Embed Size (px)
Citation preview
I
SgaBhgasvctaotfct
bmocftiiitb
ei
ACHv
2©I
Genetic Testing for Breast and Ovarian CancerSusceptibility: A Family ExperienceMarcia Van Riper, RN, PhD, and Wendy C. McKinnon, MS, CGC
The purpose of this article is to provide an overview of current knowledge concerning genetic testing forbreast and ovarian cancer susceptibility. This overview includes 1) a brief history of genetic testing for breastand ovarian cancer susceptibility, 2) a review of factors that midwives and other health care providers needto consider before offering this type of testing to their clients, 3) management options for clients at high riskfor hereditary breast and ovarian cancers, and 4) a discussion of preliminary findings from an ongoing studyconcerning the family experience of genetic testing, which illustrates some of the ethical issues that emergefor individuals and families during the family experience of genetic testing for breast and ovarian cancersusceptibility. J Midwifery Womens Health 2004;49:210–219 © 2004 by the American College ofNurse-Midwives.
keywords: breast and ovarian cancer susceptibility, genetic testing, management optionsotfgpdcni
cobsotfcotft
HC
IciaTcoks
cc
NTRODUCTION
ignificant advances have been made in understanding theenetic components of breast and ovarian cancer.1 Genesssociated with an increased risk of these cancers, such asreast Cancer 1 (BRCA1) and Breast Cancer 2 (BRCA2),ave been cloned, and genetic tests for mutations in theseenes have been available for almost a decade. The avail-bility of genetic testing for breast and ovarian cancerusceptibility affords unprecedented opportunities for indi-iduals and families to learn whether they have an in-reased risk for developing these potentially fatal condi-ions. Even more importantly for some individuals, thevailability of genetic testing gives them a chance to findut if they have the potential to transmit genetic mutationso their offspring.2 Awareness of genetic risk can alsoacilitate informed health care decisions and, in some cases,an promote risk reduction behaviors that have the potentialo reduce morbidity and mortality.3
Although the increased availability of genetic testing forreast and ovarian cancer susceptibility has the potential toake important contributions to the health and well-being
f individuals and families at increased risk for theseancers, it also has the potential to create moral quandariesor these same individuals and their families.4–9 Accordingo Thomson,10 the major risk associated with genetic testings that of gaining information: information that may resultn increased anxiety, altered family relationships, discrim-nation, or stigmatization; information that may be difficulto keep confidential; and information about which little cane done, in most cases.Currently, many health care providers lack the knowl-
dge base necessary to help individuals and families makenformed decisions about genetic testing for breast and
ddress correspondence to Marcia Van Riper, RN, PhD, School of Nursing,arolina Center for Genome Sciences, University of North Carolina at Chapelill, Carrington Hall CB #7460, Chapel Hill, NC 27599. E-mail:
102004 by the American College of Nurse-Midwives
ssued by Elsevier Inc.
varian cancer susceptibility. This is due, in part, to the facthat many health care providers have had little, or no,ormal education in genetics.11–13 In addition, advances inenetics have been occurring so rapidly, some health careroviders may find it difficult to keep abreast with newiscoveries. Finally, for some health care providers, espe-ially primary care providers, the relevance of genetics mayot be obvious14 and because of this, they may have minimalnterest in becoming better educated about genetics.12
The purpose of this article is to provide an overview ofurrent knowledge concerning genetic testing for breast andvarian cancer susceptibility. This overview includes 1) arief history of genetic testing for breast and ovarian cancerusceptibility, 2) a review of factors that midwives andther health care providers need to consider before offeringhis type of testing to their clients, 3) management optionsor clients at high risk for hereditary breast and ovarianancers, and 4) a discussion of preliminary findings from anngoing study concerning the family experience of geneticesting, which illustrates some of the ethical issues that emergeor individuals and families during the experience of geneticesting for breast and ovarian cancer susceptibility.
ISTORY OF GENETIC TESTING FOR BREAST AND OVARIANANCER SUSCEPTIBILITY
t is estimated that 5% to 10% of all breast and ovarianancers are hereditary cancers15,16 and can be attributed tonheritance of a mutation in a gene associated with breastnd ovarian cancer susceptibility, such as BRCA1, BRCA2,P53, and pTEN.17 Another 15% to 20% of female breastancers occur in women who have a strong family historyf breast and ovarian cancer but do not carry one of thenown mutations associated with breast and ovarian cancerusceptibility.18
BRCA1, the first gene associated with breast and ovarianancer susceptibility to be identified, was mapped onhromosome 17 in 1990 and cloned in 1994.19 The second
ajor gene associated with breast and ovarian cancerVolume 49, No. 3, May/June 20041526-9523/04/$30.00 • doi:10.1016/j.jmwh.2004.01.021
sctcticcBdtcmgctOm
ccmaBsT5ohgcefociBaaNi
t9fpfpa
bekamipmcpatfgc
F
Tpfcotct
CO
Twdta4wti1dBbs
R
Aactsc3B1
MNN
WFo
J
usceptibility, designated as BRCA2, was mapped onhromosome 13 in 1994 and cloned in 1995.20 BRCA2 iswice as large as BRCA1. The precise nature of theontribution of BRCA1 and BRCA2 remains a mystery, buthese genes encode for very large proteins that have beenmplicated in a number of processes fundamental to allells, including DNA repair and recombination, checkpointontrol of cell cycle, and transcription.21 Mutations in theRCA1 and BRCA2 genes are inherited in an autosomalominant pattern, so each offspring of an individual foundo carry one of these mutations has a 50% chance ofarrying the same mutation. More than 2,000 distinctutations and sequence variations BRCA1 and BRCA2
enes have been identified. Most of these mutations trun-ate the protein product.22 However, some of these muta-ions are missense mutations that alter a single amino acid.verall, mutations in BRCA genes account for approxi-ately 70% of hereditary breast and ovarian cancers.23
Genetic testing for BRCA1 and BRCA2 mutations isommercially available through Myriad Genetics, a privateompany that holds at least 17 patents worldwide on BRCAutation testing.24 The cost for this testing ranges from
round $2,760 for full sequencing of the BRCA1 andRCA2 genes to $325 for an analysis of a single mutation
ite in relatives of an individual with an identified mutation.he cost for an analysis of three mutations (185delAG,382insC, and 6174delT) commonly found in individualsf Ashkenazi Jewish descent is $385. Although manyealth insurance plans will pay all or part of the cost ofenetic testing for BRCA mutations, some individualshoose to self-pay because they are afraid of insurance andmployment discrimination.25 Others apply for assistancerom the Myriad Financial Assistance (Hardship) Programr charitable organizations, such as local and state breastancer support programs. Individuals and families involvedn research concerning BRCA mutations may be able to getRCA testing done at little or no cost. In 2000, angreement was made between the National Cancer Institutend Myriad Genetics to offer researchers funded by theational Institutes of Health access to full BRCA sequenc-
ng for $1,200 per person.26
On the basis of preliminary reports, it was predicted thathere would be strong interest in BRCA testing (72%–1%), both in the general population and for high-riskamilies.27–29 To date, actual uptake has been less than wasredicted.30,31 In a recent study of women at average riskor breast cancer,32 41% of the women indicated that theyrobably or definitely would pursue BRCA testing. Pressnd colleagues33 found that interest in genetic testing for
arcia Van Riper, RN, PhD, is an Associate Professor at the University oforth Carolina at Chapel Hill. She has a joint appointment in the School ofursing and the Carolina Center for Genome Sciences.
endy C. McKinnon, MS, CGC, is a Certified Genetic Counselor in theamilial Cancer Program and a Clinical Associate Professor in the Department
tf Pediatrics at the University of Vermont, College of Medicine.
ournal of Midwifery & Women’s Health • www.jmwh.org
reast cancer susceptibility appeared to be shaped by anxaggerated sense of vulnerability to breast cancer, limitednowledge about genetic susceptibility testing, and gener-lly positive views about information provided throughedical screening. Participants in the study were most
nterested in a genetic test that does not exist (high positiveredictive value followed by effective, non-invasive treat-ent) and were less interested in the genetic test for breast
ancer susceptibility that does exist (less than certainositive predictive value, low negative predictive value,nd limited, invasive, and objectionable therapeutic op-ions). These findings suggest that women at average riskor breast cancer may not be aware of the limitations of theenetic testing for breast cancer susceptibility that isurrently being offered.
ACTORS TO CONSIDER BEFORE OFFERING GENETIC TESTING
he main factors that midwives and other health careroviders need to consider before offering genetic testingor breast and ovarian cancer susceptibility are 1) thelient’s estimated risk of developing hereditary breast andvarian cancer, 2) benefits, risk, and limitations of geneticesting for breast and ovarian cancer susceptibility, and 3)urrent recommendations concerning when to offer geneticesting for breast and ovarian cancer susceptibility.
lient’s Estimated Risk of Developing Hereditary Breast andvarian Cancer
he American Cancer Society estimates that in 2003 thereill be 211,300 new cases of invasive breast canceriagnosed among women in the United States.34 In addi-ion, there will be 55,700 new cases of in situ breast cancernd 25,400 new cases of ovarian cancer. An estimated0,000 women will die of breast cancer in 2003 and 14,300omen will die of ovarian cancer. According to a report by
he National Cancer Institute,35 a female infant born todayn the United States has a 1 in 8 chance (approximately3.3%) of being diagnosed with breast cancer sometimeuring her lifetime. However, if she inherits a BRCA1 orRCA2 mutation from one of her parents, her chance ofeing diagnosed with breast cancer or ovarian cancer isignificantly increased.
isks Associated With BRCA Mutations
lthough it is clear that inherited mutations in the BRCA1nd BRCA2 genes confer high risks of breast and ovarianancer, the exact magnitude of these risks remains uncer-ain (Table 1). In a metanalysis36 that included data from 22tudies, the average cumulative risks in BRCA1-mutationarriers by age 70 years were 65% for breast cancer and9% for ovarian cancer. Corresponding estimates forRCA2-mutation carriers were 45% for breast cancer and1% for ovarian cancer. Recently reported findings from
37
he New York Breast Cancer Study suggest higher risks211
oBBctdatc
ltccmapaCcid
M
CmcbbpWmtamcd
pafitlma /
2
f breast cancer in BRCA mutation carriers: 69% forRCA1-mutation carriers by age 70 years and 71% forRCA2-mutation carriers. Risks of developing a secondontralateral breast cancer have been reported to be 64% byhe age of 70 years38 or 20% within 5 years of the initialiagnosis in persons who are BRCA1-mutation carriers39
nd 50% by the age of 70 years40 or 12% within 5 years ofhe initial diagnosis in persons who are BRCA2-mutationarriers.41
Men found to carry a BRCA2 mutation have a 6%ifetime risk of developing male breast cancer.40 In addi-ion, even though only a small percentage of the men whoarry a BRCA mutation develop breast cancer, all men whoarry a BRCA mutation have a 50% chance of passing theutation on to their offspring. BRCA mutations also confer
n increased risk of prostate cancer.22 The increased risk forrostate cancer is threefold for BRCA1-mutation carriers22
nd three- to sevenfold for BRCA2-mutation carriers.40
arriers of BRCA1 mutations are also at increased risk forolon cancer,23 and carriers of BRCA2 mutations are atncreased risk for pancreatic cancer, gallbladder and bileuct cancer, stomach cancer, and malignant melanoma.42,43
Table 1. Risk of Developing Cancer in Persons With BRCA1 and BRCA2 M
Type of Cancer General Popula
Breast (female)By 70 years of age (%) 11
2nd breast cancer Based on family hBy 70 years of age (%)Within 5 years of 1st breast cancer (%)
Breast (male) (%)Ovarian (%) 1.5Prostate
Table 2. Two Models for Estimating Lifetime Risk of a Women Developing
Model Factors Considered
Gail model http://www.nci.nih.gov
● Current age● Age at menarche● Age at 1st live birth● Number and outcome of
previous breast biopsies● Presence of atypical
hyperplasia● Number of 1st-degree relatives
with breast cancer
Validated asin womenmammogr
Claus model ● Current age● Number of 1st- and 2nd-
degree relatives with breastcancer
● Age of cancer onset
Most effectivrisk of brewhich onlyhave canc
12
odels for Estimating Risk
urrently, two models, the Gail model44,45 and the Clausodel,46 are widely used in research studies and clinical
ounseling to predict a woman’s lifetime risk of developingreast cancer (Table 2). Calculation of a 5-year and lifetimereast cancer risk according to the Gail model44,45 can beerformed by accessing the National Cancer Institute’seb site (http://www.nci.nih.gov) and searching for infor-ation on breast cancer risk.17 The Claus model46 projects
he probability of developing breast cancer for women withfamily history of breast cancer. As noted in Table 2, bothodels have limitations, but they are the best methods
urrently available for predicting a woman’s lifetime risk ofeveloping breast cancer.In addition to the models that have been developed to
redict lifetime risk of breast cancer, there have also beent least two models developed to estimate the likelihood ofnding a BRCA mutation (Table 3). Using the first of these,
he Myriad model, health care providers can estimate theikelihood of their client being a carrier of a BRCAutation by using a table of mutation prevalence data
vailable on the Myriad Web site (http://www.myriad.com
BRCA1 Mutation BRCA2 Mutation
56–8724,36,37,39 45–7136,37,40
6438 5040
2039 1241
? increased risk 640
39–6023,36 11–2723,36
3-fold increased risk23 3–7-fold increased risk40
Cancer
tages Limitations
ctor of breast cancerdergo regularreening
Overestimates risk in women who do not getscreening regularly
Less accurate in predicting hereditary breast andovarian cancer because it fails to take intoaccount paternal transmission of cancermutations, 2nd-degree relatives, age atdiagnosis, ethnicity, and other types of cancer
luating the lifetimecer in families intwo family members
Maximum number of affected family membersthe model can accommodate is two
Underestimates risk when there is a highlikelihood of a BRCA mutation because it doesnot consider ovarian cancer and paternaltransmission
utations
tion
istory
Breast
Advan
a prediwho unaphy sc
e in evaast canone or
er
Volume 49, No. 3, May/June 2004
gBtmpm u/b
R
AeccwgtcwtfImmFcbhhtbalob
GS
OfogoNmmfctbouit
B
Ot
J
tmp.html). The second model, a computer program calledRCAPRO,47–49 allows the health care provider to estimate
he probability of their client carrying a BRCA1 or BRCA2utation using data from published studies of prevalence,
enetrance, and mutation frequency. Information about thisodel can be found at http://www.astor.som.jhmi.edrcapro/.
ole of Family Pedigree in Estimating Risk
lthough the models described above can be helpful instimating a client’s risk of developing breast and ovarianancer, they should not be the only approach used by healthare providers. The models need to be used in conjunctionith data from a family pedigree that spans at least threeenerations. The family pedigree should include informa-ion such as who in the family had cancer, what type ofancer family members had, how old family members werehen they were diagnosed with cancer, surveillance and
reatment choices made by family members, and how oldamily members who died of cancer were when they died.t is important that the pedigree includes both paternal andaternal lineage because fathers are just as likely asothers to transmit BRCA mutations to their children.eatures revealed in the family pedigree will help healthare providers identify individuals and families who shoulde offered genetic testing because of their increased risk forereditary breast and ovarian cancer. Features suggestive ofereditary breast and ovarian cancer are listed in Table 4. Ifhe total number of female family members is small, it maye difficult to estimate the client’s risk for hereditary breastnd ovarian cancer. In addition, if the family is extremelyarge, with many female family members, the client’s riskf developing a hereditary breast and ovarian cancer may
Table 3. Two Models Available for Estimating the Likelihood of Finding a
Model Factors Considered
Myriad model ● Age at breast cancerdiagnosis
● Family history information● Presence of ovarian cancer in
the family● Ethnicity
Health care provider(http://www.myriaBRCA mutation.
BRCAPRO ● Age at breast cancerdiagnosis
● 1st- and 2nd-degree familyhistory
● Presence of male and femalebreast cancer
● Presence of ovarian cancer● Ethnicity● Size of family
Health care providerby using this compenetrance, and mwww.astor.som.jhm
e overestimated.
ournal of Midwifery & Women’s Health • www.jmwh.org
ENETIC TESTING FOR BREAST AND OVARIAN CANCERUSCEPTIBILITY
nce it has been determined that a client is at increased riskor breast and ovarian cancer, the client should be given anpportunity to discuss the benefits, risks, and limitations ofenetic testing. The client needs to understand that this typef genetic testing is inherently a family experience.5–7,50–52
ot only will the results have implications for other familyembers, but also the ability to do testing in an effectiveanner depends heavily on the willingness of one or more
amily members who have already been diagnosed withancer to undergo the testing first. In some families, theesting of an affected family member may not be possibleecause the affected family member has already died. Inther families, the affected member may be living butnwilling or uninterested in being tested. This may lead tompaired family communication and altered family rela-ionships.4,50–52
enefits of Genetic Testing
ne of the most frequently mentioned benefits of geneticesting for breast and ovarian cancer susceptibility is the
utation
Use by Health Care Providers
se a table of mutation prevalence data, available on the Myriad Web sitetmp.html ), to estimate the likelihood of their client being a carrier of a
stimate the likelihood of their client carrying a BRCA1 or BRCA2 mutationrogram, which is based on data from published studies of prevalence,
frequency. Further information about this model can be found at http://rcapro/.
Table 4. Features Suggestive of Hereditary Breast/Ovarian Cancer
● Diagnosis of breast cancer before age 50● Bilateral breast cancer● Breast and ovarian cancer in the same individual● Personal or family history of male breast cancer● Ashkenazi Jewish ancestry in association with a personal and/or
family history of breast and/or ovarian cancer● Multiple cases of early-onset breast cancer (�age 50) and ovarian
cancer at any age● Autosomal dominant pattern of inheritance● Presence of other cancers associated with mutations in BRCA genes
(i.e., prostate, pancreatic, gallbladder/bile duct, melanoma)
BRCA M
s can ud.com/g
s can eputer putationi.edu/b
213
ogsdfoibstrs
R
PctftotgroifcpteBoftdt
L
GhroBgeddmgitata
md
CT
Ipc“(stwmrbwbt
csbtrbbwa
MF
Ioiseew
2
pportunity to learn if one has the potential to transmitenetic mutations to one’s offspring.4,7,53 Another pos-ible benefit is the ability to learn one’s own risk foreveloping hereditary breast and ovarian cancer.54 Reliefrom the uncertainty associated with not knowing one’swn genetic status has the potential to dramaticallympact individual and family well-being.31 An additionalenefit of genetic testing for breast and ovarian cancerusceptibility is the ability to use the information ob-ained through genetic testing to individualize cancerisk management and promote risk reduction behaviors,uch as lifestyle changes.54,55
isks of Genetic Testing
otential risks of genetic testing for breast and ovarianancer susceptibility include: psychological distress, poten-ial loss of privacy, change in family dynamics, potentialor genetic discrimination, increased medical expenses dueo additional screening and surveillance, and a false sensef security.28,31,52,54,56–60 Findings from a recent review ofhe literature concerning the psychological implications ofenetic testing suggest that the severity of psychologicalisks posed by genetic testing may not be as great as wasriginally anticipated.61 However, certain subgroups ofndividuals may be more vulnerable to adverse ef-ects.55,56,62 Feelings of guilt may be experienced by botharriers and non-carriers of the BRCA mutation. Parents, inarticular, may feel guilty about the possibility of passinghe mutation onto their children. Non-carriers may experi-nce “survivor guilt.” Individuals found to be carriers of aRCA mutation have reported that informing their relativesf the “bad news” is stressful and burdensome.2,7 Manyamilies continue to fear genetic discrimination,26,53,54 evenhough there have been no well-documented cases thatemonstrate discrimination based on the results of a geneticest for breast and ovarian cancer susceptibility.17
imitations of Genetic Testing
enetic testing for breast and ovarian cancer susceptibilityas a number of limitations. One limitation is that theesults indicate the probability, not the certainty, of devel-ping cancer. Not all individuals who test positive forRCA mutations develop cancer. Another limitation is thatenetic testing may miss a BRCA mutation that actuallyxists in the family, especially if the mutation is a largeeletion.17 DNA sequencing may fail to pick up largeeletions because the presence of a normal copy of the geneakes the result appear normal. A third limitation of
enetic testing for breast and ovarian cancer susceptibilitys that the family may have a mutation in a gene other thanhe breast and ovarian cancer susceptibility genes that havelready been identified. A fourth limitation is that a nega-ive result is fully informative only if the mutation has
lready been identified in a family member. Finally, to date, c14
edical interventions have not been proved to prevent theevelopment of breast and ovarian cancer.
urrent Recommendations Concerning When to Offer Geneticesting
n April 2003, the American Society of Clinical Oncologyublished the following update on their policy statementoncerning genetic testing for cancer susceptibility.63
ASCO recommends that genetic testing be offered when1) the individual has personal or family history featuresuggestive of a genetic cancer susceptibility condition, (2)he test can be adequately interpreted, and (3) the resultsill aid in diagnosis or influence the medical or surgicalanagement of the patient or family members at hereditary
isk of cancer. ASCO recommends that genetic testing onlye done in the setting of pre- and post-test counseling,hich should include discussion of possible risks andenefits of cancer early detection and prevention modali-ies.”63
If a client has no family history of breast or ovarianancer, the client’s risk of developing breast cancer isimilar to that of an average-risk individual, so there woulde little justification for the client undergoing BRCAesting.64 Moreover, testing could cause harm through falseeassurance and its consequences. The client could end upelieving that her risk of breast cancer is lower than averageecause her results were negative, when in fact, her riskould stay the same because she was not expected to haveBRCA mutation.
ANAGEMENT OPTIONS FOR CLIENTS AT INCREASED RISKOR HEREDITARY BREAST AND OVARIAN CANCERS
ndividuals at increased risk for hereditary breast andvarian cancer have many options to consider, such asncreased surveillance, chemoprevention, and prophylacticurgeries (Table 5). These options are largely based onxpert opinion, and long-term studies demonstrating theirfficacy have yet to be completed. There is evidence that inomen with a strong family history of breast and ovarian
Table 5. Management Options for Individuals at Increased Risk forHereditary Breast and Ovarian Cancer
Management Options Breast Cancer Ovarian Cancer
Increased surveillance Self-breast examinationClinical breast
examinationMammographyUltrasoundMRI
Pelvic examinationCA-125Transvaginal
ultrasound
Chemoprevention Tamoxifen Oral contraceptivesProphylactic surgery Prophylactic mastectomy
Prophylactic oophorectomyProphylactic
oophorectomy
ancer, a prophylactic mastectomy can decrease the inci-
Volume 49, No. 3, May/June 2004
dttcFtrapo
asaioaaow
hdmheosnaag
EE
MgiftttaesbFttBtchht
tbsda
brupeefndtturegiiatac
aeccsmtDBoeebdmtvfaf
I
Mhrs
J
ence of breast cancer by 90%.65 There is also evidencehat a prophylactic oophorectomy can significantly reducehe risk of ovarian cancer, epithelial cancer, and breastancer in women with BRCA1 or BRCA2 mutations.66
indings from a study by Tiller and colleagues67 suggesthat undergoing a prophylactic oophorectomy may helpeduce anxiety about ovarian cancer in high-risk women,nd the benefit of anxiety reduction may outweigh theotential adverse effects of undergoing a prophylacticophorectomy.Unfortunately, findings from other studies have not been
s promising. Liede and colleagues68 concluded that inten-ive surveillance with CA-125 and ultrasound may not ben effective means of diagnosing early-stage ovarian cancern Jewish women at high risk for hereditary breast andvarian cancer. At a recent symposium on ovarian cancernd high-risk women, it was concluded that better methodsre urgently needed to prevent, detect, and screen forvarian cancer in all women, but particularly in high-riskomen carrying BRCA1 and BRCA2 mutations.69
Health care providers need to make sure that their clientsave a good understanding of available options before anyecisions are made about screening and surveillance, che-oprevention, or prophylactic surgery. Although some
ealth care providers have the training and expertise nec-ssary to adequately discuss these options with their clients,thers do not and they need to refer their clients to geneticpecialists, such as genetic counselors, advanced practiceurses and physicians assistants with expertise in genetics,nd geneticists. Many medical centers have genetics clinicsnd familial cancer programs. Some also have outreachenetic clinics. See Appendix A for a list of resources.
THICAL ISSUES THAT EMERGE DURING THE FAMILYXPERIENCE OF GENETIC TESTING
uch has been written about the ethical implications ofenetic testing for breast and ovarian cancer susceptibil-ty.9,70,71 However, little of this work has been from aamily perspective. This is unfortunate because the litera-ure that does exist about the family experience of geneticesting for breast and ovarian cancer susceptibility suggestshat the decision to undergo genetic testing is seldom anutonomous decision based solely on the needs and pref-rences of the individual being tested.2,4–7,50–52,70,74 In-tead, it is often a decision based on feelings of responsi-ility and commitment to others, usually family members.4
or example, a woman who is currently receiving radiationreatment for breast cancer may decide to undergo BRCAesting not because she wants to find out if she carries aRCA mutation, but because her two sisters have asked her
o be tested and she feels a sense of responsibility andommitment to them. Or a woman with a strong familyistory of breast and ovarian cancer, who previously deniedaving any interest in testing, decides to be tested. Again,
he reason she decided to be tested was not that she wanted uournal of Midwifery & Women’s Health • www.jmwh.org
o find out if she carries a BRCA mutation. She decided toe tested because she now has a daughter and she feels thathe “owes it to her daughter” to be tested. In both cases, theecision to be tested was based on a sense of responsibilitynd commitment to others.
The fact that decisions about genetic testing are oftenased on feelings of responsibility and commitment,2,4
ather than personal choice, means that for many individ-als and families, the genetic testing experience is aotentially life-changing experience filled with complexthical issues. Some of the ethical issues that commonlymerge during genetic testing include concerns about in-ormation and informed consent; the right to be tested orot; the rights of others; confidentiality and privacy; risk ofiscrimination; justice; direct marketing of genetic testingo consumers; and responsibility to future genera-ions.8,72–74 Individuals who feel obligated or pressured tondergo genetic testing because of familial or occupationalesponsibilities are likely to experience more difficulty withthical issues than individuals who choose to undergoenetic testing because they believe that acquiring geneticnformation will support their personal and relational activ-ties. That is, they have decided that the information theyre able to acquire through genetic testing will be useful tohem—it fits with their personal values, beliefs, and needs,nd it acknowledges their feelings of responsibility andommitment.
In the final part of this article, preliminary findings fromn ongoing study are presented to illustrate some of thethical issues experienced by individuals and families whohoose to undergo genetic testing for breast and ovarianancer susceptibility. The overall purpose of the ongoingtudy is to explore how individuals and families define andanage the ethical issues that emerge during four different
ypes of genetic testing: maternal serum screening forown syndrome, carrier screening for cystic fibrosis (CF),RCA testing for families at increased risk for breast andvarian cancer, and mutation analysis for Huntington dis-ase. Families were recruited from a variety of sites in theastern United States. Approvals from institutional reviewoards were obtained before initiation of data collection. Toate, in-depth interviews have been conducted with one orore family members from 45 families. The number and
ype of ethical issues experienced by family membersaried from one family to the next, but family membersrom all 45 families experienced ethical issues. For thisrticle, only data from the 15 families in which at least oneamily member underwent BRCA testing were used.
nformation/Informed Consent
ost of the family members who underwent BRCA testingad been seen at a familial cancer center where they hadeceived pre- and postgenetic counseling from a geneticpecialist, usually a genetic counselor. All of these individ-
als appeared to have received the information and support215
ttttTvp
R
Avfut
,
BaoisManiostgItaAs
r,
o
R
WmmhfrfvttdsowFfigsa“a3
C
Mvs
Aits
C
GicBh
2
hey needed to make well-informed decisions. Typically,hey were very pleased with the care they received. Unfor-unately, a few family members, who did not receive carehrough a familial cancer center, were not so fortunate.hey received minimal pre- and postcounseling. One indi-idual received his results, which were positive, over thehone.
ight to Be Tested or Not
lthough the genetic testing experience was typicallyiewed as a family experience—one that impacts the wholeamily, not just the individual tested—the right of individ-al family members to make their own decisions aboutesting was generally respected. One woman said,
I actually had decided not to do the genetic testingbecause I felt like, well I know I’ve got breastcancer, what difference does it make if I have thegene, the mutation. Then, I talked it over with mytwo daughters and my sisters. My sisters said, “Dowhatever you want.” One of my daughters said,“Mom, whatever you feel comfortable doing is finewith me.” The other one said, “I really would ratheryou didn’t do it because if you do have the genemutation, I don’t want that thought in my mind. Idon’t want that negative tape.”. . . Then we weretalking one day and she said, “You know, I thinkthat I am kind of interested to find out. If you stillfeel like doing the genetic testing, then go aheadand do it.” So, I did and it came out negative, whichwas surprising to me.
ecause BRCA testing requires that testing be done first onn affected family member (one who has had breast orvarian cancer), some family members who had no interestn, or were opposed to testing, were encouraged to recon-ider their decision “for the good of other family members.”ost of the time, the affected individual did eventually
gree to be tested. However, in two of the families, this didot occur. In both of these families, the affected sisterndicated that she refused testing because of something thether sister had said or done. In the first family, the affectedister refused testing because the other sister had indicatedhat if she ended up having a BRCA mutation, she was notoing to have prophylactic surgery or do chemoprevention.n the second family, the affected sister refused to undergoesting because the other sister had refused prenatal testingnd ended up giving birth to a child with Down syndrome.ccording to the sister who had a child with Down
yndrome,
My sister said that because I didn’t use genetictesting to terminate a pregnancy affected by Downsyndrome and make life better for the world, shewouldn’t use genetic testing to help me find out if wehad a family thing.. . . Personally for me there is a
difference between a baby and a breast, but every- b16
body sees the world differently. She just could neveget past that. She could just never, to her dying daybelieve that we brought this person (the child withDown syndrome) into the world. She said no womanon the planet would do what I did, refuse to have anamnio. She said that nobody who was sane would dwhat I did, nobody who was sane would bring aretarded person into the world.
ights of Others
hen asked why they chose to undergo BRCA testing,ost indicated they did it for their children and other familyembers. This was especially true for family members who
ad already had breast or ovarian cancer. All 10 of theamily members who tested positive for a BRCA mutationeported feeling a responsibility or obligation to tell otheramily members. However, who, when, and how they toldaried from person to person. Some only told members ofheir immediate family, whereas others told members ofheir extended family. Some shared the information imme-iately, whereas others waited until the “right time.” Forome family members, the right time had to do with the agef the family member being told or when key life decisionsere being made (e.g., getting married, having children).or others it was more pragmatic; they waited until the nextamily gathering to tell them. A number of individualsndicated that they needed time to make sense of their ownenetic status before they could tell others. In addition,ome family members reported experiencing what Forrestnd colleagues6 have described as a “disclosure dilemma,”they were torn between a desire to tell at the right time andneed to protect relatives from harmful information” (p.
23).
onfidentiality and Privacy
ost families had concerns about confidentiality and pri-acy. One woman, who chose to use a different name whenhe was tested for BRCA mutations said,
At that time, I didn’t want anything in my records. Itwas five years ago, so it was still pretty new as farlegislation goes. I just wanted it for me.
nother woman who had asked that her results not bencluded in her medical records was very surprised whenhe technician doing her transvaginal ultrasound said, “ Iee that you are positive for a BRCA mutation.”
ONCLUSION
enetic testing for breast and ovarian cancer susceptibilitys a family experience that often results in family membersonfronting complex ethical, legal, and psychosocial issues.ecause of this, it is imperative that midwives and otherealth care providers have a good understanding of the
enefits, risks, and limitations of the genetic tests that areVolume 49, No. 3, May/June 2004
csefa
R
J
Wg2
t
r2
cS
Lf2
Ft
l
dc
IW
v
sM
tg
W
g7
KH
o2
iJ
Ko
eN
B
IB
o
2
Hi7
r
Ri
tM
MbP
Da
J
urrently being offered for breast and ovarian cancerusceptibility. In addition, they need to be aware of thethical, legal, and social implications of these tests. Theollowing quote by Juengst75 underscores why midwivesnd other health care providers need this knowledge.
The promise of accessible genetic information lies inits ability to allow individuals and families toidentify, understand, and sometimes control theirinherited health risks. This promise puts the individ-ual and families that receive genetic services at themoral center of the enterprise: if genetic assessmentis to be judged a success, it must be from therecipient’s point of view, in terms of their ability touse the information to enrich their lives (p. 190).
The author acknowledges support from Grant KO1 NR00139, NationalInstitute of Nursing Research, National Institutes of Health.
EFERENCES
1. Wooster R, Weber BL. Breast and ovarian cancer. N EnglMed 2003;348:2339–47.
2. Hallowell N, Foster C, Eeles R, Ardern-Jones A, Murday V,atson M. Balancing autonomy and responsibility: The ethics of
enerating and disclosing genetic information. J Med Ethics 2003;9:74–83.
3. Lerman C. Psychological aspects of genetic testing: Introduc-ion to the special issue. Health Psychol 1997;16:3–7.
4. Burgess MM, d’Aincourt-Canning L. Genetic testing for he-editary disease: Attending to relational responsibility. J Clin Ethics001;12:361–72.
5. Finkler K, Skrzynia C, Evans JP. The new genetics and itsonsequences for family, kinship, medicine and medical genetics. Socci Med 2003;57:403–12.
6. Forrest K, Simpson SA, Wilson BJ, van Teijlingen ER, McKee, Haites N, et al. To tell or not to tell: Barriers and facilitators in
amily communication about genetic risk. Clin Genet 2003;64:317–6.
7. Green J, Richards M, Murton F, Statham H, Hallowell N.amily communication and genetic counseling: The case of heredi-
ary breast and ovarian cancer. J Genet Couns 1997:45–61.
8. Juengst ET. Genetic testing and the moral dynamics of familyife. Public Understand Sci 1999;8:193–205.
9. Lancaster JM, Wiseman RW, Berchuck A. An inevitableilemma: Prenatal testing for mutations in the BRCA1 breast-ovarianancer susceptibility gene. Obstet Gynecol 1996;87:306.
10. Thomson E. Ethical, legal, social, and policy issues in genetics.n Lashley FR, ed. The genetics revolution: Implications for nursing.
ashington (DC): American Academy of Nursing, 1997:15–26.
11. Burke W, Emery J. Genetics education for primary-care pro-iders. Nat Rev Genet 2002;3:561–6.
12. Greendale K, Reed P. Empowering primary care health profes- G
ournal of Midwifery & Women’s Health • www.jmwh.org
ionals in medial genetics: How soon? How fast? How far? Am Jed Genet 2001;106:223–32.
13. Hetteberg C, Prows CA, Deets C, Monsen R, Kenner C. Na-ional survey of genetics content in basic nursing preparatory pro-rams in the United States. Nurs Outlook 1999;47:168–74.
14. Wulfsberg EA. The impact of genetic testing on primary care:here’s the beef? Am Fam Physician 2000;61:971–2 , 974, 977–8.
15. Claus EB, Schildkraut JM, Thompson WD, Risch NJ. Theenetic attributable risk of breast and ovarian cancer. Cancer 1996;7:2318–24.
16. Couch FJ, Weber BL. Breast cancer. In Vogelstein B, KinzlerW, eds. The genetic basis of human cancer. New York: McGraw-ill, 1998:537–63.
17. Srivastava A, McKinnon W, Wood M. Risk of breast andvarian cancer in women with strong family histories. Oncology001;15:889–902.
18. Slattery ML, Kerber RA. A comprehensive evaluation of fam-ly history and breast cancer risk. The Utah Population Database.AMA 1993;270:1563–8.
19. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman, Tavtigian S, et al. A strong candidate for the breast cancer andvarian cancer susceptibility gene BRCA1. Science 1994;266:66–71.
20. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J,t al. Identification of the breast cancer susceptibility gene BRCA2.ature 1995;378:789–92.
21. Venkitaraman AR. Cancer susceptibility and the functions ofRCA1 and BRCA2. Cell 2002;108:171–82.
22. Eeles R. Future possibilities in the prevention of breast cancer:ntervention strategies in BRCA1 and BRCA2 mutation carriers.reast Cancer Res 2000;2:283–90.
23. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risksf cancer in BRCA1-mutation carriers. Lancet 1994;343:692–5.
24. Balter M. Transatlantic war over BRCA1 patent. Cancer Res001;292:1818.
25. Peterson EA, Milliron KJ, Lewis KE, Goold SD, Merajver SD.ealth insurance and discrimination concerns and BRCA1/2 testing
n a clinic population. Cancer Epidemiol Biomarkers Prev 2002;11:9–87.
26. Reynolds T. NCI-Myriad agreement offers BRCA testing ateduced cost. J Natl Cancer Inst 2000;92:596.
27. Chaliki H, Loader S, Levenkron JC, Logan-Young W, Hall WJ,owley PT. Women’s receptivity to testing for a genetic susceptibil-
ty to breast cancer. Am J Public Health 1995;85:1133–5.
28. Lerman C, Seay J, Balshem A, Audrain J. Interest in geneticesting among first-degree relatives of breast cancer patients. Am J
ed Genet 1995;57:385–92.
29. Struewing JP, Lerman C, Kase RG, Giambarresi TR, TuckerA. Anticipated uptake and impact of genetic testing in hereditary
reast and ovarian cancer families. Cancer Epidemiol Biomarkersrev 1995;4:169–73.
30. Botkin JR, Smith KR, Croyle RT, Baty BJ, Wylie JE, Dutson, et al. Genetic testing for a BRCA1 mutation: Prophylactic surgery
nd screening behavior in women 2 years post testing. Am J Med
enet 2003;118A:201–9.217
Aba
tr
ib
2h
Ch
JBf2
r2
Do1
is
m
Ga1
eJ
GMe
CbJ
Br1
it
PB
aA
Pgc
Dic
Nct
glB4
Lt
JdA1
s
PE
iH
Wf
a1
MmC
tc
ea
2
31. Lerman C, Narod S, Schulman K, Hughes C, Gomez-Caminero, Bonney G, et al. BRCA1 testing in families with hereditaryreast-ovarian cancer: A prospective study of patient decision makingnd outcomes. JAMA 1996;275:1885–92.
32. Gwyn K, Vernon SW, Conoley PM. Intention to pursue geneticesting for breast cancer among women due for screening mammog-aphy. Cancer Epidemiol Biomarkers Prev 2003;12:96–102.
33. Press NA, Yasui Y, Reynolds S, Durfy SJ, Burke W. Women’snterest in genetic testing for breast cancer susceptibility may beased on unrealistic expectations. Am J Med Genet 2001;99:99–110.
34. American Cancer Society. Breast cancer facts & figures 2003–004 [Internet]. American Cancer Society, 2003. Available from:ttp://www.cancer.org/docroot/STT/stt_0.asp.
35. National Cancer Institute. Cancer facts [Internet]. Nationalancer Institute, 2002 [cited September 13, 2002]. Available from:ttp://cis.nci.nih.gov/fact/5_6.htm.
36. Antoniou A, Pharoah P, Narod S, Risch H, Eyfjord J, Hopper, et al. Average risks of breast and ovarian cancer associated withRCA1 and BRCA2 mutations detected in case series unselected for
amily history: A combined analysis of 22 studies. Am J Hum Genet003;72:1117–30.
37. King MC, Marks JH, Handell JB. Breast and ovarian cancerisks due to inherited mutations in BRCA1 and BRCA2. Science003;302:643.
38. Verhoog LC, Brekelmans CT, Seynaeve C, van den Bosch LM,ahmen G, van Geel AN, et al. Survival and tumour characteristicsf breast-cancer patients with germline mutations of BRCA1. Lancet998;351:316–21.
39. Easton DF, Ford D, Bishop DT. Breast and ovarian cancerncidence in BRCA1-mutation carriers. Breast Cancer Linkage Con-ortium. Am J Hum Genet 1995;56:265–71.
40. Breast Cancer Linkage Consortium. Cancer risks in BRCA2utation carriers. J Natl Cancer Inst 1999;91:1310–6.
41. Verhoog LC, Brekelmans CT, Seynaeve C, Dahmen G, vaneel AN, Bartels CC, et al. Survival in hereditary breast cancer
ssociated with germline mutations of BRCA2. J Clin Oncol 1999;7:3396–3402.
42. Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B,t al. BRCA2 germline mutations in familial pancreatic carcinoma.Natl Cancer Inst 2003;95:214–21.
43. Murphy KM, Brune KA, Griffin C, Sollenberger JE, PetersenM, Bansal R, et al. Evaluation of candidate genes MAP2K4,ADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: Del-
terious BRCA2 mutations in 17%. Cancer Res 2002;62:3789–93.
44. Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer, Mulvihill JJ. Projecting individualized probabilities of developingreast cancer for white females who are being examined annually.Natl Cancer Inst 1989;81:1879–1986.
45. Costantino JP, Gail MH, Pee D, Anderson S, Redmond CK,enichou J, Wieand HS. Validation studies for models projecting the
isk of invasive and total breast cancer incidence. J Natl Cancer Inst999;91:1541–8.
46. Claus EB, Risch N, Thompson WD. Autosomal dominantnheritance of early-onset breast cancer: Implications for risk predic-
ion. Cancer 1994;73:643–51. 518
47. Berry DA, Parmigiani G, Sanchez J, Schildkraut J, Winer E.robability of carrying a mutation of breast-ovarian cancer geneRCA1 based on family history. J Natl Cancer Inst 1997;8:227–38.
48. Parmigiani G, Berry D, Aguilar O. Determining carrier prob-bilities for breast cancer-susceptibility genes BRCA1 and BRCA2.m J Hum Genet 1998;62:145–58.
49. Berry DA, Iversen ES, Gudbjartsson DF, Hiller EH, Garber JE,eshkin BN, Lerman C, et al. BRCAPRO validation, sensitivity ofenetic testing of BRCA1/BRCA2, and prevalence of other breastancer susceptibility genes. J Clin Oncol 2002;20:2701–12.
50. Claes E, Evers-Kiebooms G, Boogaerts A, Decruyenaere M,enayer L, Legius E. Communication with close and distant relatives
n the context of genetic testing for hereditary breast and ovarianancer in cancer patients. Am J Med Genet 2003;116A:11–9.
51. Hughes C, Lerman C, Schwartz M, Peshkin BN, Wenzel L,arod S, et al. All in the family: Evaluation of the process and
ontent of sisters’ communication about BRCA1 and BRCA2 geneticest results. Am J Med Genet 2002;107:143–50.
52. Smith KR, West JA, Croyle RT, Botkin JR. Familial context ofenetic testing for cancer susceptibility: Moderating effect of sib-ings’ test results on psychological distress one to two weeks afterRCA1 mutation testing. Cancer Epidemiol Biomarkers Prev 1999;:385–92.
53. Lynch HT, Lemon SJ, Durham C, Tinley ST, Connolly C,ynch JF, et al. A descriptive study of BRCA1 testing and reactions
o disclosure of test results. Cancer 1997;79:2219–28.
54. Thompson HS, Valdimarsdottir HB, Duteau-Buck C, Guevarra, Bovbjerg DH, Richmond-Avellaneda C, et al. Psychosocial pre-ictors of BRCA counseling and testing decisions among urbanfrican-American women. Cancer Epidemiol Biomarkers Prev 2002;1:1579–85.
55. d’Agincourt-Canning L. Experiences of genetic risk: Disclo-ure and the gendering of responsibility. Bioethics 2001;15:231–47.
56. Bredart A, Autier P, Riccardo A, Audisio A, Geraghty JG.sychosocial dimensions of BRCA testing: An overshadowed issue.ur J Cancer Care 2001;10:96–109.
57. Croyle RT, Smith KR, Botkin JR, Baty B, Nash J. Psycholog-cal responses to BRCA1 mutation testing: Preliminary findings.ealth Psychol 1997;16:63–72.
58. Meiser B, Butow P, Friedlander M, Barratt A, Schnieden V,atson M, et al. Psychological impact of genetic testing in women
rom high-risk breast cancer families. Eur J Cancer 2002;38:2025–31.
59. Pasacreta JV, Jacobs L, Cataldo JK. Genetic testing for breastnd ovarian cancer risk: The psychosocial issues. Am J Nurs 2002;02:40–7.
60. Watson M, Lloyd S, Davidson J, Meyer L, Eeles R, Ebbs S,urday V. The impact of genetic counselling on risk perception andental health in women with a family history of breast cancer. Br Jancer 1999;79:868–74.
61. Lerman C, Croyle RT, Tercyak KP, Hamann H. Geneticesting: Psychological aspects and implications. J Consult Clin Psy-hol 2002;70:784–97.
62. Appleton S, Fry A, Rees G, Rush R, Cull A. Psychosocialffects of living with an increased risk of breast cancer: An explor-tory study using telephone focus groups. Psychooncology 2000;9:
11–21.Volume 49, No. 3, May/June 2004
Sf
Gc
SB2
LPB
Mws
No
sf9
C
c
erG
Et6
aC
c1
J
63. American Society of Clinical Oncology (ASCO). Americanociety of Clinical Oncology policy statement update: Genetic testingor cancer susceptibility. J Clin Oncol 2003;21:1–10.
64. Pinsky L, Culver J, Hull J, Levy-Lahad E, Daly M, Burke W.ene scene. Why should primary care physicians know about breast
ancer genetics. West J Med 2001;175:168–74.
65. Hartmann LC, Sellers TA, Schaid DJ, Frank TS, Soderberg CL,itta DL, et al. Efficacy of bilateral prophylactic mastectomy inRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst001;93:1633–7.
66. Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van’t Veer, Garber JE, et al. Prevention and Observation of Surgical Endoints Study Group: Prophylactic oophorectomy in carriers ofRCA1 or BRCA2 mutations. N Engl J Med 2002;346:1616–22.
67. Tiller K, Meiser B, Butow P, Clifton M, Thewes B, Friedlander, Tucker K. Psychological impact of prophylactic oophorectomy inomen at increased risk of developing ovarian cancer: A prospective
tudy. Gynecol Oncol 2002;86:212–9.
68. Liede A, Karlan BY, Baldwin RL, Platt LD, Kuperstein G,arod SA. Cancer incidence in a population of Jewish women at riskf ovarian cancer. Clin Oncol 2000;20:1570–7.
69. Modugno F, Ovarian Cancer and High-Risk Women Sympo-
ournal of Midwifery & Women’s Health • www.jmwh.org
ium Presenters. Ovarian cancer and high-risk women—Implicationsor prevention, screening, and early detection. Gynecol Oncol 2003;1:15–31.
70. Haites NE. The ethical management of genetic testing. Eur Jancer 2003;39:1339–40.
71. Surbone A. Ethical implications of genetic testing for breastancer susceptibility. Crit Rev Oncol Hematol 2001;40:149–57.
72. Costalas JW, Itzen M, Malick J, Babb JS, Bove B, Godwin AK,t al. Communication of BRCA1 and BRCA2 results to at-riskelatives: A cancer risk assessment program’s experience. Am J Medenet 2003;119C:11–8.
73. Dudok de Wit AC, Tibbon A, Frets PG, Meijers-HeijboerJ, Devilee P, Kiljn JGM. BRCA1 in the family: A case descrip-
ion of the psychological implications. Am J Med Genet 1997;71:3–71.
74. Green R, Thomas AM. Whose gene is it? A case discussionbout familial conflict over genetic testing for breast cancer. J Genetouns 1997;6:245–54.
75. Juengst E. Caught in the middle again: Professional ethicalonsiderations in genetic testing for health risks. Genet Test 1998;1:89–200.
APPENDIX. Breast and Ovarian Cancer Counseling Resources for Health Care Providers
Resource Description
Cancer FactsGenetics of Breast and Ovarian Cancer
Accurate, up-to-date information on the genetics of breast and ovarian cancer provided bythe National Cancer Institute
http://www.nci.nih.gov/cancerinfo/pdq/genetics/breast-and-ovarian#Section 2
Cancer Genetics Services Directoryhttp://www.nci.nih.gov/search/geneticservices/
Directory of health care providers who provide services related to cancer genetics
Resource Link—National Society of GeneticCounselors http://www.nsgc.org/resourcelink.asp
Provides links to Genetics Resources
International Society of Nurses in Geneticshttp://www.globalreferrals.com/isong.html
Provides valuable links to a number of nursing and genetic sites, as well as links to familysupport organizations
Oncology Nursing Societyhttp://www.ons.org/xp6/ONS/Login/Splash.xml
An information service for oncology nurses, other health care providers, people with cancer,and their family and friends
Breast Cancer Genetics Network of Michiganhttp://www.mi-cancergenetics.org/index.html
Network designed to help breast cancer patients and their families make informed decisionsand become active partners in their health care
Facing Our Risk of Cancer Empowered (FORCE)http://www.facingourrisk.org/
Nonprofit organization for women who are at high risk for getting breast cancer due to theirfamily history and genetic status
219
