GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 18, Number 7, 2014 ª Mary Ann Liebert, Inc. Pp. 461–466 DOI: 10.1089/gtmb.2013.0513
OVERVIEW ARTICLE
‘‘I Do Not Want My Baby to Suffer as I Did’’; Prenatal and Preimplantation Genetic Diagnosis for BRCA1/2 Mutations: A Case Report and Genetic Counseling Considerations Efrat Dagan,1,2 Ruth Gershoni-Baruch,2,3 Alina Kurolap,2 Yael Goldberg,4 and Georgeta Fried 3,5
This article presents the complexity of prenatal genetic diagnosis and preimplantation genetic diagnosis for hereditary breast–ovarian cancer syndrome. These issues are discussed using a case report to highlight the genetic counseling process, together with decision-making considerations, in light of the clinical, psychological, and ethical perspectives, of both the mutation carriers and health professionals; and the health policy regarding these procedures in Israel compared to several European countries.
Introduction
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n Ashkenazi Jews, three predominant mutations in BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) attribute to the familial breast–ovarian cancer syndrome, which increases the lifetime risk for breast cancer between 60% and 80% and for ovarian cancer between 16% and 40% (King et al., 2003; Simchoni et al., 2006). It is well known that breast cancer in BRCA1/2 mutation carriers is often characterized by early onset, bilaterality, and an aggressive triplenegative tumor, all of which carry a poor prognosis (see review by Robson, 2004; Anders et al., 2008; Young et al., 2009; Hall et al., 2010; Comen et al., 2011; Metcalfe et al., 2011a, 2011b; Smith et al., 2011; Southey et al., 2011). Therefore, BRCA1/2 carriers are recommended to maintain intensive follow-up and to undergo prophylactic risk reduction surgeries (Eisinger et al., 1998; Hartmann et al., 2004; Schwartz et al., 2009). To prevent a BRCA1/2 mutation carriage in successive generations, two options are available. (1) Prenatal diagnosis (PND), which is performed by chorionic villus sampling (CVS) or amniocentesis during early pregnancy (10–20 weeks) and enables termination of the pregnancy if the fetus is a carrier; and (2) preimplantation genetic diagnosis (PGD), which involves in vitro fertilization (IVF) with a biopsy and genetic testing at the six- to eight-cell stage of the embryo, 3 days following insemination, when only unaffected embryos are transferred to the uterus (Ao et al., 1998). Both PGD and PND are carried out mainly for the management of inherited predisposition of incurable and early childhood diseases, in-
cluding cancer syndromes such as Li-Fraumeni, familial adenomatous polyposis (FAP), and retinoblastoma (Offit et al., 2006). Whereas both procedures have been made available and are becoming increasingly widespread, debates have arisen about extending their use to include late-onset susceptibility syndromes, such as breast and ovarian cancer (see, for example, Robertson, 2003; Menon et al., 2007; Douma et al., 2010). This article presents a case report and discusses its genetic counseling process in light of the clinical, psychological, and ethical perspectives, of both the mutation carriers and health professionals; and the health policy regarding these procedures in Israel compared to several European countries. Case Report
Sarah first attended our oncogenetic clinic at 34 years of age. At the age of 30, she had tested positive as a carrier of the hereditary mutation 5382insC in BRCA1 and had received a concurrent diagnosis of breast cancer at stage T1A (0.2 and 0.5 mm)N0M0 (tumor node metastasis). The histopathology classified the tumor as invasive ductal carcinoma grade III with triple-negative receptors. She underwent mastectomy and axillary lymph node dissection with tissue expander reconstruction; and six cycles of adjuvant chemotherapy with cyclophosphamide, adriamycin, and fluorouracil were administered. Three years later (at age 33), she had been diagnosed with contralateral breast cancer, this time at stage T1B (1 cm)N0M0. Oncotype DX revealed a high recurrence score of 31. She underwent contralateral mastectomy and
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Department of Nursing, University of Haifa, Haifa, Israel. Institute of Human Genetics, Rambam Health Care Campus, Haifa, Israel. 3 Ruth and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel. 4 Obstetrics and Gynecological Ultrasound Unit, Carmel Medical Center, Haifa, Israel. 5 Oncology Institute, Rambam Health Care Campus, Haifa, Israel. 2
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reconstruction and was treated with three cycles of adjuvant chemotherapy with Taxotere and Carboplatin. Subsequently, she had a spontaneous pregnancy and experienced a missed abortion. About a year later, Sarah became spontaneously pregnant once again. When she was already 10 weeks into the pregnancy, she came to us seeking genetic counseling and prenatal genetic molecular testing for the 5382insC mutation in BRCA1 for her fetus, after being rejected for oncogenetic counseling at several other clinics in Israel. It is important to note that Sarah already required CVS for cytogenetic testing (karyotype) due to chemotherapy treatment within the previous 2 years. CVS for cytogenetic testing does not provide the DNA required for molecular testing, unless a specific indication is presented. Sarah was the mother of two girls (aged 10 and 8 years). Her family history of cancer includes a mother diagnosed with breast cancer at 46 years of age, a maternal grandmother with skin cancer, and a paternal grandmother with lymphoma. No other family history for cancer was reported. Following the clinical intake, Sarah discussed her motives for seeking PND. Her most significant statement was ‘‘I do not want my baby to suffer as I did.’’ She and her husband were extremely determined to undergo genetic diagnosis for the fetus, whether male or female. This was the first time that we have been requested to provide PND for a mutation in BRCA1/2. Due to the complex nature of this case, we decided to invoke a multidisciplinary team, which included an oncogenetic counselor, a medical geneticist, an obstetrician, and a genetic nurse. We detailed the issues that were raised, debated, and managed along decisionmaking junctions, for example, fetal gender appraisal, cytogenetic evaluation, and whether or not to proceed with PND. Considerations in Genetic Counseling
This case embodies most of the issues regarding PND, and considers PGD, for BRCA1/2 mutation carriers. Focusing on the clinical–ethical considerations and attitudes toward these procedures, this case report gives rise to several questions. What personal and family history of cancer should be considered for PND or PGD? Does the gender of the fetus make a difference? Does the mutated gene, either BRCA1 or BRCA2, make a difference? Is it ethical to allow PND, or otherwise PGD, for late-onset diseases with incomplete penetrance? In other words, in what circumstances should the use of such procedures be considered? Moreover, should these issues be addressed differently in PND and PGD? Clinical considerations
Sarah was diagnosed with early-onset, triple-negative bilateral breast cancer, at 30 and 33 years of age, and was found to be carrying the 5382insC mutation in BRCA1. Early-onset breast cancer ( < 40 years) accounts for 7% – 2% of all breast cancer patients (http://seer.cancer.gov/statfacts/ html/breast.html; Israel Ministry of Health (2006a) National Cancer Registry) (see review by Zhou and Recht, 2004) and for about 5% of all cancer deaths (Kothari and Fentiman, 2002; see review by Zhou and Recht, 2004; Polla´n, 2010; Varga et al., 2010). BRCA1/2 carriers more often present with early-onset breast–ovarian cancer (see review by Robson, 2004) and bilateral breast cancer (Metcalfe et al., 2011a, 2011b). BRCA1-associated tumors are large, display high proliferation, and poor differentiation; and triple-negative
DAGAN ET AL.
receptors (Anders et al., 2008), associated as a rule with poor prognosis (Zhou and Recht, 2004; Young et al., 2009; Hall et al., 2010; Varga et al., 2010; Comen et al., 2011; Smith et al., 2011; Southey et al., 2011). The overall survival rate in BRCA1-associated breast cancer patients compared to agematched sporadic breast cancer patients varies among studies, some reporting a poorer prognosis in BRCA1 carriers compared to noncarriers and others showing a similar survival rate (Robson et al., 1998, 1999; Lee et al., 2010; see review by van der Groep et al., 2011). Taking the personal and family history together with the medical data, we can conclude that the potential risk of earlyonset breast cancer for Sarah’s fetus, if female, might be augmented if the 5382insC mutation will be transmitted, taking into account that breast cancer has already appeared in two generations—in Sarah’s mother and in Sarah herself (Gershoni-Baruch et al., 2000; Metcalfe et al., 2010; Litton et al., 2012). The question of poor prognosis and the fear of transmitting the mutation to her offspring, especially females, could not be eliminated, and should be taken into consideration when contemplating PND in such cases. The information presented so far illustrates the medical and clinical issues and might explain the reasons that prompt women to opt for PND or PGD in order not to transfer the bad gene to their children. Psychological considerations
As BRCA1/2 testing becomes increasingly popular, we are encountering a growing number of individuals with unique psychosocial needs and concerns regarding risk reduction modalities and cancer treatment. Moreover, the increasing availability and accessibility of PND and PGD procedures allow to, prenatally, test and thereby avert the long-term consequences of being a BRCA1/2 mutation carrier, as regards the parents and their offspring. The psychological burden in BRCA1/2 mutation carriers has multifactorial facets that relate to issues such as personal and family history of cancer, risk reduction management, and its consequences; and reproduction (see recent review by Stan et al., 2013). Several studies have shown that being at high risk for a lifethreatening inherited disease impacts daily decision-making processes and functioning, overall well-being, and quality of life (Meiser and Halliday, 2002; Meiser et al., 2002; Watson et al., 2004; Dagan and Shochat, 2009; Shochat and Dagan, 2010). These findings were not corroborated by others (see, for example, Schwartz et al., 2002; Arver et al., 2004; Reichelt et al., 2004; Bosch et al., 2012). Sarah’s statement ‘‘I do not want my baby to suffer as I did’’ may highlight the psychological concerns that anguish women with breast cancer, carriers of a BRCA1/2 mutation, regarding their offspring. Although pregnancy in such cases might be considered as a victory over the disease, BRCA1/2 carriers maintain a sense of future threat regarding themselves and their children (Adams et al., 2011; Canada and Schover, 2012; Howard-Anderson et al., 2012). Decision making following PND for a late-onset disease, which preferentially affects females, should be counseled accordingly. BRCA mutation carrier attitudes toward PND versus PGD
Little is known about PGD, and even less regarding PND, in the context of BRCA1/2 testing from the carrier’s
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perspective. It has been clearly shown that women prefer PGD over PND, and even those who were in favor of PGD expressed their concerns about broadening the regulatory guidelines to include hereditary breast–ovarian cancer syndrome (Menon et al., 2007; Ormondroyd et al., 2012). The case presented here is somewhat different. Sarah’s choice of PND seems to represent her personal experience of having coped with aggressive breast cancer for several years and the intolerable fear of transmitting the bad gene. Moreover, she was already 10 weeks into her spontaneous pregnancy, which leaves PND as the sole option. A study performed in Spain, with familial breast–ovarian cancer high-risk individuals, showed that half of the participants believed that they would consider PND or PGD if they were to receive a positive BRCA1/2 genetic test result. In addition, more than 10% of individuals reported that they would consider adoption or remaining childless if they were to receive a positive test result (Smith et al., 2004; Fortuny et al., 2009). Several reports showed that women with a BRCA1/2 mutation generally held positive attitudes toward PGD (Menon et al., 2007; Quinn et al., 2009, 2010; Vadaparampil et al., 2009), and couples who were planning future pregnancies preferred PGD over the option of terminating a pregnancy as with PND. In 2006, PGD for late-onset diseases was authorized by the Israel Ministry of Health, and the Hadassah Hebrew University Medical Center reported their clinical experience with PGD for BRCA1/2 mutation carriers. During a 2-year period, all women declined the option of PND and out of 10 BRCA1/2 mutation carriers, six women opted for IVF/PGD (Sagi et al., 2009). Although PND is less acceptable than PGD among BRCA1/2 carriers, Sarah’s story represents those cases that should be considered for PND by genetic counselors.
aspects are becoming more and more commonplace in the everyday clinical setting.
Healthcare perspectives
A review of the few surveys of the reproduction options for BRCA1/2 carriers, from a healthcare professional perspective, revealed that individuals at risk for adult-onset hereditary cancer syndromes should be offered PND and PGD. Moreover, the information should be received at high-risk and cancer prevention units and should include all of the available assistant reproduction technology (ART) options (Sermon, 2002; Smith et al., 2004). However, only 30% of those with hereditary breast–ovarian cancer syndrome or FAP are actually referred to such clinics by their primary physicians and/or their oncologists (Brandt et al., 2010). The ambiguous situation regarding PND and PGD for both patients and health professionals, especially in countries where the ruling is not yet clearly defined, is reflected by a study of cancer geneticists in France. The study showed that the information regarding ART is given spontaneously, and if PND and PGD procedures would be authorized for BRCA1/2 mutations in France, geneticists would refer their at-risk patients to authorized clinics ( Julian-Reynier et al., 2009). With the increasing availability of genetic diagnosis, healthcare professionals are continually encountering ethical questions, such as whether or not to do a PND and/or PGD for BRCA1/2 mutation carriers. With the increasing focus of genetic counseling and diagnosis on late-onset diseases, including cancer, Parkinson’s disease, and others, these ethical
Ethical considerations and regulations across countries
A review of the regulations, the selection of indications and the criteria for reimbursement regarding the PGD procedure, has revealed differences between countries. The severity and the noncurability of a disease are the two main criteria adopted in most European countries for performing PND or PGD (BOE, 2006; HFEA, 2006; Israel Ministry of Health, 2006b; Aarden et al., 2009). The patients’ personal and family clinical histories and their perspectives regarding disease susceptibility are also relevant criteria for genetic specialists to consider when offering PND or PGD to individuals at risk ( Julian-Reynier et al., 2009). For example, in the United Kingdom, on May 10, 2006, the Human Fertilization and Embryology Authority (HFEA), which regulates assisted reproduction, decided to include susceptibilities to certain cancers in the PGD permission criteria. HFEA agreed to license PGD for inherited breast, ovarian, and bowel cancer because of their aggressive nature and the extreme anxiety that mutation carriers might experience. However, they were aware that these conditions have different impacts on individual families and the authority reserved the right to review factors around a particular condition, including its treatment options, as well as the views and experience of the carriers (Braude, 2006; HFEA, 2006; Menon et al., 2007). In practice, laboratories authorized to perform PGD can offer BRCA1/2 testing for high-risk individuals whose families have known mutations. In December 2006, the Israel Ministry of Health published directives for performing PGD, in which incomplete penetrance and other types of inheritance were added to the monogenic early-onset incurable criteria. However, PGD for severe diseases, such as predisposition for cancer, is under the evaluation of the National Council for Bioethics. As a standard of care, PGD performance is based on the same criteria as PND performed for genetic disorders. Nevertheless, the Israel Society of Medical Genetics should frequently reevaluate the criteria for PGD in light of the medical and technological developments in genetic diagnosis (Israel Ministry of Health, 2006b). The directions are somewhat vague, since practically, genetic centers in Israel that offer PGD for traditional monogenic syndromes may consider diagnosis for cancer predisposition, including BRCA1/2. An analysis of the differences between countries showed that, in Germany and Italy, authorization of PGD for women with BRCA1/2 mutations still has a long way to go. In these two countries, the indication criteria for PGD are narrower than for PND. In Israel, the United Kingdom, France, Spain, and other countries, however, these procedures are permitted (BOE, 2006; HFEA, 2006; Israel Ministry of Health, 2006b; Turillazzi and Fineschi, 2008; Julian-Reynier et al., 2009). Some clinics in the United Kingdom perform PGD for BRCA1/2, but funding still depends on the region. In 2006, the Israel Ministry of Health authorized these procedures for low-penetrance susceptibilities, including cancer. In France and Spain, PGD for selection of non-BRCA1/2 embryos would require an individualized case-by-case analysis and the process might not be straightforward (Fortuny et al.,
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2009). Other countries are moving toward providing these procedures: in the Netherlands, PGD for BRCA1/2 is not yet reimbursed, but progress is being made in that direction, and in Belgium, a protocol for PGD in two couples with two different BRCA1 mutations was performed in 2007, showing that it was practically feasible to identify carrier and noncarrier embryos (Spits et al., 2007). It seems that in most Western countries, PGD is permitted under certain circumstances, and in several countries, even PND. Israel and Germany are at the opposite ends of the provision - prohibition continuum of PND/PGD for cancer susceptibilities, and the other countries are somewhere in between. Analyzing the reasons underlining the criteria for PND/PGD for late-onset diseases in each country is beyond the scope of this discussion. However, it provides food for thought regarding the complex ethical values relating to family and society with respect to ART in different countries. Summary
This report exposes complicated decision-making considerations underlying genetic counseling and diagnosis when PND is being offered for controversial diseases. Aborting a pregnancy for a late-onset disease with incomplete penetrance, for example, breast cancer, might leave clinicians with feelings of discomfort. It should be noted that even though PND and PGD tend to be discussed together, the clinical, psychological, and ethical issues they raise are essentially different. The genetic counseling provided should consider the implications of each procedure, namely, IVF and PGD or PND that may lead to a pregnancy termination. Our clinical experience shows that a multidisciplinary approach is most effective for discussing the relevant concerns. The genetic counselor’s role is to divulge the clinical and psychological facets and esteem the ethical directives and regulations of the country. In the Israeli context, PGD is acceptable for BRCA1/2 mutation carriers and the decision of whether or not to undergo this procedure rests with the parents (Israel National Bioethics Council, 2008). Nevertheless, termination of pregnancy following PND should be subject to the jurisdiction act. The genetic counseling process, in cases similar to Sarah’s, encounters several decision-making phases that incorporate the clinical and family history with the patient’s needs and preferences. Although this guideline may seem obvious, Sarah’s case indicates otherwise, as she was denied genetic counseling by several medical centers. It is important to note that attitudes may change during the counseling process. This is reflected by both Sarah’s and her husband’s approach to PND based on the baby’s gender. In the initial counseling session, Sarah and her husband were determined to undergo PND for either male or female fetus. However, they withdrew their request for PND when they realized that Sarah carried a boy, thereby concluding the genetic counseling process. About 2 years later, liver metastases and positive axillary lymph nodes were diagnosed with triple-negative receptors. Our last follow-up revealed that Sarah was having chemotherapy once again. Author Disclosure Statement
No competing financial interests exist.
DAGAN ET AL. References
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Address correspondence to: Efrat Dagan, RN, LGC, PhD Department of Nursing University of Haifa Mount Carmel Haifa 31905 Israel E-mail: [email protected]
OVERVIEW ARTICLE
‘‘I Do Not Want My Baby to Suffer as I Did’’; Prenatal and Preimplantation Genetic Diagnosis for BRCA1/2 Mutations: A Case Report and Genetic Counseling Considerations Efrat Dagan,1,2 Ruth Gershoni-Baruch,2,3 Alina Kurolap,2 Yael Goldberg,4 and Georgeta Fried 3,5
This article presents the complexity of prenatal genetic diagnosis and preimplantation genetic diagnosis for hereditary breast–ovarian cancer syndrome. These issues are discussed using a case report to highlight the genetic counseling process, together with decision-making considerations, in light of the clinical, psychological, and ethical perspectives, of both the mutation carriers and health professionals; and the health policy regarding these procedures in Israel compared to several European countries.
Introduction
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n Ashkenazi Jews, three predominant mutations in BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) attribute to the familial breast–ovarian cancer syndrome, which increases the lifetime risk for breast cancer between 60% and 80% and for ovarian cancer between 16% and 40% (King et al., 2003; Simchoni et al., 2006). It is well known that breast cancer in BRCA1/2 mutation carriers is often characterized by early onset, bilaterality, and an aggressive triplenegative tumor, all of which carry a poor prognosis (see review by Robson, 2004; Anders et al., 2008; Young et al., 2009; Hall et al., 2010; Comen et al., 2011; Metcalfe et al., 2011a, 2011b; Smith et al., 2011; Southey et al., 2011). Therefore, BRCA1/2 carriers are recommended to maintain intensive follow-up and to undergo prophylactic risk reduction surgeries (Eisinger et al., 1998; Hartmann et al., 2004; Schwartz et al., 2009). To prevent a BRCA1/2 mutation carriage in successive generations, two options are available. (1) Prenatal diagnosis (PND), which is performed by chorionic villus sampling (CVS) or amniocentesis during early pregnancy (10–20 weeks) and enables termination of the pregnancy if the fetus is a carrier; and (2) preimplantation genetic diagnosis (PGD), which involves in vitro fertilization (IVF) with a biopsy and genetic testing at the six- to eight-cell stage of the embryo, 3 days following insemination, when only unaffected embryos are transferred to the uterus (Ao et al., 1998). Both PGD and PND are carried out mainly for the management of inherited predisposition of incurable and early childhood diseases, in-
cluding cancer syndromes such as Li-Fraumeni, familial adenomatous polyposis (FAP), and retinoblastoma (Offit et al., 2006). Whereas both procedures have been made available and are becoming increasingly widespread, debates have arisen about extending their use to include late-onset susceptibility syndromes, such as breast and ovarian cancer (see, for example, Robertson, 2003; Menon et al., 2007; Douma et al., 2010). This article presents a case report and discusses its genetic counseling process in light of the clinical, psychological, and ethical perspectives, of both the mutation carriers and health professionals; and the health policy regarding these procedures in Israel compared to several European countries. Case Report
Sarah first attended our oncogenetic clinic at 34 years of age. At the age of 30, she had tested positive as a carrier of the hereditary mutation 5382insC in BRCA1 and had received a concurrent diagnosis of breast cancer at stage T1A (0.2 and 0.5 mm)N0M0 (tumor node metastasis). The histopathology classified the tumor as invasive ductal carcinoma grade III with triple-negative receptors. She underwent mastectomy and axillary lymph node dissection with tissue expander reconstruction; and six cycles of adjuvant chemotherapy with cyclophosphamide, adriamycin, and fluorouracil were administered. Three years later (at age 33), she had been diagnosed with contralateral breast cancer, this time at stage T1B (1 cm)N0M0. Oncotype DX revealed a high recurrence score of 31. She underwent contralateral mastectomy and
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Department of Nursing, University of Haifa, Haifa, Israel. Institute of Human Genetics, Rambam Health Care Campus, Haifa, Israel. 3 Ruth and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel. 4 Obstetrics and Gynecological Ultrasound Unit, Carmel Medical Center, Haifa, Israel. 5 Oncology Institute, Rambam Health Care Campus, Haifa, Israel. 2
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reconstruction and was treated with three cycles of adjuvant chemotherapy with Taxotere and Carboplatin. Subsequently, she had a spontaneous pregnancy and experienced a missed abortion. About a year later, Sarah became spontaneously pregnant once again. When she was already 10 weeks into the pregnancy, she came to us seeking genetic counseling and prenatal genetic molecular testing for the 5382insC mutation in BRCA1 for her fetus, after being rejected for oncogenetic counseling at several other clinics in Israel. It is important to note that Sarah already required CVS for cytogenetic testing (karyotype) due to chemotherapy treatment within the previous 2 years. CVS for cytogenetic testing does not provide the DNA required for molecular testing, unless a specific indication is presented. Sarah was the mother of two girls (aged 10 and 8 years). Her family history of cancer includes a mother diagnosed with breast cancer at 46 years of age, a maternal grandmother with skin cancer, and a paternal grandmother with lymphoma. No other family history for cancer was reported. Following the clinical intake, Sarah discussed her motives for seeking PND. Her most significant statement was ‘‘I do not want my baby to suffer as I did.’’ She and her husband were extremely determined to undergo genetic diagnosis for the fetus, whether male or female. This was the first time that we have been requested to provide PND for a mutation in BRCA1/2. Due to the complex nature of this case, we decided to invoke a multidisciplinary team, which included an oncogenetic counselor, a medical geneticist, an obstetrician, and a genetic nurse. We detailed the issues that were raised, debated, and managed along decisionmaking junctions, for example, fetal gender appraisal, cytogenetic evaluation, and whether or not to proceed with PND. Considerations in Genetic Counseling
This case embodies most of the issues regarding PND, and considers PGD, for BRCA1/2 mutation carriers. Focusing on the clinical–ethical considerations and attitudes toward these procedures, this case report gives rise to several questions. What personal and family history of cancer should be considered for PND or PGD? Does the gender of the fetus make a difference? Does the mutated gene, either BRCA1 or BRCA2, make a difference? Is it ethical to allow PND, or otherwise PGD, for late-onset diseases with incomplete penetrance? In other words, in what circumstances should the use of such procedures be considered? Moreover, should these issues be addressed differently in PND and PGD? Clinical considerations
Sarah was diagnosed with early-onset, triple-negative bilateral breast cancer, at 30 and 33 years of age, and was found to be carrying the 5382insC mutation in BRCA1. Early-onset breast cancer ( < 40 years) accounts for 7% – 2% of all breast cancer patients (http://seer.cancer.gov/statfacts/ html/breast.html; Israel Ministry of Health (2006a) National Cancer Registry) (see review by Zhou and Recht, 2004) and for about 5% of all cancer deaths (Kothari and Fentiman, 2002; see review by Zhou and Recht, 2004; Polla´n, 2010; Varga et al., 2010). BRCA1/2 carriers more often present with early-onset breast–ovarian cancer (see review by Robson, 2004) and bilateral breast cancer (Metcalfe et al., 2011a, 2011b). BRCA1-associated tumors are large, display high proliferation, and poor differentiation; and triple-negative
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receptors (Anders et al., 2008), associated as a rule with poor prognosis (Zhou and Recht, 2004; Young et al., 2009; Hall et al., 2010; Varga et al., 2010; Comen et al., 2011; Smith et al., 2011; Southey et al., 2011). The overall survival rate in BRCA1-associated breast cancer patients compared to agematched sporadic breast cancer patients varies among studies, some reporting a poorer prognosis in BRCA1 carriers compared to noncarriers and others showing a similar survival rate (Robson et al., 1998, 1999; Lee et al., 2010; see review by van der Groep et al., 2011). Taking the personal and family history together with the medical data, we can conclude that the potential risk of earlyonset breast cancer for Sarah’s fetus, if female, might be augmented if the 5382insC mutation will be transmitted, taking into account that breast cancer has already appeared in two generations—in Sarah’s mother and in Sarah herself (Gershoni-Baruch et al., 2000; Metcalfe et al., 2010; Litton et al., 2012). The question of poor prognosis and the fear of transmitting the mutation to her offspring, especially females, could not be eliminated, and should be taken into consideration when contemplating PND in such cases. The information presented so far illustrates the medical and clinical issues and might explain the reasons that prompt women to opt for PND or PGD in order not to transfer the bad gene to their children. Psychological considerations
As BRCA1/2 testing becomes increasingly popular, we are encountering a growing number of individuals with unique psychosocial needs and concerns regarding risk reduction modalities and cancer treatment. Moreover, the increasing availability and accessibility of PND and PGD procedures allow to, prenatally, test and thereby avert the long-term consequences of being a BRCA1/2 mutation carrier, as regards the parents and their offspring. The psychological burden in BRCA1/2 mutation carriers has multifactorial facets that relate to issues such as personal and family history of cancer, risk reduction management, and its consequences; and reproduction (see recent review by Stan et al., 2013). Several studies have shown that being at high risk for a lifethreatening inherited disease impacts daily decision-making processes and functioning, overall well-being, and quality of life (Meiser and Halliday, 2002; Meiser et al., 2002; Watson et al., 2004; Dagan and Shochat, 2009; Shochat and Dagan, 2010). These findings were not corroborated by others (see, for example, Schwartz et al., 2002; Arver et al., 2004; Reichelt et al., 2004; Bosch et al., 2012). Sarah’s statement ‘‘I do not want my baby to suffer as I did’’ may highlight the psychological concerns that anguish women with breast cancer, carriers of a BRCA1/2 mutation, regarding their offspring. Although pregnancy in such cases might be considered as a victory over the disease, BRCA1/2 carriers maintain a sense of future threat regarding themselves and their children (Adams et al., 2011; Canada and Schover, 2012; Howard-Anderson et al., 2012). Decision making following PND for a late-onset disease, which preferentially affects females, should be counseled accordingly. BRCA mutation carrier attitudes toward PND versus PGD
Little is known about PGD, and even less regarding PND, in the context of BRCA1/2 testing from the carrier’s
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perspective. It has been clearly shown that women prefer PGD over PND, and even those who were in favor of PGD expressed their concerns about broadening the regulatory guidelines to include hereditary breast–ovarian cancer syndrome (Menon et al., 2007; Ormondroyd et al., 2012). The case presented here is somewhat different. Sarah’s choice of PND seems to represent her personal experience of having coped with aggressive breast cancer for several years and the intolerable fear of transmitting the bad gene. Moreover, she was already 10 weeks into her spontaneous pregnancy, which leaves PND as the sole option. A study performed in Spain, with familial breast–ovarian cancer high-risk individuals, showed that half of the participants believed that they would consider PND or PGD if they were to receive a positive BRCA1/2 genetic test result. In addition, more than 10% of individuals reported that they would consider adoption or remaining childless if they were to receive a positive test result (Smith et al., 2004; Fortuny et al., 2009). Several reports showed that women with a BRCA1/2 mutation generally held positive attitudes toward PGD (Menon et al., 2007; Quinn et al., 2009, 2010; Vadaparampil et al., 2009), and couples who were planning future pregnancies preferred PGD over the option of terminating a pregnancy as with PND. In 2006, PGD for late-onset diseases was authorized by the Israel Ministry of Health, and the Hadassah Hebrew University Medical Center reported their clinical experience with PGD for BRCA1/2 mutation carriers. During a 2-year period, all women declined the option of PND and out of 10 BRCA1/2 mutation carriers, six women opted for IVF/PGD (Sagi et al., 2009). Although PND is less acceptable than PGD among BRCA1/2 carriers, Sarah’s story represents those cases that should be considered for PND by genetic counselors.
aspects are becoming more and more commonplace in the everyday clinical setting.
Healthcare perspectives
A review of the few surveys of the reproduction options for BRCA1/2 carriers, from a healthcare professional perspective, revealed that individuals at risk for adult-onset hereditary cancer syndromes should be offered PND and PGD. Moreover, the information should be received at high-risk and cancer prevention units and should include all of the available assistant reproduction technology (ART) options (Sermon, 2002; Smith et al., 2004). However, only 30% of those with hereditary breast–ovarian cancer syndrome or FAP are actually referred to such clinics by their primary physicians and/or their oncologists (Brandt et al., 2010). The ambiguous situation regarding PND and PGD for both patients and health professionals, especially in countries where the ruling is not yet clearly defined, is reflected by a study of cancer geneticists in France. The study showed that the information regarding ART is given spontaneously, and if PND and PGD procedures would be authorized for BRCA1/2 mutations in France, geneticists would refer their at-risk patients to authorized clinics ( Julian-Reynier et al., 2009). With the increasing availability of genetic diagnosis, healthcare professionals are continually encountering ethical questions, such as whether or not to do a PND and/or PGD for BRCA1/2 mutation carriers. With the increasing focus of genetic counseling and diagnosis on late-onset diseases, including cancer, Parkinson’s disease, and others, these ethical
Ethical considerations and regulations across countries
A review of the regulations, the selection of indications and the criteria for reimbursement regarding the PGD procedure, has revealed differences between countries. The severity and the noncurability of a disease are the two main criteria adopted in most European countries for performing PND or PGD (BOE, 2006; HFEA, 2006; Israel Ministry of Health, 2006b; Aarden et al., 2009). The patients’ personal and family clinical histories and their perspectives regarding disease susceptibility are also relevant criteria for genetic specialists to consider when offering PND or PGD to individuals at risk ( Julian-Reynier et al., 2009). For example, in the United Kingdom, on May 10, 2006, the Human Fertilization and Embryology Authority (HFEA), which regulates assisted reproduction, decided to include susceptibilities to certain cancers in the PGD permission criteria. HFEA agreed to license PGD for inherited breast, ovarian, and bowel cancer because of their aggressive nature and the extreme anxiety that mutation carriers might experience. However, they were aware that these conditions have different impacts on individual families and the authority reserved the right to review factors around a particular condition, including its treatment options, as well as the views and experience of the carriers (Braude, 2006; HFEA, 2006; Menon et al., 2007). In practice, laboratories authorized to perform PGD can offer BRCA1/2 testing for high-risk individuals whose families have known mutations. In December 2006, the Israel Ministry of Health published directives for performing PGD, in which incomplete penetrance and other types of inheritance were added to the monogenic early-onset incurable criteria. However, PGD for severe diseases, such as predisposition for cancer, is under the evaluation of the National Council for Bioethics. As a standard of care, PGD performance is based on the same criteria as PND performed for genetic disorders. Nevertheless, the Israel Society of Medical Genetics should frequently reevaluate the criteria for PGD in light of the medical and technological developments in genetic diagnosis (Israel Ministry of Health, 2006b). The directions are somewhat vague, since practically, genetic centers in Israel that offer PGD for traditional monogenic syndromes may consider diagnosis for cancer predisposition, including BRCA1/2. An analysis of the differences between countries showed that, in Germany and Italy, authorization of PGD for women with BRCA1/2 mutations still has a long way to go. In these two countries, the indication criteria for PGD are narrower than for PND. In Israel, the United Kingdom, France, Spain, and other countries, however, these procedures are permitted (BOE, 2006; HFEA, 2006; Israel Ministry of Health, 2006b; Turillazzi and Fineschi, 2008; Julian-Reynier et al., 2009). Some clinics in the United Kingdom perform PGD for BRCA1/2, but funding still depends on the region. In 2006, the Israel Ministry of Health authorized these procedures for low-penetrance susceptibilities, including cancer. In France and Spain, PGD for selection of non-BRCA1/2 embryos would require an individualized case-by-case analysis and the process might not be straightforward (Fortuny et al.,
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2009). Other countries are moving toward providing these procedures: in the Netherlands, PGD for BRCA1/2 is not yet reimbursed, but progress is being made in that direction, and in Belgium, a protocol for PGD in two couples with two different BRCA1 mutations was performed in 2007, showing that it was practically feasible to identify carrier and noncarrier embryos (Spits et al., 2007). It seems that in most Western countries, PGD is permitted under certain circumstances, and in several countries, even PND. Israel and Germany are at the opposite ends of the provision - prohibition continuum of PND/PGD for cancer susceptibilities, and the other countries are somewhere in between. Analyzing the reasons underlining the criteria for PND/PGD for late-onset diseases in each country is beyond the scope of this discussion. However, it provides food for thought regarding the complex ethical values relating to family and society with respect to ART in different countries. Summary
This report exposes complicated decision-making considerations underlying genetic counseling and diagnosis when PND is being offered for controversial diseases. Aborting a pregnancy for a late-onset disease with incomplete penetrance, for example, breast cancer, might leave clinicians with feelings of discomfort. It should be noted that even though PND and PGD tend to be discussed together, the clinical, psychological, and ethical issues they raise are essentially different. The genetic counseling provided should consider the implications of each procedure, namely, IVF and PGD or PND that may lead to a pregnancy termination. Our clinical experience shows that a multidisciplinary approach is most effective for discussing the relevant concerns. The genetic counselor’s role is to divulge the clinical and psychological facets and esteem the ethical directives and regulations of the country. In the Israeli context, PGD is acceptable for BRCA1/2 mutation carriers and the decision of whether or not to undergo this procedure rests with the parents (Israel National Bioethics Council, 2008). Nevertheless, termination of pregnancy following PND should be subject to the jurisdiction act. The genetic counseling process, in cases similar to Sarah’s, encounters several decision-making phases that incorporate the clinical and family history with the patient’s needs and preferences. Although this guideline may seem obvious, Sarah’s case indicates otherwise, as she was denied genetic counseling by several medical centers. It is important to note that attitudes may change during the counseling process. This is reflected by both Sarah’s and her husband’s approach to PND based on the baby’s gender. In the initial counseling session, Sarah and her husband were determined to undergo PND for either male or female fetus. However, they withdrew their request for PND when they realized that Sarah carried a boy, thereby concluding the genetic counseling process. About 2 years later, liver metastases and positive axillary lymph nodes were diagnosed with triple-negative receptors. Our last follow-up revealed that Sarah was having chemotherapy once again. Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to: Efrat Dagan, RN, LGC, PhD Department of Nursing University of Haifa Mount Carmel Haifa 31905 Israel E-mail: [email protected]
