The Breast 23 (2014) 38e43
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Original article
Risk reducing mastectomy, breast reconstruction and patient satisfaction in Norwegian BRCA1/2 mutation carriers Anne Irene Hagen a, b, *, Lovise Mæhle c, Nina Vedå c, Hildegunn Høberg Vetti d, Astrid Stormorken c, Trond Ludvigsen e, Bente Guntvedt f, Anne Elisabeth Isern g, h, Ellen Schlichting i, Geir Kleppe j, Anna Bofin b, Hans Petter Gullestad k, Pål Møller c a
Department of Breast and Endocrine Surgery, Trondheim University Hospital, Trondheim, Norway Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway c Department of Medical Genetics, Oslo University Hospital, Oslo, Norway d Western Norway Familial Cancer Center, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway e Department of Pathology and Medical Genetics, Trondheim University Hospital, Trondheim, Norway f Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway g Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway h Teres Stokkan, Teres Medical Group, Trondheim, Norway i Department of Breast and Endocrine Surgery, Oslo University Hospital, Oslo, Norway j Department of Breast and Endocrine Surgery, Haukeland University Hospital, Bergen, Norway k Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Oslo, Norway b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 March 2013 Received in revised form 4 October 2013 Accepted 12 October 2013
The aim of this study was to evaluate the outcome of risk-reducing mastectomy in BRCA1/2 mutation carriers with and without breast cancer. Uptake, methods of operation and reconstruction, complications, patient satisfaction and histopathological findings were registered at all five departments of genetics in Norway. Data from 267 affected and unaffected BRCA1/2 mutation carriers were analyzed, including a study-specific questionnaire returned by 178 mutation carriers. There was a steady increase in the uptake of risk-reducing mastectomies during the study period. Complications were observed in 106/266 (39.7%) women. Patient satisfaction was high. The majority of women expressed great relief after risk-reducing mastectomy and would have chosen the same option again. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: BRCA1 BRCA2 Risk-reducing mastectomy Reconstruction
Background Since the discovery of the association between BRCA1/2 gene mutations and breast cancer, mutation carriers have had the option of either surveillance or risk reducing surgery in order to prevent breast cancer and/or reduce the risk of dying from breast cancer. However, surveillance, comprising clinical examination
Abbreviations: TRAM, transverse rectus abdominal myocutaneous flap; DIEP, deep inferior epigastric perforator flap; SGAP, superior gluteal artery perforator flap. * Corresponding author. Department of Breast and Endocrine Surgery, Trondheim University Hospital, Trondheim, Norway. Tel.: þ47 91116159. E-mail addresses: [email protected], [email protected] (A. I. Hagen). 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.10.002
and annual mammography, has not been shown to improve survival in BRCA1 mutation carriers [1]. Annual breast magnetic resonance imaging (MRI) has been implemented in the surveillance of mutation carriers and high-risk women in many family cancer clinics, but Norwegian data on survival of women with BRCA1-associated breast cancer detected in a national MRI-based screening program showed that improvement in breast cancer specific survival was less than expected [2]. Risk reducing mastectomy (RRM) has been shown to be efficient in the prevention of breast cancer [3e11] Contralateral risk-reducing mastectomy has not been shown to improve overall survival in earlier studies in BRCA1/2 mutation carriers with breast cancer [12e14]. However, a more recent study by Evans et al. demonstrated a survival advantage in carriers who had undergone contralateral RRM [15]. RRM in healthy BRCA1/2 mutation carriers has been found to be highly cost-efficient [16].
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Fig. 1. Flowchart.
In recent years, family cancer clinics and breast surgeons have advocated risk reducing mastectomy and RRM has become increasingly acknowledged in the general population. In Norway, BRCA1/2 mutation carriers who opt for RRM are offered breast reconstruction financed by the Norwegian Health Care System. For mutation carriers without breast cancer bilateral reconstruction is performed immediately after mastectomy. For affected carriers both immediate and delayed reconstructions of the ipsilateral and contralateral breasts have been reported. Prior to this study no central registration of RRM had been performed and no investigation of patient satisfaction had been carried out. The aims of this study were to gain an overview of risk reducing mastectomy and breast reconstruction performed in BRCA1/2 mutation carriers in Norway including frequency, reconstructive techniques employed and complication rates and -types. Furthermore, we wanted to investigate patient satisfaction after RRM and reconstruction, if performed, and register histopathological findings in the mastectomy specimens and the efficacy of RRM. Material and methods Identification and recruitment of patients All five departments of genetics in Norway identified BRCA1/2 mutation carriers who had undergone either uni- or bilateral risk reducing mastectomy in the years from when they first started registration until June 14th. 2010. The 219 RRM patients registered at Oslo University Hospital e The Norwegian Radium Hospital included in this study have been described previously [7]. In the present study, these 219 patients were sent a study specific
questionnaire on patient satisfaction and 130 (59%) returned completed questionnaires. Previous breast cancer, operation technique, RRM, reconstruction and complications were also included in the present study. The remaining departments of genetics identified a further 83 RRM patients in their respective archives and these women were invited to join the study. Forty-nine accepted and returned the study-specific questionnaire to the Department of Genetics to which they belonged. See the flow chart for patient identification and inclusion/exclusion (Fig. 1). The questionnaire had been used previously by one of the authors (AEI) in a study of patient satisfaction in women at high risk who had undergone RRM and breast reconstruction in Malmö, Sweden [17]. Norway and Sweden are neighboring countries with similar cultures and languages. The questionnaire included 13 questions (Fig. 2). Medical charts review Data on previous breast cancer, stage, type of operation, riskreducing salpingo-oophorectomy (RRSO), type of risk-reducing mastectomy and reconstruction, date of RRM, complications, recurrence of breast cancer, death, and cause of death were obtained from the medical records at the hospitals where the patients had been treated. Follow-up data were collected until December 31st. 2010. Complications after RRM and reconstruction Postoperative complications were scored as early (within 30 days), or late (after 30 days). Early complications were surgical
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Fig. 2. Statements and scorings in study specific questionnaire.
complications such as infection, tissue necrosis, wound dehiscence, hematoma, removal of the implant due to any of the aforementioned causes, and rotation of the implant or valve. Pulmonary embolism and hematoma necessitating blood transfusion were also among the early complications registered. Late complications were both surgical and cosmetic, such as poor cosmetic outcome including asymmetry, and unacceptable position of the transplanted nipple/areola complex. Capsular formation was registered as a late surgical complication. Histopathological findings in mastectomy specimens Histopathological findings in the mastectomy specimens after RRM were obtained from the pathology reports. Tissue sections from the mastectomy specimens were not reviewed. The specimens were examined at different hospitals and the procedure for examination varied from hospital to hospital. Statistics The data from the questionnaires were registered in SPSS (IBM SPSS version 20). Frequencies (%), means and medians were used for presenting descriptive data. For analysis of differences between BRCA1 and BRCA2 regarding the study-specific questionnaire, crosstabulations and Pearson Chi Square tests were used. Results Altogether 302 mutation carriers who had undergone either uni- or bilateral RRM were identified. Among these, clinical data were available for 267 patients who were then included in the study. See Table 1 for a description of study population. A steady increase in the uptake of risk-reducing mastectomies was observed (Fig. 3). Median age at RRM for both affected and unaffected carriers was 43.7 years (range 24e73). A total of 104 (39%) women had breast cancer; 98 unilateral and six bilateral. Median age at first breast cancer was 43.4 years (range 28e73). Cancer treatment with mastectomy had been performed in 85 patients and 19 underwent breast conserving surgery (BCS). RRSO had been performed in 218/267 (81.6%).
Table 1 Description of study population. Demographics Age at RRM Mean Median BRCA-status (n [ 267) BRCA1 BRCA2 BRCA1 and 2 Previous breast cancer unilateral bilateral Surgery for br. cancer (n [ 104) Mastectomy þ ALND Mastectomy þ SN BCT þ ALND BCT þ SN Simple mastectomy Br. ca stage (n [ 104) Stage 1 Stage 2 Stage 3 No. RRSO (n [ 218) Before RRM After RRM Ovarian cancer (n [ 263) Histology of mastectomy specimens, (n [ 251) Invasive cancer Ca. in situ ADH, ALH Benign epithelial proliferations Normal breast tissue RRM and reconstructive surgery (n [ 267) Skinsparing mastectomy including nipple/areola with expander prosthesis, two-stage Skinsparing mastectomy excluding nipple/areola with anatomical prosthesis, one-stage Skinsparing mastectomy including nipple/areola with expander, one step operation TRAM, DIEP, SGAP Skinsparing mastectomy, prosthesis, nipple transplants Latissimus dorsi flap, combined prosthesis Mastectomy, delayed reconstruction with expander Mastectomy, no reconstruction
Tot % 44.6 43.7 235 31 1 104 98 6
88.0% 11.7% 0.4% 39.0% 94.2% 5.8%
48 35 6 13 2
46.2% 33.7% 5.8% 12.5% 1.9%
56 46 2
53.80% 44.2% 1.9%
197 21 21
90.4% 9.6% 8.0%
0 4 3 56 188
0% 1.6% 1.2% 22.3% 74.9%
122
45.7%
49
18.4%
17
6.4%
18 9
6.7% 3.4%
2 50
0.7% 18.7%
RRM: risk-reducing mastectomy, RRSO: risk-reducing salpingo-oophorectomy, BCT: breast conserving treatment, ALND: axillary lymph node dissection, SN: sentinel node, ADH: atypical ductal hyperplasia, ALH: atypical lobular hyperplasia, TRAM: transverse rectus abdominal muscle, DIEP: deep inferior epigastric perforator, SGAP: superior gluteal artery perforator.
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mutation carriers. One hundred and fifty seven women had both breasts reconstructed and five had unilateral breast reconstruction. Sixteen women chose to have no reconstruction after mastectomy. Regarding satisfaction, 131/176 (74%) felt relief after the RRM had been performed, and 140 of 163 (86%) said they would have done the same again. Of the 147 with submuscular implants, 66 (45%) felt the implant was a natural part of their body. Regarding consistency, 82/158 (52%) reported satisfactory results. For symmetry, the result was 86/158 (54%) and for shape and for size the results were 97/159 (61%) and 126/155 (81%) respectively. Seven per cent (9/128) of the BRCA1 mutation carriers and 18% (3/ 17) of the BRCA 2 mutation carriers would have chosen differently. Two of the BRCA1 mutation carriers would have chosen RRM without reconstruction, while seven would have preferred annual surveillance with breast MRI and mammography. For the three BRCA 2 mutation carriers the figures were one and two, respectively (Table 2). Histopathological findings Fig. 3. Uptake of RRM.
RRMs were performed at seven different hospitals using a variety of techniques. The majority, 122 (45.9%), underwent subcutaneous mastectomy with removal of the areola and nipple, and insertion of an expander prosthesis with later replacement with a permanent prosthesis. Forty-nine (18.4%) had skin sparing mastectomy including sparing of the areola and nipple and reconstruction with anatomical prostheses. Eighteen (6.7%) were reconstructed with autologous tissue, thirteen with DIEP (deep inferior epigastric perforator) flaps, four with SGAP (superior gluteal artery perforator) flaps and one with TRAM (transverse rectus abdominal myocutaneous) flap. Mastectomy without any reconstruction was performed in 50 patients (18.7%) (Table 1). Complications For the majority of patients, 160/266 (60.3%), no complications were registered. Complications were recorded in 106/266 (39.7%): 74 (27.8%) with early and 33 (12.4%) with late complications. One case with both early and late complications was registered in both groups. For one patient, operated in 1985, we were unable to retrieve information regarding complications. The most life-threatening condition, a pulmonary embolus, was noted in one patient who had a subcutaneous mastectomy and insertion of an expander prosthesis. She had a complete recovery after medical treatment. Hematomas were observed in 15/266 (5.6%) cases. One patient experienced hematoma and severe bleeding which required a blood transfusion. Four (1.5%) experienced early wound dehiscence followed by removal of the prosthesis. Skin necrosis led to removal of the prosthesis in one patient. Infection occurred in 30 cases, necessitating removal of the prosthesis in 13 patients. Other complications occurred singly: rotation of the valve, rotation of the prosthesis, poor cosmetic result including asymmetry, unacceptable position of the transplanted nipple, capsular formation, lateralization of the prosthesis, and pain with subsequent removal of the prosthesis. Satisfaction/questionnaire The study-specific questionnaire was returned by 178/302 (59%) of participants, 157 were BRCA1 and 21 were BRCA2
The results of the histopathological evaluation were available in 251 of 267 patients. No invasive lesions were reported in the mastectomy specimens. Carcinoma in situ was found in four patients (1.6%) (Table 1).
Table 2 Results from study-specific questionnaire. Statement
BRCA1
BRCA2
Unaffected
Affected
Unaffected
Affected
No. (%)
No. (%)
No. (%)
No. (%)
8 (5) 2 (1) 1 (1)
7 (4) 0 2 (1)
9 (5) 1 (1) 1 (1)
9 (5) 0 1 (1)
8 (5) 2 (1) 1 (1) 0
10 (6) 0 0 0
5 (3) 6 (3) 0 0
4 (2) 3 (2) 0 3 (2)
4 (2) 3 (2) 3 (2)
4 (2) 1 (1) 4 (2)
7 (5) 2 (1) 0
5 (3) 3 (1) 0
5 (3) 3 (2) 1 (2)
5 (3) 4 (3) 0
6 (4) 2 (1) 2 (1)
1 (1) 5 (3) 2 (1)
4 (3) 3 (2) 2 (1)
2 (1) 3 (2) 3 (2)
Chosen the same option (n [ 163)1 Yes 85 (52) 40 (25) No 2 (1) 2 (1) Do not know 10 (6) 4 (2) 2 Relief after RRM (n [ 176) Yes 73 (41) 40 (23) No 4 (2) 4 (2) Partly 25 (14) 9 (5) Content with choosing RRM (n [ 171)3 Yes 91 (53) 47 (27) No 2 (1) 2 (1) Do not know 7 (4) 0 Both yes and no 1 (1) 0 Experience of prosthesis (n [ 174) Natural part 40 (23) 17 (10) Corpus alienum 41 (24) 20 (12) Both 7 (4) 4 (2) Have no prosthesis 11 (6) 13 (7) Operative result as expected (n [ 163) Yes 51 (31) 25 (15) No 33 (20) 15 (9) Do not know 14 (9) 6 (4) Satisfactory size (n [ 155) Yes 72 (46) 32 (21) Too small 21(14) 10 (6) Too big 1 (1) 2 (1) Satisfactory shape (n [ 159) Yes 61 (38) 26 (16) No 31 (19) 14 (9) Do not know 5 (3) 4 (3) Satisfactory symmetry (n [ 158) Yes 57 (36) 22 (14) No 37 (23) 17 (11) Do not know 2 (1) 5 (3) Satisfactory consistence (n [ 158) Yes 58 (37) 28 (18) No 34 (22) 12 (8) Do not know 5 (3) 4 (3) RRM: risk reducing mastectomy. Pearson Chi Square 1: p ¼ 0.2, 2: p ¼ 0.4, 3: p ¼ 0.4.
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Table 3 Efficacy of RRM in other studies. Study group
Group of women
Meana or medianb age in years at RRM
Cancer detected/RRM (%)
Cancers detected/control group (%)
Follow-up in years Mean or median
Hartmann et al. 1999 Meijers-Heijboer et al. 2001 Rebbeck et al. 2004 Heemskerk-Gerritsen et al. 2007 Evans et al. 2009 Domchek et al. 2010 Skytte et al. 2011 Arver et al. 2011
H, unaffected M. unaffected M, unaffected H, both unaff/affected H, both unaff/affected M, both unaff/affected M, unaffected H, unaffected
42b 35.8b 38.1a 37b(unaffected)/44b(affected) 41.2a 40.7a 37.1a 40b
3/214 (1.4%) 0/76 (0%) 2/105 (1.9%) 0/358 (0%) 0/550 (0%) 0/247 (0%) 3/96 (3%) 0/223^(0%)
156/403 (38.7%) 8/63 (12.7%) 184/378 (48.7%)
14b 3a 6.4a 4.5b 7.5b 3.5a
98/1372 (7.1%) 16/211 (7.6%)
6.6a
H: high risk including mutation carriers, M: BRCA1/2 mutation carriers. a Mean. b Median.
Follow up and occurrence of cancer after RRM Median follow-up was 35 months (range 3e336). There was one case of a new primary breast cancer after RRM. This patient had undergone BCS in the ipsilateral breast and later RRM with bilateral subcutaneous mastectomy. The new primary breast cancer occurred in the reconstructed contralateral healthy breast 79 months after RRM. RRSO had been performed four months before RRM. Altogether six women have died during the follow-up period after RRM. Three had previously been treated for breast cancer and died of metastatic spread from this cancer. Two died of ovarian cancer; both were diagnosed before they had their RRM. One died of endometrial carcinoma, diagnosed after RRM. Discussion This study gives an overview over the cohort of Norwegian BRCA1/2 mutation carriers who have undergone RRM with and without reconstruction. The increased number of RRM procedures in BRCA1/2 mutation carriers in Norway during later years may be due to increased patient awareness, but also to more active advocacy of RRM by breast surgeons and geneticists (Fig. 3). The majority of RRM and reconstruction procedures were subcutaneous mastectomy with removal of the nippleeareola complex and submuscular implant insertion. One weakness of this study is the lack of data on the 35 patients who did not want to participate in the study. Complications were seen in 39.7%. They were mostly cosmetic and could be rectified. Infection and implant removal occurred in 13/197 (6.6%) patients reconstructed with implants, which is in accordance with Nahabedian et al. [18] and Lagergren et al. [19] who reported 5.8% and 7.2%, respectively. Isern et al. reported only one implant removal due to infection (1/54 (1.9%)) [17]. We analyzed the study-specific questionnaire separately for BRCA1 and BRCA2. It has been shown that survival in Norwegian BRCA2 mutation carriers with breast cancer is equal to survival for women with sporadic breast cancer, while survival in Norwegian BRCA1 mutation carriers with stage 1 breast cancer is reduced [20]. We therefore hypothesized that RRM might be of greater importance for BRCA1 mutation carriers, who might experience greater relief and a higher degree of satisfaction than BRCA2 mutation carriers. However, no statistically significant differences were found. However, these results should be interpreted with care due to the small numbers in both groups. Only 59% returned the study-specific questionnaire which may be a limitation of the study. Some patients may have received the questionnaire while still undergoing reconstruction and therefore did not answer since they did not know the final result. Despite the fact that several experienced complications, 91% (156/171) were
satisfied with RRM. The numbers are too small to test associations between surgical techniques and frequencies of complications. The majority of women were satisfied with the cosmetic result after RRM and reconstruction. Our findings are in accordance with a descriptive study by Metcalfe et al. [21]. Isern et al. [13] also report similar results. Forty-five per cent (66/147) felt that the implant was a natural part of their body compared to 53% found in Isern’s study [17] and 49% in the Dutch study by Bresser et al. [22]. According to the questionnaire the majority felt relief after RRM, but 8/155 (5%) of the BRCA1 and two of the 21 (9.5%) BRCA2 mutation carriers experienced no relief. This emphasizes the importance of thorough pre-operative information ensuring that the decision to undergo RRM is made at the right time for each individual woman. One might expect that the operation was better tolerated by women with a previous history of breast cancer. However, we found no significant difference in satisfaction among women with previous breast cancer compared to healthy mutation carriers. This was also shown by Isern et al. [17]. The lack of standardized examination procedures and review of the sections reduces the value of the histopathological findings. It is reasonable to assume that the number of premalignant lesions would have been higher if standardized examination of an increased number of sections had been performed. Previous studies have found either higher or equal numbers of malignant and premalignant lesions [4,6,7,17,23e27]. One case of primary breast cancer after RRM occurred during follow-up in our study. In other studies the frequency varies from 0% to 3.2%, (Table 3). The largest study, by Evans et al., found no cases of cancer in 550 patients after a follow-up of 7.5 years [6]. However, the Danish study by Skytte et al. found three new cases of cancer in 96 patients, diagnosed 2.5 and 7 years after mastectomy [9]. All were BRCA1 mutation carriers and all had undergone simple total mastectomy with removal of the nippleeareola complex by three different surgeons at three different centers. Longer followup of the participants in the current study is necessary. Conclusion Rates of RRM in Norway are increasing and the efficacy of RRM in this study is high. Despite a complication rate of 39.7%, the majority of mutation carriers expresses high satisfaction and relief and would be willing to undergo the same procedure again. The ultimate aim for these women seems to be the reduction of risk of breast cancer. Ethical considerations The study was approved by the Regional Committee for Medical Research Ethics, Central Norway, 4.2009.244.
A.I. Hagen et al. / The Breast 23 (2014) 38e43
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The Breast journal homepage: www.elsevier.com/brst
Original article
Risk reducing mastectomy, breast reconstruction and patient satisfaction in Norwegian BRCA1/2 mutation carriers Anne Irene Hagen a, b, *, Lovise Mæhle c, Nina Vedå c, Hildegunn Høberg Vetti d, Astrid Stormorken c, Trond Ludvigsen e, Bente Guntvedt f, Anne Elisabeth Isern g, h, Ellen Schlichting i, Geir Kleppe j, Anna Bofin b, Hans Petter Gullestad k, Pål Møller c a
Department of Breast and Endocrine Surgery, Trondheim University Hospital, Trondheim, Norway Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway c Department of Medical Genetics, Oslo University Hospital, Oslo, Norway d Western Norway Familial Cancer Center, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway e Department of Pathology and Medical Genetics, Trondheim University Hospital, Trondheim, Norway f Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway g Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway h Teres Stokkan, Teres Medical Group, Trondheim, Norway i Department of Breast and Endocrine Surgery, Oslo University Hospital, Oslo, Norway j Department of Breast and Endocrine Surgery, Haukeland University Hospital, Bergen, Norway k Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Oslo, Norway b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 March 2013 Received in revised form 4 October 2013 Accepted 12 October 2013
The aim of this study was to evaluate the outcome of risk-reducing mastectomy in BRCA1/2 mutation carriers with and without breast cancer. Uptake, methods of operation and reconstruction, complications, patient satisfaction and histopathological findings were registered at all five departments of genetics in Norway. Data from 267 affected and unaffected BRCA1/2 mutation carriers were analyzed, including a study-specific questionnaire returned by 178 mutation carriers. There was a steady increase in the uptake of risk-reducing mastectomies during the study period. Complications were observed in 106/266 (39.7%) women. Patient satisfaction was high. The majority of women expressed great relief after risk-reducing mastectomy and would have chosen the same option again. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: BRCA1 BRCA2 Risk-reducing mastectomy Reconstruction
Background Since the discovery of the association between BRCA1/2 gene mutations and breast cancer, mutation carriers have had the option of either surveillance or risk reducing surgery in order to prevent breast cancer and/or reduce the risk of dying from breast cancer. However, surveillance, comprising clinical examination
Abbreviations: TRAM, transverse rectus abdominal myocutaneous flap; DIEP, deep inferior epigastric perforator flap; SGAP, superior gluteal artery perforator flap. * Corresponding author. Department of Breast and Endocrine Surgery, Trondheim University Hospital, Trondheim, Norway. Tel.: þ47 91116159. E-mail addresses: [email protected], [email protected] (A. I. Hagen). 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.10.002
and annual mammography, has not been shown to improve survival in BRCA1 mutation carriers [1]. Annual breast magnetic resonance imaging (MRI) has been implemented in the surveillance of mutation carriers and high-risk women in many family cancer clinics, but Norwegian data on survival of women with BRCA1-associated breast cancer detected in a national MRI-based screening program showed that improvement in breast cancer specific survival was less than expected [2]. Risk reducing mastectomy (RRM) has been shown to be efficient in the prevention of breast cancer [3e11] Contralateral risk-reducing mastectomy has not been shown to improve overall survival in earlier studies in BRCA1/2 mutation carriers with breast cancer [12e14]. However, a more recent study by Evans et al. demonstrated a survival advantage in carriers who had undergone contralateral RRM [15]. RRM in healthy BRCA1/2 mutation carriers has been found to be highly cost-efficient [16].
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Fig. 1. Flowchart.
In recent years, family cancer clinics and breast surgeons have advocated risk reducing mastectomy and RRM has become increasingly acknowledged in the general population. In Norway, BRCA1/2 mutation carriers who opt for RRM are offered breast reconstruction financed by the Norwegian Health Care System. For mutation carriers without breast cancer bilateral reconstruction is performed immediately after mastectomy. For affected carriers both immediate and delayed reconstructions of the ipsilateral and contralateral breasts have been reported. Prior to this study no central registration of RRM had been performed and no investigation of patient satisfaction had been carried out. The aims of this study were to gain an overview of risk reducing mastectomy and breast reconstruction performed in BRCA1/2 mutation carriers in Norway including frequency, reconstructive techniques employed and complication rates and -types. Furthermore, we wanted to investigate patient satisfaction after RRM and reconstruction, if performed, and register histopathological findings in the mastectomy specimens and the efficacy of RRM. Material and methods Identification and recruitment of patients All five departments of genetics in Norway identified BRCA1/2 mutation carriers who had undergone either uni- or bilateral risk reducing mastectomy in the years from when they first started registration until June 14th. 2010. The 219 RRM patients registered at Oslo University Hospital e The Norwegian Radium Hospital included in this study have been described previously [7]. In the present study, these 219 patients were sent a study specific
questionnaire on patient satisfaction and 130 (59%) returned completed questionnaires. Previous breast cancer, operation technique, RRM, reconstruction and complications were also included in the present study. The remaining departments of genetics identified a further 83 RRM patients in their respective archives and these women were invited to join the study. Forty-nine accepted and returned the study-specific questionnaire to the Department of Genetics to which they belonged. See the flow chart for patient identification and inclusion/exclusion (Fig. 1). The questionnaire had been used previously by one of the authors (AEI) in a study of patient satisfaction in women at high risk who had undergone RRM and breast reconstruction in Malmö, Sweden [17]. Norway and Sweden are neighboring countries with similar cultures and languages. The questionnaire included 13 questions (Fig. 2). Medical charts review Data on previous breast cancer, stage, type of operation, riskreducing salpingo-oophorectomy (RRSO), type of risk-reducing mastectomy and reconstruction, date of RRM, complications, recurrence of breast cancer, death, and cause of death were obtained from the medical records at the hospitals where the patients had been treated. Follow-up data were collected until December 31st. 2010. Complications after RRM and reconstruction Postoperative complications were scored as early (within 30 days), or late (after 30 days). Early complications were surgical
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Fig. 2. Statements and scorings in study specific questionnaire.
complications such as infection, tissue necrosis, wound dehiscence, hematoma, removal of the implant due to any of the aforementioned causes, and rotation of the implant or valve. Pulmonary embolism and hematoma necessitating blood transfusion were also among the early complications registered. Late complications were both surgical and cosmetic, such as poor cosmetic outcome including asymmetry, and unacceptable position of the transplanted nipple/areola complex. Capsular formation was registered as a late surgical complication. Histopathological findings in mastectomy specimens Histopathological findings in the mastectomy specimens after RRM were obtained from the pathology reports. Tissue sections from the mastectomy specimens were not reviewed. The specimens were examined at different hospitals and the procedure for examination varied from hospital to hospital. Statistics The data from the questionnaires were registered in SPSS (IBM SPSS version 20). Frequencies (%), means and medians were used for presenting descriptive data. For analysis of differences between BRCA1 and BRCA2 regarding the study-specific questionnaire, crosstabulations and Pearson Chi Square tests were used. Results Altogether 302 mutation carriers who had undergone either uni- or bilateral RRM were identified. Among these, clinical data were available for 267 patients who were then included in the study. See Table 1 for a description of study population. A steady increase in the uptake of risk-reducing mastectomies was observed (Fig. 3). Median age at RRM for both affected and unaffected carriers was 43.7 years (range 24e73). A total of 104 (39%) women had breast cancer; 98 unilateral and six bilateral. Median age at first breast cancer was 43.4 years (range 28e73). Cancer treatment with mastectomy had been performed in 85 patients and 19 underwent breast conserving surgery (BCS). RRSO had been performed in 218/267 (81.6%).
Table 1 Description of study population. Demographics Age at RRM Mean Median BRCA-status (n [ 267) BRCA1 BRCA2 BRCA1 and 2 Previous breast cancer unilateral bilateral Surgery for br. cancer (n [ 104) Mastectomy þ ALND Mastectomy þ SN BCT þ ALND BCT þ SN Simple mastectomy Br. ca stage (n [ 104) Stage 1 Stage 2 Stage 3 No. RRSO (n [ 218) Before RRM After RRM Ovarian cancer (n [ 263) Histology of mastectomy specimens, (n [ 251) Invasive cancer Ca. in situ ADH, ALH Benign epithelial proliferations Normal breast tissue RRM and reconstructive surgery (n [ 267) Skinsparing mastectomy including nipple/areola with expander prosthesis, two-stage Skinsparing mastectomy excluding nipple/areola with anatomical prosthesis, one-stage Skinsparing mastectomy including nipple/areola with expander, one step operation TRAM, DIEP, SGAP Skinsparing mastectomy, prosthesis, nipple transplants Latissimus dorsi flap, combined prosthesis Mastectomy, delayed reconstruction with expander Mastectomy, no reconstruction
Tot % 44.6 43.7 235 31 1 104 98 6
88.0% 11.7% 0.4% 39.0% 94.2% 5.8%
48 35 6 13 2
46.2% 33.7% 5.8% 12.5% 1.9%
56 46 2
53.80% 44.2% 1.9%
197 21 21
90.4% 9.6% 8.0%
0 4 3 56 188
0% 1.6% 1.2% 22.3% 74.9%
122
45.7%
49
18.4%
17
6.4%
18 9
6.7% 3.4%
2 50
0.7% 18.7%
RRM: risk-reducing mastectomy, RRSO: risk-reducing salpingo-oophorectomy, BCT: breast conserving treatment, ALND: axillary lymph node dissection, SN: sentinel node, ADH: atypical ductal hyperplasia, ALH: atypical lobular hyperplasia, TRAM: transverse rectus abdominal muscle, DIEP: deep inferior epigastric perforator, SGAP: superior gluteal artery perforator.
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mutation carriers. One hundred and fifty seven women had both breasts reconstructed and five had unilateral breast reconstruction. Sixteen women chose to have no reconstruction after mastectomy. Regarding satisfaction, 131/176 (74%) felt relief after the RRM had been performed, and 140 of 163 (86%) said they would have done the same again. Of the 147 with submuscular implants, 66 (45%) felt the implant was a natural part of their body. Regarding consistency, 82/158 (52%) reported satisfactory results. For symmetry, the result was 86/158 (54%) and for shape and for size the results were 97/159 (61%) and 126/155 (81%) respectively. Seven per cent (9/128) of the BRCA1 mutation carriers and 18% (3/ 17) of the BRCA 2 mutation carriers would have chosen differently. Two of the BRCA1 mutation carriers would have chosen RRM without reconstruction, while seven would have preferred annual surveillance with breast MRI and mammography. For the three BRCA 2 mutation carriers the figures were one and two, respectively (Table 2). Histopathological findings Fig. 3. Uptake of RRM.
RRMs were performed at seven different hospitals using a variety of techniques. The majority, 122 (45.9%), underwent subcutaneous mastectomy with removal of the areola and nipple, and insertion of an expander prosthesis with later replacement with a permanent prosthesis. Forty-nine (18.4%) had skin sparing mastectomy including sparing of the areola and nipple and reconstruction with anatomical prostheses. Eighteen (6.7%) were reconstructed with autologous tissue, thirteen with DIEP (deep inferior epigastric perforator) flaps, four with SGAP (superior gluteal artery perforator) flaps and one with TRAM (transverse rectus abdominal myocutaneous) flap. Mastectomy without any reconstruction was performed in 50 patients (18.7%) (Table 1). Complications For the majority of patients, 160/266 (60.3%), no complications were registered. Complications were recorded in 106/266 (39.7%): 74 (27.8%) with early and 33 (12.4%) with late complications. One case with both early and late complications was registered in both groups. For one patient, operated in 1985, we were unable to retrieve information regarding complications. The most life-threatening condition, a pulmonary embolus, was noted in one patient who had a subcutaneous mastectomy and insertion of an expander prosthesis. She had a complete recovery after medical treatment. Hematomas were observed in 15/266 (5.6%) cases. One patient experienced hematoma and severe bleeding which required a blood transfusion. Four (1.5%) experienced early wound dehiscence followed by removal of the prosthesis. Skin necrosis led to removal of the prosthesis in one patient. Infection occurred in 30 cases, necessitating removal of the prosthesis in 13 patients. Other complications occurred singly: rotation of the valve, rotation of the prosthesis, poor cosmetic result including asymmetry, unacceptable position of the transplanted nipple, capsular formation, lateralization of the prosthesis, and pain with subsequent removal of the prosthesis. Satisfaction/questionnaire The study-specific questionnaire was returned by 178/302 (59%) of participants, 157 were BRCA1 and 21 were BRCA2
The results of the histopathological evaluation were available in 251 of 267 patients. No invasive lesions were reported in the mastectomy specimens. Carcinoma in situ was found in four patients (1.6%) (Table 1).
Table 2 Results from study-specific questionnaire. Statement
BRCA1
BRCA2
Unaffected
Affected
Unaffected
Affected
No. (%)
No. (%)
No. (%)
No. (%)
8 (5) 2 (1) 1 (1)
7 (4) 0 2 (1)
9 (5) 1 (1) 1 (1)
9 (5) 0 1 (1)
8 (5) 2 (1) 1 (1) 0
10 (6) 0 0 0
5 (3) 6 (3) 0 0
4 (2) 3 (2) 0 3 (2)
4 (2) 3 (2) 3 (2)
4 (2) 1 (1) 4 (2)
7 (5) 2 (1) 0
5 (3) 3 (1) 0
5 (3) 3 (2) 1 (2)
5 (3) 4 (3) 0
6 (4) 2 (1) 2 (1)
1 (1) 5 (3) 2 (1)
4 (3) 3 (2) 2 (1)
2 (1) 3 (2) 3 (2)
Chosen the same option (n [ 163)1 Yes 85 (52) 40 (25) No 2 (1) 2 (1) Do not know 10 (6) 4 (2) 2 Relief after RRM (n [ 176) Yes 73 (41) 40 (23) No 4 (2) 4 (2) Partly 25 (14) 9 (5) Content with choosing RRM (n [ 171)3 Yes 91 (53) 47 (27) No 2 (1) 2 (1) Do not know 7 (4) 0 Both yes and no 1 (1) 0 Experience of prosthesis (n [ 174) Natural part 40 (23) 17 (10) Corpus alienum 41 (24) 20 (12) Both 7 (4) 4 (2) Have no prosthesis 11 (6) 13 (7) Operative result as expected (n [ 163) Yes 51 (31) 25 (15) No 33 (20) 15 (9) Do not know 14 (9) 6 (4) Satisfactory size (n [ 155) Yes 72 (46) 32 (21) Too small 21(14) 10 (6) Too big 1 (1) 2 (1) Satisfactory shape (n [ 159) Yes 61 (38) 26 (16) No 31 (19) 14 (9) Do not know 5 (3) 4 (3) Satisfactory symmetry (n [ 158) Yes 57 (36) 22 (14) No 37 (23) 17 (11) Do not know 2 (1) 5 (3) Satisfactory consistence (n [ 158) Yes 58 (37) 28 (18) No 34 (22) 12 (8) Do not know 5 (3) 4 (3) RRM: risk reducing mastectomy. Pearson Chi Square 1: p ¼ 0.2, 2: p ¼ 0.4, 3: p ¼ 0.4.
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Table 3 Efficacy of RRM in other studies. Study group
Group of women
Meana or medianb age in years at RRM
Cancer detected/RRM (%)
Cancers detected/control group (%)
Follow-up in years Mean or median
Hartmann et al. 1999 Meijers-Heijboer et al. 2001 Rebbeck et al. 2004 Heemskerk-Gerritsen et al. 2007 Evans et al. 2009 Domchek et al. 2010 Skytte et al. 2011 Arver et al. 2011
H, unaffected M. unaffected M, unaffected H, both unaff/affected H, both unaff/affected M, both unaff/affected M, unaffected H, unaffected
42b 35.8b 38.1a 37b(unaffected)/44b(affected) 41.2a 40.7a 37.1a 40b
3/214 (1.4%) 0/76 (0%) 2/105 (1.9%) 0/358 (0%) 0/550 (0%) 0/247 (0%) 3/96 (3%) 0/223^(0%)
156/403 (38.7%) 8/63 (12.7%) 184/378 (48.7%)
14b 3a 6.4a 4.5b 7.5b 3.5a
98/1372 (7.1%) 16/211 (7.6%)
6.6a
H: high risk including mutation carriers, M: BRCA1/2 mutation carriers. a Mean. b Median.
Follow up and occurrence of cancer after RRM Median follow-up was 35 months (range 3e336). There was one case of a new primary breast cancer after RRM. This patient had undergone BCS in the ipsilateral breast and later RRM with bilateral subcutaneous mastectomy. The new primary breast cancer occurred in the reconstructed contralateral healthy breast 79 months after RRM. RRSO had been performed four months before RRM. Altogether six women have died during the follow-up period after RRM. Three had previously been treated for breast cancer and died of metastatic spread from this cancer. Two died of ovarian cancer; both were diagnosed before they had their RRM. One died of endometrial carcinoma, diagnosed after RRM. Discussion This study gives an overview over the cohort of Norwegian BRCA1/2 mutation carriers who have undergone RRM with and without reconstruction. The increased number of RRM procedures in BRCA1/2 mutation carriers in Norway during later years may be due to increased patient awareness, but also to more active advocacy of RRM by breast surgeons and geneticists (Fig. 3). The majority of RRM and reconstruction procedures were subcutaneous mastectomy with removal of the nippleeareola complex and submuscular implant insertion. One weakness of this study is the lack of data on the 35 patients who did not want to participate in the study. Complications were seen in 39.7%. They were mostly cosmetic and could be rectified. Infection and implant removal occurred in 13/197 (6.6%) patients reconstructed with implants, which is in accordance with Nahabedian et al. [18] and Lagergren et al. [19] who reported 5.8% and 7.2%, respectively. Isern et al. reported only one implant removal due to infection (1/54 (1.9%)) [17]. We analyzed the study-specific questionnaire separately for BRCA1 and BRCA2. It has been shown that survival in Norwegian BRCA2 mutation carriers with breast cancer is equal to survival for women with sporadic breast cancer, while survival in Norwegian BRCA1 mutation carriers with stage 1 breast cancer is reduced [20]. We therefore hypothesized that RRM might be of greater importance for BRCA1 mutation carriers, who might experience greater relief and a higher degree of satisfaction than BRCA2 mutation carriers. However, no statistically significant differences were found. However, these results should be interpreted with care due to the small numbers in both groups. Only 59% returned the study-specific questionnaire which may be a limitation of the study. Some patients may have received the questionnaire while still undergoing reconstruction and therefore did not answer since they did not know the final result. Despite the fact that several experienced complications, 91% (156/171) were
satisfied with RRM. The numbers are too small to test associations between surgical techniques and frequencies of complications. The majority of women were satisfied with the cosmetic result after RRM and reconstruction. Our findings are in accordance with a descriptive study by Metcalfe et al. [21]. Isern et al. [13] also report similar results. Forty-five per cent (66/147) felt that the implant was a natural part of their body compared to 53% found in Isern’s study [17] and 49% in the Dutch study by Bresser et al. [22]. According to the questionnaire the majority felt relief after RRM, but 8/155 (5%) of the BRCA1 and two of the 21 (9.5%) BRCA2 mutation carriers experienced no relief. This emphasizes the importance of thorough pre-operative information ensuring that the decision to undergo RRM is made at the right time for each individual woman. One might expect that the operation was better tolerated by women with a previous history of breast cancer. However, we found no significant difference in satisfaction among women with previous breast cancer compared to healthy mutation carriers. This was also shown by Isern et al. [17]. The lack of standardized examination procedures and review of the sections reduces the value of the histopathological findings. It is reasonable to assume that the number of premalignant lesions would have been higher if standardized examination of an increased number of sections had been performed. Previous studies have found either higher or equal numbers of malignant and premalignant lesions [4,6,7,17,23e27]. One case of primary breast cancer after RRM occurred during follow-up in our study. In other studies the frequency varies from 0% to 3.2%, (Table 3). The largest study, by Evans et al., found no cases of cancer in 550 patients after a follow-up of 7.5 years [6]. However, the Danish study by Skytte et al. found three new cases of cancer in 96 patients, diagnosed 2.5 and 7 years after mastectomy [9]. All were BRCA1 mutation carriers and all had undergone simple total mastectomy with removal of the nippleeareola complex by three different surgeons at three different centers. Longer followup of the participants in the current study is necessary. Conclusion Rates of RRM in Norway are increasing and the efficacy of RRM in this study is high. Despite a complication rate of 39.7%, the majority of mutation carriers expresses high satisfaction and relief and would be willing to undergo the same procedure again. The ultimate aim for these women seems to be the reduction of risk of breast cancer. Ethical considerations The study was approved by the Regional Committee for Medical Research Ethics, Central Norway, 4.2009.244.
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