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Clinical Crossroads | Clinician's Corner

Management of Women With BRCA Mutations   A 41-Year-Old Woman With a BRCA Mutation and a Recent History of Breast Cancer

Nadine Tung, MD, Discussant
JAMA. 2011;305(21):2211-2220. doi:10.1001/jama.2011.678.
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Ms E, a 41-year-old BRCA1 mutation carrier, was diagnosed 4 years ago as having breast cancer and opted for breast-conserving therapy. Prior to receiving chemotherapy, she harvested her eggs through in vitro fertilization and subsequently used preimplantation genetic diagnosis; 3 months ago she delivered a healthy boy. This review examines the prevalence of BRCA mutations in women with breast cancer, as well as current recommendations for surgery and systemic therapy in these women. In particular, the risk of a contralateral breast cancer is reviewed to help guide the choice of prophylactic mastectomies vs breast-conserving therapy. The technology of preimplantation genetic diagnosis and genetic testing in relatives of mutation carriers is discussed.

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Figure. Postcontrast Fat-Suppressed T1-Weighted Magnetic Resonance Imaging (MRI) of Primary Breast Cancer and Left Axillary Adenopathy
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A, Axial MRI showing left axillary adenopathy (arrowhead). B, Axial MRI showing the primary breast cancer (arrowhead). C, Coronal MRI reconstruction showing left axillary adenopathy (arrowheads). D. Sagittal MRI reconstruction showing the primary tumor (blue arrowhead) and axillary adenopathy (yellow arrowheads).




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Readers response
Posted on May 28, 2011
Gunda Pristauz, MD, Prof.
Medical University of Graz, Austria, Department of Obstetrics and Gynecology,
Conflict of Interest: None Declared
1)What women should consider genetic testing for breast cancer susceptibility and at what age?
Ms. E's scenario shows that recommendations regarding genetic testing for BRCA mutations differ between the U.S. and Europe. In 2002 the German Consortium for Hereditary Breast and Ovarian Cancer identified (Int J Cancer 2002;97:472-480) family groups at a very high risk of carrying a BRCA 1/2 gene mutation. Based on these we recommend genetic testing if the probability for a mutation is greater than the 11% probability of the general female population for carrying a BRCA 1/2 mutation (e.g., families with 2 or more cases of breast cancer in first-degree relatives, including 1 case diagnosed before the age of 50 years). According to these criteria the woman at the Crossroads would not have been offered genetic testing. Testing all breast cancer patients older than 35 years with a negative family history, as in Ms. E's case, would lead to many costly (and negative) tests.
2) How does a BRCA mutation affect management of breast cancer?
Knowing a BRCA mutation is present is increasingly likely to affect present and future management of patients with breast cancer. Knowing the mutation status before initial surgery would markedly alter the risks and benefits of mastectomy vs. lumpectomy because the prophylactic effect of a mastectomy would be much more relevant in a mutation carrier. Also, the implication of radiation therapy after breast-conserving therapy is still unclear. Knowing the mutation status might affect the choice of systemic therapy after surgery. PARP inhibitors are effective in treating patients with malignancies caused by BRCA mutations (Tutt et al. Lancet 2010;376:235-44) and breast cancers with BRCA mutations are more sensitive to platinum- containing chemotherapy regimens (Byrski et al. Breast Cancer Res Treat 2009;115:359-363).
3) What malignancies breast other than cancer are BRCA mutation carriers at risk for and how should that risk be managed?
The immediate issue for Ms. E is her risk of developing ovarian cancer. As a BRCA 1 mutation carrier her risk for developing ovarian cancer is about 45%. Ovarian cancer cannot be reliably detected at an early stage, and is usually fatal at an advanced stage. There is no evidence that screening has reduced the mortality or can improve overall survival in women who are at high risk for ovarian cancer. These women, like Ms. E, should be counselled accordingly and offered bilateral prophylactic salpingo-oophorectomy (BPSO) at the age of 40 or after family planning is completed (Rebbeck et al. N Engl J Med 2002; 346:1616-22; Kauff ND et al. N Engl J Med 2002;346:1609-15; Domchek SM et al. Lancet Oncol 2006;7:223-9). It is unclear whether BRCA1 mutation carriers have an increased risk for other malignancies. BRCA2 germline mutations seem to be associated with familial pancreatic cancer. Male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age (Edwards et al. Am J Hum Genet 2003;72:1-12)
4) What is preimplantation genetic diagnosis, and how is it used clinically?
Preimplantation genetic diagnosis (PGD) was developed in the United Kingdom around 1990 for couples at high risk of transmitting a genetic abnormality to their children. PGD is used to genetically analyze embryos before their transfer into the uterus. PGD is often performed with one or two cells removed from an eight-cell stage embryo on the third day after IVF. It allows couples carrying a genetic disease to test for the condition without undergoing invasive prenatal diagnosis (Harton GL et al. Hum Reprod 2011;26:41-6; Basille C, Eur J Obstet Gynecol Reprod Biol. 2009;145:9-13). Reviewis in PGD is performed for monogenetic diseases inherited in an autosomal-recessive, autosomal-dominant and X-linked manner and for carriers with reciprocal balanced translocations. Several authors use the term PGD only for the detection of monogenetic diseases whereas Preimplantation Genetic Screening (PGS) is carried out for patients undergoing IVF to test for numerical and structural chromosomal aberrations. Indications for PGS are advanced maternal age, repeated miscarriages and implantation failure. (Harton GL et al. Hum Reprod 2011;26:41-6) Ms. E could not have undergone PGD in certain countries such Austria, Germany, Italy and Switzerland, where it is illegal. Here, polar body diagnosis (PBD) is the only method for the indirect genetic analysis of oocytes. The first or second polar body can be used to study the maternal genetic contribution (Mastenbroek, S. et al. N. Engl. J. Med. 2007;357: 9- 17; Munne S. et al. Fertil. Steril. 2005;84: 331-335)
5)What breast cancer prevention strategies are appropriate for a mutation carrier who has not yet developed breast cancer?
The strategies to prevent breast cancer in mutation carriers range from close surveillance only to prophylactic surgery and chemoprevention.
Surveillance: Magnetic resonance imaging is more sensitive for the detection of breast cancer than mammography in young high-risk patients. The Dutch national study for Magnetic Resonance Imaging (MRI) screening in women with a familial or genetic predisposition demonstrated that the combination of magnetic resonance imaging, mammography, and clinical breast examination has the highest sensitivity for the detection of breast cancer (Kriege et al. Fam Cancer. 2001;1:163-8). Thus MRI mammography is recommended annually for patients like Ms. E.
Prophylactic bilateral mastectomy: In our part of the world about 10-15% of BRCA mutation carriers decide for BPM, compared with about 60% of patients in the United States. BPM decreases the risk for breast cancer by up to 95% (Rebbeck et al. J Clin Oncol 2004:22;1055-1062). Until quite recently BPM usually meant skin- sparing mastectomy with removal of the nipple-areola complex; today there is mounting evidence that the nipple-areola complex can be spared without compromising results and with a much nicer cosmetic outcome (Harness JK et al. Ann Surg Oncol. 2011;18:917-22.; Jensen JA et al Ann Surg Oncol. 2011;18:1665-70; Salgarello M et al. Plast Reconstr Surg. 2010:126;1460- 71).
Chemoprevention: Currently there are limited data regarding the possible benefit of systemic endocrine therapy as chemoprevention for mutation carriers. The NSABP-P1 trial showed a 62% risk reduction for breast cancer with tamoxifen only for BRCA 2 mutation carriers (King MC et al. JAMA 2001;286:2251-6). The risk for ovarian cancer in BRCA1 and BRCA2 mutation carriers could not be reduced. Narod et al demonstrated that tamoxifen could reduce the risk of contralateral disease in BRCA1 and BRCA2 mutation carriers with a diagnosis of breast cancer (Narod et al. Lancet 2000;356:1876-81). No data are available about the potential benefit of aromatase inhibitors or raloxifen in BRCA mutation carriers.
Conflict of Interest: None declared
Considerations for a BRCA mutation carrier after breast cancer
Posted on May 22, 2011
Beth V. Anglin, MD
The Medical Center of Plano
Conflict of Interest: None Declared
Management of Ms E should take into account her risk of a primary ovarian cancer, a second breast cancer and her personal wishes. Those in the BRCA community are often very educated in their options as demonstrated by the fact that she has gone through preimplantation genetics. In regards to the ovarian cancer, the 2011 NCCN guidelines recommend consideration of prophylactic salpingoophrectomy between the ages of 35-40 or when child bearing is completed. This has been shown to reduce her risk of ovarian cancer by 80% and reduces breast cancer risk by 50%(1). Guidelines by the Society of Gynecologic Oncologists recommend removal of the fallopian tubes along with the ovary. The surgical specimen should also be examined more carefully when one has a known BRCA mutation(2).
Ms E is also at risk for future breast cancer. Her initial cancer was not visualized on mammography so Ms E would depend on MRI evaluation in the future. Women under 50 at their initial breast cancer diagnosis are up to a 50% risk of a contralateral breast cancer by age 70(3). Another study by Kirova shows 40% of women with a BRCA mutation will be diagnosed with a contralateral cancer in 13 years(4). The risk of ipsilateral breast cancer is lowered with salpingoophrectomy (3). The study by Kirova shows no increased risk of ipsilateral cancer when one has undergone chemotherapy and radiation(4).
To lessen Ms E's concerns regarding genetic discrimination, information regarding GINA, the Genetic Information Nondescrimination Act would be helpful. This federal law prohibits increasing one's premiums or cancelling an insurance policy when any hereditary cancer mutation is found. The act also prohibitions against using genetic information as a pre-existing condition.(5)
Those with a BRCA mutation are at risk of other cancers. The actual incidence of these cancers is variable and insurance doesn't cover some screening modalities. Both the patient and their physician should be aware of the increased risk for pancreatic cancer, melanoma, and prostate cancer. Primary peritoneal cancer is also a rare but real concern after prophylactic oophrectomy. (6)
In my experience as a breast surgeon in a community private practice following over 40 BRCA positive women, knowledge about the risk of future cancer gives a sense of control that other survivors do not always have. The advances in skin and nipple sparing mastectomy along with improved reconstructive techniques help a woman make this very difficult decision. If the genetic counseling and testing can be performed at the time of the cancer diagnosis, the woman could make a fully informed decision regarding her surgical treatment.
A resource for support is FORCE:Facing Our Risk of Cancer Empowered, a non-profit international support organization(www.facingourrisk.org). There are FORCE community outreach groups in most large cities in the United States. Bright Pink (www.brightpink.org)is another support organization addressing the issues of previvors or those without cancer who are at elevated risk due to a gene mutation.
1. Rebbeck T, J Natl Cancer Inst. 2009 January 21; 101(2): 80–87.
2. Gynecol Oncol. 2005, Aug;98(2):179-81
3. Metcalfe K, Br J Cancer 2011 April 26;104(9):1484-92
4. Kirova YM, Breast Cancer Res Treat 2010 Feb;120(1):119-26
5. Pub.L. 110-233, 122 Stat. 881, enacted May 21, 2008, GINA
6. Narod S, Familial Breast Cancer Research Unit, University of Toronto
Conflict of Interest: Myriad Speakers Bureau Dallas Outreach Coordinator for Facing Our Risk of Cancer Empowered (non-profit) I received no funding in support of this work.
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