Perception of Screening and Risk Reduction Surgeries in Patients Tested for a BRCA Deleterious Mutation

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1 Perception of Screening and Risk Reduction Surgeries in Patients Tested for a BRCA Deleterious Mutation Jennifer K. Litton, MD 1, Shannon N. Westin, MD 2, Kaylene Ready, CGC 1, Charlotte C. Sun, MD 2, Susan K. Peterson, MD 3, Funda Meric-Bernstam, MD 4, Ana M. Gonzalez-Angulo, MD 1, Diane C. Bodurka, MD 2, Karen H. Lu, MD 2, Gabriel N. Hortobagyi, MD 1, and Banu K. Arun, MD 1 BACKGROUND: Women at a high risk for breast cancer are offered choices for screening or prophylactic surgeries. The aim of this study was to evaluate opinions regarding screening and surgical strategies in high-risk women. METHODS: Women at the authors institution who received BRCA1 of 2 testing before July 2005 were sent a follow-up patient survey. The authors compared responses of women who tested positive for a deleterious mutation with those who tested negative. For those who expressed an opinion (agree vs disagree), a 2-sided Fisher exact test was used to compare responses. RESULTS: A total of 540 surveys were sent, and 312 were returned (58%). Of these, 217 had breast cancer, and 86 women tested positive for a mutation. No BRCAþ women felt mammograms were difficult to get because of discomfort, whereas 5.4% of the BRCA group did (P ¼.039). Seventy percent of BRCAþ women agreed that prophylactic mastectomy (PM) is the most effective means for reducing risk, compared with 40% of BRCA women (P <.001). PM was felt to be the only way to reduce worry in 64.7% of BRCAþ and in 34.4% of BRCA women (P <.001). PM was felt to be too drastic for 36.1% of BRCAþ and 40.5% of BRCA women (P ¼.562). Difficulty in deciding between screening and PM occurred in 23.9% of BRCAþ and 12.5% of BRCA women (P ¼.046). After excluding women with bilateral breast cancers, 81.0% of women who agreed that PM was best to reduce risk underwent a PM versus 19.1% of those who disagreed (P <.001). Of women who felt PM was the only way to reduce worry, 84.2% underwent PM. Only 15.8% of women who did not believe that it was the only way to decrease worry underwent PM (P <.001). CONCLUSIONS: BRCA mutation carriers were more likely to believe PM to be the best way to reduce both risk and worry of breast cancer. High-risk women who agreed that PM was more likely to reduce risk and worry of breast cancer were more likely to proceed with this intervention. Cancer 2009;115: VC 2009 American Cancer Society. KEY WORDS: breast cancer, BRCA mutation, prophylactic mastectomy, screening. Corresponding author: Jennifer K. Litton, MD, Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 1354, 1515 Holcombe Boulevard, Houston, TX ; Fax: (713) ; jlitton@mdanderson.org 1 Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 2 Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 3 Department of Behavioral Science, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 4 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Presented in part at the 2007 ASCO Breast Symposium, San Francisco, California, September 7-8, Received: June 11, 2008; Revised: October 23, 2008; Accepted: October 24, 2008 Published online: March 11, 2009 VC 2009 American Cancer Society DOI: /cncr.24199, Cancer April 15, 2009

2 Perception of Breast Cancer Screening/Litton et al The BRCA genes were first described in families with breast and ovarian cancers through the use of genetic linkage analysis. 1-3 Since that time, over 5000 different mutations in these genes have been identified, including both private and founder mutations. 4 Overall, these mutations are estimated at 0.1% in the general population. 5-7 A recent meta-analysis of 10 studies estimated the lifetime risk of breast cancer in BRCA1 mutation-carriers to be 47% to 66% and 40% to 57% in BRCA2 mutationcarriers. The ovarian cancer risk was estimated at 35% to 46% in BRCA1 mutation-carriers and 13% to 23% in BRCA2 mutation carriers. 8 Other studies have estimated these risks to be even higher. 9 Given this increasing risk of cancers, women with cancers in the family at young age, or multiple cases of breast and/or ovarian cancer, have sought genetic testing, not only to further manage their own cancer risk, but also to share with their family members. Risk management for women with a known deleterious mutation in either the BRCA1 or BRCA2 genes has included frequent screening with mammogram, breast magnetic resonance imaging (MRI), and clinical breast exams, 10 tamoxifen therapy, 11,12 and risk reduction surgeries, including prophylactic oophorectomy and prophylactic mastectomy. 16,17 Tamoxifen therapy has been associated with a decrease in risk when used in women with BRCA mutations. Some data indicate that it is more effective in prevention when used in the BRCA2 mutation-carriers rather than in BRCA1 mutation-carriers, who tend to have more triple-negative breast cancers; however, further investigation is necessary. 12,18 Risk-reducing salpingo-oophorectomy (RRSO) has been estimated to decrease the risk of ovarian cancer by up to 85% in BRCA1 and was suggested in BRCA2 mutation carriers. 14 This same study did not show a statistically significant change in the decrease of breast cancer after RRSO in BRCA1 carriers, but it did show a 72% reduction in breast cancers in women with BRCA2 mutations. Other studies have been able to show a protective effect of RRSO in BRCA1 carriers up to a 56% decrease in breast cancer incidence. 15 Prophylactic mastectomies have been estimated to decrease the risk of developing breast cancer in 90% to 95% of patients who carry a deleterious BRCA1 or 2 mutation. 16,17 In addition, breast cancer patients with a deleterious BRCA1 mutation can have up to a 43.4% 10-year risk of contralateral breast cancer, and BRCA2 mutation-carriers can have up to a 34.6% 10-year risk. 11 During counseling with either a genetic counselor or their primary medical and surgical oncologists, women may be provided all of these options and many have significant difficulty in making these decisions. Although prophylactic surgeries are offered, women and their physicians still struggle with these decisions. Perceptions of both the patient and the caregiver regarding these interventions may play important roles in the ultimate decision. To better aid both the patient and the healthcare provider, we surveyed women who underwent genetic counseling at a single institution to evaluate their perception of these risk reduction strategies as well as to provide insight into these different emotional and physical factors. Perception was then matched with the ultimate clinical decision. Understanding of these factors may help provide better insight into this decision-making process for both the patient and her physicians. MATERIALS AND METHODS Women who were seen at the University of Texas M. D. Anderson Cancer Center (MDACC) for genetic consultation and underwent BRCA testing from 1997 to June 2005 were identified. Patients were referred for genetic counseling by their medical or surgical oncologist if the patient warranted referral as per National Comprehensive Cancer Network (NCCN) guidelines. 19 At MDACC, patients receive both pre- and post-test counseling with genetic counselors who specialize in hereditary cancer syndromes. A follow-up patient survey was developed and was approved by the MDACC Institutional Review Board. The surveys were developed as part of a multidepartmental effort with Breast Medical Oncology, Gynecologic Oncology, and Behavioral Science. Surveys were sent to all 540 patients that were identified. There were 2 separate mailings. The first comprised all 540 patients. A second reminder survey was sent to those women who did not respond to the first mailing. Three hundred twelve surveys (58%) were completed and returned. Table 1 details the patient characteristics of those women who completed the surveys. As part of the surveys, patients were asked to answer multiple questions regarding their perception of their genetic testing for breast and/or ovarian cancers. They Cancer April 15,

3 Table 1. Patient Characteristics BRCA1 BRCA2 P* No. % No. % Race White Hispanic Black Asian Other Marital status Married Divorced Widowed Never married Personal history of breast cancer Yes No Prophylactic mastectomy Yes No Menopausal status Yes No % Family history of breast cancer Yes No Family history of ovarian cancer Yes No Education level <HS graduate HS/GED Some college College graduate Parity HS indicates high school; GED, completed General Educational Development and passed the testing. * Pearson chi-square test and Fisher exact test. were also counseled on screening techniques and risk reduction options, including chemoprevention and prophylactic surgeries, which were offered to them as part of their standard genetic consultation at our institution. They were asked to answer on a scale of 1-5 with 1 ¼ strongly agree, 2 ¼ agree, 3 ¼ no opinion, 4 ¼ disagree, and 5 ¼ strongly disagree. All of the surveys were coded into a main database. Comparisons of patient characteristics between groups were performed using either Pearson chi-square analyses or a Fisher exact test. A P value of <.05 was considered statistically significant. All analyses were performed using SPSS 15.0 (Chicago, Ill). We compared responses of women who tested positive for a deleterious BRCA mutation (BRCAþ) with those who tested negative (BRCA ). For the purposes of this study, patients who tested positive for a variant of uncertain significance were excluded from this analysis Cancer April 15, 2009

4 Perception of Breast Cancer Screening/Litton et al Table 2. Responses to Survey Questions by BRCA Mutation Status Question BRCA1 BRCA2 P* Agree (%) Disagree (%) Agree (%) Disagree (%) 1. It is difficult to get mammograms because the procedure 0 (0) 77 (100) 11 (5.4) 192 (94.6).039 is uncomfortable. 2. It is difficult to get a clinical breast exam because the procedure 13 (15.5) 71 (84.5) 32 (14.9) 183 (85.1).859 is embarrassing. 3. The benefits of monthly self breast exams outweigh the risks. 55 (70.5) 23 (29.5) 159 (76.4) 49 (23.6) It is difficult for me to remember to do monthly self breast exams. 36 (48.6) 38 (51.4) 89 (49.4) 91 (50.6) I do not do monthly self breast exams because I do not feel that 16 (23.5) 52 (76.5) 35 (19.7) 143 (80.3).488 I am good at doing them. 6. The side effects of taking tamoxifen outweigh the benefits of 22 (37.9) 36 (62.1) 73 (46.5) 84 (53.5).282 reducing the risk of developing breast cancer. 7. The most effective way of reducing the risk of getting breast cancer 42 (70.0) 18 (30.0) 64 (40.0) 96 (60.0) <.001 is undergoing prophylactic mastectomies. 8. Prophylactic mastectomies are the only way to reduce my worry of 44 (64.7) 24 (35.3) 56 (34.4) 107 (65.6) <.001 developing breast cancer. 9. Prophylactic mastectomies are too drastic a measure to prevent 26 (36.1) 46 (63.9) 64 (40.5) 94 (59.5).562 breast cancer. 10. The main reason for not undergoing prophylactic surgeries is the 20 (27.8) 52 (72.2) 39 (21.9) 139 (78.1).328 fear of surgery. 11. The main reason for not undergoing prophylactic mastectomies is 25 (33.8) 49 (66.2) 49 (27.7) 128 (72.3).364 that it is too disfiguring. 12. It is difficult for me to decide between screening and prophylactic mastectomies. 16 (23.9) 51 (76.1) 22 (12.5) 154 (87.5).046 * Two-sided Fisher exact test. RESULTS Of the 312 patients who responded to this questionnaire, 217 (70%) women had breast cancer, and 86 (28%) tested positive for a deleterious mutation in either the BRCA1 or BRCA2 gene. Table 1 describes the differences in baseline characteristics of the BRCAþ and BRCA women who responded to the survey. We analyzed the data by including those women who responded to selected survey questions as either agree (score of 1 or 2) or disagree (score of 4 or 5). Table 2 demonstrates the answers to these questions. Mammograms When asked if it was too difficult to get mammograms because the procedure was too uncomfortable, 280 women expressed an opinion. No BRCAþ women agreed with this statement and 11 (5.4%) of the BRCA women agreed. (P ¼.039). Self Breast Exams When asked if the benefits of monthly self breast exams (SBEs) outweigh the difficulties, or if monthly SBEs were embarrassing, or they felt they were not good at performing SBEs, or if it was too difficult to remember to do SBEs, there was no statistically significant difference between BRCAþ and BRCA women. Tamoxifen When asked if the side effects of taking tamoxifen outweigh the benefits of reducing the risk of developing breast cancer, again there was no statistically significant difference, with a positive response from 37.9% of the BRCAþ and 46.5% of the BRCA women (P ¼.282). Prophylactic Surgeries Seventy percent of BRCAþ women felt that prophylactic mastectomies (PMs) were the most effective means of reducing the risk of getting breast cancer, compared with 40% of the BRCA women (P <.001). In addition, when asked if PM is the only way to reduce the worry of developing breast cancer, 64.7% of BRCAþ agreed versus 34.4.% of BRCA women who agreed (P <.001). Participants were also asked if they felt that prophylactic mastectomy was too drastic a measure to prevent breast cancer; 36.1% of BRCAþ women versus 40.5% of BRCA Cancer April 15,

5 women agreed (P ¼.562). When asked if the main reason for not undergoing PM is the fear of surgery, 27.8% of BRCAþ versus 21.9% of BRCA women agreed (P ¼.328). When asked whether the main reason for not undergoing PM is that it is too disfiguring, 33.8% of BRCAþ and 27.7% of BRCA women agreed (P ¼.364). Finally, when asked if it was difficult to decide between screening and PM, 23.9% of BRCAþ and 12.5% of BRCA women agreed (P ¼.046). Decision of Intervention When looking at those women who responded either positively or negatively to the above questions, we compared their answers using a 2-sided Fisher exact test with their ultimate clinical decision. Women who underwent bilateral mastectomies for bilateral breast cancer at the time of their cancer treatment were excluded from this analysis. Of the 312 women who returned surveys, 89 underwent prophylactic mastectomy. Of the women who underwent PM, 47 (81%) agreed that PM was the most effective means of reducing the risk of breast cancer versus only 11 (35.6%) of those that disagreed with this statement (P <.001). Of the women who underwent PM, 48 women (84.2%) believed it was the only way to reduce worry versus only 9 women (15.8%) who did not believe it was the only way to reduce worry (P <.001). When looking at factors that influenced the choice of PM, of the 312 responders, 217 had breast cancer, and 29 women were excluded from the analysis because of bilateral mastectomy for bilateral cancers, leaving 283 responders. Table 3 shows the results of different demographic factors on the decision to undergo PM. Interestingly, patients with breast cancer had a higher rate of PM, but there was no difference based on age, parity, marital status, BRCA mutation status, menopausal status, or family history. Of note, women of Ashkenazi Jewish ancestry had a significantly lower rate of PM than women of non- Ashkenazi ancestry in our study group. DISCUSSION Women who were seen through our institution s Clinical Cancer Genetics Program and underwent genetic testing of deleterious BRCA1 or 2 mutations were surveyed regarding their perceptions of different screening and risk reduction strategies. We evaluated the responses by comparing the women who had tested positive or negative and their opinions regarding these different strategies. Women who tested positive for a deleterious BRCA mutation tended not to have as much difficulty with screening or minding the discomfort of mammography. There was no significant difference in SBE. However, opinions regarding PM and the ultimate choice to undergo PM were dependent upon their genetic testing results. Of the women who were BRCAþ, PM was viewed as the most effective means of decreasing ultimate risk and worry of breast cancer. The majority of women who agreed with these viewpoints ultimately went on to choose a PM. Previous studies have looked at smaller numbers of patients and described worry as a major factor in ultimate decision making in high-risk women. 20 In addition, Scheuer et al have shown the importance of genetic counseling in promoting increased surveillance, earlier detection, and even surgical intervention in mutation carriers. 21 Genetic counseling often involves a detailed discussion of genetic test results (including positive, negative, and uncertain results), cancer family history, and cancer risks and risk reduction options associated with each test result. Patients cite each of these points of discussion as influential factors in their risk reduction surgery decisions, including PM. 22 Furthermore, although breast cancer risk reduction decision aids have proven to be useful in reducing patients decisional conflict regarding their risk reduction options, they have not been shown to be effective in the absence of counseling, further reinforcing the importance of genetic counseling in the decision-making process. 23 Other studies have shown that when high-risk women undergo intensive screening they may not tend to want to undergo PM. 24 Our study further evaluates these opinions regarding PM in this patient population and expands the underlying perceptions of this surgery. Despite women being willing to undergo SBEs and mammography, as well as the recent American Cancer Society MRI screening guidelines, 25 prophylactic surgeries are still significantly viewed in this patient population as the most effective means of decreasing risk and worry. Interestingly, the majority of both BRCAþ and BRCA women did not believe that PMs were either too drastic, too scary, or too disfiguring, which is often a major concern of caregivers when counseling and providing this intervention, as some analyses have shown mixed 1602 Cancer April 15, 2009

6 Perception of Breast Cancer Screening/Litton et al Table 3. Patient Characteristics and Decision to Undergo PM Characteristic No PM (%) PM (%) P Median age, y BRCA status.477 BRCA1 52 (65) 28 (35) BRCA2 142 (70) 61 (30) Median parity* Parity* Nulliparous 31 (64.6) 17 (35.4) Parous 152 (69.4) 67 (30.6) Marital status Single/separated/widowed 47 (74.6) 16 (25.4) Married/living with partner 147 (66.8) 73 (33.2) Menopausal statusy Premenopausal 78 (75.0) 26 (25.0) Postmenopausal 109 (65.7) 57 (34.3) Ashkenazi Jewishz Yes 22 (53.7) 19 (46.3) No 166 (71.6) 66 (28.4) Family history of breast cancer* Yes 164 (68.0) 77 (32.0) No 28 (70.0) 12 (30.0) First-degree relative with breast cancer Yes 103 (66.5) 52 (33.5) No 89 (70.6) 37 (29.4) Personal history of breast cancery <.001 Yes 107 (53.6) 81 (58.4) No 86 (91.5) 8 (8.5) PM indicates prophylactic mastectomy. * Missing data for 2 patients. y Missing data for 1 patient. z Missing data for 10 patients. satisfaction with PM and reconstruction in high-risk populations. 20 However, more recent studies have shown similar quality of life between women who choose to undergo PM compared with women who do not, and overall satisfaction with the decision to undergo PM These data in addition to the data presented in the current study suggest that caregivers may be overestimating patients negative feelings regarding PM. Limitations of our analysis include that this is a retrospective questionnaire, and women who tended to return the questionnaire may have had stronger opinions either positively or negatively. The women were also answering the questionnaire at different time points after their screening or PM decision had been made or completed. Each of the women also underwent genetic counseling as per our institutional guidelines and may be influenced by the information provided in the counseling session. A prospective questionnaire both before and after genetic testing may show more clearly the impact of genetic testing and disclosure of results on these riskreducing strategies. Our analysis provides insight into the decision making regarding risk reduction strategies in BRCAþ and BRCA patients. Patients with a deleterious BRCA mutation may find PM to be the only effective way to reduce their worry. Healthcare providers and genetic counselors must take this into account when assessing a woman s needs at the time of genetic testing and results disclosure. Conflict of Interest Disclosures Supported by the Nellie B. Connally Breast Cancer Research Fund and the NIH T32 Training Grant (5 T32 CA ). Cancer April 15,

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