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© 2000 American Society for Clinical Oncology Intention to Undergo Prophylactic Bilateral Mastectomy in Women at Increased Risk of Developing Hereditary Breast CancerFrom the Hereditary Cancer Clinic and Department of Liaison Psychiatry, Prince of Wales Hospital; Medical Psychology Unit, University of Sydney; Familial Cancer Clinic, Westmead Hospital, Sydney; Queensland Clinical Genetics Service, Brisbane; and South Australian Clinical Genetics Service, Women’s and Children’s Hospital, Adelaide, Australia. Address reprint requests to Katherine Tucker, MD, Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia; email tuckerk{at}sesahs.nsw.gov.au
PURPOSE: To assess intention to undergo prophylactic bilateral mastectomy and psychologic determinants in unaffected women at increased risk of developing hereditary breast cancer. PATIENTS AND METHODS: Three hundred thirty-three women who were awaiting their initial appointments for risk assessment, advice about surveillance, and prophylactic options at one of 14 familial cancer clinics participated in a cross-sectional, questionnaire-based survey.
RESULTS: Nineteen percent of women would consider and 47% would not consider a prophylactic mastectomy, should genetic testing identify a mutation in a breast cancer–predisposing gene, whereas 34% were unsure and 1% had already undergone a prophylactic mastectomy. In a bivariate analysis, women at a moderately increased risk of developing breast cancer had the highest proportion of subjects reporting that they would consider a prophylactic mastectomy (25%), compared with women at high risk (16%) ( CONCLUSION: A significant proportion of women at increased risk of developing hereditary breast cancer would consider prophylactic mastectomy. Although prophylactic mastectomy may be appropriate in women at high risk of developing breast cancer, it is perhaps less so in those who have a moderately increased risk. Such moderate-risk women are likely to benefit from interventions aimed at reducing breast cancer anxiety and correcting exaggerated breast cancer risk perceptions.
THE CLONING OF THE two breast cancer genes BRCA1 and BRCA2 has made it possible to use mutation detection to identify currently unaffected carriers of high-risk breast cancer mutations.1-4 The features of dominantly inherited breast cancer are well-established and include the presence of multiple relatives affected with breast cancer in more than one generation, early age of onset in affected relatives, bilateral breast cancer or multiple primary cancers, and the presence of other types of cancer in some families.5-7 The significance of mutation detection lies in its potential to accurately distinguish carriers of high-risk mutations from noncarriers and to have a major impact on early cancer detection and prevention strategies. Although there has been rapid progress in the identification of genes responsible for hereditary breast cancer, optimum early detection strategies remain controversial because of a lack of evidence of mortality reduction as a result of screening high-risk women. Guidelines on surveillance and prophylactic measures are largely based on expert opinion, because no controlled trials of surveillance and prevention methods have been conducted among individuals at high risk of developing breast cancer.8 Prophylactic bilateral mastectomy has been considered one of the management options for high-risk women,9-11 even though—until recently—no evidence for mortality reduction was available. However, with the publication of findings from a retrospective study of 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy, evidence for a significant reduction of risk and mortality has now become available. In that study, Hartmann et al12 conducted a retrospective study of 214 women at high risk and 425 women at moderate risk, with a mean follow-up period of 14 years from the time of surgery. For the high-risk group, a case-control design was used. For both risk groups, the number of predicted cancers and deaths far exceeded the number of those observed, and bilateral mastectomy led to a 90% reduction in expected breast cancer incidence and mortality. These findings confirm results from a previous, less rigorously designed retrospective study.13 Theoretical modeling of the effect of prophylactic mastectomy on predicted average life expectancy in BRCA1 or BRCA2 carriers suggests that prophylactic mastectomy leads to substantial gains in life expectancy in young women.14,15 For example, the model predicts an average gain of between 3.2 to 7.6 years in a 30-year-old BRCA1 or BRCA2 mutation carrier.14 Gains in life expectancy must be weighed against the potentially disfiguring and psychologically damaging effects of prophylactic mastectomy.16 Medical and psychosocial factors will impact women’s attitudes toward and decision-making about prophylactic mastectomy.12 There may also be individual differences regarding what it means to have breasts and, after undergoing prophylactic mastectomy, what it means not to have them. A high-risk woman’s decision to undergo prophylactic mastectomy is therefore likely to be highly individual and complex. Only one study has examined intention to undergo prophylactic mastectomy. In that study, Stefanek et al17 reported that the 14 women who decided to have the procedure reported significantly more breast cancer anxiety at baseline, compared with women who decided not to undergo mastectomy. The study made an important contribution to the literature because of its prospective design. However, it had methodologic and analytic shortcomings, including sample-size limitations, nonvalidated measures, and a lack of generalizability to women at increased risk of developing hereditary breast cancer. The objective of our study was to assess intention to undergo prophylactic mastectomy in a large sample of women at increased risk of developing hereditary breast cancer, using validated measures. The study investigated the role of several factors that may lead women to consider prophylactic mastectomy, including accuracy of perceived risk, breast cancer anxiety, generalized psychologic distress, and objective risk factors.
Patients Data were collected as part of a more comprehensive assessment of attitudes toward genetic testing, knowledge of breast cancer genetics, and cancer screening uptake involving the same sample, the results of which will be reported separately. The findings reported here are based on a sample of 333 unaffected women at increased risk of developing hereditary breast cancer. Women who approached one of 14 familial cancer clinics and six associated outreach clinics in five Australian states (New South Wales, Victoria, South Australia, Queensland, and Western Australia) between November 1996 and January 1999 were eligible for participation. These familial cancer clinics provide a comprehensive service according to national guidelines that includes risk assessment, genetic testing, and advice regarding early detection and prophylactic strategies.11 Currently, only women at risk of developing hereditary breast cancer who have an affected, living relative willing to provide a blood sample are eligible for genetic testing, because the test is informative only when a known mutation is segregating in a particular family.11 Women were considered ineligible for study participation if they had a prior diagnosis of ovarian or breast cancer; were unable to give informed consent; or had limited literacy in English, because data were collected using self-report questionnaires. The study was approved by 16 regional ethics committees.
Methods
Measures Demographic characteristics. Sex, age, educational level, marital status, and number of biologic children were determined. Impact of Event Scale. This 15-item scale measures anxiety responses in relation to a specific stressor and has well-documented psychometric properties.18,19 The scale has been used in related studies.20,21 In the study presented here, the particular stressor was concern about being at risk of developing breast cancer. Participants were asked to rate symptoms of anxiety (for example, "I had strong waves of feelings about being at risk for breast cancer") on a scale ranging from "not at all" to "often." The scale was included because being at risk for breast cancer may be construed as a traumatic stressor by some individuals, thereby giving increase to intrusive and avoidant thoughts. A score of 40 or higher on the Impact of Event Scale is considered to be strongly predictive of a significant stress-response syndrome.22 General Health Questionnaire 28. This 28-item scale is a measure of generalized psychologic distress and has been validated for a wide range of samples and a variety of settings.23 Scores of 5 or higher indicate psychologic distress levels consistent with a need for psychologic intervention.23 Breast cancer–related life events. Breast cancer–related life events were assessed because they may act as psychologic risk factors. Two items were specifically designed for this study. Participants were asked whether they had experienced a stressful life event in the past year. Those women who reported a stressful life event were then asked to select the type of event from a list of events (both related and unrelated to the experience of breast cancer). This list had been developed specifically for the study, using a qualitative methodology. A new variable was created that classified women in terms of absence or presence of a breast cancer–related life event in the past year. Objective breast cancer risk. Age of breast cancer onset in the youngest person in the family was collected from study participants. To provide an estimate of objective risk, clinic staff were asked to make a judgment on whether a participant’s family history was either consistent or not consistent with a dominantly inherited predisposition to breast cancer, and participants were thus classified as being at "high risk" or "moderately increased risk," respectively.7 Women at or slightly above the Australian population risk (lifetime risk of one in 13 women)7 were not included in the sample because they were not eligible for genetic counseling. Women at moderately increased risk had a family history of breast cancer which suggested that they had an increased risk of developing breast cancer (range, lifetime risk of one in four women to one in eight women), relative to women at the Australian population risk level. Women who had a family history suggesting the presence of a dominantly inherited predisposition of cancer had a range in lifetime risk of developing breast cancer of one in two women to one in four women. After the risk assessment interview at the familial cancer clinic and once pedigree information5,6 and relatives’ diagnoses as confirmed by medical records were available, clinic staff categorized participants into objective risk groups. For women at high risk, clinic staff made a judgment about whether the participant was at either a 50% or 25% mutation carrier risk. An approximately 25% mutation carrier risk would apply to a woman from a high-risk family whose closest affected relative is a second-degree relative or to a woman from a family with an identified mutation whose closest relative of known mutation status is a second-degree relative. A woman from a high-risk family whose closest affected relative is a first-degree relative or a woman from a family with an identified mutation whose closest relative of known mutation status is a first-degree relative was classified as being at a 50% mutation carrier risk. This was defined because of the current uncertainty associated with risks imparted by breast cancer gene mutations and the inappropriateness of the models of Claus and Gail et al to high-risk women.24,25 The expert opinion of clinical geneticists was used as a reference standard because there are currently no universally accepted standards to estimate breast cancer risk in high-risk women. The number of first- and second-degree relatives who developed breast or ovarian cancer were collected from study participants. Accuracy of breast cancer risk perception. One item asked participants to state their approximate perceived lifetime breast cancer risk. The following response options were available for this item: 1%, 4%, 8%, 12%, 16%, 25%, 33%, 50%, 85%, and 100%. Risk was expressed both as a percentage and as odds (eg, one in eight women). A new variable was created that classified women in terms of their accuracy of risk perception; namely, as underestimators, accurate estimators, or overestimators. Classifications were defined on the basis of geneticists’ estimated risks and women’s risk perceptions. The best estimate of lifetime breast cancer risk in high-risk women was made on the basis of the assumption that breast cancer gene mutations are dominantly inherited and that the real penetrance rate imparted by mutations is 60%. For women at a moderately increased risk and a 25% mutation risk, a breast cancer lifetime risk of one in six women was used as a benchmark, and for women at a 50% mutation carrier risk, a breast cancer risk of one in three women. Participants whose estimate of their own risk fell either one response option below or above the category used as a benchmark were categorized as accurate estimators, and as overestimators above and underestimators below those levels. Intention to undergo prophylactic mastectomy. This item was the outcome variable and asked women whether they would consider prophylactic mastectomy if a genetic test were to show that they are carriers. The response options were "no," "yes," "don’t know," and "done/in progress."
Data Analysis
Characteristics of the Sample Of the 374 women who met the eligibility criteria, 41 women declined participation or never returned the questionnaire (response rate, 89%). Table 1 summarizes the sociodemographic and family history variables of the study sample. The median age of the sample was 39 years (range, 18 to 75 years). Sixty-nine percent had postschool qualifications, compared with 37% of women in the general Australian population.26 The mean age of breast cancer onset in the youngest person in the family was 41 years (SD = 9.6). The number of self-reported first- and second-degree relatives with a diagnosis of breast or ovarian cancer ranged from one to 18, with a median of three. All women were assessed before their attendance at the familial cancer clinic and before receiving a genetic testing result. Clinic staff judged 67% of participants to be at high risk and 50% mutation carrier risk and 11% at high risk and 25% mutation carrier risk. The remaining 22% were thought to be at moderately increased risk of developing breast cancer. Fifty-four women (16%) had a family history that included ovarian cancer in addition to breast cancer. Of the 192 women eligible for and interested in genetic testing, only 24 (13%) had received a genetic testing result as of August 1999. For ethical reasons, the proportion of carriers and noncarriers among women who received a result had not been revealed to the central research team at the time of the analysis, although results will be requested once follow-up of the cohort has been completed and data can be de-identified.
Forty-seven high-risk women (14%) were not eligible for genetic testing because they did not have a living, affected relative who could undergo mutation detection. Participation in the International Breast Intervention Study was also assessed as a potential confounder. However, only five women (2%) reported participating in this placebo-controlled tamoxifen chemoprevention trial.
Intention to Undergo Prophylactic Mastectomy
Contingency-table analysis for objective risk and intention showed that women at a moderately increased risk for developing breast cancer had the highest proportion of women (25%) considering mastectomy, compared with 13% of high-risk women at 25% mutation carrier and 17% of high-risk women at 50% mutation carrier. Women at a moderately increased risk were significantly more likely to consider prophylactic mastectomy (25%), compared with women at high risk (16%; those at 25% and 50% mutation carrier risk were included) (  2 = 7.79; P = .051). A higher percentage (37%) of women at high risk responded "don’t know," compared with women at a moderately increased risk (21%). Examination of the association between age group and intention to undergo prophylactic mastectomy suggested a curvilinear relationship. The highest proportion (27%) of women who would consider prophylactic mastectomy were in the 30- to 39-year age group, compared with women aged less than 30 (20%), 40 to 49 (17%), and those older than 50 (7%). In the full model, neither objective risk (P = .89), occurrence of a breast cancer–related event in the past year (odds ratio [OR] = 1.15; 95% confidence interval [CI], 0.66 to 2.01; P = .63), age of breast cancer onset in the youngest person in the family (OR = 1.01; 95% CI, 0.97 to 1.06; P = .61), number of first- and second-degree relatives with breast or ovarian cancer (OR = 0.96; 95% CI, 0.72 to 1.27; P = .75), or generalized psychologic distress (OR = 0.99; 95% CI, 0.39 to 2.51; P = .98) were significantly associated with intention to undergo prophylactic mastectomy. Age, accuracy of risk perception, and breast cancer anxiety exhibited associations, with P < .05, and were entered into the final model. Objective risk was also entered into the final model as a control variable. Table 2 shows the final logistic regression model. Objective risk was not significantly associated with intention (P = .60). Women with breast cancer anxiety levels that indicated a stress response were significantly more likely to consider mastectomy, compared with women with lower anxiety levels (OR = 17.40; 95% CI, 4.35 to 69.71; P = .0001). Overestimating one’s risk was also significantly associated with intention (OR = 3.01; 95% CI, 1.43 to 6.32; P = .0036). Compared with women older than 50 years of age, women aged 30 to 39 years were significantly more likely to consider mastectomy (OR = 5.27; 95% CI, 1.47 to 18.72; P = .010).
Breast cancer anxiety and generalized psychologic distress were correlated with each other, with a Spearman rank correlation of 0.292 (P < .01). Because correlations of this magnitude may lead to multicollinearity, two additional regressions (each with age, objective risk, and accuracy of risk perception included) were performed. The first regression included generalized psychologic distress instead of breast cancer anxiety as one of the predictor variables. Results were highly similar in that generalized distress was significantly associated with consideration of mastectomy (OR = 2.03; 95% CI, 1.00 to 4.15; P = .051), whereas objective risk was not. As a next step, both breast cancer anxiety and generalized psychologic distress were entered into the regression. Breast cancer anxiety remained a highly significant predictor (P = .0001), whereas generalized psychologic distress was no longer significant (P = .66). These findings raise questions about the relationship between breast cancer anxiety and generalized psychologic distress. One plausible interpretation is that breast cancer anxiety may be a partial cause of generalized psychologic distress. According to this interpretation, psychologic distress is no longer significant in the last regression because its cause has been controlled for.
The results of this study demonstrate that 19% of women at increased risk of developing hereditary breast cancer would consider prophylactic mastectomy, should a genetic test for breast cancer predisposition indicate presence of a mutation, although women indicated this intention in a hypothetical situation. The results may still have implications for the majority of women for whom predictive testing is currently not possible and who must therefore make their decision under conditions of uncertainty. In our sample, a small proportion of high-risk women (14%) were not eligible for genetic testing. Only 13% of women who were eligible for and interested in genetic testing have received a test result so far. For these women, genetic testing is an important step in the decision-making process about prophylactic mastectomy because it can provide a definitive answer concerning their mutation status and, therefore, their risk. However, many women experience delays in receiving their test results, reflecting the technical challenges presented by mutation detection of the large BRCA1 and BRCA2 genes. The lower rate of mutations found in familial cancer clinic populations,27-29 compared with kindreds studied by the Breast Cancer Linkage Consortium,6 must also be considered a contributing factor. This study’s findings demonstrated that consideration of prophylactic mastectomy was associated positively with high levels of breast cancer anxiety and overestimating one’s breast cancer risk but not with objective breast cancer risk. These results correspond to previous findings in the area of psychologic aspects of genetic testing which show that psychologic factors, rather than objective risk, guide interest in genetic testing and psychologic adjustment to test results. Among individuals at risk of developing Huntington’s disease, hereditary breast cancer, or hereditary nonpolyposis colorectal cancer, interest in genetic testing is significantly associated with perceived risk but not objective risk,30,31 and adjustment to results has been found to depend more on pretest psychologic adjustment than the test result itself.32,33 The association between breast cancer anxiety and intention to undergo prophylactic mastectomy suggests that it is advisable to identify women with high levels of breast cancer anxiety by using formal assessment tools, such as those used in the study presented here. With regard to women at a moderately increased risk and 25% mutation carrier risk, our findings raise concern. For these women, prophylactic surgery is not recommended, on the basis of the small magnitude of its risk-reducing effect. Therefore, it seems particularly important to create opportunities in the clinical setting to explore and discuss their concerns. The highest proportion of women considering mastectomy was that among women at a moderately increased risk. Women at a moderately increased risk with high anxiety levels are therefore more likely to seek referrals to surgeons in an attempt to relieve their anxiety. The clinical implications for mutation carriers and women at 50% mutation carrier risk who have not received an informative genetic-testing result are different. Breast cancer anxiety may be an appropriate emotional response to being at high risk for development of such cancer. Prophylactic mastectomy has been shown to reduce breast cancer incidence and mortality.12 Therefore, it is understandable that high-risk women might consider mastectomy in an attempt to reduce both their breast cancer risk and their anxiety level. The study presented here demonstrated that women who overestimated their breast cancer risk were significantly more likely to consider prophylactic mastectomy, compared with women who accurately estimated or underestimated their risk. This positive association was found to be independent of breast cancer anxiety, suggesting that both excessive breast cancer anxiety and inflated risk perceptions need to be corrected before a decision can be made about prophylactic mastectomy. Several studies have demonstrated that genetic counseling succeeds in improving the accuracy of perceived breast cancer risk34-38 and decreasing breast cancer anxiety.39 There is evidence to suggest that breast cancer anxiety may interfere with comprehension of risk information,36 thereby further giving support to an approach that combines interventions aimed at reducing breast cancer anxiety and correcting excessive risk perceptions. The study also showed that women aged 30 to 39 years had the highest proportion of women considering prophylactic mastectomy, and women older than 50 years had the lowest. Risk of being a mutation carrier decreases with age in unaffected women from families with hereditary breast cancer. Because the relationship between age and consideration of prophylactic mastectomy was curvilinear, differences in objective risk are unlikely to account for this age effect. Several possible factors may account for the differences between age groups. It is possible that the attitudes of women of different ages are influenced by their perception of how much life is left for them and the price they are willing to pay to prolong life. It is also plausible that cultural and educational experiences of women born during World War II and in the postwar era differ considerably from those born subsequent to these events. Compared with women in their 30s, women aged 50 and older are unlikely to have had the same exposure to health education and information about genetics. Two limitations of this study should be noted. Because of the cross-sectional design of the study, it is not known whether intention to undergo mastectomy would necessarily translate into actual behavior. The prospective study by Stefanek et al,17 despite its drawbacks, lends support to our findings; we are also collecting follow-up data. Second, the sample, as a whole, was highly educated, as has also been true of other studies that assessed women who attended familial cancer clinics.37 The high educational levels of the study sample in our report suggest that generalizations to the broader population of women at increased risk of developing hereditary breast cancer need to be made cautiously. Nonetheless, because of the high participation rate (89%), findings are highly relevant to those women who are most likely to seek information about prophylactic surgery from familial cancer clinics. Our findings strongly suggest that women with breast cancer anxiety levels that are suggestive of the presence of a stress syndrome may require alternative strategies to deal with excessive anxiety, regardless of their objective risk. These may include the scheduling of several genetic counseling sessions or referral to liaison staff with expertise in psychiatry or clinical psychology. Very high levels of anxiety are likely to interfere with the decision-making process, and techniques in anxiety reduction may need to be used before the issues can be discussed. Surgeons and familial cancer clinic staff may also benefit from training in anxiety reduction and supportive counseling techniques.
Supported by project grant no. 970929 from the National Health and Medical Research Council of Australia, Sydney, Australia. We thank the following individuals for their contributions to this study: Alex Barratt, PhD, Robert A. Boakes, PhD, and Stewart Dunn, PhD, for their methodologic advice; Morag Clifton, for data collection and management; Maggie Watson, PhD, for generously discussing similar work undertaken in the United Kingdom; Jack Chen, PhD, for statistical advice; Meryl Smith, Margaret Gleeson, Karen Harrop, Helen Hopkins, Annette Hattam, Lucille Stace, Julie White, Anne Baxendale, Susan White, Step Daly, Mary-Anne Young, Bronwyn Burgess, Monica Tucker, Clara Gaff, PhD, Agnes Bankier, MD, Ian Walpole, MD, Kristiina Aittomäki, MD, Mac Gardner, MD, Alison Colley, MD, Tracy Dudding, MD, Jack Goldblatt, MD, Elizabeth Thompson, MD, and Gillian Turner, MD, for assistance with patient recruitment, data collection, and the ethics application process. Finally, we are most grateful for the valuable contribution of all the women who participated in this study.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
