- Email: [email protected]
The breast surgeon’s role in BRCA1 and BRCA2 testing
The Breast Surgeon’s Role in BRCA1 and BRCA2 Testing Ellen T. Matloff, MS
Five percent to 10% of all women who develop breast cancer carry a hereditary mutation in the genes BRCA1 or BRCA2. Genetic testing is now clinically available, and the results of such testing can dramatically alter a patient’s risks for an ipsilateral or contralateral primary breast cancer and ovarian cancer. Therefore, genetic testing will become integral in tailoring surveillance, chemoprevention, and surgical management plans for patients at risk for hereditary cancer syndromes. Such results will also impact the cancer risks for the patient’s nuclear and extended family members. Surgeons will play a pivotal role in eliciting personal and family histories from patients, determining which of those histories is suggestive of a germline mutation, facilitating referrals for genetic counseling and testing, and incorporating the results of genetic testing into the patient’s short- and long-term management plans. Am J Surg. 2000;180:294 – 298. © 2000 by Excerpta Medica, Inc.
S
urgeons have long recognized that a subset of their patient population is at increased risk to develop breast cancer based on a strong family history of the disease. Informal risk assessments based on family histories have guided surgical recommendations for surveillance, biopsy, and oral contraceptive and hormone replacement usage. In fact, before the advent of genetic testing, women and their surgeons were forced to make decisions about prophylactic surgery based solely on the family history, without specific information about the patient’s personal risk to develop the disease.
BRCA1 AND BRCA2 Genetic counseling and testing have made more definitive risk assessment possible. Approximately 7% to 10% of all breast cancers are attributable to mutations within a cancer susceptibility gene.1 Most hereditary breast cancer is caused by deleterious mutations in the breast/ovarian cancer susceptibility genes, BRCA1 (breast cancer-1) and
From the Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. Requests for reprints should be addressed to Ellen T. Matloff, MS, Associate Research Scientist, Genetics, Director, Cancer Genetic Counseling, Yale Cancer Center/Yale School of Medicine, 333 Cedar Street, Box 208028, New Haven, Connecticut 06520-8028. Presented at the Annual Meeting of the American Society of Breast Surgeons, Charleston, South Carolina, April 13–16, 2000. Manuscript submitted May 19, 2000 and accepted in revised form June 25, 2000.
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© 2000 by Excerpta Medica, Inc. All rights reserved.
BRCA2 (breast cancer-2). The cloning of BRCA1 and BRCA22,3 has made clinically based testing a reality over the past 5 years. The cancer risks observed in women who carry BRCA1 or BRCA2 mutations have been the subject of some debate. Early studies performed on high-risk families revealed that the risk for female mutation carriers to develop breast cancer by age 70 was 87%, and that the risk to develop ovarian cancer was 60%.4 More recent studies performed in populations selected by Jewish ancestry alone, regardless of cancer history, have revealed lower cancer risks in BRCA carriers.5 It is most accurate to present mutation carriers with a range of cancer risk.6 This range for female carriers is likely 50% to 85% for breast cancer, and 15% to 60% for ovarian cancer by age 70 years.3–9 Because hereditary BRCA1 and BRCA2 mutations are germline, versus sporadic, mutations, they are present from conception and are found in most cells of the body. Each of the cells in the breast and ovarian tissue are therefore predisposed to become cancerous. The risk of bilateral breast cancer is increased in carriers,10 and has been estimated to be as great as 64% in BRCA1 mutation carriers diagnosed with their first breast cancer by the age of sixty.4 Male carriers of BRCA1 and BRCA2 carriers are at slightly increased risk to develop prostate cancer,4,5 and male BRCA2 carriers have an increased lifetime risk of developing breast cancer.8 The lifetime risk of pancreatic cancer also appears to be increased among BRCA2 carriers.11 Both of the BRCA genes are passed down in families in an autosomal dominant pattern of inheritance; therefore, mutation carriers have a 50% chance of passing the mutation on with each pregnancy. People who do not inherit the mutation are not at risk to pass on the mutation to their children. The BRCA genes are not sex-linked, meaning that mutations are passed on to, and by, men and women with equal frequency. This means that when eliciting a history, both maternal and paternal histories must be assessed.
RISK ASSESSMENT Risk assessment is a complicated process that has evolved over time. Early risk models set precise guidelines of the number of affected first- or second-degree relatives needed to determine a family’s eligibility for testing. It is now clear that these models are not realistic in most small- to medium-size families, and that clinicians must examine each family individually for the relevant risk factors. There are six risk factors that are common among hereditary cancer families (Table I). The first is early age of breast cancer onset. This risk factor, even in the absence of a family history, has been shown to be associated with an increased frequency of BRCA mutations.12–14 The second risk factor is the presence of the same cancer in multiple affected 0002-9610/00/$–see front matter PII S0002-9610(00)00460-8
BREAST SURGEON’S ROLE IN GENETIC TESTING/MATLOFF
TABLE I
TABLE II Risks Factors for BRCA1/BRCA2
Genetic Counseling and Testing Resources
1. Early age of onset 2. Presence of the same cancer in multiple family members on the same side of the pedigree 3. The presence of breast and ovarian cancer in the same family 4. Multiple primary cancers in one individual 5. Jewish ancestry 6. Breast cancer in a male
CancerNet (800) 4-CANCER http://cancernet.nci.nih.gov/wwwprot/genetic/genesrch.shtml A free service designed to locate providers of cancer risk counseling and testing services, both in the context of research and clinical fee-for-service programs. GeneTests: Genetic Testing Resource (206) 527-5742 http://www.genetests.org Offers current information on testing availability for specific conditions, and sites that offer such testing. Includes resources for DNA banking. National Society of Genetic Counselors (610) 872-7608 http://www.nsgc.org For a listing of genetic counselors in your area who specialize in cancer.
Figure 1. A 42-year-old woman presents with a large, unilateral breast cancer. She is opting for unilateral mastectomy with immediate reconstruction via a TRAM flap. Her surgeon takes a family history and learns that in addition to her patient’s earlyonset breast cancer, there is a history of Jewish ancestry and a male cousin diagnosed with breast cancer. The surgeon refers the patient to genetic counseling, and the patient elects genetic testing for the three common Jewish BRCA mutations. The results reveal that the patient carries the common Jewish BRCA2 mutation. Upon learning of the increased risks for a contralateral primary, the patient and her surgeon decide upon bilateral mastectomy with bilateral reconstruction via TRAM flap.
relatives on the same side of the pedigree. These cancers do not necessarily have to be of similar histologic type in order to be caused by a single mutation. The third risk factor is the presence of both breast and ovarian cancer in the same family. Age of onset of ovarian cancer is not a factor. The fourth risk factor is the occurrence of multiple primary cancers in one individual. Ethnicity also plays a role in determining who is at greatest risk to carry a hereditary cancer mutation. Individuals of Jewish ancestry are at increased risk to carry three specific BRCA mutations.5 The final risk factor for hereditary breast cancer is the presence of a male breast cancer in the family (Figure 1). These risk factors should be viewed in the context of the entire family history, and must be weighed in proportion to the number of individuals who have not developed cancer.
GENETIC TESTING Genetic testing should always be preceded by in-depth genetic counseling, which covers the risks, benefits, and limitations of testing as well as the options for surveillance and risk reduction in those who test positive (Table II). Testing can be performed on peripheral blood, a buccal
smear (cheek-brush sample), or a tissue block; however, most commercial labs prefer peripheral blood samples. The price of testing can range in price from $330 for the three most common mutations found in Ashkenazi Jews, to $2600 for full sequencing of both BRCA1 and BRCA2. Turnaround time varies from 2 to 14 weeks depending on the test ordered and the laboratory used. Informative testing is only possible when the mutation in the family has been pinpointed. It is therefore optimal to first test the person in the family most likely to carry a mutation. This person is almost always an affected family member. Stored tissue blocks from deceased, affected relatives may sometimes be tested for this reason, although such testing is more expensive and more difficult than testing of peripheral blood. Once the mutation in the family is established, other unaffected relatives can be tested for the same mutation with ⬎99% accuracy. If unaffected family members test negative for the mutation in their family, their result is interpreted as a “true negative” (Figure 2). The breast and ovarian cancer risks for a true negative are that of the general population. If no mutation is found in the affected family member, the result must be deemed uninformative. Unaffected members of these families should assume they are at increased risk and their surveillance and/or risk reduction program should be planned accordingly. It is impossible to determine whether a negative result in such a case means that (a) there is simply another undetectable mutation in the family, (b) the patient has not inherited the mutation in the family, and is a true negative or (c) the cancers in the family are not hereditary. It is critical to avoid misinterpretation of such results. In high-risk families in which DNA testing is uninformative, the option of DNA banking should be recommended (Table II). This will allow for future testing when more breast cancer susceptibility genes are known.
SURGICAL IMPLICATIONS Data showing that lumpectomy/radiation and total mastectomy provide the same degree of disease-free survival15 have had a major impact on breast surgical decision-mak-
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Figure 2. A healthy 40-year-old woman is followed by her breast surgeon owing to her strong family history of breast and ovarian cancer. The patient’s mother was diagnosed with breast cancer at age 44 and died later that year. The patient’s maternal aunt was diagnosed with breast cancer at age 45 and ovarian cancer at age 51, dying 1 year later. The patient is extremely anxious about her breast cancer risks and wants a prophylactic bilateral mastectomy and oophorectomy. Her surgeon refers the patient for genetic counseling. Because no tissue blocks are available on either deceased affected relative, the patient is offered testing for the three common Jewish BRCA mutations. The patient is found to be negative. This result cannot be interpreted as a “true negative” because the mutation in the family has not been identified. At this point, the result is deemed uninformative. Three months later, the patient’s brother agrees to have genetic testing, as he has a 23-year-old daughter who would be affected by his carrier status. The brother is found to carry one of the common Jewish BRCA1 mutations. The original patient in this family can now be interpreted as a “true negative” because the mutation in the family is now known. This patient’s risks for breast and ovarian cancer are reduced to that of the general population.
ing. Breast-conserving surgery is an attractive option to patients and their physicians, and is often preferred over total mastectomy. It is well known that breast cancer survivors are at increased risk for cancer in the contralateral breast.16 –19 Perhaps less recognized is that breast cancer survivors who have a personal or family history suggestive of a hereditary breast cancer syndrome have a greater risk of contralateral breast cancer than does the average breast cancer patient.20 Recent data have suggested that carriers of BRCA mutations are also at increased risk for multiple ipsilateral primaries.21 This is theoretically quite likely since these mutations are present in every breast cell. This information could obviously have a great impact on surgical decisionmaking. A BRCA carrier who learns that she is at increased risk for a second ipsilateral tumor in remaining breast tissue may opt for total mastectomy instead of lumpectomy. In fact, some women in this position may choose immediate bilateral mastectomy with or without reconstruction. The timing of this decision would be espe296
cially critical in women who choose transverse rectus abdominis myocutaneous (TRAM) flap as their method of reconstruction, as this procedure can be performed only one time (Figure 1). Although prophylactic mastectomy does not reduce the risk of breast cancer to zero,22–23 it is currently the most effective method of breast cancer risk reduction. The efficacy of this procedure has been shown to be greater than 90% in women at high risk to develop the disease, based on their family history.23 A recent follow-up study of women with strong family histories who elected bilateral prophylactic mastectomy showed that none of the known BRCA1 or BRCA2 mutation carriers in the sample have developed breast cancer thus far.24 These data provide reassuring evidence that prophylactic mastectomy is an effective method to reduce breast cancer risk, even in BRCA1/2 carriers. Prophylactic mastectomy should not be offered to healthy women (in the absence of personal risk factors, such as LCIS) with a family history of the disease until they have first been offered genetic counseling and testing to learn if they have inherited the mutation found in their family. Studies suggest that the minority of carriers intend to have their breasts removed prophylactically.25 Women at increased risk to carry a breast cancer susceptibility gene must understand that prophylactic mastectomy is not their only option. Chemoprevention is an exciting new option for women at increased risk to develop breast cancer. Tamoxifen has been shown to reduce the risk of invasive breast cancer by 49% in healthy women at increased risk to develop the disease.26 The efficacy of tamoxifen in women who carry BRCA1 or BRCA2 mutations is currently unknown, although these data should be available from the NSABP P-1 trial within the next few years. Because a greater proportion of tumors found in BRCA1 mutation carriers appear to be estrogen-receptor negative,27 it is premature to conclude that tamoxifen will have equal success in this population. However, it is quite possible that tamoxifen, or other selective estrogen-receptor modulators (such as raloxifene) will have a role in risk reduction in BRCA carriers (Figure 3). Even if high-risk women are not interested in prophylactic mastectomy or chemoprevention, they are still candidates for genetic counseling. During genetic counseling they will learn their risks for other cancers, their options for increased surveillance, and the risks to their family members. Surgeons can play a central role in developing surveillance plans for women at high risk for breast cancer. Recommended screening can begin as early as age 25 years and may include annual mammography; clinician breast examinations annually or semiannually; breast self-examination education; and monthly breast self-examinations.28 Clinical breast examinations and mammography can be spaced out around the calendar year so that women are receiving some sort of intervention every 4 months.
OTHER CANCER RISKS Many women do not realize that their family history of breast cancer may also put them at increased risk for ovarian cancer, or vice versa. The risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers is between 15% and 60% by age 70,4 –9 even in families in which only breast
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SURGEON’S ROLE IN GENETIC TESTING
Figure 3. A 60-year-old woman was diagnosed with unilateral breast cancer at age 51 and was successfully treated with lumpectomy and radiation. Her tumor was estrogen-receptor negative and she was not offered tamoxifen. The patient presents to her surgeon for her annual check-up and reveals that her maternal first cousin has just been diagnosed with ovarian cancer. The surgeon urges the patient to explore the family history in greater depth, and the patient learns that a maternal aunt also died of ovarian cancer. The patient is offered genetic counseling and testing and learns that she carries a BRCA1 mutation. After discussions with her surgeon and the genetics team, the patient elects to have a prophylactic hysterectomy and bilateral salpingo-oophorectomy and to go on tamoxifen in hopes of reducing her risk of a second breast primary.
cancer has been observed thus far. The rates of early detection and successful treatment are low in women who develop ovarian cancer. One option available to mutation carriers for reducing the risk of ovarian cancer is prophylactic oophorectomy. This procedure is not 100% effective in preventing intra-abdominal carcinomatosis that histologically resembles ovarian cancer,29 but appears to reduce the risk substantially.30 This procedure is not ideal in premenopausal women owing to loss of fertility and immediate surgical menopause. Women who have their ovaries removed and do not take hormone replacement therapy are at increased risk to develop osteoporosis and heart disease.31,32 These women are also at risk for menopausal symptoms, including vasomotor and gynecologic symptoms, depression, and sleep disturbance. A recent study demonstrated that prophylactic oophorectomy in BRCA1 carriers reduces their risk of future breast cancer, even in those women who take hormone replacement therapy.33 However, HRT use in women who have had, or are at increased risk for breast cancer, is controversial.31 A less-invasive option for premenopausal BRCA carriers is to use oral contraceptives to reduce their risk of ovarian cancer. Use of oral contraceptives has been shown to significantly reduce the risk of ovarian cancer in BRCA1 carriers.34 Again, the use of exogenous estrogen in women at increased risk to develop breast cancer is controversial. However, it is possible that, given the likelihood of mortality from ovarian versus breast cancer, a risk/benefit analysis would favor the use of oral contraceptives in carriers of BRCA mutations.35
Genetic counseling and testing have already begun to have a major impact on surgical decision-making for breast cancer. Women diagnosed with breast cancer may seek genetic testing before choosing between lumpectomy and mastectomy, or even bilateral mastectomy. Genetic test results can influence decision-making for adjuvant tamoxifen, oophorectomy, or even chemotherapy. It is quite possible that in the future all patients, even those without a family history of the disease, will be offered a broad genetic screen for germline mutations that will help guide their physicians in choosing the most appropriate and effective treatment plan for that patient. Many surgeons do not have the time or the specialized training required to provide patients with the detailed genetic counseling, result interpretation, psychological support, and long-term follow-up that must be part of the genetic testing process.36 However, surgeons will play a central role in genetic testing by eliciting detailed histories from their patients and choosing the subset that should be referred for genetic counseling. Surgeons will also need to interpret the test results and integrate them into short- and long-term management plans for their patients. It is quite possible that in the future genetic testing will be one of the surgeon’s most valuable instruments in the treatment of breast cancer.36
REFERENCES 1. Claus EB, Schildkraut JM, Thompson WD, et al. The genetic attributable risk of breast and ovarian cancer. Cancer. 1996;77: 2318 –2324. 2. 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 –71. 3. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789 – 792. 4. Ford D, Easton DF, Bishop DT, et al. Risks of cancer in BRCA1mutation carriers. Lancet. 1994;343:692– 695. 5. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashenazi jews. NEJM. 1997;336:1401–1408. 6. Matloff ET, Peshkin BN. Complexities in cancer genetic counseling: breast and ovarian cancer. PPO Updates. 1998;12(1): 1–11. 7. Easton DF, Ford D, Bishop T, et al. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Am J Hum Genetics. 1995; 56:265–271. 8. Easton DF, Steele L, Fields P, et al. Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. Am J Hum Genetics. 1997;61:120 –128. 9. Phelan CM, Lancaster JM, Tonin P, et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nature Genetics. 1996;13:120 –122. 10. Weber BL, Garber JE. Familial breast cancer: recent advances. In: Harris JR, Lippman ME, eds. Diseases of the Breast Updates. Vol 1, no 1. Philadelphia: Lippincott-Raven; 1997:1–19. 11. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91:1310 –1316. 12. FitzGerald MG, MacDonald DJ, Krainer M, et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with earlyonset breast cancer. NEJM. 1996;334:143–149. 13. Langston AA, Malone KE, Thompson JD, et al. BRCA1 mu-
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tations in a population-based sample of young women with breast cancer. NEJM. 1996;334:137–142. 14. Krainer M, Silva-Arrieta S, FitzGerald MG, et al. Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer. NEJM. 1997;336:1416 –1421. 15. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst. 1996;88:1529 –1542. 16. Nemecek JR, Young L, Lopez MJ. Indications for prophylactic mastectomy. Missouri Med. 1993;90(3):136 –140. 17. Robbins GF, Berg JW. Bilateral primary breast cancers. Cancer. 1964;17:1501–1527. 18. Adair F, Berg J, Jourbert L, et al. Long-term follow-up of breast cancer patients: the 30-year report. Cancer. 1974;33:1145–1150. 19. Hayes DF, Kaplan W. Evaluation of patients after primary therapy. In: Lippman ME, Morrow M, Hellman S, eds. Diseases of the Breast. Philadelphia: Lippincott-Raven; 1996;629 – 643. 20. Harris RE, Lynch HT, Guirgis HA. Familial breast cancer: risk to the contralateral breast. J Natl Cancer Inst. 1978;60:955–960. 21. Turner BC, Harold E, Matloff E, et al. BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations. J Clin Oncol. 1999;17:3017–3024. 22. Bilimoria MM, Morrow M. The woman at increased risk for breast cancer: evaluation and management strategies. Ca Cancer J Clin. 1995;45:263–278. 23. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. NEJM. 1999;340:77– 84. 24. Hartmann LC, Schaid D, Sellers T, et al. Bilateral prophylactic mastectomy (PM) in BRCA1/2 mutation carriers. Proc Am Assoc Cancer Res. 2000;41:1417. Abstract. 25. Lerman C, Narod S, Schulman K, et al. BRCA1 testing in families with hereditary breast-ovarian cancer: a prospective study of patient decision making and outcomes. JAMA. 1996;275:1885– 1892.
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26. Fisher B, Costantino JP, Wickerman DL, et al. Tamoxifen for the prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;90:1371–1388. 27. Karp SE, Tonin PN, Begin LR, et al. Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women. Cancer. 1997;80:435– 441. 28. Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer: II. BRCA1 and BRCA2. JAMA. 1997;277:997–1003. 29. Streuwing JP, Watson P, Easton DF, et al. Prophylactic oophorectomy in inherited breast/ovarian cancer families. JNCI Monographs. 1995;17:33–35. 30. Piver MS, Jishi MF, Tsukada Y, et al. Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer: a report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer. 1993;71:2751–2755. 31. Roy JA, Sawka CA, Pritchard KI. Hormone replacement therapy in women with breast cancer: do the risks outweigh the benefits? J Clin Oncol. 1996;14:997–1006. 32. King M, Rowell S, Love SM. Inherited breast and ovarian cancer: what are the risks? what are the choices? JAMA. 1993;269: 1975. 33. Rebbeck TR, Levin AM, Eisen A, et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst. 1999;91:1475–1479. 34. Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. NEJM. 1998;339:424 – 428. 35. Olopade OI, Weber BL. Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part II. PPO Updates. 1998;12(11):1– 8. 36. Matloff ET, Peshkin BN, Ward BA. The impact of genetic screening on surgical decision making in breast cancer. In: Szabo Z, Lewis JE, Fantini GA, Savalgi RS, eds. Surgical Technology International VII: International Developments in Surgery and Surgical Research. San Francisco: Universal Medical Press; 1998.
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Five percent to 10% of all women who develop breast cancer carry a hereditary mutation in the genes BRCA1 or BRCA2. Genetic testing is now clinically available, and the results of such testing can dramatically alter a patient’s risks for an ipsilateral or contralateral primary breast cancer and ovarian cancer. Therefore, genetic testing will become integral in tailoring surveillance, chemoprevention, and surgical management plans for patients at risk for hereditary cancer syndromes. Such results will also impact the cancer risks for the patient’s nuclear and extended family members. Surgeons will play a pivotal role in eliciting personal and family histories from patients, determining which of those histories is suggestive of a germline mutation, facilitating referrals for genetic counseling and testing, and incorporating the results of genetic testing into the patient’s short- and long-term management plans. Am J Surg. 2000;180:294 – 298. © 2000 by Excerpta Medica, Inc.
S
urgeons have long recognized that a subset of their patient population is at increased risk to develop breast cancer based on a strong family history of the disease. Informal risk assessments based on family histories have guided surgical recommendations for surveillance, biopsy, and oral contraceptive and hormone replacement usage. In fact, before the advent of genetic testing, women and their surgeons were forced to make decisions about prophylactic surgery based solely on the family history, without specific information about the patient’s personal risk to develop the disease.
BRCA1 AND BRCA2 Genetic counseling and testing have made more definitive risk assessment possible. Approximately 7% to 10% of all breast cancers are attributable to mutations within a cancer susceptibility gene.1 Most hereditary breast cancer is caused by deleterious mutations in the breast/ovarian cancer susceptibility genes, BRCA1 (breast cancer-1) and
From the Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. Requests for reprints should be addressed to Ellen T. Matloff, MS, Associate Research Scientist, Genetics, Director, Cancer Genetic Counseling, Yale Cancer Center/Yale School of Medicine, 333 Cedar Street, Box 208028, New Haven, Connecticut 06520-8028. Presented at the Annual Meeting of the American Society of Breast Surgeons, Charleston, South Carolina, April 13–16, 2000. Manuscript submitted May 19, 2000 and accepted in revised form June 25, 2000.
294
© 2000 by Excerpta Medica, Inc. All rights reserved.
BRCA2 (breast cancer-2). The cloning of BRCA1 and BRCA22,3 has made clinically based testing a reality over the past 5 years. The cancer risks observed in women who carry BRCA1 or BRCA2 mutations have been the subject of some debate. Early studies performed on high-risk families revealed that the risk for female mutation carriers to develop breast cancer by age 70 was 87%, and that the risk to develop ovarian cancer was 60%.4 More recent studies performed in populations selected by Jewish ancestry alone, regardless of cancer history, have revealed lower cancer risks in BRCA carriers.5 It is most accurate to present mutation carriers with a range of cancer risk.6 This range for female carriers is likely 50% to 85% for breast cancer, and 15% to 60% for ovarian cancer by age 70 years.3–9 Because hereditary BRCA1 and BRCA2 mutations are germline, versus sporadic, mutations, they are present from conception and are found in most cells of the body. Each of the cells in the breast and ovarian tissue are therefore predisposed to become cancerous. The risk of bilateral breast cancer is increased in carriers,10 and has been estimated to be as great as 64% in BRCA1 mutation carriers diagnosed with their first breast cancer by the age of sixty.4 Male carriers of BRCA1 and BRCA2 carriers are at slightly increased risk to develop prostate cancer,4,5 and male BRCA2 carriers have an increased lifetime risk of developing breast cancer.8 The lifetime risk of pancreatic cancer also appears to be increased among BRCA2 carriers.11 Both of the BRCA genes are passed down in families in an autosomal dominant pattern of inheritance; therefore, mutation carriers have a 50% chance of passing the mutation on with each pregnancy. People who do not inherit the mutation are not at risk to pass on the mutation to their children. The BRCA genes are not sex-linked, meaning that mutations are passed on to, and by, men and women with equal frequency. This means that when eliciting a history, both maternal and paternal histories must be assessed.
RISK ASSESSMENT Risk assessment is a complicated process that has evolved over time. Early risk models set precise guidelines of the number of affected first- or second-degree relatives needed to determine a family’s eligibility for testing. It is now clear that these models are not realistic in most small- to medium-size families, and that clinicians must examine each family individually for the relevant risk factors. There are six risk factors that are common among hereditary cancer families (Table I). The first is early age of breast cancer onset. This risk factor, even in the absence of a family history, has been shown to be associated with an increased frequency of BRCA mutations.12–14 The second risk factor is the presence of the same cancer in multiple affected 0002-9610/00/$–see front matter PII S0002-9610(00)00460-8
BREAST SURGEON’S ROLE IN GENETIC TESTING/MATLOFF
TABLE I
TABLE II Risks Factors for BRCA1/BRCA2
Genetic Counseling and Testing Resources
1. Early age of onset 2. Presence of the same cancer in multiple family members on the same side of the pedigree 3. The presence of breast and ovarian cancer in the same family 4. Multiple primary cancers in one individual 5. Jewish ancestry 6. Breast cancer in a male
CancerNet (800) 4-CANCER http://cancernet.nci.nih.gov/wwwprot/genetic/genesrch.shtml A free service designed to locate providers of cancer risk counseling and testing services, both in the context of research and clinical fee-for-service programs. GeneTests: Genetic Testing Resource (206) 527-5742 http://www.genetests.org Offers current information on testing availability for specific conditions, and sites that offer such testing. Includes resources for DNA banking. National Society of Genetic Counselors (610) 872-7608 http://www.nsgc.org For a listing of genetic counselors in your area who specialize in cancer.
Figure 1. A 42-year-old woman presents with a large, unilateral breast cancer. She is opting for unilateral mastectomy with immediate reconstruction via a TRAM flap. Her surgeon takes a family history and learns that in addition to her patient’s earlyonset breast cancer, there is a history of Jewish ancestry and a male cousin diagnosed with breast cancer. The surgeon refers the patient to genetic counseling, and the patient elects genetic testing for the three common Jewish BRCA mutations. The results reveal that the patient carries the common Jewish BRCA2 mutation. Upon learning of the increased risks for a contralateral primary, the patient and her surgeon decide upon bilateral mastectomy with bilateral reconstruction via TRAM flap.
relatives on the same side of the pedigree. These cancers do not necessarily have to be of similar histologic type in order to be caused by a single mutation. The third risk factor is the presence of both breast and ovarian cancer in the same family. Age of onset of ovarian cancer is not a factor. The fourth risk factor is the occurrence of multiple primary cancers in one individual. Ethnicity also plays a role in determining who is at greatest risk to carry a hereditary cancer mutation. Individuals of Jewish ancestry are at increased risk to carry three specific BRCA mutations.5 The final risk factor for hereditary breast cancer is the presence of a male breast cancer in the family (Figure 1). These risk factors should be viewed in the context of the entire family history, and must be weighed in proportion to the number of individuals who have not developed cancer.
GENETIC TESTING Genetic testing should always be preceded by in-depth genetic counseling, which covers the risks, benefits, and limitations of testing as well as the options for surveillance and risk reduction in those who test positive (Table II). Testing can be performed on peripheral blood, a buccal
smear (cheek-brush sample), or a tissue block; however, most commercial labs prefer peripheral blood samples. The price of testing can range in price from $330 for the three most common mutations found in Ashkenazi Jews, to $2600 for full sequencing of both BRCA1 and BRCA2. Turnaround time varies from 2 to 14 weeks depending on the test ordered and the laboratory used. Informative testing is only possible when the mutation in the family has been pinpointed. It is therefore optimal to first test the person in the family most likely to carry a mutation. This person is almost always an affected family member. Stored tissue blocks from deceased, affected relatives may sometimes be tested for this reason, although such testing is more expensive and more difficult than testing of peripheral blood. Once the mutation in the family is established, other unaffected relatives can be tested for the same mutation with ⬎99% accuracy. If unaffected family members test negative for the mutation in their family, their result is interpreted as a “true negative” (Figure 2). The breast and ovarian cancer risks for a true negative are that of the general population. If no mutation is found in the affected family member, the result must be deemed uninformative. Unaffected members of these families should assume they are at increased risk and their surveillance and/or risk reduction program should be planned accordingly. It is impossible to determine whether a negative result in such a case means that (a) there is simply another undetectable mutation in the family, (b) the patient has not inherited the mutation in the family, and is a true negative or (c) the cancers in the family are not hereditary. It is critical to avoid misinterpretation of such results. In high-risk families in which DNA testing is uninformative, the option of DNA banking should be recommended (Table II). This will allow for future testing when more breast cancer susceptibility genes are known.
SURGICAL IMPLICATIONS Data showing that lumpectomy/radiation and total mastectomy provide the same degree of disease-free survival15 have had a major impact on breast surgical decision-mak-
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Figure 2. A healthy 40-year-old woman is followed by her breast surgeon owing to her strong family history of breast and ovarian cancer. The patient’s mother was diagnosed with breast cancer at age 44 and died later that year. The patient’s maternal aunt was diagnosed with breast cancer at age 45 and ovarian cancer at age 51, dying 1 year later. The patient is extremely anxious about her breast cancer risks and wants a prophylactic bilateral mastectomy and oophorectomy. Her surgeon refers the patient for genetic counseling. Because no tissue blocks are available on either deceased affected relative, the patient is offered testing for the three common Jewish BRCA mutations. The patient is found to be negative. This result cannot be interpreted as a “true negative” because the mutation in the family has not been identified. At this point, the result is deemed uninformative. Three months later, the patient’s brother agrees to have genetic testing, as he has a 23-year-old daughter who would be affected by his carrier status. The brother is found to carry one of the common Jewish BRCA1 mutations. The original patient in this family can now be interpreted as a “true negative” because the mutation in the family is now known. This patient’s risks for breast and ovarian cancer are reduced to that of the general population.
ing. Breast-conserving surgery is an attractive option to patients and their physicians, and is often preferred over total mastectomy. It is well known that breast cancer survivors are at increased risk for cancer in the contralateral breast.16 –19 Perhaps less recognized is that breast cancer survivors who have a personal or family history suggestive of a hereditary breast cancer syndrome have a greater risk of contralateral breast cancer than does the average breast cancer patient.20 Recent data have suggested that carriers of BRCA mutations are also at increased risk for multiple ipsilateral primaries.21 This is theoretically quite likely since these mutations are present in every breast cell. This information could obviously have a great impact on surgical decisionmaking. A BRCA carrier who learns that she is at increased risk for a second ipsilateral tumor in remaining breast tissue may opt for total mastectomy instead of lumpectomy. In fact, some women in this position may choose immediate bilateral mastectomy with or without reconstruction. The timing of this decision would be espe296
cially critical in women who choose transverse rectus abdominis myocutaneous (TRAM) flap as their method of reconstruction, as this procedure can be performed only one time (Figure 1). Although prophylactic mastectomy does not reduce the risk of breast cancer to zero,22–23 it is currently the most effective method of breast cancer risk reduction. The efficacy of this procedure has been shown to be greater than 90% in women at high risk to develop the disease, based on their family history.23 A recent follow-up study of women with strong family histories who elected bilateral prophylactic mastectomy showed that none of the known BRCA1 or BRCA2 mutation carriers in the sample have developed breast cancer thus far.24 These data provide reassuring evidence that prophylactic mastectomy is an effective method to reduce breast cancer risk, even in BRCA1/2 carriers. Prophylactic mastectomy should not be offered to healthy women (in the absence of personal risk factors, such as LCIS) with a family history of the disease until they have first been offered genetic counseling and testing to learn if they have inherited the mutation found in their family. Studies suggest that the minority of carriers intend to have their breasts removed prophylactically.25 Women at increased risk to carry a breast cancer susceptibility gene must understand that prophylactic mastectomy is not their only option. Chemoprevention is an exciting new option for women at increased risk to develop breast cancer. Tamoxifen has been shown to reduce the risk of invasive breast cancer by 49% in healthy women at increased risk to develop the disease.26 The efficacy of tamoxifen in women who carry BRCA1 or BRCA2 mutations is currently unknown, although these data should be available from the NSABP P-1 trial within the next few years. Because a greater proportion of tumors found in BRCA1 mutation carriers appear to be estrogen-receptor negative,27 it is premature to conclude that tamoxifen will have equal success in this population. However, it is quite possible that tamoxifen, or other selective estrogen-receptor modulators (such as raloxifene) will have a role in risk reduction in BRCA carriers (Figure 3). Even if high-risk women are not interested in prophylactic mastectomy or chemoprevention, they are still candidates for genetic counseling. During genetic counseling they will learn their risks for other cancers, their options for increased surveillance, and the risks to their family members. Surgeons can play a central role in developing surveillance plans for women at high risk for breast cancer. Recommended screening can begin as early as age 25 years and may include annual mammography; clinician breast examinations annually or semiannually; breast self-examination education; and monthly breast self-examinations.28 Clinical breast examinations and mammography can be spaced out around the calendar year so that women are receiving some sort of intervention every 4 months.
OTHER CANCER RISKS Many women do not realize that their family history of breast cancer may also put them at increased risk for ovarian cancer, or vice versa. The risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers is between 15% and 60% by age 70,4 –9 even in families in which only breast
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Figure 3. A 60-year-old woman was diagnosed with unilateral breast cancer at age 51 and was successfully treated with lumpectomy and radiation. Her tumor was estrogen-receptor negative and she was not offered tamoxifen. The patient presents to her surgeon for her annual check-up and reveals that her maternal first cousin has just been diagnosed with ovarian cancer. The surgeon urges the patient to explore the family history in greater depth, and the patient learns that a maternal aunt also died of ovarian cancer. The patient is offered genetic counseling and testing and learns that she carries a BRCA1 mutation. After discussions with her surgeon and the genetics team, the patient elects to have a prophylactic hysterectomy and bilateral salpingo-oophorectomy and to go on tamoxifen in hopes of reducing her risk of a second breast primary.
cancer has been observed thus far. The rates of early detection and successful treatment are low in women who develop ovarian cancer. One option available to mutation carriers for reducing the risk of ovarian cancer is prophylactic oophorectomy. This procedure is not 100% effective in preventing intra-abdominal carcinomatosis that histologically resembles ovarian cancer,29 but appears to reduce the risk substantially.30 This procedure is not ideal in premenopausal women owing to loss of fertility and immediate surgical menopause. Women who have their ovaries removed and do not take hormone replacement therapy are at increased risk to develop osteoporosis and heart disease.31,32 These women are also at risk for menopausal symptoms, including vasomotor and gynecologic symptoms, depression, and sleep disturbance. A recent study demonstrated that prophylactic oophorectomy in BRCA1 carriers reduces their risk of future breast cancer, even in those women who take hormone replacement therapy.33 However, HRT use in women who have had, or are at increased risk for breast cancer, is controversial.31 A less-invasive option for premenopausal BRCA carriers is to use oral contraceptives to reduce their risk of ovarian cancer. Use of oral contraceptives has been shown to significantly reduce the risk of ovarian cancer in BRCA1 carriers.34 Again, the use of exogenous estrogen in women at increased risk to develop breast cancer is controversial. However, it is possible that, given the likelihood of mortality from ovarian versus breast cancer, a risk/benefit analysis would favor the use of oral contraceptives in carriers of BRCA mutations.35
Genetic counseling and testing have already begun to have a major impact on surgical decision-making for breast cancer. Women diagnosed with breast cancer may seek genetic testing before choosing between lumpectomy and mastectomy, or even bilateral mastectomy. Genetic test results can influence decision-making for adjuvant tamoxifen, oophorectomy, or even chemotherapy. It is quite possible that in the future all patients, even those without a family history of the disease, will be offered a broad genetic screen for germline mutations that will help guide their physicians in choosing the most appropriate and effective treatment plan for that patient. Many surgeons do not have the time or the specialized training required to provide patients with the detailed genetic counseling, result interpretation, psychological support, and long-term follow-up that must be part of the genetic testing process.36 However, surgeons will play a central role in genetic testing by eliciting detailed histories from their patients and choosing the subset that should be referred for genetic counseling. Surgeons will also need to interpret the test results and integrate them into short- and long-term management plans for their patients. It is quite possible that in the future genetic testing will be one of the surgeon’s most valuable instruments in the treatment of breast cancer.36
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