Opinions of women with high inherited breast cancer risk about prophylactic mastectomy: an initial evaluation from a screening trial including magnetic resonance imaging and ductal lavage

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 = 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 = 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.

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 deleterious 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 , ⁵ , 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 , ⁹ , ¹⁰ Bilateral prophylactic mastectomy (PM) has been more widely evaluated, and is reported to reduce risk of breast cancer by approximately 90%. ¹¹ , ¹² , ¹³ Prophylactic bilateral salpingooophorectomy (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 However, women in their twenties, thirties and forties, many of whom desire to preserve fertility, avoid early menopause and potentially disfiguring physical changes, may find prophylactic surgery unacceptable. Rates of PM vary, from 21 to >50%, throughout the United States and Europe. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ Recent evaluations have reported decreased fear of cancer after surgery, but increased depression, less favourable body image and adverse effects on sexual function. 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. However, 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 multiple 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 , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , 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 prophylactic 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 pronounced 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 experience. 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 measures with such screening, but did report an anxiety rate of 37% associated with screening breast MRI; the impact of specific screening 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‐consuming 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 preliminary 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 techniques and their opinion of PM after experiencing 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 procedures 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 imaging 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 pedigrees and risk as estimated by the Claus and BRCAPRO models. ⁴⁶ , ⁴⁷ , 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 procedures were compliant with regulations of the Health Insurance Portability and Accountability Act of 1996. Alternatives to participation in the protocol, including PM, or screening breast MRI off‐protocol, were presented 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 , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ As this protocol is optimized 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 suspicious morphological or dynamic enhancement features, underwent biopsy.

Ductal lavage protocol

The DL protocol began with a topical anaesthetic of 4% lidocaine cream applied to the nipple approximately 20 min before the procedure. Lavage of ducts which did and which did not yield fluid on suction aspiration was performed. 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 diagnosis, 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 = minimal discomfort, 2 = moderate discomfort, 3 = maximal discomfort). Item 4 asked patients to compare their experience of MRI vs. mammography on a scale of 1 to 5 (1 = much better, 2 = somewhat better, 3 = same, 4 = somewhat worse, 5 = much 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 = more opposed to PM, 2 = unchanged, 3 = less opposed to PM); these response possibilities were chosen because we assumed that participants 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 mutation, history of breast or ovarian cancer, and history and outcome of breast or ovarian cancer 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, compression mammogram views or computed 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 protocol 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 protocol, 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 reassigned as benign, and therefore discontinued participation.

Table 1.

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

Patients screened	Biopsy with normal results	Biopsy with malignant results1	Biopsy with high‐risk results2	No biopsy
All patients (n = 46)	11	1	4	30
BRCA 1 or BRCA2 mutation (n = 28)	6	1	3	18
Personal history of breast cancer (n = 12)	2	0	0	10
Personal history of ovarian cancer3 (n = 3)	0	0	1	2
Current or prior tamoxifen use (n = 8)	2	0	0	6
Prophylactic bilateral salpingo‐oophorectomy before or during study (n = 20)	8	0	0	12
Subsequent prophylactic mastectomy (n = 6)	0	1	1	4
Atypical cells on ductal lavage (n = 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.

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 participants (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 difference in rating‐based BRCA mutation status, or cancer history. In contrast, participants were more likely to rate DL [28.6% (14.6–46.3%)], than MRI [5.6% (0–18.7%)] or mammogram [2.8% (0–14.5%)], as maximally uncomfortable; the comparison of ratings of maximal discomfort for DL vs. mammogram and MRI combined reached statistical significance (P =0.035). There appeared to be a trend towards association of personal cancer history with better 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%)].

Table 2.

 Patient tolerance of screening techniques

Procedures	Minimal discomfort	Moderate discomfort	Maximal discomfort
Mammogram ratings
All responders (n = 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 = 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 = 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 = 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 = 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 = 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 = 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 = 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 = 13)	3 [23.1% (5.0–53.8%)]	9 [69.2% (38.6–90.9%)]	1 [7.7% (0–36.0%)]

The results of items 4 and 5 are summarized in Table 3. No definite trends emerged regarding 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 conclusions about the effect of sedation on procedure tolerance.

Table 3.

 Patient comparison of breast screening techniques

Comparisons	Much better	Somewhat better	Same	Somewhat worse	Much worse
Comparison of MRI to mammogram
All responders (n = 36)	9 [25.0% (12.1–42.2%)]	6 [16.7% (6.4–32.8%)]	7 [19.4% (8.2–36.0%)]	10 [27.8% (14.2–45.2%)]	4 [11.1% (3.1–26.1%)]
BRCA 1 or BRCA2 mutation (n = 22)	6 [27.3% (10.7–50.2%)]	3 [13.6% (2.9–34.9%)]	6 [27.3% (10.7–50.2%)]	5 [22.7% (7.8–45.4%)]	2 [9.1% (1.1–29.2%)]
Prior history of breast or ovarian cancer (n = 13)	4 [30.8% (9.1–61.4%)]	3 [23.1% (5.0–53.8%)]	2 [15.4% (1.9–45.5%)]	4 [30.8% (9.1–61.4%)]	0 [0% (0–24.7%)]
Comparison of DL to MRI
All responders (n = 35)	4 [11.4% (3.2–26.7%)]	0 [0% (0–10.0%)]	7 [20.0% (8.4–36.9%)]	13 [37.1% (21.5–55.1%)]	11 [31.4% (16.9–49.3%)]
BRCA 1 or BRCA2 mutation (n = 22)	3 [13.6% (2.9–34.9%)]	0 [0% (0–15.4%)]	3 [13.6% (2.9–34.9%)]	7 [31.8% (13.9–54.9%)]	9 [40.9% (20.7–63.7%)]
Prior history of breast or ovarian cancer (n = 13)	2 [15.4% (1.9–45.5%)]	0 [0% (0–24.7%)]	3 [23.1% (5.0–53.8%)]	4 [30.8% (9.1–61.4%)]	4 [30.8% (9.1–61.4%)]

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 = 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.

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 = 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 = 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 = 8)	0 [0% (0–37.8%)]	7 [87.5% (51.2–100%)]	1 [12.5% (0.3–49.7%)]
Biopsy (n = 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 = 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 = 5)	0 [0% (0–49.6%)]	3 [60.0% (23.3–88.8%)]	2 [40.0% (12.0–77.6%)]
PM (n = 2)	0 [0% (0–71.8%)]	2 [100% (29.8–100%)]	0 [0% (0–71.8%)]
Clinical characteristics1
BRCA 1 or BRCA2 mutation (n = 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 = 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 = 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 = 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 = 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 = 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.

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 differences between responders and non‐responders. Despite the small sample size, these findings do not suggest that high‐risk women who undergo many screening‐prompted interventions are likely to abandon screening for PM.

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 participation. 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 comparable 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 statistically significant associations, patterns of clinical characteristics distinguished patients with different 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 population, 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 by 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 comments 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 management 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 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 population, 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 responders 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 participants 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 invasive procedures, or greater interest in potential early diagnosis.

Limitations of this study include retrospective administration of the questionnaire; ideally, an instrument would be administered prospectively 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 univariate 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 information about the tolerability of these interventions 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 accurate measurement of high‐risk women's preferences 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.

Appendix: Questionnaire sent to participants in comprehensive breast screening 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 screening examination by mammography, MRI or ductal lavage?		Comments:
Yes	No

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.