Multidisciplinary one-stage risk-reducing gynaecological and breast surgery with immediate reconstruction in BRCA-gene carrier women

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ScienceDirect EJSO 39 (2013) 1346e1350

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Multidisciplinary one-stage risk-reducing gynaecological and breast surgery with immediate reconstruction in BRCA-gene carrier women M.F. Khadim a,*, P. Eastwood a, J. Price b, P. Morrison c, K. Khan a a

Department of Plastic Surgery, Belfast City Hospital, Belfast, Northern Ireland BT16 1QN, United Kingdom b Department of Gynaecology, Belfast City Hospital, Belfast, Northern Ireland, United Kingdom c Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland, United Kingdom Accepted 14 September 2013 Available online 25 September 2013

Abstract Familial breast cancer accounts for 5e10% of all breast cancers. Due to BRCA1/2 tumour suppressor gene mutation, hereditary breast and ovarian syndrome is the most common form. Risk-reducing gynaecological and breast surgery is offered to such patients in everincreasing numbers. Hence, the development of a multi-specialty combined treatment approach is called for. Twenty-two BRCA genemutation carrier women underwent one-stage gynaecological and breast risk-reducing surgery and immediate reconstruction between January 2005 and December 2011 at the Belfast City Hospital. Their mean age was 41.2 years (median 41 years). Nearly half of the patients were BRCA2 and a quarter were BRCA1 carriers. The rest were positive for both genes. Hormone-replacement therapy was initiated in 14 women. Average theatre time and stay in the hospital were three hours and two and a half days, respectively. Two patients developed complications unrelated to combining the procedures. Both were treated conservatively and recovered. The one-stage approach logically proves economical by limiting the time the patients are in the hospital and away from work. We describe our multidisciplinary team service that is offering safe and economical one-stage risk-reducing surgery and reconstruction to young BRCA gene-mutation carrier women in Northern Ireland. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: BRCA; Breast cancer; Ovarian cancer; Risk-reducing surgery

Introduction BRCA1 (17q21) is a human tumour-suppressor gene that encodes for the BRCA1 protein. The BRCA1 protein repairs double-stranded DNA breaks to prevent uncontrolled cellular proliferation.1 Although the BRCA2 gene (13q12.3) is structurally very different, it is functionally very similar to BRCA1. The risk of ovarian cancer is around 1 in 45 women. A clustering of breast and ovarian cancer within a family is strongly suggestive of a molecular defect in BRCA1 or 2. These two highly penetrant genes account for approximately 40e50% of hereditary breast cancer-only families and 95% of families with both breast and ovarian cancer. Five to ten percent of breast cancers are hereditary.2 Over * Corresponding author. E-mail addresses: [email protected], drfaheemk2002@ gmail.com (M.F. Khadim). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.09.018

the course of their lifetime, women with BRCA1 or 2 mutation carry a 50e80% chance of developing breast cancer, a 60% chance of developing contralateral breast cancer and a 15e25% chance of ovarian cancer.3 These women develop breast cancer at a significantly younger age than women with sporadic breast cancer.4 With a BRCA1 or BRCA2 mutation, bilateral salpingo-oophorectomy not only reduces the risk of ovarian associated cancers from up to 40% to around 1e2%, but the risk of breast cancer (up to 70% in BRCA1 and up to 50% in BRCA2) can be reduced by approximately 50%. There is scarce evidence on the effectiveness of screening tests in early detection of disease, so until such evidence is available, riskreducing surgery (RRS) remains the treatment of choice.5 An increasing number of women who might previously have been treated for breast or ovarian cancers are now requesting prophylactic RRS, necessitating the development of an integrated process for assessment, informed counselling and a multi-specialty combined-treatment approach.6

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and BRCA2 females is currently being evaluated in the UKFOCSS trial in the UK.5

Methods Team

Referral to specialist surgical clinics Patients with BRCA1 and BRCA2 positive gene testing are offered referral to both the Plastic Surgery and Gynaecology clinics for consideration of breast and ovarian cancer risk-reduction surgery (RRS). Women assessed as “high risk” await gene test results but still benefit from a consultation with surgeons to offer them a better understanding of the benefits, risks and complications associated with RRS. They also have the opportunity to meet with patients who have previously undergone the procedures.8

Since 2001, our multidisciplinary team has consisted of a consultant geneticist, a gynaecologist, a plastic surgeon and their respective registrars and nurse members. Screening and risk assessment Patients are referred to the Northern Ireland Regional Cancer Genetics Service (NICGS) by general practitioners and hospital consultants. Risk is assessed by means of a family history of neoplasia and molecular genetic testing (Tables 1 and 2). The genetic counsellor advises the patient in writing whether their cancer risk has been assessed as “average”, “moderate” or “high”. Patients in the last category are offered a genetics outpatient clinic appointment where diagnoses and histology in family members with cancer is confirmed where possible. The patient is counselled regarding the advantages and disadvantages of intensified screening or prophylactic risk-reduction surgery. For women who carry BRCA mutations, the Cancer Genetics Studies Consortium for surveillance of women at high risk for the development of breast cancer recommends monthly self- and biannual clinical examination of breast and annual mammograms beginning between the ages of 25 and 35 years.7 Ovarian cancer surveillance in BRCA1

Risk-reduction surgery Patients are referred to the regional familial ovarian cancer screening clinic and counselled regarding the advantages and limitations of ovarian cancer screening by annual ultrasound, four-monthly serum scan and CA125 estimation. They are also informed of the option of prophylactic laparoscopic bilateral salpingo-oophorectomy and/or hysterectomy and consequent infertility. If patients are premenopausal, hormone replacement therapy (approximately the age of 50) post-oophorectomy is discussed. In the plastic surgery clinic, prophylactic skin and nipple-sparing mastectomy and immediate reconstruction are discussed with the patient. Both autologous and

Table 1 Breast cancer (n ¼ 1 in 10). Family history of breast cancer 1 Relativec 50e59 yrs 40e49 yrs 30e39 yrs 20e29 Bilateral breast cancer <50 yrs Male with breast cancera 2 Relatives 2 relatives >60 yrs 2 relatives 50e60 yrs 2 relatives <50 yrs 2 relatives <40 yrs 3 Relatives Average age >60 yrs Average age <60 yrs 1 or more relative <50 yrs þ>1 relative ovarian cancerb Individual with mutation in BRCA1 or BRCA2 Individual with Neurofibromatosis I 1 or more relative <40 yrs plus relative with childhood cancer

Lifetime risks Ratio

%

1 1 1 1 1 1

in in in in in in

9 8 6 5 3 4

11% 12% 17% 20% 33% 25%

1 1 1 1

in in in in

7 4 3 3

14% 25% 33% 33%

1 in 4 1 in 3 1 in 3

25% 33% 33%

>1 in 2 w1 in 2 1 in 6 1 in 3

50e70% 30e50% 17% 33%

Population risk e reassurance

Medium risk

High risk

Yes Yes Yes Yes Yes Yesa Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Guidelines are the result of multidisciplinary consensus group meetings and GP focus groups and are subject to ongoing validation. a Any male with breast cancer should be referred for genetic risk assessment. b One relative may be a second degree relative. c First degree relative e parent or sibling or child, Second degree relative e grand parent, aunt/uncle, nephew or neice. GUIDELINES FOR RISK ESTIMATION IN INDIVIDUALS WITH A CANCER FAMILY HISTORY. Revised April 2008. [Incidence/prevalence risks of cancer from NI cancer registry data, 2007].

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Table 2 Ovarian cancer (n ¼ 1 in 45). Low risk e reassurance

Family history of ovarian cancer

Lifetime risks

1 Relative e any age 1 Relative with ovarian ca. and one with breast cancer <50 yrs 1 Relative with ovarian and two with breast cancer <60 yrs 2 Relatives or more e 1st degree relatives Affected individual with a mutation in a known ovarian cancer predisposing gene 3 Individuals with CRC, one <50 yrs and 1 case ovarian cancer

1 in 23 1 in 5

4% 20%

1 in 5

20%

Yes

1 in 3

30%

Yes

>1 in 3

w20e50%

Yes

1 in 10

w10%

Yes

implant-based reconstruction options are placed on the table. On the day of the procedure, under general anaesthetic (GA), gynaecological surgery is performed first followed by breast surgery and reconstruction. Postoperatively, both teams jointly look after the patients. They are routinely reviewed at the clinics at two, six and twelve weeks and 12 months. To logically estimate the cost-effectiveness of the onestage procedure, the Department of Health’s official report on reference costs9 was used. It includes inpatient, intheatre and individual procedure costs (Table 3). Results Using our multidisciplinary team (MDT), 22 BRCA gene mutation carrier women underwent one-stage gynaecological and breast risk-reduction surgery and immediate reconstruction between January 2005 and December 2011. Patient information was collected retrospectively from theatre ledgers. Twenty-five patients were identified; however, three were excluded as they had undergone unilateral breast cancer surgery in the past. The mean age of the patients was 41.2 years and ranged from 31 to 60 years. In all cases, the Genetics Department was the first point of contact.

Medium risk

High risk

Yes Yes

carriers. A quarter (6/22) were BRCA1 carriers, and the rest were positive for both genes. Surgery All but one patient underwent bilateral nipple- and skinsparing mastectomy and implant-based immediate reconstruction with bilateral laparoscopic salpingooophorectomy and hysterectomy. The remaining patient had already had hysterectomy for a benign condition. The MDT carried out all procedures under GA in one stage. In one case, due to technical difficulties, hysterectomy was performed through abdominal approach. In majority of the patients fixed volume implants were used for immediate reconstruction. Average theatre time and stay in hospital were three hours and two and a half days, respectively. Complications Two patients experienced surgical complications including small haematoma, accidental bladder perforation and breast wound infection. The latter patient needed formal wound debridement in theatre with subsequent healing. The others responded well to expectant supportive treatment. Hormone replacement therapy (HRT) was initiated in 14 women after careful counselling.

Genetics

Economy

The gene testing performed before prophylactic surgery revealed nearly half (10/22) of the patients to be BRCA2

Cost-effectiveness logical analysis (Table 3) showed that the one-stage approach is clearly economical.9

Table 3 Estimated cost analysis for risk reducing gynaecological and breast surgery. 2-Stage procedure Average Average Average Average

GA/Prep/drape time ¼ 30 þ 30 min ¼ £1216.00 operation time ¼ 180 min ¼ £3650.00 hospital stay ¼ 2.5 þ 2.5 days ¼ £1400.00 estimated total cost ¼ £6400.00

1-Stage procedure Average Average Average Average

GA/Prep/drape time ¼ 30 min ¼ £608.00 operation time ¼ 180 min ¼ £3650.00 hospital stay ¼ 2.5 days ¼ £750.00 estimated total cost ¼ £5000.00

DHSSPS Reference Cost 2006/2007. The Department of Health, Social Services and Public Safety, Northern Ireland. http://www.dhsspsni.gov.uk.

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Patient satisfaction

Surgical complications

None of the patients regretted choosing one-stage surgery and all expressed satisfaction with the clinical and aesthetic outcome at one year follow-up.

In our study group, the surgical complications were not found to be the consequence of combining surgeries. In one case, laparoscopic hysterectomy was converted to open hysterectomy due to technical difficulties. She developed a small upper-quadrant superficial haematoma at the port site that resolved itself with conservative management. Another patient had accidental intra-operative urinary bladder injury that was managed successfully with urinary catheterisation only. In addition, she developed a superficial burn to the breast skin with a hot-water bottle, leading to infection and patch of skin necrosis. Although it healed with debridement and dressings, she subsequently chose delayed pedicled myocutaneous Latissimus dorsi flap with implant reconstruction to replace the scarred skin. All patients were followed up with for a year after surgery. Some of them required corrective surgeries for implant capsule and/or exchange. Contant et al. found a complication rate of 21%, i.e. 10% early and 11% late among 112 women, whereas Lagergren et al. had 13% local complications in a 5-year follow-up among 249 women with cancer who underwent surgery with immediate breast reconstruction.16

Discussion Gene testing Prior to the advent of genetic screening, women with a significant family history of breast and ovarian cancer were faced with the difficult decision of prophylactic surgery or high risk of cancer at an early age. Some of those who had surgery were later found to be gene negative. Genetic screening allows women to make more informed choice about risk-reduction surgery (RRS). Risk stratification Various scoring systems for risk assessment of BRCA mutation exist.10 All patients in this report had a Manchester score of 10 or more and were tested for either BRCA1 or 2 mutation (equivalent to around a 10% chance of finding a mutation in each gene). The mutation carriers are given a free and informed choice between yearly surveillance or RRS. The UKFOCSS trial recommends RRS that is safer but has its own drawbacks.11e15 Multi-stage risk reducing surgery Traditionally, each specialty separately performs organspecific RRS on different occasions. This multi-stage approach warrants multiple surgical admissions. Understandably, RRS disturbs patient’s body image, psychological stability, social confidence and family life. If it is multi-staged, episodic, progressively escalating RRS, the consequences are even worse. The entire process can span over the most productive and active years of these young women’s lives. Single-stage risk reducing surgery In Northern Ireland, a team of consultant plastic surgeon, a consultant gynaecologist and a consultant geneticist are performing one-stage RRS and reconstruction in BRCA gene mutation carriers since 2001. The lack of an established structured multidisciplinary team approach, perceived concerns about long hospital stays and increased potential risk of complications blur the advantages of onestage RRS. This study disproves such concerns and provides evidence for the safety, efficacy and economy of one-stage RRS.

Patient’s choice Patients undergoing prophylactic RRS do not have an established neoplastic process and are often young, working women with dependent families. Therefore, they almost invariably opt for the advantages offered by the combined approach and implant-based reconstruction with quick recovery. The patients do not require any adjuvant therapy and hence reconstruction is not at risk of being jeopardised. We have used this combined one-stage RRS approach consecutively for the last ten years. The process itself is streamlined and is well received by patients who are pleased with the results.8 Cost analysis The costs of referral, counselling (geneticist, surgeon, gynaecologist), gene testing, clinic reviews, preassessment clinics etc. remain unchanged regardless of whether the multi-stage or one-stage RRS is selected. However, the latter is cost-effective (Table 3) in avoiding multiple hospital admissions, perioperative investigations, in-hospital care, general anaesthetic (and associated risks), operation theatre attendances/recovery and medications (analgesics, DVT prophylaxis etc). There are added savings from patient’s perspective, such as one admission to the hospital, fewer outpatient visits, fewer arrangements for paid child care and savings on travelling to and from hospital etc. Moreover, where health care is free and provided by the State, there are indirect savings from patient’s lost days at

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work and the employer’s cost of labour (including salary, pension, social costs) etc.17 Patient satisfaction Women who undergo bilateral prophylactic mastectomy are often young and can exhibit reduced body image satisfaction and adverse effects in their sexual lives,6,18 which can be minimised with immediate reconstruction.19 At one-year follow-up, all patients agreed that if they had to choose again, they would prefer the combined approach.8 Conclusion Risk-reduction surgery has been advocated as a viable treatment modality in patients with high risk for breast and ovarian cancer based on their genetic makeup. Although far from perfect, RRS allows us to treat high-risk patients before definitive malignancy occurs. In this study, we discussed our combined multidisciplinary surgical approach for treatment and immediate reconstruction in Northern Ireland. We recommend one-stage RRS to other centres in the UK and claim that it is safe, economical and efficient and has the added benefit of patient satisfaction. Conflict of interest None.

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