects in controlled trials should be encouraged. Prophylactic surgery has been shown to decrease cancer risk, but it is less than expected and should only be considered in specific conditions.
REFERENCES 1. 2. 3. 4. 5. 6.
7. 8. 9. 10.
11.
12. 13.
28
Lynch HT, Fitzsimmons ML, Conway TA, et al. Hereditary carcinoma of the ovary and associated cancers: a study of two families. Gynecol Oncol 1990;36:48. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset breast cancer to chromosome 17q21. Science 1990;250:1684. Easton DF, Bishop DT, Ford D, et al. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 1993;52:678. Narod SA, Ford D, Devilee P, et al. An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Am J Hum Genet 1995;56:254. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66. 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 1998;90:1371. Brinton LA, Schairer C, Hoover RN, et al. Menstrual factors and risk of ovarian cancer. Cancer Invest 1988;6:245. Parazzini F, Braga C, LaVecchia C, et al. Hysterectomy, oophorectomy and premenopause, and risk of breast cancer. Obstet Gynecol 1997;90:453. Tobacman JK. Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian cancer prone families. Lancet 1982;2:795. Rebbeck TR, Levin AM, Eisen A, et al. Reduction in breast cancer risk following bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst In press. Piver MS, Baker TR, Jishi MF, et al. Familial ovarian cancer: a report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991. Cancer 1993;71:582. Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339:424. Tavani A, Negri E, Franceschi S, et al. Risk factors for epithelial ovarian cancer in women under age 45. Eur J Cancer 1993;29A:1297.
Curr Probl Cancer, January/February 2003