Karima_932474

Advanced Medical Science

Risk Reductions Of Breast Cancer In Unaffected BRCA Mutation Carrier Who Underwent Bilateral Prophylactic Mastectomy: A Systematic Review

Chadijah Karima 932474 Supervised by: Prof Michael Henderson MBBS, BMedSc, MD, FRACS University of Melbourne Department of Surgery, Peter MacCallum Cancer Centre Division of Cancer Surgery; Breast, Melanoma and Skin. Peter MacCallum Cancer Centre, Melbourne December 2017

Student Declaration I declare that all material presented in this systematic review is the original work of the author unless stated otherwise. There are no references or other person’s work that has been used without due acknowledgement. Prof Michael Henderson has given me direction, assistance and feedback in writing this review.

Chadijah Karima

Prof Michael Henderson

18th November 2017

18th November 2017

  i    

Table of Contents Student Declaration............................................................................................................ i List of Tables…………………………………………………………………………….iii List of Figure…..………….…………………………………….……………………….iii Acknowledgement....…………………………………………………………………….iv Abstract .............................................................................................................................. v   1.   Introduction ................................................................................................................ 1   1.1   Breast Cancer ......................................................................................................................... 1   1.2   Diagnosis of Breast Cancer .................................................................................................... 2   1.2.1.   Breast Examination ............................................................................................................ 2   1.2.2.   Mammography ................................................................................................................... 3   1.2.3.   Ultrasound and Magnetic Resonance Imaging .................................................................. 4   1.3   Management and Treatment .................................................................................................. 5   1.4   Risk Factors for Breast Cancer .............................................................................................. 6   1.4.1.   BRCA genes and Breast cancer ......................................................................................... 7   1.5   Prophylactic Mastectomy As A Preventative Measure ......................................................... 7   1.6   Objectives ..……………………….………………………………………………………..9  

2.   Methods ..................................................................................................................... 10   2.1.   Search Strategy ................................................................................................................... 10   2.2.   Eligibility Criteria and Study Selection .............................................................................. 10   2.2.1.   Inclusion Criteria ............................................................................................................. 10   2.2.2.   Exclusion Criteria ............................................................................................................ 11   2.3.   Data Extraction ................................................................................................................... 11   2.4.   Outcome Measures.............................................................................................................. 11   2.5.   Risk of Bias Assessment ..................................................................................................... 12  

3.   Results ........................................................................................................................ 13   3.1.   Search Findings................................................................................................................... 13   3.2.   Quality Assessment of included studies ............................................................................. 15   3.3.   Data Extraction ................................................................................................................... 17   3.3.1.   Characteristics of Included Studies .................................................................................. 18   3.4.   Outcome Measures.............................................................................................................. 21   3.4.1.   Risk Reduction of Developing Breast Cancer ................................................................. 21   4.   Discussion .............................................................................................................................. 24   4.1.   Risk Reduction of Developing Breast Cancer .................................................................... 24   4.2.   Limitation on the review ..................................................................................................... 26  

Conclusion ........................................................................................................................ 27   Future directions ......................................................................................................................... 27 Reference  ……………………………………………………………………………………………………………………..28  

Appendices ....................................................................................................................... 33   Appendix 1. Newcastle - Ottawa Quality Assessment Scale (NOS) - Cohort ………………38 Appendix 2. Newcastle –Ottawa Quality Assessment Scale (NOS) – Case Control ............. 34  

  ii    

List of Tables Table 1: Quality Assessment of Cohort Studies Based On Newcastle–Ottawa Quality Assessment Scale (NOS) .............................................................................................................. 16   Table 2. Quality Assessment of Case-Control Studies Based on Newcastle-Ottawa Quality Assessment Scale (NOS) .............................................................................................................. 17   Table 3. Characteristics of Included Studies................................................................................. 19   Table 4. Risk Reduction of Developing Breast Cancer ................................................................ 23      

List of Figures

    Figure 1. Cancer in lymph nodes around the breast27 ..................................................................... 2   Figure 2. Illustration of self-breast examination7 ........................................................................... 3   Figure 3. Ultrasound of left breast showing a suspicious mass with irregular margin10 ................ 4   Figure 4. Flowchart of article selection process ........................................................................... 14                                                             iii    

Acknowledgement Firstly, I would like to show my gratefulness to Allah SWT, as this review will not be done successfully without His blessings. I would like to express my sincerest gratitude to my supervisor, Prof Michael Henderson MBBS, BMedSci, MD, FRACS for his time to help me in the clinical exposure module and guidance throughout the conduct of this systematic review. I am also very thankful for Dr. Krithika Sundaram and Dr. Anita Horvath, for their assistance in guidance to this review. Lastly, I would like to give my deepest appreciation to all the staff at the Department of Surgery, Peter MacCallum Cancer Centre, for their kindness and assistance throughout the clinical exposure.

(Chadijah Karima)

  iv    

Abstract Introduction Bilateral prophylactic mastectomy (BPM) has been associated in reducing the occurrence of breast cancer in women carrying the BRCA1 and BRCA2 mutation genes. Furthermore, it is believed that it contributes in lowering the risk of breast cancer in patients with BRCA gene mutation carriers. Hence, as it is important to review the risk-reduction outcome of prophylactic mastectomy, this systematic review aims to evaluate whether BPM had successfully lower the risk of developing breast cancer on unaffected patients with BRCA mutation genes.

Methods An electronic search of published literature was performed using the PubMed, Ovid MEDLINE, ClinicalKey, and the University of Melbourne Library Catalogue (Discovery) with the last searched carried out in the 12th of November 2017, that conducted the study to evaluate the risk reduction of breast cancer in unaffected BRCA mutation carrier patient who underwent prophylactic mastectomy. The outcome measures evaluated include occurrence of breast cancer after prophylactic mastectomy with 5 studies included were comparing the outcomes with surveillance subjects, risk reduction, and length of follow-up. The qualities of all the studies were then assessed with the Newcastle-Ottawa Scale (NOS).

Results There were eight studies that have met the eligibility criteria and were included in this systematic review. The studies are all non-RCTs with three studies were prospective cohort,   v    

other three studies were retrospective cohort and one was a case-control study. In general, the studies reported bilateral prophylactic mastectomy decrease the risk of developing breast cancer in patients with BRCA mutation carriers.

Conclusion Bilateral prophylactic mastectomy is associated with substantial risk reduction of developing breast cancer in patients with BRCA mutation carrier genes. However, a longer follow-up and larger sample size are still necessary to obtain a more precise estimation of the risk reduction benefits in bilateral prophylactic mastectomy.

Keywords: risk reduction, breast cancer, BRCA genes, BRCA 1, BRCA 2, bilateral prophylactic mastectomy, systematic review

  vi    

1. Introduction

1.1. Breast Cancer Breast cancer is a pathological condition where the lining of the cells grows abnormally from the breast tissue resulting in malignant tumor. Breast cancer is reported to be the most common type of cancer diagnosed in women worldwide, and is the leading cause of mortality in women in developing countries.1 In the year of 2017, there were an estimated of 17,730 new cases of breast cancer in Australia with a total of 3,114 deaths following breast cancer were also reported in the same year. This has contributes to a percentage of 6,5% of all Australian deaths caused by cancer in 2017. Breast cancer is generally characterized by the presence of palpable lump in the breast, which in most cases does not involve any pain. Other symptoms vary depending on the severity of the cancer, and include unsymmetrical appearance of both breasts, sense of “pulling” within the breast area, abnormal discharge from nipples and presence of lumps in the axillary region of the lymph nodes.1

 

  1  

  Figure 1. Cancer in lymph nodes around the breast27

1.2. Diagnosis of Breast Cancer The best way to treat breast cancer is to undergo early screening and diagnosis, which will result in a much better prognosis. For instance, in case when a non-palpable mass is detected or identified during the screening, it may indicate a very early stage of breast cancer that will require less advanced treatments and much higher survival rates.5

1.2.1. Breast Examination Breast examination is a physical examination to assess any abnormalities in the breast. There are two types of breast examination; self and clinical breast examination. Breast self-examination (BSE) is a technique, which allows patients to examine their own breast. On the other hand, clinical breast examination is done by health professionals in their office. Although the efficiency of breast BSE in lowering the mortality rate of breast cancer has not been established, it is highly recommended to have BSE at least once in a month to detect any abnormalities in the breast. BSE is the cheapest and least time consuming early screening method. In order for patients to

 

  2  

be able to perform BSE accurately, trained clinician will taught them during their appointment in clinical breast examination.

  Figure 2. Illustration of self-breast examination7

1.2.2. Mammography Mammography is diagnostic method that uses a low-dose x-rays screening for diagnosing any presence of breast tumor. Screening or diagnosing with mammography can be very beneficial as it can locate any presence of non-palpable lump, locate any small tumors, and only radiate small amount of radiation to the patient.1 However, there are several downsides in mammography like the possibility of having false-positive results, experiencing discomfort during the procedure, and inefficiency in screening or diagnosing in patients with higher breast density or in patients with breast implants.8

Mammography is usually not recommended for patient under 40 years old due to high breast density, as it may interfere with reading the results. It is recommended by the National Comprehensive Cancer Network (NCCN) guidelines for women above 40 years old with high risk of breast cancer to undergo annual mammography screening.5 Annual screening via mammography has contributed to lowering breast cancer mortality rates.8

 

  3  

1.2.3. Ultrasound and Magnetic Resonance Imaging In cases of patients with high breast density, it may indicate a higher chance of developing breast cancer and screening it using a mammogram will frequently gives a false-negative result. Thus, other screening techniques such as Magnetic Resonance Imaging (MRI) or ultrasound are recommended.

Detection of any palpable mass during physical examination is an indication for clinicians to perform further test with ultrasound. In ultrasound, it is possible to distinguish whether the palpable mass is a breast tumor or breast cyst, hence it can be very useful to prevent misdiagnosis. Other than being accessible and affordable, ultrasounds has been a very popular choice as it is considered as a safe method for not using any radiation.9

  Figure 3. Ultrasound of left breast showing a suspicious mass with irregular margin10

Another diagnostic tool in detecting breast cancer is the MRI. Compared to mammography, MRI has higher sensitivity in detecting cancer nonetheless it also has less specificity property. In order to achieve a better MRI results, patients will have a dye (Gadolinium) injected to them through an intravenous line. However, as

 

  4  

Gadolinium has side effects on kidneys, a thorough anamnesis for patient’s kidney history will be performed.8 The NCCN guidelines have also recommend patient with very high risk of developing breast cancer to undergo annual MRI screening of their breast starting at age 25.5

1.3. Management and Treatment There are many choices when it comes to treating breast cancer. Options such as surgery and adjuvant therapy are administered depending on the progression of the cancer. However, treatment option that includes surgeries like lumpectomy and mastectomy has remained as the first line treatment for breast cancer. In cases where the patient is diagnosed in early stages of breast cancer, surgery to remove the lump or the whole breast may be recommended as the preventive measure.1 Lumpectomy includes complete resection of the lumps or the primary tumor to lower the risk of local recurrences. Mastectomy includes removing of one or both breast including the breast tissue and lymph nodes. Patients who underwent mastectomy may have the following condition or reasons; to remove the breast cancer cells to reduce the risk of re-occurrence, breast were too small and would make to give good cosmetic result after lumpectomy, multifocal disease, or in case where patients refuse to do radiotherapy treatment.11

The adjuvant therapy of breast cancer is administered to prevent re-occurrence in the future and to treat any micro metastatic disease caused from the spreading of previous breast cancer cells that can happened in the regional lymph nodes (if not yet been removed) as well as other deposits of disease in other sides like bones, lung or liver. Adjuvant therapies for breast cancer includes the administration of chemotherapy,  

  5  

endocrine therapy or in some cases include the combination of both chemotherapy and endocrine therapy. The most common endocrine type for breast cancer adjuvant therapy is the anti-estrogen tamoxifen citrate.12

1.4. Risk Factors for Breast Cancer There are many risk factors that contribute to the occurrence of breast cancer. The first factor is age of the patient3, as it is studied that the risk of breast cancer is increases, as the patients get older. In addition, other contributing factors such as exposure to carcinogenic agents (i.e.; smoking, radiation), unhealthy lifestyle (patients with obesity, high alcohol consumption or lack of physical activity) and hormones also play a role in the development of breast or any other cancer.1 However, one of the most associated risk factors for breast cancer is the presence of strong family history or genetic factors, which accounts for 5 – 10% of the reported cases of breast cancer.2 The genetic factors that contributes to almost all the reported high-risk patient is the BRCA mutation genes. The BRCA mutation genes or the breast cancer susceptibility gene is a tumor suppressor gene that plays role in the development of both breast and ovarian cancer. A tumor suppressor gene is a gene that control cell growth by encoding proteins to prevent proliferation. Cases where there are mutations in the tumor suppressor genes will results in unrestrained cellular proliferation that will then develop into cancer. Breast and ovarian cancer may develop in case of mutation in the BRCA genes, . There are two types of BRCA genes; the BRCA 1 and BRCA 2 genes. Both BRCA genes are large with 100,000 base pairs of genomic DNA distributed, encoding

 

  6  

negatively charged proteins. Although they were both breast cancer susceptibility gene, both are two entirely different genes where BRCA 1 mutation is on chromosome 17 while BRCA 2 mutation genes is on chromosome 13. In addition, studies has shown that patient with BRCA 1 gene mutation has a slightly higher risk in developing breast cancer compare to patients with BRCA 2 mutation. Women who carry the BRCA mutation genes will have a much higher risk to develop breast cancer compare to other with no hereditary factors. It is estimated that the lifetime risk of developing breast cancer in patient with BRCA gene mutations is 56% to 84%.4 However, strong family history of breast cancer is not always linked with having BRCA genes, so further genetic testing needs to be done.1

1.4.1. BRCA genes and Breast cancer Once women are diagnosed to carry the BRCA mutation genes, they will be suggested to undergo several risk-reducing strategies. The current risk-reducing strategies of breast cancer in patients with BRCA mutation genes include constant surveillance (self-examining the breast, routine medical checkup, regular screening with mammography or breast MRI), chemoprevention and prophylactic mastectomy.5

1.5.

Prophylactic Mastectomy As A Preventative Measure

Prophylactic mastectomy is a preventive procedure to lower the risk of developing breast cancer in the future in high-risk patient. The procedure includes the surgeon removing the healthy tissue of the patient’s breast.13 There are several choices in choosing the prophylactic mastectomy; bilateral (which includes removing both breast) and unilateral (removing only one part of the breast). However, unilateral

 

  7  

prophylactic mastectomy (such as ipsilateral or contralateral) would only be performed if the other breast has been removed previously. The bilateral prophylactic mastectomy (BPM) is the most popular choice of the preventive treatment.1 Patients who underwent prophylactic mastectomy are reported not only those who were carrying the BRCA mutant genes, but women who has complaints such as breast tenderness for long period, phobia of developing cancer and patient who had undergo breast biopsies.14 Although bilateral prophylactic mastectomy has shown to be effective in lowering the occurrence of breast cancer and is one of the most popular preventive methods of cancer, the procedure still remains controversial.15

There are many things to consider before removing healthy parts of our organ, as it will also affect many other things such as psychological state.15 Other thing to consider is the outcome of the preventive treatment, as there are no mastectomy that can reduce all part of the breast tissue therefore there are chances for patient who underwent BPM to still develop breast cancer in the future.16 Therefore, it is important for patient who consider prophylactic mastectomy to consult their choices with their oncologist before proceeding the operation as the biggest concerns of the postprophylactic mastectomy are the possible decreased of quality of life like lost of significant loss of sensation in chest area, unable to breastfeed, chances that breast cancer may still develop and more.17

 

  8  

1.6.

Objectives

This systematic review aims to examine the prophylactic mastectomy as strategy for reducing the risk of developing breast cancer in patients with BRCA mutation carrier genes in the future. Many surgeons are faced with the case of performing prophylactic mastectomy on BRCA carrier patients, however some of them may have struggled in weighing the benefit of the procedure such as risk-reduction rates with other factors such as side effects. Therefore, the assessment of the effectiveness of the riskreducing surgery is really important to help surgeons’ decision.

In this systematic review, the effectiveness in reducing the incidence of breast cancer in BRCA mutation carrier patients will be assessed by looking at the risk-reduction rates from the selected studies. Identification of whether bilateral prophylactic mastectomy is effective in reducing the risk of developing breast cancer is very beneficial for the surgeons to make decision as well as in reducing the global morbidity and mortality rate of breast cancer especially in high-risk patients.

 

  9  

2. Methods This systematic review was conducted by referring to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

2.1. Search Strategy A comprehensive electronic search for published literature was performed using the PubMed, Ovid MEDLINE, ClinicalKey, and the University of Melbourne Library Catalogue (Discovery) between 13th of October to 12th of November 2017. The search terms included a combination of: “risk reduction”, “breast cancer”, “BRCA”, and “bilateral prophylactic mastectomy”. The studies included were not limited to any publication date or publication status. However, only studies published in English language were included in this systematic review. 2.2. Eligibility Criteria and Study Selection In conducting the study selection, process like screening the study titles and abstracts, removing any duplicates of the same study and eventually evaluate the full-text article were performed in order to determine the study eligibility for the systematic review. The inclusion and exclusion criteria were then applied before determining which articles that will be used for this systematic review.

2.2.1. Inclusion Criteria Selected studies that fulfilled the following criteria was included in the review: 1. A case control, prospective cohort or retrospective cohort original study 2. Participant involved were BRCA mutation carrier patient who underwent prophylactic mastectomy 3. The outcome measures evaluated were the risk reduction of developing breast cancer in selected participants  

  10  

2.2.2. Exclusion Criteria Studies were excluded if any the following criteria were found: 1) Literature review or meta-analysis 2) Not written in English language 3) Participants who were not BRCA mutation carrier but underwent prophylactic mastectomy 4) The outcome measures evaluated were not focused on risk reduction of developing breast cancer in selected participants

2.3. Data Extraction The following information was extracted from the included studies and recorded: 1) Intervention used 2) Outcomes (occurrence of breast cancer and the risk reduction) 3) Duration of the follow up

2.4. Outcome Measures The outcome measures evaluated were whether the bilateral prophylactic mastectomy can reduce the risk of developing breast cancer in the future in patients with BRCA genes mutation carrier. There were 5 studies included that compared the outcome of the patient who underwent BPM to surveillance subjects and this data were inserted in Table 2. The data were extracted from certain time of follow-up (with mean follow-up period stated) of whether any participant involved in the study has developed breast cancer several times after.

 

  11  

2.5. Risk of Bias Assessment The methodical quality of all the articles included in this systematic review was appraised using the Newcastle-Ottawa Scale (NOS) scale. The NOS quality assessment tool includes assessing quality of selection, comparability and outcome.

 

  12  

3. Results 3.1. Search Findings The initial search using a combination of search terms “risk reduction”, “breast cancer”, “BRCA”, and “bilateral prophylactic mastectomy” yielded a total of 446 studies. Upon further screening based on the titles and abstracts and application of eligibility criteria (as highlighted in Section 2.2), a total of 432 articles were excluded because they were either duplicates or did not answer the research question or full text was unavailable or they were not published in English resulting in fourteen potential relevant studies. Full text screening of the fourteen articles resulted in a total of eight studies, which met the eligibility criteria and were included in this systematic review. A flowchart of the study selection process is represented in Figure 4.

 

  13  

  Figure 4. Flowchart of article selection process

 

 

  14  

3.2. Quality Assessment of included studies The eight studies included in this review were non-RCT and hence assessed using the Newcastle-Ottawa Scale Quality Assessment Scale (NOS). The NOS consists of nine multiple-choice questions categorized into three different sections; selection, comparability and outcome. A study can be given a maximum of one star for each criteria within the Selection and Outcome category and a maximum of two stars in the Comparability category. In order for studies to be denoted a good quality, 3 or 4 stars in selection and 1 or 2 stars in comparability and 2 or 3 stars in outcome are required. A fair quality study expects 2 stars in selection, 1 or 2 stars in comparability and 2 or 3 stars in outcome domain. Poor quality studies would be indicated with 0 or 1 star in the selection, 0 stars in comparability and 1 stars in outcome domain. All the included studies in this review scored 7 or more indicating they are of good quality. A summary of methodological quality for 7 cohort studies is presented in Table   1 while Table  2 presented the summary of studies quality assessment for 1 case control study. A summary of methodological quality of the included studies is presented in Table 1 and assessment for each of the study is included in the appendices (   Appendix   1.   Newcastle   –Ottawa   Quality   Assessment   Scale   (NOS)   –   Cohort and Appendix   2.   Newcastle  –Ottawa  Quality  Assessment  Scale  (NOS)  –  Case  Control ).

 

  15  

Table 1: Quality Assessment of Cohort Studies Based On Newcastle–Ottawa Quality Assessment Scale (NOS)

Categories

Study Hartmann. et al. (2001)18

HeemskerkSkytte. et al. Gerritsen. et al. (2011)20 (2013)19

MeijersHeijboer. et al. (2001)21

Ingham. et al. (2013)22

Kaas. et al. (2010)23

Domchek. et al. (2010)24

1

*

*

*

*

*

*

*

2

*

*

*

*

*

3

*

*

*

*

*

*

*

4

*

*

*

*

*

*

*

1

*

*

*

*

*

2

*

*

*

*

Selection *

Comparability

Exposure

Total

 

1

*

*

*

*

*

*

*

2

*

*

*

*

*

*

*

3

*

*

*

*

*

*

7 out of 9

9 out of 9

8 out of 9

9 out of 9

6 out of 9

9 out of 9

8 out of 9

  16  

Table 2. Quality Assessment of Case-Control Study Based on Newcastle-Ottawa Quality Assessment Scale (NOS) Categories  

Study Rebbeck. et al. (2004)25   *

Selection  

1   * 2   * 3   * 4   Comparability 1   * 2   * Exposure   1   * 2   * 3   *   Total  

 

9  out  of  9  

  17  

3.3. Data Extraction 3.3.1. Characteristics of Included Studies The extracted data to present each of the included studies’ characteristics are study design, study population (with interventions specified), follow-up period and main findings of the study. All of the studies involved BRCA genes mutation carrier patients who underwent the prophylactic mastectomy for prevention of breast cancer occurrence in the future. Among the eight included studies, six studies

(19,20,21,22,24,25)

included women with

BRCA mutation carrier patient who underwent prophylactic mastectomy being compared to a surveillance group for monitoring. Only two studies (Hartmann et al, Kaas et al) did not have a control group and included only patient undergoing BPM. Two out of ten studies did not differentiate between the BRCA 1 and BRCA 2 mutation carrier patients in respect to the occurrence of breast cancer after BPM (18,25). However, Domchek et al found that the BPM decrease breast cancer in both BRCA 1 and BRCA 2 mutation carrier patient. The studies involved in this systematic review all include a long-term follow up with the longest length of follow-up of 13.4 years of follow-up (median) 18 while the shortest length of follow-up being 3 years of followup (median) 24. The characteristics of the included studies are shown in Table  3.

 

  18  

Table 3. Characteristics of Included Studies Study

Study design

Study population

Follow-up length (median)

Hartmann et al

Retrospective cohort study

BPM: 26

13.4 years

Heemskerk-Gerritsen et al

Retrospective cohort study

BPM: 212 Surveillance: 358

8.5 years

Main Findings None of the 26 women has developed BC after BPM No incident BC cases were observed in BPM group 57 women were diagnosed with BC in the surveillance group

Skytte et al

Retrospective cohort study

BPM: 96 Surveillance: 211

10 years

No incident of BC in women who underwent BPM

Meijers-Heijboer et al

Prospective cohort study

BPM: 76 Surveillance: 63

BPM: 2.9±1.4 years

None of BPM group women developed BC

Surveillance: 3±1.5 years

8 women in surveillance group developed BC Ingham et al

Prospective cohort study

BPM: 126 Surveillance: 457

13.3 years

Women who underwent BPM had increased survival rates compared to those who did not underwent BPM

Kaas et al

Prospective cohort study

BPM: 147

BRCA 1: 6.1 years BRCA 2: 3.7 years

No incident of BC was observed in the

 

  19  

Domchek et al

Rebbeck et al

Prospective cohort study

Case-control study

BPM: 75 Surveillance: 585

BPM: 105 Surveillance: 378

3 years

BPM: 5.3 years Surveillance: 7.5 years

asymptomatic BRCA carrier group after BPM None of the women in BPM group develop BC 8% of the surveillance group develop BC 1.9% of women in BPM group develop BC 48.7% of women in surveillance group develop BC

 

  20  

3.4. Outcome Measures 3.4.1. Risk Reduction of Developing Breast Cancer After a careful selection, a total of 8 articles were included in the systematic review. The studies involved has described and reported the occurrence of breast cancer after bilateral prophylactic mastectomy (BPM). The risk reduction of developing breast cancer is demonstrated with successful rates of more than 89.5% reported18. However, there are 2 studies that looked up on to the effect of risk reduction surgery but did not report any statistic of the risk reduction’s rate (23,24).

A total of 2 studies only includes patient who underwent BPM with no surveillance group as comparison (18,23). Hartmann et al reported a risk reduction of more than 89.5% in 26 BRCA patients who underwent BPM after 13.4 years of follow-up18. Kaas et al reported that there were zero incidence of breast cancer in 147 BRCA patients who underwent BPM after 3.7 to 6.1 years of follow up. There are a total of 6 studies that compared patients who underwent BPM and patients under surveillance (19,20,21,22,24,25)

. A study by Domchek et al compared BPM with surveillance and found

that all patient who underwent BPM has not develop breast cancer, compared to approximately 6% of surveillance patient within 3 years length of follow-up. Rebbeck et al study also involved patients who underwent BPM and classified them by those who had done prophylactic oophorectomy and those with intact ovaries. It is reported that the risk reduction of occurring breast cancer after BPM in patient whose ovaries are removed are 95%, which are slightly higher than those with intact ovaries with risk reduction rate of 90%. Skytte et al performed a study comparing 96 BRCA mutation carrier patients who eventually underwent prophylactic mastectomy with 211 others as surveillance. However, one of the 96 patients was diagnosed with breast  

  21  

cancer at the same day the prophylactic mastectomy was performed and hence, she was not included in the mastectomy group. There are differences in the annual incidence of breast cancer between two groups with the “mastectomy” group breast cancer incidence was 0.8% compared with the “no mastectomy” group with annual incidence of 1.7%.

Another study comparing the incidence of breast cancers after bilateral prophylactic mastectomy with the surveillance group is done by Meijers-Heijboer. The study conclude that the bilateral prophylactic mastectomy reduces the incidence of breast cancer as shown by the results at three years of follow-up whereas no breast cancer were observed in patients who underwent BPM compared to the eight breast cancer incidences in the surveillance group. A study done by Heemskerk-Gerritsen has a median follow-up range of 8.5 years and found that there is one breast cancer incidence occurred in 212 patients with BRCA cancer who underwent the riskreducing prophylactic mastectomy while the surveillance group is reported to have 57 breast cancer incidence out of 358 patients. The last study done by Ingham et al compared patients underwent BPM and patients under surveillance with 13.3 years follow-up length (median). It is found that only 1 patient develop breast cancer out of 126 patients who underwent BPM. In contrast, 202 out of 457 surveillance patients have developed breast cancer. The details of the risk-reduction results in all study can be seen in Table 3.

 

  22  

Table 4. Risk Reduction of Developing Breast Cancer Study

Study population

Breast cancer after BPM

Risk reduction

Hartmann et al

BPM: 26

BPM: 0

89.5% - 100%

Heemskerk-Gerritsen et al

BPM: 212 Surveillance: 358

BPM: 1 Surveillance: 57

Breast cancer mortality HR, .29 (95% CI, .02–2.61)

Skytte et al

BPM: 96 Surveillance: 211

BPM: 3 Surveillance: 16

Compared breast cancer rate in BPM and surveillance HR, .394 (95% CI, .115–1.355, P 5.14)

Meijers-Heijboer et al

BPM: 76 Surveillance: 63

BPM: 0 Surveillance: 8

BPM significantly decreased incidence of BC: HR = 0 (95% CI 0.0, 0.36); p=0.003

Ingham et al

BPM: 126 Surveillance: 457

BPM: 1 Surveillance: 202

Kaas et al

BPM: 147

BPM: 0

Hazard of death was statistically significantly lower (P < 0.001) in BPM groups NR

Domchek et al

BPM: 75 Surveillance: 585

BPM: 0 Surveillance: 34

NR

Rebbeck et al

BPM: 105 Surveillance: 378

BPM: 2 Surveillance: 184

Up to 90%; Reduction in breast cancer risk HR, .09 (95% CI, .02– 38) - intact ovaries patient

NR = Not reported  

  23  

4. Discussion 4.1. Risk Reduction of Developing Breast Cancer Bilateral prophylactic mastectomy has been shown to be effective in reducing the risk of developing breast cancer in high-risk patients18. However, high-risk patients who are not diagnosed to carry the BRCA mutation genes are more likely to be suggested to have an annual mammogram and routine medical check-up for prevention instead due to several side effects and risks from BPM17. On the other hand, patient who are clinically confirmed to be carrying the BRCA mutation gene carriers are recommended to undergo bilateral prophylactic mastectomy as the risk of developing breast cancer in the future are much higher5. This systematic review aimed to evaluate whether bilateral prophylactic mastectomy is beneficial with respect to risk-reduction in patients with BRCA mutation genes.

A total of eight studies (3 retrospective cohort, 4 prospective cohort and 1 case-control study) were included in this systematic review. A number of six studies included have compared the number of participants who underwent BPM to surveillance group for monitoring in which there are significant differences in the incidence of breast cancer reported after years of followup

(19, 20, 21, 22, 24, 25)

. The remaining two studies did not involve any surveillance group but has

also resulted in a significant result of risk-reduction

(18, 23)

. There were eights studies that has

classified the patient into BRCA1 and BRCA2 mutation gene carriers with respect to the occurrence of breast cancer after BPM(19,20,21,22,23,24). However, Domchek et al found that the risk-reduction of developing breast cancer after BPM are similar for both BRCA1 and BRCA2 mutation carriers24. The study characteristics of the sample might also be affected by any competing events such as ovarian cancer25 (as BRCA mutation genes is associated with both

 

  24  

breast and ovarian cancer). Therefore, this systematic review has excluded any women who have developed cancer before undergoing BPM.

The findings of the included studies in the systematic review report that there were only 7 patients who underwent BPM develop breast cancer after a median follow-up of 2 to 13.5 years. This may indicate that all the studies included show a significant risk-reduction in the occurrence of breast cancer in BRCA mutation carrier patients who underwent BPM. Although it is clear that BPM is the most effective strategy in reducing the incidence of breast cancer in BRCA mutation carrier patient, risk of developing breast cancer after BPM is still possible. There were 4 studies with zero breast cancer reported in all the patients who underwent BPM after years of follow-up

(18,21,23,24)

. The remaining 4 studies have reported the incidence breast

cancer in follow-up patients who underwent BPM, although the data is very low

(19,20,22,25)

.

There were 2 studies that reported more than 1 incidence of breast cancer after BPM. Rebbeck et al reported 2 incidence of breast cancer in patients who underwent BPM, which turns out that these 2 patients underwent a skin-sparing type of bilateral mastectomy. Skin-sparing mastectomy is a type of prophylactic mastectomy that preserves the skin of the breast and may leave more breast tissue compared to total BPM resulting in a higher chance of developing breast cancer. The reasons why some patients prefer skin-sparing mastectomy is due to the inferior cosmetic result after total mastectomy as it requires much more extensive reconstruction25. Skytte et al reported 3 patients with breast cancer after BPM, however it is not specified which type of bilateral prophylactic mastectomy was performed20. The study done by Kaas and Domchek et al did not specify statistical data of the risk reduction, however the results of their study indicates zero incidence of breast cancer after BPM and concluded that BPM has significantly reduce the risk of breast cancer (23,24).

 

  25  

Current evidence regarding the effectiveness of BPM in terms of risk reduction are still very limited. While BPM is regarded as an effective prevention strategy for women with a high risk of breast cancer, it is still important to note that BPM might not be appropriate for every woman and making decision to whether they should undergo BPM is not a straightforward task. The procedure has also been linked with many psychological disadvantages such as anxiety and low self-esteem, which can worsen to bigger problem like depression28. There are also surgical as well as anesthetic risks that should be appraised before deciding to undergo BPM. In a study involving 112 high-risk patients (with 79 of them were BRCA mutation carrier), it is reported that there were 21% of the participants that had complications. The complications include infection, hematoma, contracture and implant rupture29. Therefore, it is very important for patient to weigh the benefits and risks of the procedure and discuss on whether they should undergo BPM with their doctor, as the decision must be personalized between patients and their doctors.

4.2. Limitation on the review One of the limitations in this systematic review is that all the studies included are non-RCT. The methodologically ideal approach for evaluating the efficacy of BPM in terms of riskreduction would be randomized controlled study, however it would clearly be unethical and will therefore never be performed. As no RCT studies available, the risk of bias are possible due to all the data are limited to observational studies. There is also a significant gap between the sample sizes between the studies, where the smallest sample size only involve 18 participants in contrast with the largest sample size study which involve 660 participants. There is possibility of patients involved to be asymptomatic during the clinical trials, which could interfere with the results as all of the studies included are supposed to only involved healthy and unaffected

 

  26  

patient. Moreover, only two studies have length of follow-up more than 10 years. The short follow-up period from other most of the study may reduce the accuracy of the results, as there is a high chance for patients to develop breast cancer in longer years. Therefore, longer followups are necessary to increase the strength of the results. Finally, not all of the studies included have given statistical results of the risk-reduction, which results in difficulty in making comparison and evaluating the overall results.

Conclusion In conclusion, bilateral prophylactic mastectomy is associated with substantial risk reduction of developing breast cancer in patients with BRCA mutation carrier genes. All of the studies included in the systematic review have reported that most of BRCA carrier patients who underwent bilateral prophylactic mastectomy have a substantially reduce risk in developing breast cancer. This systematic review could serve as helpful references for doctors and patients when it comes to discussing the effectiveness of bilateral prophylactic mastectomy before making final decisions. However, in order to obtain a more precise estimation of the risk reduction benefits in bilateral prophylactic mastectomy, a longer follow-up and larger sample size are still necessary.

Future directions In order to improvise the accuracy of the results, future studies with large sample sizes and longer length of follow-up are necessary. A more specific type of the bilateral prophylactic mastectomy should also be specified in every studies which whether the operation is a nipplesparing or skin-sparing type of bilateral prophylactic mastectomy, as this may also contribute the results. Finally, the methodologically ideal approach for evaluating the risk reduction of breast cancer in BRCA mutation carriers would involve randomized controlled study. However,  

  27  

such trial is not practicable as only few subjects would willing to be randomly assigned to undergo BPM for that it would neither be ethical nor acceptable.

 

  28  

References   1. Rupen Shah. Pathogenesis, prevention, diagnosis and treatment of breast cancer. World J Clin Oncol 2014 August 10; 5(3): 283-298 2. Incidence and Mortality: GLOBOCAN 2012. 5-Year Prevalence: Bray F, Ren JS, Masuyer E, Ferlay J. Estimates of global cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 2013 Mar 1;132(5):1133-45. 3. Hartmann LC, Sellers TA. Benign breast disease and the risk of breast cancer. N Engl J Med 2005; 353: 229-237 [PMID: 16034008 DOI: 10.1056/NEJMoa044383] 4. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401-1408. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9145676. 5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology v.1.2013. Breast Cancer Screening and Diagnosis. Available from: URL: http: // www.nccn.org/professionals/physician_gls/pdf/breast.pdf Accessed: December 8, 2013 6. Kösters JP, Gøtzsche PC. Regular self-examination or clinical examination for early detection of breast cancer. Cochrane Database Syst Rev 2003; (2): CD003373 [PMID: 12804462 DOI: 10.1002/14651858.CD003373] 7. Bryson Editorial Team. The Five Steps of a Breast Self-Exam [Internet]. Breastcancer.org; 2017 [cited 2017 February 22]. Available from: http://www.breastcancer.org/symptoms/testing/types/self_exam/bse_steps 8. Shapiro S, Strax P, Venet L. Periodic breast cancer screening in reducing mortality from breast cancer. JAMA 1971; 215: 1777-1785 [PMID: 5107709 DOI: 10.1001/jama.1971.0318024 0027005] 9. Berg WA. Combined screening with ultrasound and mammography vs mammography

 

  29  

alone in women at elevated risk of breast cancer. JAMA 2008; 299: 2151-2163 [PMID: 18477782 DOI: 10.1001/jama.299.18.2151] 10. Emedicine.medscape.com. Mammography in Breast Cancer [Internet]. 2016. Cited 18th October 2016. Available from: https://emedicine.medscape.com/article/346529overview 11. Fisher B. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347: 1233-1241 [PMID: 12393820 DOI: 10.1056/NEJMoa022152] 12. Hortobagyi GN. Current status of adjuvant systemic therapy for primary breast cancer: progress and controversy. CA Cancer J Clin 1995; 45: 199-226 [PMID: 7600278 DOI: 10.3322/canjclin.45.4.199] 13. Lostumbo L, Carbine NE, Wallace J. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database of Systematic Reviews 2010, Issue 11. 14. Roxanne Nelson. Prophylactic Surgery Reduces Cancer Risk and Lowers Mortality in BRCA Mutation Carriers. Medscape 2010. Available at https://www.medscape.com/viewarticle/727807 15. Francois Eisinger. Prophylactic mastectomy: ethical issues. British Medical Bulletin, Volume 81-82. 2007. 16. Kerstin Rhiem. Impact of Prophylactic Mastectomy in BRCA1/2 Mutation Carriers. Breast Care 2014; 9:385-389. 17. Geiger, A.M., Nekhlyudov, L., Herrinton, L.J. et al, Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol. 2007;14:686–694. 18. Hartmann LC, Sellers TA, Schaid DJ, et al. Efficacy of bilateral pro- phylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst

 

  30  

2001;93:1633–7. 19. Heemskerk-Gerritsen BA, Menke-Pluijmers MB, Jager A, et al. Sub- stantial breast cancer risk reduction and potential survival benefit after bilateral mastectomy when compared with surveillance in healthy BRCA1 and BRCA2 mutation carriers: a prospective analysis. Ann Oncol 2013;24:2029–35. 20. Skytte AB, Cruger D, Gerster M, et al. Breast cancer after bilateral risk-reducing mastectomy. Clin Genet 2011;79:431–7. 21. Meijers-Heijboer H, van Geel B, van Putten WL, Henzen-Logmans SC, Seynaeve C, Menke-Pluymers MB, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:159–64. 22. Ingham SL, Sperrin M, Baildam A, et al. Risk-reducing surgery in- creases survival in BRCA1/2 mutation carriers unaffected at time of family referral. Breast Cancer Res Treat 2013;142:611–8. 23. Kaas R, Verhoef S, Wesseling J, et al. Prophylactic mastectomy in BRCA1 and BRCA2 mutation carriers: very low risk for subsequent breast cancer. Ann Surg 2010;251:488– 92. 24. Domchek SM, Friebel TM, Singer CF, et al. Association of risk- reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967–75. 25. Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastec- tomy reduces breast cancer risk in BRCA1 and BRCA2 mutation car- riers: the PROSE study group. J Clin Oncol 2004;22:1055–62.

 

  31  

26. Newcastle-Ottawa Quality Assessment Scale Cohort Studies. Ottawa: Ottawa Hospital Research Institute [cited 2014 November 25]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf. 27. Terese Winslow. Breast, Male, Anatomy. National Cancer Institute [Internet]. 2012 [cited 2012 February 6] Available from: https://visualsonline.cancer.gov 28. Borgen, P. I., Hill, A. D., Tran, K. N., Van Zee, K. J., Massie, M. J., Payne, D., et al. (1998). Patient regrets after bilateral pro- phylactic mastectomy. Annals of Surgical Oncology, 5(7), 603–606. 29. Contant CM, Menke-Pluijmers MB, Seynaeve C, et al: Clinical experience of prophylactic mastectomy followed by immediate breast reconstruction in women at hereditary risk of breast cancer (HB(O)C) or a proven BRCA1 and BRCA2 germ-line mutation. Eur J Surg Oncol 28::627,2002-632

 

 

  32  

Appendices Appendix 1. Newcastle –Ottawa Quality Assessment Scale (NOS) – Cohort

 

  33  

Appendix 2. Newcastle –Ottawa Quality Assessment Scale (NOS) – Case Control

 

  34