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Predictors of Prophylactic Bilateral Salpingo-Oophorectomy Compared With Gynecologic Screening Use in BRCA1/2 Mutation Carriers

Joanna B. Madalinska, Marc van Beurden, Eveline M.A. Bleiker, Heiddis B. Valdimarsdottir, Lottie Lubsen-Brandsma, Leon F. Massuger, Marian J.E. Mourits, Katja N. Gaarenstroom, Eleonora B.L. van Dorst, Hans van der Putten, Henk Boonstra, Neil K. Aaronson

From the Division of Psychosocial Research and Epidemiology, Department of Gynecology, the Netherlands Cancer Institute; Department of Gynecology, Academic Medical Center, Amsterdam; Department of Gynecology, University Medical Center Nijmegen, Nijmegen; Department of Gynecology, University Medical Center Groningen, Groningen; Department of Gynecology, Leiden University Medical Center, Leiden; Department of Gynecological Oncology, University Medical Center Utrecht, Utrecht; Department of Gynecology, Academic Hospital Maastricht, Maastricht, the Netherlands; and the Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY

Address reprint requests to Neil K. Aaronson, PhD, Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: n.aaronson{at}nki.nl

	ABSTRACT

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PURPOSE: Women with BRCA1/2 gene mutations who have completed their childbearing are strong candidates for risk-reducing prophylactic bilateral salpingo-oophorectomy (PBSO). The aim of the current study was to identify baseline predictors of PBSO versus gynecologic screening (GS) in this group of high-risk women.

PATIENTS AND METHODS: Baseline questionnaires were available from 160 BRCA1/2 carriers who participated in a nationwide, longitudinal, observational study of the psychosocial consequences of prophylactic surgery versus periodic screening. Topics addressed by the questionnaire included generic quality of life, cancer-specific distress, risk perception, knowledge of ovarian cancer, and perceived pros and cons of surgery versus screening. PBSO use during the 12-month period after the first gynecologic consultation was determined on the basis of medical record data.

RESULTS: During the 12-month follow-up period, 74% of women had undergone PBSO, and 26% opted for screening. Statistically significant multivariate predictors of PBSO included education, general health perceptions, perceived incurability of ovarian cancer, and perceived benefits of surgery.

CONCLUSION: Women with lower educational levels, with poorer general health perceptions, who view ovarian cancer as an incurable disease, and who believe more strongly in the benefits of surgery are more likely to undergo PBSO. Clinicians should ensure that high-risk women are well informed about the low predictive value of GS techniques and about the lethal threat posed by ovarian cancer because of its limited curability.

	INTRODUCTION

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BRCA1 and BRCA2 gene mutation carriers have a lifetime risk of developing ovarian cancer of between 39% and 54% (BRCA1) and between 11% and 23% (BRCA2).^1-3 Women from hereditary breast/ovarian cancer (HBOC) families may opt either for periodic gynecologic screening (GS) or prophylactic bilateral salpingo-oophorectomy (PBSO) to manage their cancer risk.

The available screening techniques, transvaginal ultrasonography and CA-125 serology, have low predictive value for early cancer detection.^4,5 In contrast, PBSO reduces substantially the risk of both ovarian (96%) and breast cancers (53%).^6,7 The earlier PBSO is performed, the greater its beneficial effect,⁸ with the most risk-reducing effect being observed among premenopausal women.⁹ PBSO is usually recommended as a treatment option for women who carry BRCA1/2 mutations, have completed their childbearing, and who are older than 35 years.^10-12

Among premenopausal women, PBSO results in infertility and immediate onset of menopause, including vasomotor and urogenital symptoms.^13,14 Compared with natural menopause, surgical menopause may cause more severe symptoms¹⁵ and compromised quality of life (QOL).¹⁶ Although hormone replacement therapy should, in principle, compensate for endocrine deficiencies, there is evidence that it may be less effective in alleviating PBSO-induced menopausal symptoms than is often assumed.¹⁷

Few studies have investigated factors related to intentions to undergo PBSO or to actually undergoing PBSO among high-risk women.^18-25 Two cross-sectional studies found that older age, greater perceived risk of developing ovarian cancer, strongly perceived benefits of PBSO,¹⁹ and increased cancer anxiety²⁰ were associated positively with interest in surgery. Prospective studies have found PBSO use to be associated with older age,^21,22 parity,²² family history of ovarian cancer, high perceived risk of cancer,²⁴ and early breast tumor stage.²⁵ However, these latter, prospective studies did not focus on BRCA1/2 carriers only, but rather included all women from HBOC families who were undergoing genetic counseling and/or testing^21,23-25; these studies also included relatively small numbers of women with known BRCA1/2 status,^22,24 used single-center designs,^23-25 or did not include psychosocial measures.^23,25 In this article, we report the results of a prospective, observational, nationwide, multicenter study of factors associated significantly with PBSO among women who are strong candidates for such preventive surgery (specifically, BRCA1/2 carriers, women older than 35 years, and women who have completed their childbearing).

	PATIENTS AND METHODS

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Sample and Procedures
This study was part of a larger prospective investigation focusing on the psychosocial impact of ovarian cancer prevention. Study participants were recruited between 2002 and 2004 from the gynecology departments of seven of the eight hospitals in the Netherlands that have a clinical genetics center. The inclusion criteria for the larger, parent study were age between 30 and 70 years, HBOC in the family, and referral to the gynecology clinic by a clinical geneticist specifically for purposes of discussing the prevention of ovarian cancer. Exclusion criteria were prior oophorectomy performed as treatment for breast cancer or for any pathology in the ovaries and metastatic cancer or any other severe comorbidity. The current analysis was limited to BRCA1/2 carriers older than 35 years who had completed their childbearing.

All eligible women were invited to participate in the study by their gynecologist during the first consultation during which ovarian cancer prevention was discussed. This was followed by a mailed letter, an informed consent form, and a baseline questionnaire. In case of nonresponse, systematic reminders by mail and telephone were used. For nonrespondents, age and type of ovarian cancer prevention ultimately chosen were registered. Women who completed the baseline assessment received two follow-up questionnaires at 3 and 9 months after surgery (PBSO group) or at 6 and 12 months after baseline (GS group). The study was approved by the institutional review boards of all participating hospitals.

Sociodemographic and Clinical Data
The respondents' sociodemographics, reproductive history, current menstrual status, and the type of ovarian cancer prevention discussed with the gynecologist were obtained via questionnaire. Information about family history of breast/ovarian cancer, personal history of cancer and its treatments, mutation status, and the date of PBSO were abstracted from the medical records by specially trained research assistants under the supervision of the senior investigators. These records were complete, and in cases where there was any uncertainty, contact was sought with the responsible gynecologist.

Psychosocial Measures
Overall health perceptions, generic mental health, and overall QOL. General health perceptions and generic mental health were assessed with the relevant scales from the Short Form-36 Health Survey.^26,27 Overall QOL was assessed with the single QOL item of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30.²⁸ All raw scale scores were linearly converted to a 0 to 100 scale, with higher scores indicating better perceived health, mental health, and QOL.^29,30 The internal consistency reliability of the two Short Form-36 scales was high ( = .81 and .85).

Cancer-specific distress. Five items adapted from previous research³¹ were used to form a cancer-related worries scale (ovarian and breast cancer worries, impact of worries on mood and functioning, and worries about cancer risk in the family; score range, 5 to 20), with higher scores representing more frequent worries ( = .70). The seven-item intrusive thoughts subscale of the Impact of Event Scale assessed ovarian cancer–specific distress.^32,33 A higher sum score (range, 0 to 35) corresponds to more distress ( = .91). A cutoff score of 20 was used to identify individuals with clinically relevant levels of distress.³⁴

Risk perception. Four items adapted from previous studies^35,36 assessed current perceived breast/ovarian cancer risk. Women were asked to rate that risk on a continuous scale from 0% to 100%. Additionally, two questions were posed about the perceived curability of breast/ovarian cancer.

Knowledge about hereditary ovarian cancer and its prevention. Knowledge about hereditary issues in ovarian cancer was assessed by 11 statements about objective cancer risk, preventive options, and possible consequences of PBSO (eg, premature menopause). Each statement could be rated as true or false. The total score reflected the number of correct answers (range, 0 to 11).

Perceived benefits and barriers of PBSO. Eleven items, adapted from previous research, assessed women's perceptions of the potential benefits (five statements) and barriers (six statements) of PBSO.^37,38 Sum scores for the pro and con subscales were calculated (ranges, 5 to 25 and 6 to 30, respectively).

Statistical Analysis
Classification of women into the PBSO and GS groups was based on medical record data covering the 12-month period after study entry. Univariate predictors of PBSO versus GS were tested using ² and t tests. Significant univariate predictors (P < .05) were entered in a forward, stepwise multivariate logistic regression model to identify the most parsimonious set of variables predicting subsequent use of PBSO. All tests were two sided, with P < .05 considered statistically significant.

	RESULTS

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Sample Characteristics
In total, 426 high-risk women were invited to participate in the study, of whom 359 (84%) completed the baseline assessment. The causes for nonresponse were no interest (n = 50), previous oophorectomy (n = 6), participation in other studies (n = 4), health or emotional problems (n = 4), insufficient knowledge of Dutch (n = 2), and emigration (n = 1). Nonrespondents did not differ significantly from respondents regarding age or choice of preventive measure. Because of restrictions by the medical ethics committees, no other clinical data on the nonrespondents were available (eg, DNA status).

Of the respondent group, 160 women (43%) were BRCA1/2 carriers, were more than 35 years of age, and indicated no wish to have (more) children. These women met criteria for discussion of both PBSO and GS during the consultation with their gynecologist. Within 12 months after that initial consultation, 118 (74%) of these 160 women had undergone PBSO, and 42 (26%) had opted for GS. PBSO was performed, on average, 4 months after the initial gynecologic consultation (median, 2.8 months).

Sociodemographic and Clinical Predictors of PBSO
Women who opted for PBSO were significantly older, were more likely to be married, had lower educational levels, and were more likely to be postmenopausal than those who chose periodic screening (all P < .05; Table 1).

Basic knowledge about prevention and perceived pros and cons of preventive strategies. The PBSO and GS groups had similar levels of knowledge about risk of hereditary ovarian cancer and available preventive options and their consequences (Table 2). Eighty-three percent of the PBSO group and 90% of the GS group reported that both surgery and screening had been discussed by their gynecologist. There was no statistically significant between-group difference in the proportions of women who reported receiving strong recommendation for PBSO from their gynecologist.

Women who underwent PBSO had significantly higher overall scores for perceived benefits of surgery and significantly lower scores for perceived benefits of screening than the GS group (both P < .05). No significant differences were observed in perceived barriers to PBSO and GS. At the individual item level (data not reported in the tables), significantly more women in the PBSO group than the GS group perceived surgery as an effective method to prevent ovarian cancer (87% v 74%, respectively; P < .05) and as a method that would give them a feeling of certainty (88% v 74%, respectively; P < .05). Women in the GS group, compared with women in the PBSO group, were significantly more likely to perceive GS as an effective method to detect ovarian cancer (81% v 62%, respectively; P < .05) and to report that GS had an anxiety-reducing effect (79% v 61%, respectively; P < .05).

Multivariate Predictors of PBSO
Education, general health perceptions, perceived curability of ovarian cancer, and perceived pros of surgery remained in the final multivariate logistic regression model (Table 3). Women with lower (odds ratio [OR], 18.25; 95% CI, 2.10 to 48.53) or intermediate education (OR, 3.42; 95% CI, 1.10 to 9.22) were more likely to undergo PBSO, as were women with poorer general health perceptions (OR, 6.25; 95% CI, 1.79 to 21.80), those who viewed ovarian cancer as an incurable disease (OR, 12.42; 95% CI, 4.18 to 36.90), and those who believed more strongly in the benefits of surgery (OR, 1.23; 95% CI, 1.03 to 1.46).

	DISCUSSION

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Women with BRCA1/2 gene mutations have at least a 10-fold greater risk of developing ovarian cancer than women in the general population, often at a relatively early age.¹¹ Given the high probability of developing this potentially lethal disease, it is important to understand the factors that are associated significantly with risk-reducing behavior and preventive health actions. In this prospective, observational study, we investigated sociodemographic, medical, and psychosocial factors associated with the use of PBSO versus screening among BRCA1/2 mutation carriers in the Netherlands who met prevailing eligibility criteria for preventive surgery.

Within 12 months after the first gynecologic consultation about prevention of ovarian cancer, almost three quarters of the sample had undergone PBSO. This percentage is higher than that reported in studies in the United States, United Kingdom, and Australia (ranging from 23% to 60%).^6,21-24 Younger mean age of the study participants,^21,22,24 a shorter follow-up period,^22,24 and greater variability in objective cancer risk^21,24 may explain, at least in part, these differences. Moreover, financial issues may also impact the decision to undergo PBSO.³⁹ The costs of both PBSO and GS are fully covered by health insurance policies in the Netherlands, and all of the study participants were insured. Insurance coverage is more variable in other countries.

Consistent with previous reports,^6,21-24 we found that women who underwent PBSO were significantly older and more likely to be postmenopausal. Women who have reached menopause naturally may be more inclined to undergo PBSO because the expected consequences of the surgery may be less severe than for women who are premenopausal at the time of surgery. This latter group of women is more likely to experience abrupt, relatively severe, surgically induced menopausal symptoms.

Women who underwent PBSO had significantly lower educational levels than those who opted for screening. We observed a similar negative association between education and PBSO use in a previous retrospective study.⁴⁰ Two other studies^24,41 reported no significant differences in educational level between women who underwent PBSO versus surveillance. However, these latter studies had relatively small sample sizes consisting primarily of college-educated women recruited from a single hospital.

Consistent with previous reports,^19,24,42 higher levels of cancer-specific distress and perceived ovarian cancer risk were associated positively with undergoing PBSO. More than one quarter of the PBSO group compared with 7% of the GS group exhibited symptoms suggesting the presence of PTSD, with ovarian cancer risk as the underlying stressor. Previous research has observed a 20% prevalence of PTSD among patients with genetic risk of developing serious disease.⁴³

During the period of observation, more than one quarter of the women opted for GS rather than PBSO. These women were significantly less convinced of the health benefits of surgery and more convinced of the benefits of screening. Of particular importance is the finding that more than half of the women who opted for periodic GS believed that ovarian cancer could (almost) always be cured compared with 19% of women who opted for PBSO. This would suggest that a substantial percentage of women who choose screening may be uninformed about ovarian cancer's high mortality rate and may overestimate the efficacy of screening in detecting ovarian cancer at an early stage. These issues merit further investigation.

A physician's recommendation may be a powerful determinant of PBSO, and conversely, the failure to discuss this option (in any detail) may be perceived by women as an indirect recommendation against surgery.²¹ Lobb et al⁴⁴ found that prophylactic surgery was discussed in only half of consultations. Our data suggest that such reluctance is not an issue in the Dutch health care system, in that the large majority of women in our sample, irrespective of the type of subsequent prevention undertaken, indicated that both surgery and screening were discussed by their physician, and there was no significant group difference in the proportion of women who reported having received strong, directive advice to undergo surgery.

At the multivariate level, lower educational levels, poorer perceived general health, belief that ovarian cancer is an incurable disease, and higher levels of perceived benefits of surgery significantly predicted PBSO use. All of these associations were in the expected direction, with the exception of education. This latter finding seems counterintuitive because better educated women had higher levels of knowledge about hereditary cancer. However, perceptions of the curability of ovarian cancer were not significantly associated with education or with knowledge of hereditary issues. This would suggest that emotional rather than cognitive factors may underlie beliefs about the curability of ovarian cancer. Also, women with lower educational levels may be more inclined to promptly follow PBSO advice from their gynecologist, possibly without fully understanding the potential limitations and consequences of surgery in the short term. Conversely, women with higher educational levels may include a larger range of considerations in their decisions about prophylactic surgery (eg, desire to delay onset of menopausal symptoms, or realization that each year of delay brings with it a relatively small increase in risk). Qualitative investigations are needed to better understand the association between education and choice of preventive strategy.

We believe that the study sample was representative of BRCA1/2 mutation carriers in the Netherlands. The response rate was high, and the one hospital that declined to participate did so because of competing studies of BRCA1/2 carriers. In practice, all women in the Netherlands with proven BRCA1/2 gene mutation are referred to a gynecologist. Although we did not have access to appointment-keeping data, feedback from the participating clinicians indicated that very few women did not follow through with these referrals. PBSO use was ascertained by medical record audit for all women recruited onto the study.

Several limitations of the study should be noted. PBSO versus GS may be influenced by other factors not assessed in this study, including cultural or religious background, preferences of a partner or other family members, influence of the media or other health care professionals, or personal circumstances (eg, new job, illness of a family member). Moreover, participation in the study and administration of the questionnaires may have raised women's awareness of certain health issues, which could have influenced to some unknown degree decisions regarding PBSO versus GS.

In conclusion, this study identified a number of significant predictors of PBSO use among BRCA1/2 carriers who are at high risk of developing ovarian cancer and who are eligible for risk-reducing surgery. Women's education, general health perceptions, perceived incurability of ovarian cancer, and perceived benefits of surgery predict use of PBSO. High-risk women should be provided with more information about the low predictive value of the current screening techniques for early cancer detection and about the lethal threats posed by ovarian cancer as a result of its limited curability. Additionally, we recommend that women who opt for PBSO be screened for possible PTSD and other relevant psychological problems because these problems may affect their post-treatment adjustment.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Joanna B. Madalinska, Marc van Beurden, Eveline M.A. Bleiker, Heiddis B. Valdimarsdottir, Henk Boonstra, Neil K. Aaronson

Administrative support: Neil K. Aaronson

Provision of study materials or patients: Joanna B. Madalinska, Marc van Beurden, Eveline M.A. Bleiker, Heiddis B. Valdimarsdottir, Lottie Lubsen-Brandsma, Leon F. Massuger, Marian J.E. Mourits, Katja N. Gaarenstroom, Eleonora B.L. van Dorst, Hans van der Putten, Henk Boonstra

Collection and assembly of data: Joanna B. Madalinska

Data analysis and interpretation: Joanna B. Madalinska, Marc van Beurden, Neil K. Aaronson

Manuscript writing: Joanna B. Madalinska, Marc van Beurden, Eveline M.A. Bleiker, Heiddis B. Valdimarsdottir, Henk Boonstra, Neil K. Aaronson

Final approval of manuscript: Joanna B. Madalinska, Marc van Beurden, Eveline M.A. Bleiker, Heiddis B. Valdimarsdottir, Lottie Lubsen-Brandsma, Leon F. Massuger, Marian J.E. Mourits, Katja N. Gaarenstroom, Eleonora B.L. van Dorst, Hans van der Putten, Henk Boonstra, Neil K. Aaronson

	ACKNOWLEDGMENTS

 
The authors thank all of the women who took part in this research, Miranda Gerritsma and Esther Janssen for their logistical and administrative support, and the nursing and administrative staff of the participating hospitals for their assistance in identifying and recruiting patients.

	NOTES

 
Supported by Grant No. NKI 2001-2382 from the Dutch Cancer Society.

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

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Submitted May 17, 2006; accepted October 27, 2006.

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