Week 10 Discussion: Takeaway Thoughts from the Article

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Perioperative Management of Women Undergoing Risk-reducing Surgery for Hereditary Breast and Ovarian Cancer

Mariam M. AlHilli, MD, and Zahraa Al-Hilli, MD

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ABSTRACT Carriers of genetic mutations that predispose to cancer syndromes are often faced with complex decisions. For women with hereditary breast and ovarian cancer in particular, the decision to undergo risk-reducing mastectomy or bilateral salpingo- oophorectomy is burdensome from a physical and psychological perspective. Although risk-reducing surgery is the most effective preventative measure in reducing a genetic mutation carrier’s risk of breast or ovarian cancer, the success of these procedures requires a multidisciplinary approach that centers on careful counseling regarding the risks and benefits of risk- reducing surgery. The physical and psychological distress associated with risk-reducing surgery often makes a combined surgical approach attractive to some patients. In this review, we present the evidence surrounding the comprehensive surgi- cal care of women with hereditary breast and ovarian cancer syndromes and evaluate the perioperative factors that influence

on behalf of AAGL. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Keywords: Risk-reducing surgery; Risk-reducing mastectomy; Hereditary breast and ovarian cancer syndrome; BRCA; genetic screening

Approximately 5% to 10% of breast cancers are attrib- uted to deleterious mutations in BRCA1 or BRCA2 genes, which are key genes in DNA repair through homologous recombination [1]. The cumulative risk of breast cancer by 80 years of age is 67% in BRCA1 carriers and 66% in BRCA2 carriers [2,3].

After a diagnosis of breast cancer, BRCA mutation carriers continue to have a substantial risk of developing a new breast cancer. The likelihood of developing breast cancer in an unaffected BRCA mutation carrier is influenced by multiple factors such as the presence of affected family members with the gene mutation and age (calculated lifetime risk). A study by Van Den Broek et al [4] of 6294 women diagnosed with breast cancer under 50 years of age (including 271 women with BRCA1 or BRCA2 mutations) showed that the

The authors declare that they have no conflict of interest.

Corresponding author: Mariam M. AlHilli, MD, Cleveland Clinic, 9500 Euclid Avenue, A81, Cleveland, OH 44195.

E-mail: alhillm@ccf.org

Submitted July 11, 2018, Accepted for publication September 6, 2018. Available at www.sciencedirect.com and www.jmig.org

10-year cumulative contralateral breast cancer risk was 5.1% for noncarriers, 21.1% for BRCA1 mutation carriers, and 10.8% for BRCA2 mutation carriers (hazard ratio = 3.31 for BRCA carriers compared with noncarriers). Interestingly, the age of first cancer was a significant risk factor for contralateral breast cancer. In women with a gene mutation who were diagnosed with breast cancer before 41 years, the risk of contralateral breast cancer was 23.9% compared with 12.6% for those diagnosed between 41 and 49 years. This risk was found to be even lower in women with no family history of breast cancer.

Approximately 3% to 5% of women assessed for hereditary breast cancer through multigene panel testing are found to have mutations in genes of moderate pene- trance such as PALB2, CHEK2, and ATM (Table 1). In relation to these breast cancer−related genes, providing accurate estimates for breast cancer risk based on age and life expectancy has been challenging because of the limited availability of data. Furthermore, the success of breast cancer screening may mitigate some of the increased risks. Risk-reducing surgery is currently not recommended for carriers of low to moderate

https://doi.org/10.1016/j.jmig.2018.09.767

Table 1

Hereditary Syndromes Associated with Breast and Ovarian Cancer¹

Genetic Mutation/Syndrome Estimated Breast Cancer Estimated Ovarian Management Recommendations Risk Up to Age 70 Years Cancer Risk Up to Age 70

Years

BRCA1 »55%−70% »39%−46% Annual screening MRI (or mammogram with tomosynthe-

sis) at age 25 years Discuss RRM

RRSO by age 35−40 years

Transvaginal ultrasound and CA 125 at age 30-35 years*

BRCA2 »45%−70% »10%−27% Annual screening MRI (or mammogram with tomosynthe-

sis) at age 25 years Discuss RRM

RRSO by age 40−45 years

Transvaginal ultrasound and CA 125 at age 30−35 years*

BRIP1 No increased risk »7%−10% RRSO by age 45−50 years

CDH1: hereditary diffuse Increased risk of lobular No increased risk Annual screening mammogram

gastric cancer carcinoma »60% Breast MRI with contrast at age 30 years Insufficient evidence for RRM

CHEK2 »37% No increased risk Annual screening mammogram

Breast MRI with contrast at age 30 years Insufficient evidence for RRM

MSH2, MLH1, MSH6, PMS2, Unknown risk MLH1 »11%−20% RRSO by age 40 years or after completion of childbearing

EPCAM: Lynch syndrome MSH2 »15%−24% Transvaginal ultrasound and CA 125 at age 30−35 years*

MSH6 »1% PMS2 »0%

ATM »24% No increased risk Annual screening mammogram

Breast MRI with contrast at age 40 years Insufficient evidence for RRM

PALB2 »35%−70% Unknown risk Annual screening mammogram

Breast MRI with contrast at age 30 Insufficient evidence for RRM

PTEN: Cowden syndrome; »50% No increased risk Annual screening mammogram

PTEN hamartoma tumor Breast MRI with contrast at age 30 years

syndrome Discuss RRM

RAD51C Unknown risk »5%−12% RRSO by age 50−55 years

RAD51D Unknown risk »5%−12% RRSO by age 45−50 years

STK11: Peutz-Jeghers »45%−50% »18%−21% risk of none- Annual screening mammogram and breast MRI at age 25 syndrome pithelial ovarian cancer Annual pelvic examination at age 18−20 years

TP53: Li-Fraumeni syndrome »50% No increased risk Annual breast MRI with contrast at age 20 years

Breast MRI with contrast at age 30 years Discuss RRM

CA 125 = cancer antigen 125; MRI = magnetic resonance imaging; RRM = risk-reducing mastectomy; RRSO = risk-reducing salpingo-oophorectomy.

* If RRSO not performed, transvaginal ultrasound/CA 125 are offered. There is insufficient evidence (National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology 2018; Genetics/ Familial High-Risk Assessment: Breast and Ovarian Cancer).

penetrance genes. However, the available data do sup- port risk-reducing mastectomy (RRM) for carriers of BRCA1, BRCA2, PTEN, and TP53 mutations.

Ovarian Cancer Risk

Carriers of BRCA1 or BRCA2 mutations have a cumula- tive lifetime risk of ovarian cancer of 15% to 40% [1]. Women with a BRCA1 mutation have a 39% to 46% risk for ovarian, fallopian tube, or primary peritoneal cancer (referred to cumulatively as ovarian cancer) by age 70.

Women with mutations in BRCA2 have a 10% to 27% risk of ovarian cancer [5,6]. Additionally, up to 25% of women with ovarian cancer may harbor germline mutations in homologous recombination genes (e.g., RAD51C, RAD51D, and BRIP1) other than BRCA1 and BRCA2 [3]. Table 1 shows other genes associated with hereditary ovarian cancer and management recommendations. Given the substantial risk of identifying a genetic mutation in a patient diagnosed with ovarian cancer, genetic testing is currently recommended for all women with epithelial ovarian cancer [1,6].

Approach to the Management of Women with Hereditary Breast and Ovarian Cancer

Genetic Risk Evaluation and Testing

Criteria for genetic risk evaluation for hereditary breast and ovarian cancer (HBOC) include a personal history of ovarian cancer; a personal history of breast cancer in the

setting of a known mutation in the family; breast cancer diagnosed ≤ 50 years of age; triple-negative breast cancer; 2 breast primaries in a single individual; breast cancer with multiple family members with breast, ovarian, or prostate cancer; family history of male breast cancer; Ashkenazi

Jewish descent; family history of multiple primary cancers; and a first- or second-degree relative with breast cancer

≤ 45 years of age [1].

Genetic counseling is a key component in the manage-

ment of women with HBOC. The primary goal of genetic counseling is to formally assess a patient’s personal and family history with respect to hereditary cancers and to provide an estimate of the likelihood that an inherited genetic mutation is present [1,6]. The patient’s knowledge, concerns, goals, and needs are evaluated at the time of genetic consultation and before genetic testing. Education regarding differential diagnosis, inheritance patterns and penetrance, possible outcomes of testing, screening, pre- vention, and risk-reducing strategies is initiated at that time [6]. Post-test counseling is an important aspect of patient management and education. Details of the results, their sig- nificance, and impact of recommendations should be discussed; family members are to be informed, and testing and resources should be provided [1].

At this time, most centers offer genetic testing through commercially developed multigene panel tests instead of single gene testing unless a specific inherited genetic mutation has been previously identified in a family mem- ber. Multigene panel tests are based on next-generation sequencing and allow the simultaneous evaluation of multiple genes including those with moderate penetrance [16]. This approach has some limitations including uncer- tainty regarding the management of genes of intermediate penetrance, variants of uncertain significance, and individu- als with negative testing but strong family histories [1].

Breast Cancer Screening

Recommendations for breast cancer screening for women with HBOC include breast awareness, clinical breast examinations, and breast imaging. In general, breast awareness and regular monthly self-breast examinations start at the age of 18 years. Clinical breast examinations begin at 25 years of age. Between the ages of 25 and 29 years, annual breast magnetic resonance imaging (MRI) with contrast is performed (this should be performed on days 7−15 of the menstrual cycle) or annual mammograms if MRI is not available. Between the ages of 30 and

75 years, annual mammography is recommended,

alternating every 6 months with annual breast MRI. Tomo- synthesis can be considered with or without 2-dimensional mammography, particularly in women with increased breast density, because it is superior to mammography in the detection of abnormalities within the breast. However, this is not routinely performed or may not be widely avail- able. Screening beyond 75 years is unclear and is consid- ered on a case-by-case basis based on patient current health and life expectancy [1].

Mammography has a sensitivity and specificity of 77% to 95% and 94% to 97%, respectively [7]. The most recent update for the US Preventive Services Task Force included a review of 8 randomized trials of mammographic screen- ing [8]. Mammographic screening was found to reduce the risk of breast cancer mortality for women between 39 and 69 years old. A reduction in cancer mortality of 15% was observed for women aged 39 to 49 years (relative risk [RR] = 0.85; 95% confidence interval [CI], 0.75−0.96). Data regarding women aged 70 years or older are lacking. In comparison with mammography, MRI screening has been shown to have a higher sensitivity. However, it is important to note that MRI screening may be associated with higher false-positive rates and a higher cost.

Ovarian Cancer Screening

In comparison with breast cancer screening, there are no screening tests that have been deemed effective in improv- ing the detection of ovarian or fallopian tube cancer [9]. Studies that evaluate ovarian cancer screening strategies have not shown an improvement in survival [1]. The cur- rently available screening modalities including transvaginal ultrasound and cancer antigen 125 (CA 125) have not been shown to reduce mortality related to ovarian cancer [10,11]. Other large prospective studies in high-risk women have suggested the possibility of early detection of ovarian cancer through screening with transvaginal ultrasound and CA 125 (using the risk of ovarian cancer algorithm) [12]. However, the impact on mortality in these patients has not been established. As such, risk-reducing surgery is the rec- ommended strategy for reduction in ovarian cancer risk in carriers of genetic mutations. Based on National Compre- hensive Cancer Network guidelines, performing CA 125 and pelvic ultrasound starting at age 30 to 35 years is left to the provider’s discretion [1].

Chemoprophylaxis

Breast cancer risk reduction elements include lifestyle modification, surgical prophylaxis, and chemopreven- tion. Risk-reducing chemoprevention agents include the selective estrogen receptor modulators tamoxifen and raloxifene and the aromatase inhibitors anastrozole and exemestane. (The latter 2 are yet to be Food and Drug Administration approved for breast cancer risk reduction purposes.) Tamoxifen is used for premenopausal

women, whereas all 4 can be used for postmenopausal woman; this choice will be influenced by patient comor- bidities and risk considerations. The challenge with che- moprevention recommendations in gene mutation carriers is the limited data available on the use of these agents for risk reduction in this cohort. Studies have shown that the use of tamoxifen was associated with an approximately 45% to 60% reduction in the risk of con- tralateral breast cancer in affected women with BRCA1 and 2 mutations [13,14]. The National Surgical Adju- vant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) was a randomized trial evaluating the role of tamoxifen for the prevention of breast cancer in unaf- fected women considered to be high risk for the disease [15]. BRCA2 patients, who typically develop estrogen receptor−positive tumors, achieved a 62% reduction in breast cancer risk with the use of tamoxifen compared with placebo. On the other hand, BRCA1 mutation car- riers did not achieve risk reduction with tamoxifen, likely because of the propensity for developing estrogen receptor−negative tumors in these patients. It is impor- tant to interpret chemoprevention benefit data in muta- tion carriers with caution because of the small number of patients included in studies. In addition, little is known about the role of chemoprevention in non-BRCA gene mutation carriers.

With regard to ovarian cancer risk reduction, the use of combined oral contraceptive pills has been shown to be associated with a 40% to 50% reduction in the risk of ovarian cancer [16]. In a case-control study by Narod et al [17], the use of oral contraceptives was associated with a significant reduction in the risk of ovarian cancer in both BRCA1 and BRCA2 mutation carriers [5]. This risk decreased with increasing duration of the use of oral contraceptives. As such, the use of combined oral contraceptives is considered to be a potential chemo- preventive strategy in women with BRCA mutations [16]. Data on the effect of oral contraception on breast cancer risk among BRCA1/2 mutation carriers have been conflicting. Some case-control studies have reported a modest increased risk of breast cancer among BRCA1 but not BRCA2 mutation carriers, whereas others have reported no increased risk [17,18]. However, at least 2 meta-analyses showed no increased risk of breast cancer in women with a BRCA1/2 mutation who used oral con- traception [19,20].

Risk-reducing Surgical Options for Women with HBOC

Risk-reducing salpingo-oophorectomy (RRSO) has been shown to reduce the risk of ovarian cancer by 96%, breast cancer by 50% to 75%, and all-cause mortality in unaf- fected women [5,21−23]. Therefore, RRSO is the most effective strategy for decreasing the incidence of ovarian cancer and mortality in high-risk women with hereditary mutations. For women identified to have a BRCA1

mutation, national guidelines recommend RRSO between the ages of 35 to 40 years because risk begins to increase in these patients in their late 30s [6,16]. Carriers of the BRCA2 mutation have a later age of onset of ovarian can- cer, and RRSO is recommended between ages 40 and 45 years in these patients. Prospective studies of women with BRCA1 and BRCA2 mutations show that approxi- mately 60% of women will opt for RRSO [24].

RRM reduces the risk of breast cancer by 90% to 97%. RRM can occur in conjunction with or as an alternative to high-risk screening. Bilateral RRM (BRRM) may be con- sidered in women without a personal history of breast can- cer. On the other hand, women with a diagnosis of breast cancer continue to carry an elevated risk for breast cancer in the affected or contralateral breast. Therefore, these patients may consider contralateral RRM (CRRM).

In general, women with a confirmed genetic mutation in BRCA1 or BRCA2 or other genes with an elevated risk for breast or ovarian cancer are offered risk-reducing surgery. Women with negative genetic testing but a first-degree rela- tive with epithelial ovarian cancer are estimated to have a risk of 5% of developing ovarian cancer and also qualify for RRSO. In the absence of a pathogenic mutation, an ele- vated risk based on family history assessment of breast and/ or ovarian cancer risk is an appropriate indication for risk- reducing surgery [3] (Fig. 1).

RRSO

Preoperative Counseling

Investigations into the psychosocial impact of risk- reducing surgery show that surgery is associated with a sig- nificant decline in psychological morbidity and anxiety without an increase in negative body impact or a decrease in sexual functioning [9]. Nevertheless, the decision to undergo RRSO is complex and requires early consultation with a gynecologic oncologist as well as a provider with expertise in genetic counseling and testing [6]. At the time of counseling, a thorough discussion on the impact of RRSO on reproduction, breast and ovarian cancer risk, and the long-term risk of premature menopause (including oste- oporosis, cardiovascular disease, and sexual concerns) must be had. A review of the impact of this intervention on qual- ity of life is of high importance [1]. In addition, hormone replacement therapy (HRT) is encouraged in women with- out contraindications for estrogen and/or progesterone replacement. This strategy of HRT after surgical meno- pausal minimizes and ameliorates the potential detrimental consequences of surgical menopause [3]. Although con- cerns have been raised about a possible increase in breast cancer risk with the use of HRT in premenopausal women, it is important to discuss with patients that HRT has been deemed to be safe in women with BRCA1 mutations, and an increase in the risk of breast cancer among women taking HRT has not been observed in prospective studies [22,25].

Fig. 1

Evaluation and management of women with suspected or confirmed hereditary breast and ovarian cancer syndrome.

Personal history of high grade epithelial ovarian cancer Personal history of breast cancer:

– ≤50 years

– Triple negative breast cancer

– Two breast cancer primaries

– Family history of breast or ovarian or other cancers

– Male breast cancer Ashkenazi Jewish descent

First or second degree family member with breast cancer ≤45 years

Family history of breast or ovarian cancer Family history of multiple cancers

Referral for consultation with a genetics counselor

Genetic testing if indicated

Hereditary breast and ovarian cancer conﬁrmed

Breast cancer risk management Ovarian cancer risk management

Breast cancer high-risk screening Oﬀer screening with transvaginal

Risk –reducing mastectomy when ultrasound and CA125 age 30-35

sufficient evidence to recommend Risk-reducing salpingo-

oophorectomy between 35-40 years (BRCA1 mutation carriers) and 40-45 (BRCA2 mutation carriers) or after completion of childbearing

Rebbeck et al [21] showed that the short-term use of HRT until the average age of menopause in premenopausal women undergoing RRSO generally did not increase the risk of breast cancer. A strategy of limiting HRT duration to the age of 51 years (the average age of menopause) is gener- ally recommended. In a decision analytic model developed by Armstrong et al [26], RRSO was found to be associated with an increase in life expectancy in patients with a BRCA1/2 mutation regardless of HRT use. A decrement in life expectancy was noted when HRT was continued for life versus when HRT was stopped at age 50 years [26].

Patients should be counseled about the risk of detec- tion of occult ovarian, fallopian tube, or primary perito- neal carcinoma at the time of risk-reducing surgery, which would necessitate surgical staging [9,27]. Furthermore, women who opt for RRSO before the completion of childbearing should be counseled about alternative reproductive options and referred appropri- ately to a reproductive endocrinology specialist. They should be informed about the option of undergoing embryo or ovarian cryopreservation as well as preim- plantation genetic diagnosis [1].

Decision Regarding Concurrent Hysterectomy

Counseling regarding the risks and benefits of con- current hysterectomy at the time of RRSO is an impor- tant point of discussion. Hysterectomy is currently offered electively to women undergoing RRSO. Women with a gynecologic indication for hysterectomy includ- ing those with a known history of Lynch syndrome are likely to benefit from the addition of hysterectomy. Pre- menopausal women without a personal history of breast cancer who undergo RRSO are also offered hysterec- tomy to simplify hormone replacement [9]. The use of estrogen alone after hysterectomy is considered to be safer than combined estrogen and progesterone with regard to breast cancer risk [28].

It has been suggested that concurrent hysterectomy at the time of RRSO may provide long-term survival bene- fits when the risk of uterine cancer is taken into consid- eration [16]. Data regarding the increased risk of uterine serous carcinoma among BRCA mutation carriers are conflicting. BRCA1 mutation carriers have been pro- posed to be at highest risk. In a prospective review of 1083 women with BRCA mutations who underwent RRSO with uterine conservation, an increased risk of serous endometrial carcinoma was noted in BRCA1 mutation carriers (observed:expected risk ratio = 22.2;

95% CI, 6.1−56.9; p < .001) [29,30]. However, at this

time, the decision to perform hysterectomy at the time of RRSO is individualized after balancing the surgical risks and benefits of the procedure.

Delayed Oophorectomy

Delayed oophorectomy has been proposed to avoid premature menopause. The performance of risk-reducing salpingectomy alone in genetic mutation carriers who wish to preserve fertility and ovarian function is based on the accepted paradigm that serous tubal intraepithe- lial carcinoma is a precursor lesion for invasive carci- noma [31]. Although retrospective studies in low-risk women suggest a 35% to 42% reduction in the risk of ovarian cancer after salpingectomy, this is not consid- ered to be sufficient evidence to recommend salpingec- tomy in high-risk women [1]. Furthermore, carriers of BRCA1/2 mutations who undergo salpingectomy may not receive the benefit of a reduction of breast cancer risk (by 50%) if oophorectomy is delayed [1]. Other concerns include the possibility that serous tubal intrae- pithelial carcinoma lesions may represent metastases from ovarian primary lesions in about 50% of cases [3]. Furthermore, 70% of occult carcinomas are found to originate in the fallopian tubes, which implies that one third of occult carcinomas that arise outside of the fallo- pian tubes would not be prevented with salpingectomy. Therefore, despite its feasibility, bilateral salpingectomy

alone is not considered the standard of care with regard to risk reduction because the role of this procedure in BRCA mutation carriers has not been adequately vali- dated. Prospective studies are currently underway including the TUBA study (NCT02321228), which explores the impact of bilateral salpingectomy with delayed oophorectomy on quality of life as well as ovar- ian and breast cancer risk [3,32].

Intraoperative Considerations

As described by the Society of Gynecologic Oncology and the American College of Obstetrics and Gynecology, the opti- mal technique for RRSO involves a systematic approach [33]. This process involves minor modifications in comparison with standard bilateral salpingo-oopherectomy (BSO) per- formed for other indications. A laparoscopic approach is gen- erally undertaken [9]. An abdominal survey is performed, and all peritoneal surfaces are inspected. Peritoneal washings are routinely obtained [6,34]. To ensure complete removal of the adnexa, the retroperitoneal space is entered. If adhesions between the ovary and pelvic side wall are encountered, they must be resected along with the ovary [9]. Prevention of ovar- ian remnant syndrome is of high importance in this patient population. The fallopian tubes are removed at their insertion point in the uterus if hysterectomy is not performed. The importance of complete removal of the fallopian tube is attributed to the high rate of occurrence of fallopian tube can- cers among BRCA mutation carriers [35]. These patients have a 120-fold increased risk of fallopian tube cancer compared with the general population [9]. The ovarian vessels are ligated at the pelvic brim.

Postoperatively, meticulous histologic evaluation of the fallopian tubes and ovaries with sectioning in 2 to 3 mm is performed. This protocol, known as Sectioning and Exten- sively Examining the Fimbriated End of the fallopian tube, has been shown to increase the detection of serous carcinoma that arises in the fimbriated end of the fallopian tube in 50% of patients regardless of BRCA status [22,36,37]. Box 1 describes best practice recommendations for RRSO. Adher- ence to these guidelines may impact prognosis and minimize the risk of missing an occult malignancy. In a retrospective study of 263 patients undergoing RRSO performed by gen- eral gynecologists compared with gynecologic oncologists, it was found that gynecologic oncologists are more likely to adhere to best practice guidelines and a meticulous RRSO technique [34,38]. Particularly, gynecologic oncologists were more likely to perform pelvic washings, include a description of the upper abdomen in the operative report, use a retroperi- toneal approach, and undergo careful pathologic examination of the specimens. In order to maximize the benefit from RRSO, referral of women desiring RRSO to surgeons with specialized training in pelvic surgery and those with expertise in caring for high-risk women is advocated.

Box 1

Best Practice Recommendations for Risk-reducing Bilateral Sal- pingo-oophorectomy

Preoperative

Ⓧ Pelvic ultrasound and cancer antigen 125 at least within 6 months of surgery

Ⓧ Counseling regarding reproductive desires, menopausal symp- toms, cancer risk, and hormone replacement

Intraoperative

Ⓧ Abdominal and pelvic survey and close evaluation of peritoneal surfaces, bowel, and pelvic organs

Ⓧ Pelvic washings (50 mL normal saline instilled and aspirated)

Ⓧ Complete removal of the fallopian tube at isthmus

Ⓧ Ligation of ovarian vessels at pelvic brim (at least 2 cm proximal to ovary)

Ⓧ Removal of all peritoneum around ovaries/fallopian tubes, espe- cially if adhesions present

Postoperative

Ⓧ Histologic evaluation and processing using the Sectioning and Extensively Examining the Fimbriated End of the fallopian tube approach (2- to 3-mm sections)

Ⓧ Referral to genetics and gynecologic or surgical oncology if occult malignancy or serous tubal intraepithelial carcinoma is diagnosed

RRSO. Similarly, Bogani et al [42] recently reported a complication rate of 4.7% within 30 days of surgery, which included fever and postoperative ileus. Severe complications were not observed, and all complications were managed conservatively.

In a review of all RRSO procedures performed during a 10-year period at Brigham and Women’s Hospital, Boston, MA, it was found that the conversion rate to laparotomy was 2% for laparoscopic RRSO (5 because of adhesions, 1 because of a difficult entry, and 1 because of malignancy) [41]. Other

outcome measures studied included estimated blood loss, which was reported to be negligible ( < 50 mL in 97% of patients), and absence of intraoperative complications.

Risk of Occult Malignancy at the Time of RRSO

The detection of an occult ovarian malignancy and sub- sequent management has important implications. The inci- dence of occult malignancy at the time of RRSO has been described to range between 0.6% and 18.5% [39,40]. An analysis of 966 RRSO procedures estimated a rate of inva- sive ovarian/tubal or peritoneal carcinoma of 4.6% in BRCA1 mutation carriers and 3.5% in BRCA2 carriers [39]. This risk increases with age to 20% over the age of 45 years [28]. It has been proposed that the surgical technique may account for the variability in the detection rate of occult malignancy at the time of RRSO, which has been described in the literature [27,34,38]. Given the elevated risk of occult malignancy in genetic mutation carriers, preoperative eval- uation with transvaginal ultrasound and CA 125 is warranted before RRSO. The risk of development of pri- mary peritoneal cancer after RRSO has been reported to be 2% to 4% in women over 20 years old [22].

Perioperative Morbidity Associated with RRSO

A laparoscopic approach to RRSO is considered the standard of care in the management of women with an increased risk for ovarian cancer. This procedure is per- formed as an outpatient procedure, and over 98% of patients are able to be dismissed home on the same day as surgery [41]. Complications related to RRSO are rare. Reports vary with regard to the described compli- cation rates from RRSO. Kauff et al [24] reported

4 complications among 80 patients (5%) undergoing

RRM

Extent of Cancer Risk Reduction and Mortality Associated with RRM

A recently published Cochrane Review update reported on the effects of RRM on breast cancer incidence, overall mortality, breast cancer−related mortality, disease-free sur- vival, physical morbidity, and psychosocial outcomes [43]. The review included 61 studies (no randomized trials avail- able for analysis) of 15 077 women who underwent RRM. The data were analyzed separately for BRRM and CRRM. The publication concluded that BRRM was effective in reducing both the incidence and mortality from breast can- cer. On the other hand, although CRRM was found to reduce the incidence of contralateral breast cancer, there was insufficient evidence that CRRM improves survival because of ongoing risk of recurrence or metastases from the original cancer.

A meta-analysis by Li et al [44] investigated the effec- tiveness of risk-reducing surgery in women with BRCA1 and BRCA2 mutations. In 2555 patients, breast cancer risk corresponded to a relative risk [RR] of 0.114 for gene muta- tion carriers undergoing BRRM compared with those who did not have surgery. BRRM decreased the incidence of breast cancer in BRCA1 (RR = 0.134; 95% CI, 0.019

−0.937) and BRCA2 gene mutation carriers (RR = 0.183; 95% CI, 0.072−0.468). Furthermore, CRRM decreased the incidence of contralateral breast cancer (BRCA1 and 2: RR = 0.072; 95% CI, 0.035−0.148) and significantly decreased all-cause mortality compared with patients who did not undergo CRRM (hazard ratio = 0.512; 95% CI, 0.368−0.714).

Surgical Options for Breast Cancer Risk Reduction

There are a number of techniques available, including total or simple mastectomy (removal of both breasts, nip- ple-areolar complex [NAC], and the overlying skin), skin- sparing mastectomy (removal of both breasts and NAC with preservation of the overlying skin), and nipple-sparing mastectomy (NSM) (removal of both breasts with

preservation of the NAC and the overlying skin). Subcuta- neous mastectomy was a traditional approach that has been abandoned as a therapeutic or prophylactic option in breast surgery because of the risk of leaving a significant amount of residual tissue. Furthermore, modified radical mastec- tomy (total mastectomy with axillary lymph node dissec- tion) is not performed without an oncologic indication because of the risk of axillary and arm morbidity.

NSM has emerged over recent decades as an option for the treatment and prevention of breast cancer in selected women (Fig. 2). This procedure has the advantage of pre- serving the NAC to optimize cosmesis after mastectomy and also facilitates the process of breast reconstruction [45,46]. Studies have shown high patient satisfaction with the procedure [45]. In addition, NSM is associated with higher patient psychosocial and sexual well-being when compared with patients having skin-sparing mastectomy with removal of the NAC [47]. There are several reports of bilateral NSM for breast cancer risk reduction focusing mainly on patients with mutations in the BRCA1 and BRCA2 genes [48−51]. The main concern with NSM and surgical prophylaxis is the insufficient oncologic follow-up data available compared with other procedures. In addition, it is unknown if the presence of residual terminal duct lobu- lar units in the NAC confers a potential risk of cancer. Despite this, NSM with reconstruction has become a favored option for select women undergoing RRM.

Breast reconstruction is an integral part of breast sur- gery, both in the therapeutic and prophylactic setting. A multidisciplinary team approach to patient management, with inclusion of a reconstructive surgeon as part of the team, is key to ensuring appropriate patient and procedure selection. Reconstruction options broadly include immedi- ate or delayed reconstruction with 1 or 2 staged procedures that could involve the use of breast implants or autologous tissue reconstruction. In the setting of secondary

prevention, in women with a diagnosis of breast cancer, considerations to bear in mind include the potential need for radiation to the chest wall and/or nodal basins because this could potentially increase the risk of complications with reconstruction. Therefore, careful planning of timing and the type of procedure are important.

More importantly, women should be counseled that RRM does not completely eliminate the risk of breast can- cer after mastectomy. Furthermore, although RRM may increase psychological peace of mind, it can be associated with surgical morbidity, potential for multiple surgical pro- cedures, reduced tactile sensation of the breast and NAC, and potential for diminished satisfaction with body image. The optimal surgical and reconstruction approach must be individualized, taking into consideration patient factors and, in the case of secondary prevention, oncologic and treatment factors.

Risk of Occult Malignancy at the Time of RRM

Occult cancers have been found in up to 15% of patients undergoing RRM [52−55]. As such, the role of sentinel lymph node biopsy with RRM has been debated, and rec- ommendations are conflicting. The finding of occult cancer would require additional axillary staging, which could mean a return to the operating room for a second surgery (axillary lymph node dissection). This second surgery can potentially add surgical and psychological morbidity to the patient. Some studies examining the rate of occult invasive breast cancer have suggested that the addition of MRI and sentinel lymph node biopsy are neither cost-effective nor do they reduce overall morbidity. A study investigating risk factors associated with the identification of occult malig- nancy in high-risk lesion women undergoing CRRM revealed that the rate of occult malignancy was similar among patients with a genetic mutation, those who test

Fig. 2

Bilateral nipple-sparing mastectomy. (a) The preoperative image. (b) The postoperative image.

negative, and those who had no testing [52,56]. Further- more, neither MRI nor genetic testing were associated with the identification of a high-risk lesion or occult malignancy. Therefore, upon balancing the risks and benefits of the procedure, sentinel lymph node surgery is not routinely performed or recommended. Obtaining up-to-date imaging is recommended before surgery in order to help identify a potential occult breast cancer.

Perioperative Morbidity Associated with RRM

In general, breast surgery is associated with low postop- erative complication rates and an even lower mortality rate. Complication rates after mastectomy with reconstruction have been reported to be in the range of 2% to 49% [57−60]. Data from the American College of Surgeons National Surgical Quality Improvement Program database (including breast cancer patients with or without a genetic mutation) revealed a total complication rate of 11.2% in women undergoing immediate reconstruction compared

with 9.2% in those undergoing mastectomy alone (p < .001). Predictors of complications included obesity, autologous reconstruction, smoking, bilateral procedures, patient comorbidity, and diabetes [61].

A limited number of studies report on morbidity associ- ated with RRM. Reoperation rates range from 4% in women undergoing RRM without reconstruction to 64% in women undergoing RRM with reconstruction [43,62−68]. Reported complications include wound infection, flap complications (skin necrosis, flap loss, and donor-site com- plications), hematoma, seroma, implant complications (including capsular contraction, implant loss or rupture, and expander port leakage), and pain. A higher risk of com- plications is noted to be associated with increasing body mass index and smoking.

Concurrent RRM and BSO

Rationale for Concurrent Risk-reducing Surgery

RRSO can be performed before, concurrently, or after mastectomy and reconstruction as a staged procedure [69,70]. There is no consensus on the optimal sequence of procedures in women without a diagnosis of malignancy who are found to be carriers of a genetic mutation [69]. Practice patterns generally vary by provider and institution. From a patient perspective, the oncologic status often dic- tates the timing of surgery (i.e., some patients undergoing mastectomy for the treatment of breast cancer may not be aware of their genetic risk before surgery and cancer treat- ment). On the other hand, BRCA mutation carriers are often diagnosed in the setting of strong family history and usually undergo prophylactic procedures under elective conditions [69]. BRRM with immediate reconstruction is the most common procedure performed in this patient population.

Breast reconstruction options can range from implant- based reconstruction to more complex autologous recon- struction options. Autologous breast reconstruction is the preferred reconstructive approach in young healthy patients where possible. These procedures are typically lengthy and technically complicated. Importantly, the timing of these procedures may have implications on abdominal wall com- plication risk. Performing a staged procedure (with RRSO at the staged procedure) can be coordinated with 1 of the secondary reconstructive procedures a few months after ini- tial surgery. The benefits of a staged procedure include potentially lowering of infection rates, protection of the myocutaneous flap, and allowing secure closure of the abdominal wall [71].

Feasibility of Breast Reconstruction after RRSO

Prior abdominal surgery can hinder microsurgical breast reconstruction. Hysterectomy and BSO performed before breast reconstruction (particularly if through a midline inci- sion) place limitations on the use of an autologous flap as well as concerns regarding perfusion across the scar. Even after a laparoscopic or robotic approach, there is a theoretic risk that perforators of the deep inferior epigastric vessels would be injured during placement of ports or scarring of the rectus muscle, which would potentially compromise breast reconstruction [69]. Khansa et al [69] found that microsurgical breast reconstruction performed after hyster- ectomy and BSO did not increase the risk of abdominal wall hernia or the use of mesh. However, the ability to per- form an abdominal flap reconstruction is minimized. In addition, a prior Pfannenstiel incision can exclude a patient from autologous reconstruction because of injury to the superficial inferior epigastric vessels.

Feasibility of RRSO after Breast Reconstruction

Approximately 70% of patients undergoing RRSO have a personal history of breast cancer [24]. As such, some of these patients may have had prior abdominal flap recon- struction [24,72]. Although risk-reducing gynecologic sur- gery performed after breast reconstruction is feasible, the duration of surgery is significantly increased in this setting [69]. Abdominal insufflation during laparoscopy can be hindered by previous flap harvest. The increased tightness of the abdominal wall, particularly if fascia is harvested or mesh is placed, makes abdominal exposure difficult and increases the risk of conversion [69].

Studies that have evaluated the safety of RRSO after transverse rectus abdominus muscle (TRAM) flap recon- struction show high rates of success after gynecologic pro- cedures. Awtrey et al [72] reported on their experience with RRSO in 102 patients with prior history of breast cancer, 10 of whom had previously undergone TRAM flap recon- struction. No difference was noted in estimated blood loss, length of hospital stay, or intraoperative/postoperative

complication rates. However, patients who had undergone prior TRAM were noted to have significantly longer opera- tive times (91 vs 70 minutes, p < .01) [72].

Concurrent RRSO with Mastectomy and Breast Reconstruction

An increasing number of women undergoing RRM are electing to undergo immediate reconstruction [73]. Hence, performing concurrent RRSO with breast surgery is a ratio- nal choice. Patient satisfaction with combined procedures in general has been reported to be high without incurring an increase in postoperative morbidity [74]. Concurrent RRSO with mastectomy and breast reconstruction has important advantages. It provides patients with the convenience of having a single operation and recovery, shortens recovery time, and reduces cost of care [75]. It has been further pro- posed that the burden of having 2 separate procedures could impact a woman’s decision to undergo RRSO in the setting of a diagnosis of breast cancer, whereas coordinated sur- gery may mitigate this factor.

Safety and Efficacy of Concurrent Risk-reducing Procedures

Some potential risks of concurrent mastectomy with RRSO, particularly in the setting of breast reconstruction, have been raised. The placement of patients in the Trende- lenburg position after flap revascularization could also increase the risk of vascular compromise, flap avulsion, or compromise of vascular pedicle [69,72]. In addition, there is concern for an increase in the risk of wound infections after hysterectomy leading to infection and/or loss of tissue implant [69].

Batista et al [76] reported on a small series of high-risk women who underwent combined RRM and RRSO, 10 of whom had a history of prior breast cancer and 10 patients underwent autologous breast reconstruction. The mean operative time was 9.3 hours (range, 3−16 hours), and the mean postoperative hospitalization duration was 5.4 days (range, 4−8 days).

In the largest series of patients undergoing simultaneous breast and gynecologic surgery, Ma et al [75] reported on 73 patients, 48 of whom (80%) underwent BSO (55% had a concurrent hysterectomy and 25% did not). The remainder of patients underwent other procedures for benign indica- tions. The mean operative time was 5.6 hours (range, 47 minutes−14.6 hours). The average hospital length of stay was 3.3 days (range, 0−9 day). The length of stay increased with the addition of reconstructive procedure with a median length of 2.4 days for those undergoing implant reconstruc- tion and 6.5 days for those undergoing autologous recon- struction. Chapman et al [77] showed that total operating times are increased in patients undergoing sequential

surgery (median of 1 hour 52 minutes longer than concur- rent surgery). In addition, the length of hospital stay was found to be on average 1 day and 8 hours longer in the con- current surgery group.

Postoperative Morbidity Associated with Concurrent Surgery

In the series by Ma et al [75], the rate of postopera- tive complications was determined to be 37% within 30 days of surgery. The vast majority (80%) of compli- cations were considered to be minor and did not require hospitalization or surgical intervention. Del Corral et al

[78] reported on 42 patients undergoing bilateral mas- tectomy, reconstruction, and BSO with or without hys- terectomy. Among 18 patients who experienced a complication in this series, 15 were noted to be minor, including delayed wound healing, fat necrosis, seroma, or superficial infection. Three major complications of postoperative thrombosis/ flap loss occurred. Although there may be a numeric increase in complication rates with concurrent surgery, this has not been shown to translate into a statistically significant difference in complication rates between concurrent surgery and indi- vidual procedures [77,78]. Batista et al [76] reported no major intraoperative complications in their review. However, postoperative morbidity included abdominal wound dehiscence, reoperation for flap congestion, 1 case of superficial epidermolysis, and 1 case of aspira- tion pneumonia. The rate of these complications is believed to be in line with previously reported rates of postoperative complications for autologous reconstruc- tion, which have been estimated to be approximately 24% (flap complications) and 15% (donor-site compli- cations). Therefore, the addition of gynecologic sur- gery, while increasing operative time, does not seem to significantly increase the risk of postoperative breast complications.

Increased blood loss and need for postoperative blood transfusion have been reported in patients undergoing com- bined abdominoplasty and gynecologic surgery [79]. Ma et al [75] reported a rate of 15% of blood transfusion in their series. These patients received autologous reconstruc- tion and required blood transfusion because of intraopera- tive blood loss, and 1 patient developed a breast hematoma after discharge. However, it is noteworthy that the addition of laparoscopic BSO did not alter the risk for needing blood transfusion in these patients.

To improve outcomes of combined procedures, Del Cor- ral et al [78] described the technique of raising abdominal flaps, transferring and anastomosing them to the chest, and finally setting the flaps. This allows the gynecologic proce- dure to be completed with adequate visualization and minimal risk of flap avulsion or vascular injury. RRSO is

performed through an open incision in the posterior rectus sheath. The plastic surgery team then performs closure of the peritoneum and fascia with or without mesh. There was no difference in intraoperative complications, rate of flap loss, fat necrosis, or wound complications found in this study.

Cost-effectiveness

It is proposed that a single procedure provides economic benefit by decreasing postoperative visits, anesthesia charges, and total hospital charges. This would also allow faster return to work and improved productivity. Del Corral et al [78] performed a cost analysis of patients undergoing concurrent breast and gynecologic procedures. It was found that operating room direct variable cost and total direct var- iable cost did not differ significantly between the groups. However, the average total cost was higher in the concur- rent surgery group. Factors found to be predictive of increased cost were simultaneous procedures, body mass index, operating room time, and immediate major surgical complications [78].

Optimal Patient Selection

Although performing a concurrent procedure is not rou- tine practice at this time, there is an opportunity for comb- ing the procedures with some technical refinements and adequate team coordination. It must also be noted that per- forming the procedure at high-volume centers may impact surgical outcomes of concurrent surgery. In a study of 62 BRCA mutation carriers, 43 (69%) of whom opted for con- current surgery, it was found that patients undergoing con- current surgery were more likely to be older (median age 45 vs 39 years) and were more likely to receive neoadjuvant chemotherapy. No difference in complication rates was noted between the 2 patient groups [77]. An individualized approach is preferred.

Conclusion

Breast and ovarian cancer risk reduction is an area of ongoing research. Enhanced efforts have been spent on risk reduction through risk estimation, lifestyle modification, surgical prophylaxis, and chemoprevention. A key chal- lenge lies in the development and use of breast cancer risk reduction modalities that are evidence based and provide maximum benefit with low and acceptable morbidity and minimal impact on quality of life. Women with HBOC ben- efit from a multidisciplinary discussion of individual risk (taking into account the type of gene mutation, age and life expectancy, and family history), degree of risk reduction offered by surgery, associated risk of surgical morbidity, and alternatives to surgery. Concurrent RRM with RRSO can be performed when resources are available. This gener- ally requires a coordinated multidisciplinary effort and an individualized patient selection.

References

Brigham and Women’s experience. Int Sch Res Netw ISRN Minim Invasive Surg. 2012:763290.

predisposed women. Plast Reconstr Surg. 2006;117:1675–1682. discussion 1683−1684.

A Sample Of This Assignment Written By One Of Our Top-rated Writers

Week 10 Discussion

Takeaway Thoughts from the Article

In the article “Perioperative management of women undergoing risk-reduction surgery for hereditary breast and ovarian cancer,” AlHilli & Al-Hilli (2019) present the evidence surrounding the comprehensive surgical care of women with hereditary breast and cancer syndromes and explore the perioperative factors that influence surgical management. According to the researchers, deleterious mutations in BRCA1 and BRCA2 genes, as well as age are the primary risk factors for breast, ovarian, fallopian tube, and primary peritoneal cancer. The article recommends various approaches for detecting and assessing the genetic risk of hereditary breast and ovarian cancer (HBOC). These strategies are mammography, breast imaging, clinical breast examinations, and regular monthly self-breast examinations that start at the age of 18. According to AlHilli & Al-Hilli (2018), the available screening modalities for ovarian cancer are transvaginal ultrasound and cancer antigen 125 (CA 125). These screening approaches can determine the risk of HBOC and inform decisions, such as prophylactic surgeries and counseling.

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As a strategy for preventing and reducing the risks of hereditary breast and ovarian cancer, AlHilli & Al-Hilli (2018) present risk-reducing salpingo-oophorectomy (RRSO) as an ideal approach. Also, the researchers identify various surgical techniques for reducing ye risk of breast cancer. These approaches are total or simple mastectomy, skin-sparing mastectomy, and nipple-sharing mastectomy (AlHilli & Al-Hilli, 2018). Although these interventions reduce the risk of hereditary breast and ovarian cancer, patients and healthcare professionals face dilemmas in harmonizing the ethical underpinnings of these surgical options.

Ethical Dilemmas to Consider with Prophylactic Surgeries

Ethical dilemmas in prophylactic surgeries manifest through confusion regarding the potential benefits and adverse ramifications of such surgical options. According to Mrayyan & Shawish (2020), prophylactic surgeries have unanticipated secondary effects of sterility despite their importance in reducing the risk of hereditary breast and ovarian cancer. Therefore, ethical dilemmas emanate from the confusion in safeguarding beneficence (patient’s benefits) while eliminating harm (maleficence). Equally, it is vital to uphold patients’ autonomy in decision-making before commencing prophylactic surgeries.

Screening and Education Interventions for a Patient with a Strong Family History of Ovarian Cancer

A patient with a strong family history of ovarian cancer is highly susceptible to the disease, considering the potential gene mutations. As a healthcare professional, I would recommend various early screening and education interventions to prevent the disease. According to Patni (2019), a transvaginal ultrasound, CA-125, and bimanual pelvic examination are ideal screening tests for ovarian cancer. Equally, educating patients on the disease’s risk factors and self-management approaches can improve knowledge and awareness of healthy habits that reduce the risk of ovarian cancer.

What if the patient has no health insurance?

If the patient has no health insurance, I would provide free or low-cost healthcare services, including free consultations, linking the patient with clinical health clinics that provide general healthcare services, and providing information about financial aid for medical treatment. Equally, I would educate the patient about self-monitoring activities and vital sign identification and reporting. These approaches are consistent with the overarching need for cost-effective care for uninsured and low-income people.

What resources could you to assist the patient?

I would use educational materials, including infographics and modules for educating the patient about risk factors, clinical manifestations, and preventative approaches for ovarian cancer. Secondly, I would access online websites for reputable organizations that provide insights into the hereditary breast and ovarian cancer (HBOC) and preventive interventions. These organizations include the American Cancer Association (ACA) and the Centers for Disease Control and Prevention (CDC). Finally, it would be vital to link the patient with community-based resources, including nearby nonprofit cancer organization(s).

References

AlHilli, M. M., & Al-Hilli, Z. (2019). Perioperative management of women undergoing risk-reducing surgery for hereditary breast and ovarian cancer. Journal of Minimally Invasive Gynecology, 26(2), 253–265. https://doi.org/10.1016/j.jmig.2018.09.767

Mrayyan, M. T., & Shawish, M. (2020). Prophylactic mastectomy and salpingo-oophorectomy: Ethics and policy. Middle East Journal of Cancer, 11(1), 114–119. https://doi.org/10.30476/mejc.2019.78702.0

Patni, R. (2019). Screening for ovarian cancer: An update. Journal of Mid-Life Health, 10(1), 3. https://doi.org/10.4103/jmh.jmh_46_19

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