Originally published as JCO Early Release 10.1200/JCO.2007.11.0262 on November 26 2007

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Cancer Risk Management Practices of Noncarriers Within BRCA1/2 Mutation–Positive Families in the Kathleen Cuningham Foundation Consortium for Research Into Familial Breast Cancer

Sarah-Jane Dawson, Melanie A. Price, Mark A. Jenkins, Joanne M. McKinley, Phyllis N. Butow, Sue-Anne McLachlan, Geoffrey J. Lindeman, Prue Weideman, Michael L. Friedlander, John L. Hopper, Kelly-Anne Phillips

From the Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre; Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne; Department of Medical Oncology, St Vincent's Hospital, Fitzroy; Familial Cancer Centre, Department of Medical Oncology, Royal Melbourne Hospital, Parkville; The University of Melbourne, Department of Medicine, St Vincent's Hospital, Victoria; Medical Psychology Research Unit, School of Psychology, University of Sydney, Sydney; Department of Medical Oncology, Prince of Wales Hospital, Randwick; Australia

Corresponding author: Kelly-Anne Phillips, MD, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag No. 1, A'Beckett St, Victoria, 8006, Australia; e-mail: Kelly.Phillips{at}petermac.org

	ABSTRACT

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Purpose Women from BRCA mutation–positive families who do not carry the family-specific mutation are generally at average cancer risk and therefore do not require intensive risk management.

Methods Participants were female noncarriers from BRCA mutation–positive families who had responded to 3 yearly follow-up questionnaires and had chosen to either receive or not receive their genetic test result. In the former group, undertaking mammography younger than age 40 years or more than once every 2 years, clinical breast examination (CBE) more than yearly, breast self-examination (BSE) more than monthly, or any transvaginal ultrasound (TVU) or CA-125 was considered overscreening. Screening behaviors of women who did and did not know their genetic test result were compared. Logistic regression and nonparametric analyses were performed to identify demographic and psychosocial factors (respectively) associated with overscreening.

Results Of 325 eligible women, 116 knew their mutation status and 209 did not. For the first group, proportions overscreening were mammography, 53%; CBE, 10%; BSE, 11%; TVU, 7%; and CA-125, 10%. There were no significant differences in screening behaviors between the groups. In those aware of their mutation status, parous women were more likely to overuse mammography (odds ratio [OR] = 4.4; 95% CI, 1.1 to 17; P = .03) and women with one or more first-degree relative with ovarian cancer (OC) were more likely to overuse OC screening (TVU: OR = 6.00; 95% CI, 1.0 to 35.1; P = .047, and CA-125: OR = 6.50; 95% CI, 1.49 to 28.4; P = .013).

Conclusion The reasons for overuse of screening (particularly mammography) by mutation noncarriers require additional elucidation given the potential for harm.

	INTRODUCTION

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Women carrying a germline mutation in BRCA1 or BRCA2 have a significantly elevated lifetime risk of breast cancer (BC) and ovarian cancer (OC).¹ An important motivation for genetic testing is to refine risk estimates for the individual to guide management decisions. Female mutation carriers are encouraged to undertake intensified BC and OC screening, risk-reducing surgery, and chemoprevention.² Conversely, individuals from mutation-positive families who do not carry a mutation are considered at the same risk level as the general population for BC and OC. They are dissuaded from risk-reducing surgery and chemoprevention, and are advised to reduce cancer screening to levels recommended for the general population.

Breast cancer screening recommendations for the general population are far less intensive than those for carriers of BRCA mutations.³ For the general population, Australian guidelines recommend mammography once every 2 years from ages 50 to 69 years; however, mammography once every 2 years within the 40- to 49-year age group is also accepted.⁴ The potential benefits of clinical breast examination (CBE) and breast self-examination (BSE) remain unproven.^5,6 The Australian guidelines do not recommend for or against these strategies.⁴ The American Cancer Society guidelines for the general population recommend annual mammography and CBE from age 40 years, CBE once every 3 years for women between 20 and 39 years and monthly BSE as an option starting at age 20 years.⁷ OC screening is not recommended for the general population because of its low sensitivity and specificity.⁸

There are limited published data on the use of BC and OC risk management strategies in women from BRCA mutation–positive families.^9-15 To date, no study has focused exclusively on the screening practices of noncarriers from these families. In addition, little is known about factors that play a role in the decision making of these women regarding health-related behavior after predictive testing. The aims of this study were to evaluate prospectively and compare the risk management practices of true BRCA1 and BRCA2 noncarriers who did versus did not choose to learn their negative mutation result, and to explore factors associated with use of risk management practices. The primary hypotheses, based on clinical experience and the limited published literature, was that true noncarriers aware of their negative mutation result would be overusing BC and OC screening, and that overuse would be associated with family history of cancer and higher levels of perceived cancer risk.

	METHODS

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Study Sample
Women in this study were participants in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab; Appendix, online only).^16,17 Clinical follow-up data and psychosocial information were collected in parallel using self-report questionnaires once every 3 years.^18,19 All participants provided written informed consent. The clinical follow-up and psychosocial studies have ethics approval at all kConFab recruitment sites.

To be eligible for the current study, women had to have no history of cancer (except nonmelanoma skin cancer), be a proven noncarrier within a family carrying a pathogenic BRCA mutation, and be a blood relative (not spouse) of a mutation carrier. Women aware of their negative mutation status had to have received their result at least 2 years before completion of the follow-up questionnaires.

Data Collection
Demographics. Demographic information was collected at entry into kConFab using an interviewer-administered questionnaire.¹⁸ Mutation status for BRCA1/BRCA2 was determined from the kConFab database. In the follow-up questionnaire, women were asked if they knew their mutation result, and when this information was disclosed.

Risk management practices. Women reported on their uptake of screening, risk-reducing surgery (bilateral mastectomy [BM] and bilateral oophorectomy [BO]) and chemoprevention using the follow-up questionnaire. Self-reports of risk-reducing surgery were confirmed with operative and pathology reports.

Psychosocial variables. Perceived cancer risk was assessed using a numerical differential scale ranging from 0 (no chance) to 100 (definitely).^20,21 Cancer-specific anxiety was assessed using the Intrusive Thoughts subscale of the Impact of Event Scale.^21-23 General anxiety and depression were assessed using the Hospital Anxiety and Depression Scale.^24,25 Dispositional optimism was measured using the Life Orientation Test.^26,27 Satisfaction with available social support was measured using the Duke-University of North Carolina Functional Social Support Questionnaire.²⁸

Local Screening Guidelines
Australian guidelines were used to determine the recommended screening practices for the Australian population.⁴ Where specific guidelines were not available (CBE and BSE), criteria for the recommended frequency of these risk management practices were adapted from the American Cancer Society guidelines.⁷ These guidelines were then used to determine definitions of overscreening for the study cohort. Undertaking mammography younger than age 40 years or more often than once every 2 years, CBE more often than yearly, BSE more often than monthly, and any TVU or CA-125 analysis was considered overscreening on the basis of actual genetic result.

Statistical Analysis
Proportions of women who underwent screening, surgery, or chemoprevention were calculated for decades of age. The proportions of noncarriers overscreening were compared in women aware of their negative mutation status and those who had chosen not to receive their mutation result.

Univariate logistic regression was used to explore the association between screening and the explanatory variables: age, time since disclosure of mutation results, education (tertiary v other), parity (any live births v none), city residence (living in a major city v other), country of birth (Australia or New Zealand v other), marital status (married or living as married v other), family history of BC (at least two first-degree or at least two first- or second-degree female relatives with BC v others), and family history of OC (at least one first-degree or at least one first- or second-degree relative with OC v others). Scores for the psychosocial variables (cancer risk perception, cancer-specific anxiety, general anxiety, depression, optimism, and social support) were not normally distributed, therefore, the rank-sum statistic was used to compare those who overscreened and those who did not. All statistics were calculated using STATA version 8.0 (STATA Corp, College Station, TX).

	RESULTS

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Study Participants
Until June 2006, there were 404 female unaffected noncarriers participating in follow-up (participation rate, 74%). Twenty-one women were excluded because they were spouses of participants enrolled onto kConFab, resulting in 383 women. Mean follow-up was 4.5 years (range, 2.8 to 7.0 years).

Women aware of negative mutation status (n = 116). Of the 383 eligible women, 167 had chosen to be informed of their mutation status. Of these, 51 were ineligible because they completed the follow-up questionnaire within 2 years of result disclosure (n = 47) or because they developed cancer during the follow-up period (n = 4). Additional women were excluded in each screening behavior analysis (mammography, n = 6; BSE, n = 6; CBE, n = 7; TVU, n = 26; CA-125, n = 22) if they failed to provide sufficient information on screening practices, if they had previously undergone BM or BO, or if they were pregnant during follow-up. Mean time since disclosure of the negative mutation result was 4.6 years (range, 2 to 9.5 years).

Women unaware of negative mutation status (n = 209). Most (216 of 383) female unaffected noncarriers had chosen not to be informed of their negative mutation status. Seven were excluded because they developed cancer during the follow-up period. Additional women were excluded in each screening behavior analysis (mammography, n = 16; BSE, n = 17; CBE, n = 18; TVU, n = 56; CA-125, n = 43), as described for women aware of their negative mutation result.

The characteristics of study participants are listed in Table 1. Women aware of their negative mutation status were 14 times more likely to have had a BM (P < .001) and 75% less likely to have had a BO (P = .01) compared with women who did not know their mutation status.

Women aware of negative mutation status. The proportions of women overscreening were as follows: mammography, 53%; CBE, 10%; BSE, 11; TVU, 7%; and CA-125, 10% (Table 2). Of the fifty-eight women overscreening for mammography, 46 were aged between 40 and 69 years and undergoing mammography yearly rather than once every 2 years.

Women unaware of negative mutation status. Parous women were more likely to use mammography compared with nulliparous women (OR = 2.8; 95% CI, 1.1 to 7.7; P = .02; Tables 4 and 5). In addition, women with a strong family history of BC were more likely to use mammography (at least two first-degree relatives (OR = 5.5; 95% CI, 2.2 to 14.7; P < .001); at least two first- or second-degree relatives (OR = 2.2; 95% CI, 1.1 to 4.8; P = .02). Women living in a major city were more likely to use CBE (OR = 4.4; 95% CI, 0.9 to 42.2; P = .045). For OC screening, women with at least one first-degree relative with OC were more likely to use TVU (OR = 6.3; 95% CI, 0.9 to 72; P = .04). Women with lower levels of social support were more likely to use CA-125 screening (P = .02).

Risk-Reducing Surgery
One woman underwent risk-reducing BM 6 weeks after disclosure of a negative result at age 31 years and one woman underwent risk-reducing BO 3 years after disclosure of a negative result at age 52 years (Table 6). No malignancy was identified in either specimen. Of the participants unaware of their mutation result, five underwent BO during the follow-up period, but all were for benign conditions rather than risk-reducing surgery.

	DISCUSSION

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For a woman from a family with a documented BRCA mutation, a major advantage of learning her negative mutation status is that she can reduce her risk management practices to that appropriate for the general population. However, the current study identified a high rate of overuse of mammography in noncarriers. Identification of overscreening has important implications with respect to minimizing potential harm from false-positive results and limiting inappropriate use of health resources.

In the current study, 53% of true noncarriers aware of their negative mutation status were overusing mammography. Thirty-one percent of participants younger than age 40 years were overscreening, consistent with other smaller studies of noncarriers (range, 19% to 30%).^10-13 In addition, 62% of participants age 40 years or older were overscreening. Previous studies have shown that noncarriers older than 40 years demonstrate high uptake of mammography when compared with the general population.^11,13 In Australia, approximately 54%, 70%, and 58% of women in their 40s, 50s, and 60s, respectively, participate in the free mammography screening program.³⁰ An additional proportion undergo screening through private services. In the current study, 93% of women in their 40s and 97% age 50 to 69 years were undergoing mammography, which is considerably higher than that reported for the general population. These women seem to recognize the importance of ongoing screening after a negative mutation result; however, a large proportion are continuing to overscreen.

When considering screening practices other than mammography, approximately 10% of participants aware of their negative mutation status were overscreening. Of particular concern is the overuse of OC screening given the ineffectiveness of current techniques.⁸ Schwartz et al¹⁴ also identified overuse of OC screening in 44 noncarriers: 9% had CA-125, 21% had TVU, and 2% had BO in the 12 months after negative result disclosure.

The disclosure of a negative mutation result is expected to lead to a reduction in screening behavior. Our study suggests that screening intensity is similar in women aware of their negative mutation status compared with those who have chosen not to be informed. First, it is possible that learning a negative mutation result may not actually alter screening behavior (ie, reduce intensity). Alternatively, those women who chose to know their mutation status may have been undergoing more frequent screening before result disclosure and may have reduced their screening after result disclosure, but not to the level recommended for the general population.

In this study, for women aware of their negative mutation status, the only factor statistically associated with overuse of mammography was parity. The fear of leaving behind children may be an independent factor promoting excessive screening in these women. The overuse of OC screening was associated with having a first-degree relative with OC. Individuals previously considered to be high risk may be reluctant to cease frequent screening immediately because of the desire for reassurance in the context of a family history with many persons affected by cancer. Parity and family history of OC were also associated with higher use of BC and OC screening, respectively, in women unaware of their negative mutation status. For this group, higher use of mammography was also associated with family history of BC, most likely reflecting family experiences. In addition, those women living in a major city were more likely to use CBE, perhaps relating to access to doctors.

Cognitive and affective factors have been identified previously as key motivators of health-protective behavior.³¹ Previous studies have performed combined analyses (of both carriers and noncarriers) examining the use of screening strategies according to levels of cancer specific distress. We did not observe any statistically significant associations between psychosocial variables and overscreening in women aware of their mutation status; however, we cannot exclude such associations that may be detected in a larger study. For women unaware of their negative mutation status, lower levels of social support were associated with higher use of CA-125 screening. This result is difficult to interpret given that no other associations were identified.

Risk reducing surgery and chemoprevention are not recommended for women at population risk of BC or OC. The use of these strategies in a small proportion of women after result disclosure suggests they may not have shared their mutation-negative status with their treating doctor.

The effectiveness of genetic counseling and risk management advice given to noncarriers at the time of negative result disclosure may influence subsequent risk management practices. After positive mutation result disclosure, women routinely have ongoing follow-up to support their adjustment and to encourage appropriate health-protective behavior over time. However, after negative mutation result disclosure, women usually have no ongoing contact with genetic counseling services. Given that the current study identifies a large proportion of women who do not follow local screening guidelines, and a small number who had unnecessary risk-reducing surgery or chemoprevention, additional follow-up after result disclosure should be considered.

The strengths of this study include the prospective nature of the cohort, the multi-institutional recruitment of families, and the follow-up period (considerably longer than other published studies). Overuse of screening does not seem to be isolated to the immediate period after negative result disclosure, but continues for an extended period, suggesting that the factors that govern the decision making of women with respect to health-protective behavior are complex and persist over time.

This study had a number of limitations. First, the screening rates observed are generalizable to noncarriers of BRCA1 and BRCA2 mutations in multiple BC families in which a BRCA1 or BRCA2 mutation is segregating and may not generalize to noncarriers without a strong family history. Second, to understand the true effect of result disclosure on screening practices, a longitudinal study would be required. However, observing women both preresult and postresult disclosure would be methodologically challenging, given that any change in screening behavior may be confounded by increasing age where screening recommendations vary. Third, although this is the largest study of this type to our knowledge, the sample size provided limited statistical power to detect associations between factors and overscreening. The low number of women undertaking some screening practices is reflected in the confidence interval. Fourth, the assessment of use of screening strategies was based on self-reporting, not on medical record verification. Self-reports of screening practices are generally accurate and reliable.³² Fifth, women who agreed to participate in kConFab may represent a highly motivated group that is more likely to participate in health-protective behavior than the general population. Finally, our questionnaire did not ask qualitative questions regarding reasons for overscreening, although such work is being undertaken elsewhere (L. Keogh, personal communication, April 2007).

Our identification of individuals who are hypervigilant in their screening practices after learning their mutation-negative status warrants additional investigation to determine the motivation for overscreening and to institute effective interventions. The process of genetic counseling requires comprehensive consideration of medical, psychological, and social issues to provide accurate information, facilitate appropriate decision making, promote behavior consistent with recommendations, and assist in the adaptation process for clients and their families.³³ It is likely that attention to all of these factors is necessary to influence subsequent adherence to recommended screening guidelines and ultimately lead to the improved care of this specific group.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Melanie A. Price, Mark A. Jenkins, Phyllis N. Butow, Sue-Anne McLachlan, Geoffrey J. Lindeman, Prue Weideman, Michael L. Friedlander, John L. Hopper, Kelly-Anne Phillips

Administrative support: Sarah-Jane Dawson, Melanie A. Price, Joanne M. McKinley, Prue Weideman

Collection and assembly of data: Sarah-Jane Dawson, Melanie A. Price, Joanne M. McKinley, Phyllis N. Butow, Prue Weideman, Kelly-Anne Phillips

Data analysis and interpretation: Sarah-Jane Dawson, Melanie A. Price, Mark A. Jenkins, Joanne M. McKinley, Phyllis N. Butow, Sue-Anne McLachlan, Geoffrey J. Lindeman, Prue Weideman, Michael L. Friedlander, John L. Hopper, Kelly-Anne Phillips

Manuscript writing: Sarah-Jane Dawson, Melanie A. Price, Mark A. Jenkins, Joanne M. McKinley, Phyllis N. Butow, Sue-Anne McLachlan, Geoffrey J. Lindeman, Prue Weideman, Michael L. Friedlander, John L. Hopper, Kelly-Anne Phillips

Final approval of manuscript: Sarah-Jane Dawson, Melanie A. Price, Mark A. Jenkins, Joanne M. McKinley, Phyllis N. Butow, Sue-Anne McLachlan, Geoffrey J. Lindeman, Prue Weideman, Michael L. Friedlander, John L. Hopper, Kelly-Anne Phillips

	Appendix

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The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a cohort of more than 1,100 multiple-case families with breast cancer (BC), consisting of 9,000 individual participants from Australia and New Zealand. Families are recruited after an initial family member attends a consultation in one of 16 Family Cancer Clinics (FCCs). Eligibility criteria for families are complex but include a strong family history of BC and/or OC, or a documented BRCA mutation. Blood is drawn for BRCA mutation analysis at the time of enrolment and an epidemiology and family history questionnaire is completed. Unless the individual has herself/himself attended an FCC, genetic counseling is not performed before this research-based genetic testing. When conclusive genetic test results become available, all enrolled family members who consented to receive such information are notified (but not given the result) and have the option of attending an FCC for genetic counseling and clinical genetic testing (for the family mutation) if they have not already done so.

Cancer events, risk management practices, epidemiologic risk factors, and lifestyle risk factors of participants are updated every 3 years. In addition, women enrolled onto the study are asked to participate in a psychosocial study collecting information on cancer risk perception, psychological variables, personality characteristics, and levels of social support.

	ACKNOWLEDGMENTS

 
We thank Joanne Lee Dow for her role in questionnaire development; Lucy Burnham for data management and manuscript preparation; and Heather Thorne, Eveline Niedermayr, the kConFab research nurses and the heads and staff of the Family Cancer Clinics for their contributions to the kConFab resource.

	NOTES

 
published online ahead of print at www.jco.org on November 26, 2007.

Supported by National Health and Medical Research Council of Australia (NHMRC; Grants No. 145684, 288704, 301930, and 153824). kConFab is supported by grants from the National Breast Cancer Foundation, the NHMRC; the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. K.-A.P. is the Cancer Council Victoria, Dr John Colebatch Clinical Research Fellow. G.J.L. is supported by an NHMRC (Australian) Research Fellowship.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted January 30, 2007; accepted October 10, 2007.

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