Langenbecks Arch Surg (2003) 388:3–8 DOI 10.1007/s00423-003-0355-9 CURRENT CONCEPTS IN CLINICAL SURGERY

Susanne Taucher Preventive in patients Michael Gnant Raimund Jakesz at risk due to genetic alterations in the BRCA1 and BRCA2 gene

Received: 4 November 2002 Abstract Background: The avail- cancer risk in high-risk patients are Accepted: 17 January 2003 ability of genetic testing for inherited often strongly recommended. A pa- Published online: 21 February 2003 mutations in the BRCA1 and BRCA2 tient’s life-time risk to develop © Springer-Verlag 2003 gene provides potentially valuable breast cancer in the presence of information to women at high risk of BRCA1 and BRCA2 mutations is breast and ovarian cancer. Methods 50–90%. Despite the reduction in the and focus: We review the literature risk of developing breast cancer, pro- on the value of prophylactic surgical phylactic mastectomy often leads to S. Taucher (✉) · M. Gnant · R. Jakesz strategies in patients with hereditary significant physical and psychologi- Department of Surgery, Medical School, predisposition to develop breast can- cal sequelae. Vienna University, cer and discuss the surgical options Waehringer Guertel 18–20, 1090 Vienna, available in high-risk cancer pa- Keywords BRCA1 · BRCA2 · Austria e-mail: [email protected] tients, decision analyses, and possi- Prophylactic mastectomy · Breast Tel.: +43-1-404005621 ble complications. Results: Preven- cancer · Fax: +43-1-404005641 tive surgical interventions to reduce

Introduction Women who carry germline BRCA1 and BRCA2 mu- tations have a strongly increased risk of breast and ovari- The BRCA1 and BRCA2 genes encode proteins that par- an cancer. The cumulative risk is estimated to range from ticipate in the cellular response to DNA damage; inacti- 40% to 85% for breast cancer and from 5% to 60% for vating mutations in these genes increase susceptibility to ovarian cancer, depending on the population from which breast and ovarian cancer. BRCA1 and BRCA2 mutations the data were derived [3]. With the known and theoreti- were first identified in 1994 [1, 2]. Tests for BRCA1 and cal limitations of breast and ovarian cancer surveillance BRCA2 mutations are now widely available and are per- and chemoprevention strategies in BRCA1 and BRCA2 formed increasingly on samples taken from women who mutation carriers it is understandable that many of these were diagnosed with breast or ovarian cancer at a young women and their clinicians have an interest in prophylac- age, or whose first-degree relatives have experienced a tic surgery as a cancer risk reduction strategy. cancer of this kind (families with three affected members Even if precise estimates of the efficacy of prophylac- in a maternal or paternal lineage over the course of three tic surgery were available, decisions concerning whether generations). or when to undergo these procedures would be complex The prevalence of germline (inherited) BRCA1 and and ultimately individual. The magnitude of the potential BRCA2 mutations in the general population is 0.1–0.2%. benefit depends on the risk of cancer associated with Overall these mutations contribute only to a small frac- specific mutations, the prognosis of the tumors in carri- tion of all cases of breast cancer, but as many as 10% of ers of mutations, and the extent to which relief of anxiety cases diagnosed in women younger than 40 years of age could result from surgical prophylaxis. These benefits and approximately 75% of familial cases occur in carri- must be weighed against an array of potential surgical ers of these mutations. complications and the impact of mastectomy or oopho- 4 rectomy on a woman’s self-image and potential social or by musculocutaneous latissimus dorsi flap. The shape consequences of such a decision. of the breast can be reconstructed very well with a mus- To address this clinical dilemma we discuss the cur- culocutaneous flap; the volume required varies depend- rent literature on surgical options in BRCA1 and BRCA2 ing on the original volume of the breast. The main draw- mutation carriers. back associated with the musculocutaneous flap tech- nique is an additional abdominal or dorsal scar and the risk of abdominal or dorsal sequelae. Prophylactic mastectomy: surgical considerations

Two different techniques are currently performed, and Breast reconstruction with prosthetic material the choice between the two requires detailed discussions with the woman herself. The first is subcutaneous mas- After mastectomy the retromuscular plan is undermined tectomy (SCM) which preserves the nipple areola com- and wide enough to allow good symmetry once the pros- plex, with a certain amount of breast tissue remaining thesis has been introduced. The controversy over the behind the nipple and the areola. This procedure is less medical complications of silicone implants is widely re- mutilating, but it does not completely avoid the risk of flected in the literature. It is preferable to use saline im- cancer developing in the remaining breast tissue. The plants which can be filled in situ to introduce the pros- second option is skin-sparing mastectomy with complete thesis more easily and to prevent damage to scar mar- removal of the nipple areola complex. gins. Modifications in shape and consistency occur in 15–20% of cases and can become evident as late as sev- eral months or years after breast reconstruction [5]. The Surgical complications most common indications for surgical interventions after implant reconstruction of the breast are capsular contrac- Any surgical procedure is associated with potentially ad- ture, implant rupture, hematoma, and wound infection. A verse outcomes that should be considered when recom- study of 92 women who had implant reconstruction after mending an elective prophylactic procedure to a healthy prophylactic mastectomy reported that the 5-year cumu- woman. There is little information about the complica- lative incidence of complications requiring surgical in- tions of mastectomy performed for the prevention of tervention was as high as 30.4% [6]. breast cancer. The rate of surgical complications in a se- ries of 163 patients who had SCM between 1974 and 1980 has been reported [4]. More than 80% of the proce- Efficacy of prophylactic mastectomy dures were bilateral prophylactic . The re- ported incidence of hematoma was 14%, the incidence of Most data on the efficacy of prophylactic mastectomy pain was 9%, and that of nipple necrosis and infection are based on retrospective analysis of patients at high was 6%. However, these data were obtained with surgi- risk. Only one study has evaluated this question prospec- cal techniques in use 20 years ago and most likely do not tively, although patients were not randomized (Table 1). reflect current standards of practice. Women at high risk are often not ready to participate in a prospective randomized trial in prophylactic breast sur- gery. Tambor et al. [7] assessed patients’ willingness to Reconstructive surgery participate in hypothetical research studies for breast and ovarian cancer risk reduction. After counseling sessions Reconstructive surgery can be performed either with for BRCA1 and BRCA2 in 87 at-risk women, only 19% prosthetic material or by autologous tissue transfer. for breast cancer and 17% for ovarian cancer were will- There is still some debate as to whether this procedure ing to participate in such a trial. It seems unlikely that a should be immediate or delayed in breast cancer patients. large cohort of high-risk women could be motivated to In general the concerns regarding immediate reconstruc- participate in a trial in which they would be randomized tion are related to potential adverse effects on the subse- to have their breasts surgically removed or not. Greater quent ability to administer radiation or chemotherapy feasibility combined with fewer ethical concerns make and do not apply to the prophylactic setting. nonrandomized trials a more viable alternative to ran- domized trials in terms of evaluating preventive inter- ventions for breast and ovarian cancer when prophylactic Breast reconstruction with autologous material surgery is one of the investigated treatments. Meijers-Heijboer et al. [8] conducted a prospective The best cosmetic results are usually obtained with au- study of 139 women with a pathogenic BRCA1 or tologous tissue reconstruction either by the free or pedi- BRCA2 mutation who were enrolled in a breast-cancer cled transverse rectus abdominal musculocutaneous flap surveillance program at the Rotterdam Family Cancer 5

Table 1 Published series of patients with bilateral prophylactic breast surgery

Meijers-Heijboer et al. [8] Hartmann et al. [9] Penissi and Capozzi [10] n 139 639 1500 Analysis Prospective Retrospective Retrospective Median follow-up (years) 3 14 9 Surgical strategy Total mastectomy 90% SCM, 10% total mastectomy SCM Expected breast cancer incidence 8/63 Moderate risk 37.4/425, high risk 30/214 Not stated Observed breast cancer incidence 0/76 Moderate risk 4/425, high risk 3/214 6/1046 Risk reduction (95%CI) Hazard ratio 0 (0–0.36), P=0.003 90% (70.8–97.9) Not stated

Clinic. At the time of enrollment none of the women had ate risk. The median length of follow-up was 14 years. a history of breast cancer. Of these women 76 eventually The median age at prophylactic mastectomy was underwent prophylactic mastectomy, and the other 63 re- 42 years. By the Gail model 37.4 breast cancers were ex- mained under regular surveillance. The effect of mastec- pected in the moderate-risk group; 4 breast cancers oc- tomy on the incidence of breast cancer was analyzed by curred (reduction in risk 89.5%, P<0.001). The number the Cox proportional hazards method in which mastecto- of breast cancers among the 214 high-risk probands was my was modeled as a time-dependent covariate. No compared to that among their 403 sisters who had not cases of breast cancer were observed after prophylactic undergone prophylactic mastectomy. Of the latter 156 mastectomy after a mean follow-up of 2.9±1.4 years, (38.7%) had been given a diagnosis of breast cancer (115 whereas eight breast cancers developed in women cases were diagnosed before the respective proband’s under regular surveillance after a mean follow-up of prophylactic mastectomy, 38 were diagnosed thereafter, 3.0±1.5 years [hazard ratio 0, 95% confidence interval and the time of diagnosis was unknown in 3). By con- (CI) 0–0.36, P=0.003). The actuarial mean 5-year inci- trast, breast cancer was diagnosed in 3 of 214 (1.4%) of dence of breast cancer among all women in the surveil- the probands. Thus, prophylactic mastectomy was asso- lance group was 17±7%. On the basis of an exponential ciated with a reduction in the incidence of breast cancer model the annual incidence of breast cancer in this group of at least 90%. was 2.5%. The observed number of breast cancers in the Pennisi and Capozzi [10] reported another retrospec- surveillance group was consistent with the expected tive analysis of 1500 patients who underwent SCM. number (ratio of observed to expected cases 1.2, 95% CI These authors’ data suggest that most patients treated 0.4–3.7, P=0.80). In women with a BRCA1 or BRCA2 with SCM experienced proliferative fibrocystic or mac- mutation undergoing prophylactic bilateral total mastec- rocystic disease, among other high-risk factors. The data tomy reduces the incidence of breast cancer at 3 years of also suggest that thoroughly performed SCM is an effec- follow-up. tive means of providing prophylaxis in women who are A retrospective cohort analysis of efficacy was car- at high risk for breast cancer. In 39% of the study sub- ried out in 639 women with a family history of breast jects there was a family history of breast cancer in at cancer who had bilateral SCM (90%) or total mastecto- least one first- or second-degree relative. The mean fol- my (10%) and were treated at the Mayo Clinic between low-up time was 9 years; 88% of the patients were 1960 and 1993 [9]. Approximately two-thirds of the younger than 50 years of age at time of surgery. The women were classified as being at high risk on the basis 10-year incidence of breast cancer after prophylactic of some features of autosomal dominant breast-ovarian mastectomy was 0.57% (six cases), but 30% of the pa- cancer syndrome (multiple cases of breast and/or ovarian tients were lost to follow-up, giving a slight underesti- cancer in close relatives, including early onset and bilat- mation of the true incidence of breast cancer after pro- eral disease). A subgroup at moderate risk was also de- phylactic mastectomy [11]. fined to include all other women with a family history of breast cancer who failed to meet the more stringent high- risk criteria. A control study involving high-risk pro- Other prophylactic surgical options: bands’ sisters was included together with the Gail model prophylactic oophorectomy to estimate the efficacy of surgery and to calculate the number of breast cancers expected in these two groups in Preventive surgery of the breast in BRCA1 and BRCA2 the absence of prophylactic mastectomy. carriers is not limited to removal of breast tissue. Pro- Of 639 women with a family history of breast cancer phylactic oophorectomy is another surgical option that who had undergone bilateral prophylactic mastectomy has received attention as risk-reducing management pro- 214 were identified to be at high risk and 425 at moder- cedure in high-risk patients. Recently reported data sup- 6

Table 2 Studies of prophylactic oophorectomy Table 3 Decision analysis in a hypothetical cohort of women car- rying mutations of BRCA1 and BRCA2; estimated gains in life ex- Rebbeck et al. [12] Kauff et al. [13] pectancy in a 30-year-old woman n 551 170 Schrag et al. [15] Grann et al. [16] Analysis Retrospective Prospective Follow-up (years) 9 (ovarian) 11 (breast) 2 Statistical model Markov model Markov model Ovarian cancer incidence Years gain in life expectancy Surveillance group 58/292 (19.9%) 5/72 (6.9%) Mastectomy 2.9–5.3 3.5 Oophorectomy group 8/259 (3.1%) 4/98 (4.1%) Oophorectomy 0.3–1.7 2.6 Breast cancer incidence Estimated risk reduction in breast cancer associated with Surveillance group 60/142 (42.3%) 8/62 (12.9%) Mastecomy 85% 90% Oophorectomy group 21/99 (21.2%) 3/69 (4.3%) Oophorectomy 40% Not stated

port the beneficial effect of salpingo-oophorectomy in phylactic options at one of 14 familial cancer clinics par- these patients after the completion of childbearing. ticipating in a cross-sectional, questionnaire-based sur- Decreases in ovarian hormone following bilateral oo- vey. The women were asked whether they would consid- phorectomy appear to reduce the cancer risk among er prophylactic mastectomy if genetic testing identified a BRCA1 mutation carriers (Table 2). Rebeck et al. [12] re- mutation in a breast cancer-predisposing gene; 19% said port the results of a multicenter, retrospective analysis of yes, 47% said no, 34% were unsure, and 1% had already 551 women carrying mutations in either BRCA1 or undergone prophylactic mastectomy. Bivariate analysis BRCA2. Ovarian cancer developed in 58 of 292 women showed the highest proportion of women, 25%, reporting (19.9%) who underwent surveillance during a mean fol- that they would consider prophylactic mastectomy low-up of 9 years. By contrast, stage I ovarian cancer among those at moderately increased risk of developing was identified in only 6 of 259 women (2.3%) who un- breast cancer, while only 16% of those at high risk did derwent bilateral prophylactic oophorectomy; primary so. Multivariate analyses revealed that consideration of peritoneal cancer subsequently developed in another 2 prophylactic mastectomy was strongly correlated with (0.8%). During 11 years of follow-up breast cancer was high levels of breast cancer anxiety [odds ratio (OR) diagnosed in 60 of the 142 women (42.3%) with no his- 17.4, 95% CI 4.35–69.71, P=0.0001) and overestimation tory of breast cancer who were followed conservatively, of one’s breast cancer risk (OR 3.01, 95% CI 1.43–6.32, compared with 21 of the 99 similar women (21.2%) who P=0.0036) while there was no association with objective had undergone prophylactic oophorectomy. breast cancer risk (P=0.60). Kauff et al. [13] reported the results of a prospective Means are available for the hypothetical calculation study of 170 BRCA mutation carriers with a mean fol- of gains in life expectancy in a 30-year-old woman car- low-up of 2 years. Ovarian cancer or a papillary serous rying a mutation of BRCA1 and BRCA1 related to pro- carcinoma of the peritoneum developed in five of phylactic surgical procedures (Table 3). Schrag et al. 72 women who elected intensive surveillance (6.9%). [15] reported a decision analysis comparing prophylactic Among 98 women who underwent prophylactic salpin- mastectomy and prophylactic oophorectomy with no go-oophorectomy three had early-stage tumors that were prophylactic surgery among BRCA1 and BRCA2 carriers. diagnosed at the time of surgery (3.1%), and primary On average 30-year-old women who carry BRCA1 or peritoneal cancer developed in one patient during fol- BRCA2 mutations gain 2.9–5.3 years of life expectancy low-up (1%). Among women who had not undergone from prophylactic mastectomy and from 0.3–1.7 years of prophylactic bilateral mastectomy breast cancer devel- life expectancy from prophylactic oophorectomy, de- oped in 8 of 62 in the surveillance group (12.9%), and in pending on their cumulative risk of cancer. Gains in life 3 of 69 in the oophorectomy group (4.3%). expectancy decline with age at the time of prophylactic surgery and are minimal for 60-year-old women. Among 30-year-old women oophorectomy may be delayed by Decision analysis 10 years with little loss of life expectancy. Similar findings have been published by Grann et al. The likelihood of an individual patient considering risk- [16]. Markov modeling of outcomes was performed in a reduction surgery is not necessarily correlated with actu- simulated cohort of 30-year-old women who tested posi- ally calculated risk. Meiser et al. [14] questioned 333 tive for BRCA1 and/or BRCA2 mutations. The model in- women who were awaiting their initial appointments for corporated breast and ovarian cancer incidence rates risk assessment, advice regarding surveillance, and pro- from the literature and mortality rates from the Surveil- 7 lance, Epidemiology, and End Results Program. A 30- pain, lack of education about the procedure, concerns year-old woman was able to prolong her survival beyond about consequent body image, and sexual dysfunction. that associated with surveillance alone by use of preven- The Manchester protocol [18] assessed mental health tive measures: 1.8 years with tamoxifen, 2.6 years with and body image outcomes in 52 patients after bilateral prophylactic oophorectomy, 4.6 years with both tamoxi- prophylactic mastectomy using self-report question- fen and prophylactic oophorectomy, 3.5 years with pro- naires, the General Health Questionnaire and the Body phylactic mastectomy, and 4.9 years with both surgeries. Image Scale. No negative change in body image was re- Quality-adjusted survival was improved by 2.8 years ported by 21% of women following surgery and the ma- with tamoxifen, by 4.4 years with prophylactic oopho- jority of changes that were reported were of only a minor rectomy, by 6.3 years with tamoxifen and oophorectomy, degree. The most frequently reported changes were in and by 2.6 years with mastectomy or with both surgical sexual attractiveness (55%), feeling less physically at- modalities. The benefits arising from all of these strate- tractive (53%), and self-consciousness about appearance gies would decrease if they were initiated at later ages. (53%); one-third of women felt less feminine to a mini- mal degree. A minority of women had more serious psy- chological or body image concerns, usually in relation to Concerns about prophylactic surgery surgical complications.

We know very little regarding the psychosocial sequelae experienced by women following bilateral prophylactic Conclusions mastectomy. Women’s regret following preventive breast surgery is a major consideration that must be addressed Prophylactic surgery reduces the likelihood of develop- preoperatively with these patients. In a study performed ing breast cancer among women at heightened risk for among 370 women having undergone prophylactic mas- breast cancer, but at significant personal risk. Thus tectomy at the Memorial Sloan-Kettering Cancer Center BRCA1 and BRCA2 testing must be performed to obtain 21 expressed regret about their decision [17]. The most objective confirmation of the genetic risk. Although pro- common regrets were articulated in physician-initiated phylactic mastectomy statistically reduces the chances of rather than patient-initiated discussions about the pre- a woman at high risk of developing breast cancer, the ventive breast surgery procedure. Psychological distress possibility of significant physical and psychological se- and the lack of psychological and rehabilitative support quelae remains. Counseling these woman preoperatively throughout the process were reported, and there were ad- is highly recommended since the ultimate decision must ditional regrets about prophylactic mastectomy cosmesis, be made after individual risk assessment and thorough perceived difficulty of detecting breast cancer in the re- weighing of advantages and disadvantages associated maining breast tissue, surgical complications, residual with such a strategy.

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