opinions of women with high inherited breast cancer risk about prophylactic mastectomy: an initial...

Opinions of women with high inherited breast cancerrisk about prophylactic mastectomy: an initialevaluation from a screening trial including magneticresonance imaging and ductal lavage

Allison W. Kurian MD,* Anne-Renee Hartman MD,� Meredith A. Mills BA,**James M. Ford MD,*** Bruce L. Daniel MD– and Sylvia K. Plevritis PhD�*Clinical Instructor in Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, �AssistantProfessor of Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, **Research Associate,

Department of Medicine, Stanford University School of Medicine, Stanford, CA, ***Assistant Professor of Medicine, Department

of Medicine, Stanford University School of Medicine, Stanford, CA, –Assistant Professor of Radiology, Department of Radiology,

Stanford University School of Medicine, Stanford, CA and �Assistant Professor of Radiology, Department of Radiology, Stanford

University School of Medicine, Stanford, CA, USA

Correspondence

Allison W. Kurian

Division of Oncology

Stanford University School of Medicine

875 Blake Wilbur Drive

Stanford

CA 94305-5820, USA

E-mail: [email protected]

Accepted for publication

11 March 2005

Keywords: BRCA, breast cancer, ductallavage, magnetic resonance imaging,

patient satisfaction, prophylactic

mastectomy

Abstract

Objective Prophylactic mastectomy (PM) is often considered, but

variably chosen by women at high inherited risk of breast cancer;

few data exist on patient tolerance of intensive breast screening as an

alternative to PM. We performed an evaluation of high-risk

women’s tolerance of a breast screening protocol using clinical

breast examination, mammography, breast magnetic resonance

imaging (MRI) and ductal lavage (DL), and of change in attitudes

toward PM after screening.

Design A questionnaire assessing tolerance of screening procedures

and change in opinion towards PM was designed and administered

to 43 study participants, after a median follow-up of 13 months.

Responses were evaluated according to patient characteristics,

including type of study-prompted interventions, BRCA mutation

status, and prior history of cancer, via univariate analysis.

Results Most patients [85.3% (68.9–95.1%)] were more opposed or

unchanged in their attitudes towards PM after study participation,

with only 14.7% (5.0–31.1%) less opposed (P ¼ 0.017) despite a

short-interval follow-up MRI rate of 71.7% and a biopsy rate of

37%. Lower rates of maximal discomfort were reported with

mammogram [2.8% (0–14.5%)] and MRI [5.6% (0–18.7%)] than

with DL [28.6% (14.6–46.3%)], with P ¼ 0.035.

Conclusions Most high-risk women tolerated intensive breast

screening well; they were not more inclined towards PM after

participating. Future studies should prospectively evaluate larger

numbers of high-risk women via multivariate analysis, to determine

characteristics associated with preference for breast screening vs. PM.

� Blackwell Publishing Ltd 2005 Health Expectations, 8, pp.221–233 221

Introduction

Yearly approximately 9–18 000 cases of breast

cancer in the United States have a hereditary

basis;1 60–75% of these cases are attributable to

the breast cancer susceptibility genes BRCA1

and BRCA2. An estimated one in 45 women of

Ashkenazi Jewish descent, and one in 500 to 800

women in the general population, carry dele-

terious BRCA mutations.2,3 The remaining

25–40% of such cases is of suspected inherited

origin given convincing family histories, and

may be associated with other known or

unknown genes, including ATM, PTEN and

CHEK2.4–6 The need for effective and tolerable

risk-reducing interventions in this group of

women is clear.

Prophylactic surgery is the most effective

intervention to reduce breast cancer risk in

women with inherited predisposition, although

chemoprevention with tamoxifen may also be

effective. Tamoxifen has been found to decrease

risk of oestrogen-receptor positive breast cancer

by approximately 50% in women at elevated

risk;7 data suggesting similar efficacy in women

with BRCA mutations are emerging.8–10 Bilat-

eral prophylactic mastectomy (PM) has been

more widely evaluated, and is reported to

reduce risk of breast cancer by approximately

90%.11–13 Prophylactic bilateral salpingo-

oophorectomy (BSO), used to reduce ovarian

cancer risk in BRCA mutation carriers, also

reduces breast cancer risk by approximately

50% in premenopausal women.10,12,14,15 How-

ever, women in their twenties, thirties and for-

ties, many of whom desire to preserve fertility,

avoid early menopause and potentially disfig-

uring physical changes, may find prophylactic

surgery unacceptable. Rates of PM vary, from

21 to >50%, throughout the United States and

Europe.16–19 Recent evaluations have reported

decreased fear of cancer after surgery, but

increased depression, less favourable body

image and adverse effects on sexual func-

tion.20,21 Although prophylactic surgery

remains an important option in women at high

risk, less invasive risk-reducing strategies could

preserve greater quality of life.

Breast cancer screening is an alternative to

prophylactic surgery in this population. How-

ever, conventional mammography frequently is

inadequately sensitive in women in their thirties

and early forties, who have dense breast tissue,

and in women with BRCA1 mutations, whose

tumours are difficult to detect on mammography

because of pushing borders.22 Breast magnetic

resonance imaging (MRI) is emerging as a key

screening modality in this population. In mul-

tiple trials of breast MRI screening of women at

high inherited risk, MRI has generally shown

improved sensitivity over mammogram, but

decreased specificity, for detection of invasive

and in situ cancer.23–38 Because of breast MRI’s

high sensitivity and usually lower specificity,

biopsy rates in the 20–30% range, and false-

positive rates from 5.2 to 83%, are reported in

high-risk women.30,39 No survival advantage has

been demonstrated with screening MRI. Thus,

women at high risk must choose between pro-

phylactic surgery, with serious physical and

psychological consequences but significant

decrease in risk, and less invasive screening

techniques which are incompletely proven, and

often generate recurrent procedures and anxiety.

Various authors have evaluated perceptions of

breast screening techniques. Some have found

that women overestimate the benefit of screening

mammography.40 Studies on false-positive

mammograms, one estimating an 11% incidence

in the United States, reported no decrease in

screening attendance, but found increases in

measures of psychological distress, more pro-

nounced in women with family history of breast

cancer.41,42 A Norwegian study reported short-

term decreases in quality of life among women

with false-positive mammograms, related to

anxiety and biopsy-related side-effects; 5%

considered the event their worst life experi-

ence.43 A recent study from the Netherlands

evaluated short-term changes in health status

and health-related quality of life associated with

breast MRI screening in high-risk women, and

found no evidence for a decline in these meas-

ures with such screening, but did report an

anxiety rate of 37% associated with screening

breast MRI; the impact of specific screening

Opinions of women with high inherited breast cancer risk about PM, A W Kurian et al.

� Blackwell Publishing Ltd 2005 Health Expectations, 8, pp.221–233

222

outcomes were not assessed.44 These reports

suggest that inherited risk, biopsies and false-

positive screening examinations may predict

reduced quality of life related to mammographic

screening, and that high-risk women experience

significant anxiety in the short-term period of

MRI screening. There is a clear need to evaluate

the experience of high-risk women undergoing

MRI-based screening, with particular attention

to whether high rates of invasive or time-con-

suming screening-related outcomes, such as

breast biopsies and false-positive results, affect

their willingness to continue such screening.

The goal of this study was to perform a pre-

liminary exploration of the opinions of women

enrolled in a MRI-based screening protocol,

including multiple interventions and follow-up

visits, with particular attention to whether they

were inclined to abandon screening for PM.

Rather than answering a defined question, our

aim was to generate hypotheses which might

guide future study in this field. In order to

achieve this goal, we designed and administered

a questionnaire to a cohort of high-risk women

participating in a breast screening research

protocol at our institution, which incorporates

clinical breast examination (CBE), MRI and

mammogram. Our protocol also included ductal

lavage (DL), a technique for the evaluation of

potentially pre-cancerous cytological changes in

breast duct cells.45 The preliminary report of our

screening protocol noted a significant rate of

high-risk breast lesions on MRI and DL.39 We

asked for women’s evaluation of these tech-

niques and their opinion of PM after experien-

cing screening. We evaluated responses

according to type of interventions undergone,

and clinical characteristics.

Methods

Breast screening protocol

The breast screening protocol was initiated in

order to test the hypothesis that breast MRI and

DL could identify early-stage breast cancer and

high risk breast lesions among women at high

inherited risk for breast cancer, when compared

with mammography and CBE alone.39 It is an

intensive, multi-modality programme requiring

a minimum of four clinic visits, including pro-

cedures such as placement of intravenous and

breast duct catheters, during a 2-week period at

least once each year. The protocol consisted of

biannual CBE, annual mammogram, breast

MRI and DL. Abnormality detected on CBE

required 3 to 4-month follow-up CBE or biopsy,

as determined by clinical features; further ima-

ging was performed as prompted by clinical

findings. Abnormal MRI or mammogram

required 6-month follow-up or biopsy, as

determined by radiographic features. Atypical

cells on DL required 6-month interval follow-up

DL, and 6-month follow-up MRI of the affected

breast. The preliminary results of this screening

protocol have previously been published.39

Participant eligibility and enrolment

After study approval by the Stanford University

Institutional Review Board, patients were

recruited from the Stanford University Cancer

Genetics Clinic. Women were pre-screened by a

genetic counsellor: family history was obtained

via interview. Patients were offered testing for

BRCA1 and BRCA2 mutations based on pedi-

grees and risk as estimated by the Claus and

BRCAPRO models.46–48 Eligibility criteria

included a documented BRCA1 or BRCA2

mutation or a >10% risk of developing breast

cancer at 10 years based on the Claus model. In

patients with personal history of breast cancer

and no BRCA mutation, the Claus model was

used to calculate predicted risk for a hypothetical

unaffected sister; if this risk was >10%, the

patient was eligible for participation. Patients had

to be at least 25 years of age, or 5 years younger

than the earliest age at which a relative was

diagnosed with breast cancer. Patients with a

history of breast or ovarian cancer (stage III or

lower only) had to have completed adjuvant

therapy at least 1 year previously, and to have no

evidence of disease at study entry. Informed

consent was obtained from all patients, and all

study procedureswere compliantwith regulations

of the Health Insurance Portability and



223

Accountability Act of 1996. Alternatives to par-

ticipation in the protocol, including PM, or

screening breast MRI off-protocol, were presen-

ted to all patients. Patients were told that neither

breast MRI nor DL was expected to prevent

cancer, nor was either associated with any proven

survival benefit. Enrolment began in September

2001 and accrual is ongoing.Median follow-up at

the time of questionnaire administration was

13 months, with a range of 1–29 months.

Breast MRI protocol

The breast MRI protocol has been published in

detail elsewhere.39,49–53 As this protocol is opti-

mized as a unilateral breast examination, women

underwent two separate examinations, each

requiring an intravenous catheter and lying prone

in a coil of 60 cm diameter, 1.2 m bore, for

45 min; no compression was used. Focally

enhancing lesions of 5 mm or larger generally led

to follow-up MRI. Dominant lesions 5 mm or

larger, with suspiciousmorphological or dynamic

enhancement features, underwent biopsy.

Ductal lavage protocol

The DL protocol began with a topical anaes-

thetic of 4% lidocaine cream applied to the

nipple approximately 20 min before the pro-

cedure. Lavage of ducts which did and which did

not yield fluid on suction aspiration was per-

formed. After a duct was identified via a dilator,

a catheter was inserted, through which 3–5 ml of

1% lidocaine was injected. Fifteen millilitre of

0.9% saline was injected through the afferent

port of the catheter, with fluid collection via the

efferent port. A histopathological diagnosis of

normal, insufficient cellular material for diag-

nosis, mild atypia, marked atypia, or malignant

cells was given to each sample. Attempt was

made to lavage 2–3 ducts per breast.

Questionnaire design

The questionnaire consisted of eight items, and

is attached in the Appendix. Items 1 through 3

asked patients to rate mammography, MRI, and

DL on a scale of 1 to 3 (1 ¼ minimal discom-

fort, 2 ¼ moderate discomfort, 3 ¼ maximal

discomfort). Item 4 asked patients to compare

their experience of MRI vs. mammography on a

scale of 1 to 5 (1 ¼ much better, 2 ¼ somewhat

better, 3 ¼ same, 4 ¼ somewhat worse, 5 ¼much worse), and item 5 did the same for DL vs.

MRI. Items 6 and 7 assessed whether patients

had used a sedative, and for which procedure.

Item 8 asked patients to state whether their

participation in this screening protocol had

caused a change in attitude towards PM (1 ¼more opposed to PM, 2 ¼ unchanged, 3 ¼ less

opposed to PM); these response possibilities

were chosen because we assumed that partici-

pants had been opposed to immediate, although

not necessarily to eventual, PM at the time of

study entry. Patient comments were elicited.

Questionnaire administration

At the time of questionnaire administration, the

trial had continued for 2 years, and had 46

participants, 36 currently participating and 10

having ceased to participate. The questionnaire

was mailed to 43 of these participants; three

were lost to follow-up. Patients were not asked

to give their names on the questionnaire, but

were identified by study numbers assigned to

questionnaires.

Linkage of responses to clinical research

database

Information from questionnaires was linked to

a clinical research database via responders�study numbers. Analysis of responses according

to clinical characteristics obtained from the

research database, including age, BRCA muta-

tion, history of breast or ovarian cancer, and

history and outcome of breast or ovarian can-

cer in a first-degree relative, was performed.

Evaluation was also performed according to

interventions prompted by the breast screening

protocol, including short-interval follow-up

MRI, short-interval follow-up DL, biopsy,

other imaging including ultrasound, com-

pression mammogram views or computed



224

tomography (CT) scan, and choice of BSO

or PM. Statistical analysis included calculation

of 95% confidence intervals using the exact

binomial distribution, and of P-values using

Fisher’s exact test and the exact binomial test,

two-sided.

Results

Results of breast screening protocol

Preliminary results of this breast screening pro-

tocol have been published elsewhere.39,53 They

are summarized in Table 1. Of the 18 women

without BRCA mutations, four tested negative

for a BRCA mutation by full sequencing of

BRCA1 and BRCA2 (three of these women had

prior breast or ovarian cancer; one had not but

had no available living first-degree relatives to be

tested); 10 were untested, because a first-degree

relative affected with breast or ovarian cancer

had tested negative for a BRCA mutation; four

had BRCA1 or BRCA2 variants of uncertain

significance. Median age was 41 years, with 36

patients (78.2%) less than age 50 and, 20

(43.5%) premenopausal at study entry. Of the 46

women ever screened, 35 continue in the proto-

col, three have been lost to follow-up, six have

chosen PM, one has been diagnosed with

recurrent ovarian cancer and stopped being

screened, and one has been found to have a

BRCA variant of unknown significance reas-

signed as benign, and therefore discontinued

participation.

Results of questionnaire: response rate

A questionnaire was mailed to 43 participants,

and 36 responded, giving a response rate of

83.7%. Two patients who had chosen PM

answered the questionnaire. Twenty-two of 28

participants (78.6%) who carried a BRCA

mutation responded, compared with 14 of 18

non-carriers (77.8%). Thirteen of 15 participants

(86.7%) with a history of breast or ovarian

cancer responded, compared with 23 of 31 par-

ticipants (74.2%) without. Fourteen of 17

patients (82.4%) who underwent biopsy

responded, compared with 21 of 29 (72.4%) who

did not.

Results of questionnaire: procedure rating

The results of items 1–3 are summarized in

Table 2. Participants tolerated mammogram

best, with similar tolerance of MRI. For both

mammogram and MRI, there was little differ-

ence in rating-based BRCA mutation status, or

cancer history. In contrast, participants were

more likely to rate DL [28.6% (14.6–46.3%)],

Table 1 Patient characteristics, magnetic resonance imaging (MRI)-prompted biopsy, and ductal lavage (DL) results

Patients screened

Biopsy with

normal results

Biopsy with

malignant results1Biopsy with

high-risk results2 No biopsy

All patients (n ¼ 46) 11 1 4 30

BRCA 1 or BRCA2 mutation (n ¼ 28) 6 1 3 18

Personal history of breast cancer (n ¼ 12) 2 0 0 10

Personal history of ovarian cancer3 (n ¼ 3) 0 0 1 2

Current or prior tamoxifen use (n ¼ 8) 2 0 0 6

Prophylactic bilateral salpingo-oophorectomy

before or during study (n ¼ 20)

8 0 0 12

Subsequent prophylactic mastectomy (n ¼ 6) 0 1 1 4

Atypical cells on ductal lavage (n ¼ 10) 2 0 1 7

1High-grade ductal carcinoma in situ, 6.9 cm in size.2Radial scar or atypical lobular hyperplasia.3One patient had stage I ovarian cancer; two other patients had stage III ovarian cancer, all without evidence of disease for at least 1 year before

entry into the study.



225

than MRI [5.6% (0–18.7%)] or mammogram

[2.8% (0–14.5%)], as maximally uncomfortable;

the comparison of ratings of maximal discom-

fort for DL vs. mammogram and MRI com-

bined reached statistical significance (P ¼0.035). There appeared to be a trend towards

association of personal cancer history with bet-

ter tolerance of DL, although it did not reach

statistical significance: one of 13 such patients

rated it maximally uncomfortable [7.7% (0–

36.0%)], vs. 9 of 22 with no cancer history

[40.9% (20.7–63.7%)].

The results of items 4 and 5 are summarized

in Table 3. No definite trends emerged regard-

ing preference of MRI over mammogram,

although cancer history associated with a non-

statistically significant preference for MRI. For

comparison of DL to MRI, most responders

rated DL worse. Five patients used sedation for

MRI and nine for DL, yielding an inadequate

sample size from which to draw conclu-

sions about the effect of sedation on procedure

tolerance.

Results of questionnaire: changes in attitudes

towards prophylactic mastectomy

A minority of patients [14.7% (5.0–31.1%)]

was less opposed to PM; the majority [61.8%

(43.6–77.8%)] had no change in opinion, and

23.5%, (10.8–41.2%) were more opposed.

Comparison of proportions of patients who

were and were not less opposed to PM reached

statistical significance (P ¼ 0.017). Given the

small sample size, there was insufficient power

to detect statistically significant associations

between clinical characteristics and patients

with different opinions about PM, but patterns

did emerge. Among the more opposed group,

no patient had had atypical cells on DL. A

higher biopsy rate, and a lower BSO rate, was

found among those more opposed (Table 4).

There was no difference in median follow-up

between groups who were more or less

opposed.

Discussion

To our knowledge, this is the first preliminary

report of high-risk women’s perceptions of

breast screening with MRI and DL, and of

their subsequent opinions about PM. Although

the number of patients was small, the response

rate was high, at 83.7%, with no evident dif-

ferences between responders and non-respond-

ers. Despite the small sample size, these

findings do not suggest that high-risk women

who undergo many screening-prompted inter-

ventions are likely to abandon screening for

PM.

Table 2 Patient tolerance of screening techniques

Procedures Minimal discomfort Moderate discomfort Maximal discomfort

Mammogram ratings

All responders (n ¼ 36) 22 [61% (43.5–76.9%)] 13 [36.1% (20.8–53.8%)] 1 [2.8% (0–14.5%)]

BRCA 1 or BRCA2 mutation [n ¼ 22) 14 [63.6% (40.7–82.8%)] 8 [36.4% (17.2–59.3%)] 0 [0% (0–15.4%)]

Prior history of breast or

ovarian cancer (n ¼ 13)

8 [61.5% (31.6–86.1%)] 5 [38.5% (13.9–68.4%)] 0 [0% (0–24.7%)]

MRI ratings

All responders (n ¼ 36) 19 [52.8% (35.5–69.6%)] 15 [41.7% (25.5–59.2%)] 2 [5.6% (0–18.7%)]

BRCA 1 or BRCA2 mutation (n ¼ 22) 13 [59.1% (36.4–79.3%)] 7 [31.8% (13.9–54.9%)] 2 [9.1% (1.1–29.2%)]

Prior history of breast or

ovarian cancer (n ¼ 13)

7 [53.9% (25.1–80.8%)] 6 [46.2% (19.2–74.9%)] 0 [0% (0–24.7%)]

DL ratings

All responders (n ¼ 35) 8 [22.9% (10.4–40.1%)] 17 [48.6% (31.4–66.0%)] 10 [28.6% (14.6–46.3%)]

BRCA 1 or BRCA2 mutation (n ¼ 22) 6 [27.3% (10.7–50.2%)] 11 [50% (28.2–71.8%)] 5 [22.7% (7.8–45.4%)]

Prior history of breast

or ovarian cancer (n ¼ 13)

3 [23.1% (5.0–53.8%)] 9 [69.2% (38.6–90.9%)] 1 [7.7% (0–36.0%)]



226

Of the 46 patients who participated in the

screening protocol, 6, or 13%, subsequently

underwent PM. One had determined on PM

prior to participation, and intended only one

round of screening; she reported her attitude as

unchanged. Four did not respond; one of these

four underwent contralateral PM after diagnosis

of a large focus of high-grade ductal carcinoma

in situ (DCIS) on MRI-prompted biopsy and

unilateral mastectomy. The sixth, who had two

high-risk lesions found on MRI-prompted

biopsy, reported her attitude unchanged, which

may reflect an initial decision that screening

would serve as a temporizing measure.

Perhaps the most striking of the current

results was the fact that 85.3% (68.9–95.1%) of

responders were either unchanged or more

opposed towards PM than prior to study parti-

cipation. It is important to note that this was a

population biased against PM, consisting of

women who had already made the decision to

postpone or forego it; as such, they are com-

parable with participants in any high-risk breast

screening protocol. Despite a short-interval

follow-up MRI rate of 71.7%, a biopsy rate of

37%, and a false-positive biopsy rate (excluding

high-risk lesions such as ALH and radial scar) of

68.8%, a considerable majority of patients were

not more in favour of abandoning screening for

PM than when they entered the study. These

results are consistent with preliminary findings

of other authors, who have not found an

increase in anxiety with greater duration of

breast screening in the majority of high-risk

women.54,55

Although the small number of responders

afforded inadequate power to detect statisti-

cally significant associations, patterns of clinical

characteristics distinguished patients with dif-

ferent opinions about PM. Those who were

more opposed to PM were slightly more likely

than those less opposed to have had biopsies;

this finding likely reflects heightened concern

about breast cancer among this high-risk popu-

lation, and a sense of protection via a greater

number of diagnostic procedures. It is consistent

with results of a study of average-risk women,

which found that those with relatives affected byTable

3Patientcomparisonofbreast

screeningtechniques

Comparisons

Much

better

Somewhatbetter

Same

Somewhatworse

Much

worse

ComparisonofMRIto

mammogram

Allresponders

(n¼

36)

9[25.0%

(12.1–4

2.2%)]

6[16.7%

(6.4–3

2.8%)]

7[19.4%

(8.2–3

6.0%)]

10[27.8%

(14.2–4

5.2%)]

4[11.1%

(3.1–2

6.1%)]

BRCA1orBRCA2mutation(n

¼22)

6[27.3%

(10.7–5

0.2%)]

3[13.6%

(2.9–3

4.9%)]

6[27.3%

(10.7–5

0.2%)]

5[22.7%

(7.8–4

5.4%)]

2[9.1%

(1.1–2

9.2%)]

Priorhistory

ofbreast

orovariancancer(n

¼13)

4[30.8%

(9.1–6

1.4%)]

3[23.1%

(5.0–5

3.8%)]

2[15.4%

(1.9–4

5.5%)]

4[30.8%

(9.1–6

1.4%)]

0[0%

(0–2

4.7%)]

ComparisonofDLto

MRI

Allresponders

(n¼

35)

4[11.4%

(3.2–2

6.7%)]

0[0%

(0–1

0.0%)]

7[20.0%

(8.4–3

6.9%)]

13[37.1%

(21.5–5

5.1%)]

11[31.4%

(16.9–4

9.3%)]

BRCA1orBRCA2mutation(n

¼22)

3[13.6%

(2.9–3

4.9%)]

0[0%

(0–1

5.4%)]

3[13.6%

(2.9–3

4.9%)]

7[31.8%

(13.9–5

4.9%)]

9[40.9%

(20.7–6

3.7%)]

Priorhistory

ofbreast

or

ovariancancer(n

¼13)

2[15.4%

(1.9–4

5.5%)]

0[0%

(0–2

4.7%)]

3[23.1%

(5.0–5

3.8%)]

4[30.8%

(9.1–6

1.4%)]

4[30.8%

(9.1–6

1.4%)]



227

breast cancer were less reluctant to have a biopsy

than other responders.56 Comments from

patients included, �A questionable area was

found on MRI. It was surgically removed and

found negative. I have great confidence that any

cancer would be found by screening�, �I am more

confident in this study’s screening process than I

was with just mammogram�, and �I would be

leaning towards a PM if these screening methods

were not available�.Some of the cited comments of participants

seem to reflect a concerning reliance upon

screening methods which have not yet been

proven to save lives. This finding is reminiscent

of reports of patients� overestimates of the

benefits of screening mammography.40 Study

participants were repeatedly advised of the fact

that MRI and DL are emerging procedures,

neither of which is expected to prevent cancer,

and neither of which has been associated with a

survival benefit. Moreover, patients were

advised that atypical cells on DL are of

unknown clinical relevance; their absence

should not be considered a benign prognostic

factor, and their presence should not prompt

PM. Nonetheless, patients� optimistic com-

ments about these techniques emphasize the

need for accurate evaluation of the efficacy of

these and other breast screening methods, so

that any false sense of security may be

addressed.

Of note, no patient who was more opposed

to PM had been found to have atypical cells

on DL, although patients in other groups had.

This finding may reflect anxiety generated by a

test result for which appropriate clinical man-

agement remains investigational.45,57,58 Such an

uncertain but potentially concerning result

might incline patients towards PM. Although

not statistically different, other factors which

appeared more prevalent in those less, than in

those more opposed included having BSO

during the study. Patients who had recently

undergone BSO, often a laparoscopic

Table 4 Patient characteristics associated with changes in attitudes towards prophylactic mastectomy (PM)

Attitude towards PM More opposed Same opinion Less opposed

All responders (n ¼ 34) 8 [23.5% (10.8–41.2%)] 21 [61.8% (43.6–77.8%)] 5 [14.7% (5.0–31.1%)]

Study interventions1

Six-month follow-up magnetic

resonance imaging (MRI) for

abnormal finding (n ¼ 26)

6 [23.1% (10.8–42.6%)] 16 [61.5% (42.6–77.8%)] 4 [15.4% (5.6–34.3%)]

Six-month follow-up ductal lavage (DL)

for atypical cells (n ¼ 8)

0 [0% (0–37.8%)] 7 [87.5% (51.2–100%)] 1 [12.5% (0.3–49.7%)]

Biopsy (n ¼ 13) 3 [23.1% (7.7–51.2%)] 9 [69.2% (42.3–87.9%)] 1 [7.7% (0–35.8%)]

No extra study intervention (n ¼ 5) 2 [40.0% (12.0–77.6%)] 3 [60.0% (23.3–88.8%)] 0 [0% (0–49.6%)]

Prophylactic surgery during study1

Prophylactic oophorectomy (BSO) (n ¼ 5) 0 [0% (0–49.6%)] 3 [60.0% (23.3–88.8%)] 2 [40.0% (12.0–77.6%)]

PM (n ¼ 2) 0 [0% (0–71.8%)] 2 [100% (29.8–100%)] 0 [0% (0–71.8%)]

Clinical characteristics1

BRCA 1 or BRCA2 mutation (n ¼ 21) 5 [23.8% (10.3–45.7%)] 13 [61.9% (40.9–79.5%)] 3 [14.3% (4.2–35.7%)]

Personal history of cancer (n ¼ 13) 3 [23.1% (7.7–51.2%)] 7 [53.9% (29.3–77.0%)] 3 [23.1% (7.7–51.2%)]

All affected first-degree relatives

survived cancer (n ¼ 10)

2 [20.0% (4.8–52.4%)] 6 [60% (31.4–83.6%)] 2 [20.0% (4.8–52.4%)]

All affected first-degree relatives

did not survive cancer (n ¼ 12)

3 [25.0% (8.5–54.2%)] 8 [66.7% (39.0–86.7%)] 1 [8.3% (0–37.9%)]

Some affected first-degree

relatives survived,

some died from cancer (n ¼ 7)

2 [28.6% (7.8–65.2%)] 3 [42.9% (16.1–75.4%)] 2 [28.6% (7.8–65.2%)]

No first degree relatives

affected by cancer (n ¼ 4)

1 [25% (3.8–71.7%)] 3 [75% (29.4–97.0%)] 0 [0% (0–55.3%)]

1Proportion reflects participants in each opinion category divided by total number who had the intervention described in each row.



228

procedure not requiring overnight hospital

stay, might have concluded that prophylactic

surgery was less traumatic than expected, and

therefore be more inclined towards PM.

Having a BRCA mutation did not associate

with tolerance of procedures or with opinion

towards PM. This may reflect the strict criteria

for study entry, which selected a population

comparable in risk and breast cancer anxiety to

mutation carriers. Previous studies both of

mammography screening in the general popu-

lation, and of BRCA mutation carriers, have

identified death of a close relative from breast or

ovarian cancer as predictive of cancer-related

anxiety and distress.20,41 In our results, there was

no trend towards patients with a first-degree

relative who had died from cancer being less

opposed to PM. However, of the four respond-

ers with no first-degree relative affected by

cancer, none was less opposed to PM. The small

numbers of patients in each category make it

difficult to be confident about these results; a

future analysis should evaluate larger numbers,

and consider variables such as total number of

affected relatives, along with their cancer

outcomes.

Patients with history of cancer rated study

procedures differently than did others. History

of cancer associated with preferring MRI to

mammogram, which might reflect familiarity

with intravenous infusions (as required for

gadolinium contrast with MRI) or mistrust of

mammogram. Comments about mammogram

from breast cancer survivors included �it never

identified my or my sister’s cancer�. Of note, a

study assessing tolerance of diagnostic breast

MRI in average-risk women without cancer

history found that a significant number of par-

ticipants also found it less uncomfortable than

mammogram.56 Cancer survivors also showed a

trend towards tolerating DL somewhat better

than others did, although this finding did not

reach statistical significance. If confirmed, such a

finding might reflect their experience with inva-

sive procedures, or greater interest in potential

early diagnosis.

Limitations of this study include retrospec-

tive administration of the questionnaire; ideally,

an instrument would be administered prospec-

tively to assess attitudes to screening and to PM

prior to participation, and then re-administered

subsequently at annual intervals, in order to

minimize recall bias. A second limitation is the

absence of an externally validated instrument

to measure screening-related anxiety and

quality of life, which could be incorporated

into a prospectively administered questionnaire.

Another limitation is the small sample size,

which restricted evaluation of results to a uni-

variate analysis only, and yielded inadequate

statistical power for rigorous subset analyses.

Finally, no data are available on the total

number of high-risk women approached for

participation in the comprehensive breast

screening study, or on their rate of choosing

PM; comparison of women who chose PM to

study participants could provide important

information about patient preferences and

associated characteristics. However, the current

approach nonetheless yielded significant infor-

mation about the tolerability of these inter-

ventions in this population.

In conclusion, an intensive breast screening

protocol using breast MRI and DL was well

tolerated on initial assessment in this group of

high-risk women, and an acceptable alternative

to PM in most cases. Future studies should

evaluate a larger sample size, with prospective

administration of a validated instrument, longer

follow-up, and comparison with women of

similar risk who have chosen PM instead of

screening. Work should also address the accu-

rate measurement of high-risk women’s prefer-

ences about breast screening, which will permit

more reliable estimation of quality-adjusted life

years gained by any new screening measure.

Finally, future study must establish efficacy of

these and other breast screening interventions as

alternatives to prophylactic surgery in women at

high inherited risk.

Acknowledgements

The study was supported in part by grants from

the California Breast Cancer Research Program

(to A.R.H., J.M.F., and S.K.P.), the California



229

Cancer Research Program (to J.M.F.), the V

Foundation (to J.M.F. and S.K.P.) and NIH

RO1 CA66785 (to B.L.D).

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Appendix: Questionnaire sent toparticipants in comprehensive breastscreening protocol

Dear Study participant

This is a questionnaire designed to evaluate your

experience with the Comprehensive Breast

Screening Protocol at Stanford University

Medical Center. We would greatly appreciate

your participation. It should take <5 min to

complete.

Please answer all questions which apply to

you, and return the questionnaire by mail in the

enclosed stamped envelope. If you have any

questions, please do not hesitate to contact

Meredith Mills or Dr Allison Kurian.

Table A1 Please circle an answer in the left-hand column,

and then please feel free to add any comments about your

circled answer in the right-hand column

1) Please rate your experience of having a

mammogram:

1

No or

minimal

discomfort

2

Moderate

discomfort

3

Maximal

discomfort

2) Please rate your experience of having an

MRI:

Comments:

1

No or

minimal

discomfort

2

Moderate

discomfort

3

Maximal

discomfort

3) Please rate your experience of having a

ductal lavage:

Comments:

1

No or

minimal

discomfort

2

Moderate

discomfort

3

Maximal

discomfort

4) Compared to having a mammogram, how

would you rate your experience of having an

MRI?

Comments:

1

Much

better

2

Somewhat

better

3

Same

worse

4

Somewhat

worse

5

Much

5) Compared to having an MRI, how would you

rate your experience of having a ductal

lavage?

Comments:

1

Much

better

2

Somewhat

better

3

Same

worse

4

Somewhat

worse

5

Much

6) Did you use sedative medication

like ativan before having a screen-

ing examination by mammography,

MRI or ductal lavage?

Comments:

Yes No



232

7) If you answered yes to question 6,

for which procedure did you use sedative

medication (please circle all that apply)?

Comments:

Mammogram MRI Ductal lavage

8) Has your screening experience changed

your opinion about having a prophylactic

mastectomy?

Comments:

1

More opposed

to having a

prophylactic

mastectomy

2

No change

to having a

prophylactic

mastectomy

3

Less opposed

Thank you for taking the time to answer and

return this questionnaire.



233

opinions of women with high inherited breast cancer risk about prophylactic mastectomy: an initial...

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