Notes
Editorial note
This protocol will not progress to a review because the scope of the topic is too broad with an unmanageable volume of eligible studies. Any new protocol on this topic would need to have more focussed review criteria.
Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To assess the effects of risk‐reducing mastectomy on unaffected women with a strong family history of breast cancer with a specific focus on breast cancer incidence, psychosocial outcomes (including satisfaction with decision and cosmetic outcomes), surgical complications, and mortality.
Background
Description of the condition
Breast cancer is the most commonly diagnosed cancer in women with the average woman having a lifetime risk of 12% (about 1 in 8; Cancer Australia 2018). Risk factors for breast cancer include family history, genetic, lifestyle, and reproductive factors. Healthcare agencies stratify women’s risk into high (> 30%), moderate (17% to 30%) and average (< 17%) categories (National Institute for Health and Care Excellence (NICE) ‐ NICE guideline 2019).
A family history of breast or ovarian cancer is associated with an increased risk of breast cancer. A potential explanation for this is an inherited gene fault (pathogenic or likely pathogenic variant) in a breast/ovarian cancer susceptibility gene. This occurs for around 5% of all individuals with breast cancer. Known high‐risk genes include BRCA1, BRCA2, PALB2, ATM 7271T>G, and TP53. Other rare high‐risk genes associated with breast cancer (PTEN, CDH1, and STK11) have clinical phenotypes or additional cancer types in the family. For those with heritable BRCA1/2 pathogenic variants, Kuchenbaecker 2017 reported a large study involving women from multiple western countries. The cumulative breast cancer risk to age 80 years for BRCA1 carriers was 72% (95% confidence interval (CI) 65% to 79%) and 69% (95% CI 61% to 77%) for BRCA2 carriers. Lifetime risks of breast cancer for women with heritable pathogenic variants in PALB2 is 53% to age 80 (95% CI, 43.7% to 62.7%) (Yang 2020). Lifetime breast cancer risks for rare high‐risk genes (ATM 7271T>G, TP53 gene, PTEN, CDH1, STK11) are over 50%. Moderate‐risk susceptibility genes include CHEK2 and other parts of the ATM gene (17% to 29% lifetime risk; Southey 2016). Women with extensive family history of breast cancer and heritable mutations in moderate‐risk susceptibility genes may be at high risk of breast cancer, though it is likely that the high risk is due to the moderate‐risk susceptibility gene mutation combined with the presence of additional heritable factors (Robson 2021). Most women with moderate‐risk breast cancer susceptibility genes are not recommended to have risk‐reducing mastectomies (National Comprehensive Cancer Network 2022).
There are however, many families with a strong family history of breast cancer where a molecular basis has not been found. Women who do not carry a known heritable pathogenic variants in high‐risk genes appear to have lower risks of breast cancer based on data from screening trials (Saadatmand 2015). There is increasing evidence that some of the familial risk can be explained by polygenic risk (Mavaddat 2019). This refers to multiple common breast cancer susceptibility markers variants (known as single nucleotide polymorphisms) which individually confer negligible risks but their combined effect, when summarised as a polygenic risk score (PRS), may be substantial. Women can be stratified by their PRS, with those with the lowest score having personal lifetime risk of 2% compared to 32.6% lifetime risks for those with the highest PRS scores (Mavaddat 2019). Polygenic risk may explain the heritable cause of breast cancer for 40% of families who do not carry known high‐risk genes, however these scores still require prospective validation studies which are ongoing. There are still many families whose increase in breast cancer risk cannot be explained by known genetic factors.
Lifestyle factors, such as increasing exercise levels and minimising alcohol intake lower the risk of breast cancer, and reproductive factors, such as lower lifetime exposure to oestrogen with later menarche, earlier menopause, multiple pregnancies, and breastfeeding are associated with decreased breast cancer risk. The presence of personal risk factors such as proliferative breast disease such as atypical ductal hyperplasia and in situ lobular carcinoma can increase the risk of developing breast cancer for unaffected women (that is, women who have not been diagnosed with breast cancer).
There are many models that can estimate breast cancer risk. The CanRisk tool (Carver 2021) uses the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model (Lee 2019) and incorporates known high‐risk genes and residual polygenic component that takes into account other genetic, familial, and lifestyle factors. The International Breast Cancer Intervention Study (IBIS) model (Tyrer‐Cuzick 2004) can estimate breast cancer risk using family history and lifestyle risk factors such as age at menarche, menopause, breastfeeding, and childbearing. In a recent validation study of risk models, the two most accurate risk prediction models are BOADICEA and IBIS, and they performed better than other models (e.g. BRCAPRO and Breast Cancer Risk Assessment Tool (BCRAT)) (Terry 2019).
Description of the intervention
Progress in understanding the genetic basis of breast cancer has led to an increased interest in predicting breast cancer risk and identifying women at high risk through the use of genetic testing. Identification of a high‐risk gene in a family allows estimation of breast cancer risk for unaffected women, and may inform some women they are at high risk or conversely, that they are at close to population risk of breast cancer if they test negative for the known family mutation. For families where a molecular cause for breast cancer has not been found, genetic testing for the family is considered uninformative and at‐risk women are still considered to be at potentially high risk of breast cancer.
High‐risk women, who have no previous personal history of breast cancer, may consider bilateral risk‐reducing mastectomy (BRRM) as a means of primary prevention of breast cancer. Some women have breast cancer found incidentally at surgery, and there is a low risk of developing breast cancer following bilateral mastectomy due to residual breast tissue remaining in the subcutaneous tissues (Hartmann 1999). A woman's decision to have BRRM is found to be strongly correlated with her BRCA1 or BRCA2 mutation test results and with a physician's recommendation to have genetic testing or BRRM (Schwartz 2004).
Other options to lower the risk of developing hormone receptor‐positive breast cancer include the use of risk‐reducing medication such as tamoxifen (Cuzick 2013) or aromatase inhibitors (Cuzick 2014) which lower the risk by 30% to 40%, and premenopausal oophorectomy (removal of ovaries). Alternatively, women may have close surveillance with annual imaging which may include magnetic resonance imaging (MRI) and mammography.
How the intervention might work
Risk‐reducing mastectomy is a complex decision for unaffected women. Potential benefits include a substantial reduction of breast cancer risk and increase in psychological peace of mind. No breast imaging surveillance is required, and there is no need for breast biopsies or additional investigations due to abnormal screening results. Potential disadvantages of risk‐reducing mastectomy are the invasiveness of the procedure and consequent surgical related morbidity, as well as diminished satisfaction with body image, and reduced tactile sensations in the breast which may impact on quality of life. A paradox now exists in which the surgical management of invasive breast cancer has become less radical, with many women opting for breast‐conserving surgery, while removal of the breast is required for breast cancer prevention. Furthermore, no mastectomy can remove all breast tissue, and therefore cannot eliminate all risk of breast cancer.
Because no test is available that can determine which women will actually develop breast cancer in the absence of risk‐reducing mastectomy, it is likely that some individuals will undergo risk‐reducing mastectomy needlessly. Other possible options to manage the high risk of breast cancer include chemoprevention with drugs such as tamoxifen and aromatase inhibitors, close surveillance with imaging studies which may include breast MRI in addition to mammography, or oophorectomy (removal of ovaries) which may reduce the risk of oestrogen receptor (ER)‐positive breast cancer if performed premenopausally (Evans 2013; Heemskerk‐Gerritsen 2015; Ingham 2013; Kiely 2010; Metcalfe 2004; Van Sprundel 2005).
For women who do not elect to have bilateral risk‐reducing mastectomies, breast cancer screening is advised which may include use of annual MRI and mammography. Screening aims to detect breast cancer early where cure rates for early stage cancer are higher than late stage cancers. Women may still need surgery, radiotherapy, chemotherapy or endocrine therapy following breast cancer diagnosis. Survival outcomes for BRCA carriers having surveillance were reported in the MRI screening (MRISC) study which included 599 women with high‐risk gene mutations. At 10 years follow‐up, metastasis‐free survival was 88% for BRCA1 and BRCA2 carriers and overall survival was 88% (Saadatmand 2015). Another study reporting screening outcomes for BRCA1 and BRCA2 carriers reported the risk of dying from breast cancer was 2% at 20 years (Warner 2020).
Why it is important to do this review
This is a new protocol based on a Cochrane Review first published in 2004 and recently updated in 2018 (Carbine 2018). This new protocol focuses specifically on unaffected women defined as women who fall into the high‐risk criteria for breast cancer based on either genetic testing results or family history, but have not had a previous diagnosis of breast cancer. A separate review will assess the effects of risk‐reducing mastectomy for women with a previous diagnosis of breast cancer.
Given the irreversible nature of risk‐reducing mastectomy, it is essential that women contemplating this procedure be aware of the best available evidence, to consider both the benefits and harms of the procedure, and weigh the risks and benefits of other alternatives. Risk‐reducing mastectomy can have a negative impact on self‐esteem, sexual relations, and satisfaction with body appearance (Boughey 2015; Brandberg 2008; Brandberg 2012; Bresser 2006; Frost 2000; Frost 2005; Gahm 2010; Gopie 2013; Unukovych 2012).
We will evaluate the existing research literature on the effectiveness of risk‐reducing mastectomy in terms of breast cancer incidence, satisfaction with decision to have the surgery and cosmetic results following breast reconstruction, psychological wellbeing assessed by the quality of life, potential adverse effect by causing physical morbidity, early surgical complications, late surgical complications, breast cancer mortality, and overall survival for women. This review will focus on the best available evidence and update the search to include any new evidence published since 2016. We will assess the methodological quality of the included studies.
Objectives
To assess the effects of risk‐reducing mastectomy on unaffected women with a strong family history of breast cancer with a specific focus on breast cancer incidence, psychosocial outcomes (including satisfaction with decision and cosmetic outcomes), surgical complications, and mortality.
Methods
Criteria for considering studies for this review
Types of studies
It is extremely unlikely that this review topic will be studied in randomised controlled trials. This is because a randomised controlled trial would not be ethical and the intervention is likely to elicit preferences by study participants. As the original version of this review searched for and recorded no randomised controlled studies on this topic, this study design will not be included in this updated review topic.
Instead, we will include comparative studies (i.e. non‐randomised, cohort, and case‐control studies) and case series that have at least 20 participants. We will include studies conducted during any time period, in any country, settings, or ethnicity.
Types of participants
Participants will comprise women at increased risk from breast cancer due to their family history. This includes women with a positive family history of breast cancer and/or carriers of known high‐risk or moderate‐risk breast cancer susceptibility genes (estimated lifetime risks over 17% or 10 year‐risk 40 to 50 years > 3%) (NICE guideline 2019).
We will include studies where most participants are considered at high risk of breast cancer due to family history, and exclude studies where increased risk is defined only due to high‐risk proliferative breast diseases such as atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS). Studies will be included if most participants have high‐risk family histories and less than 20% of trial participants were included due to high‐risk biopsies such as ADH/invasive lobular carcinoma (ILC).
We will report positive family history (as defined by the authors of each reported study) in the characteristics of included studies tables, and where possible, lifetime risks. We will record age at risk‐reducing mastectomy in groups as under 30, 30 to 39, or greater than 40 years of age. If possible, we will report whether women had completed childbearing prior to surgery. We will include women who have had premenopausal risk‐reducing salpingo‐oophorectomy (RRSO). If data are available, we will report relationship status at the time of surgery.
Types of interventions
All types of risk‐reducing mastectomy (RRM), including subcutaneous mastectomy, total or simple mastectomy, skin‐sparing mastectomy, nipple‐sparing mastectomy, modified radical mastectomy, and radical mastectomy.
The comparator group may have no surveillance or any surveillance with any type of breast imaging including ultrasound, mammography, and MRI.
Types of outcome measures
Primary outcomes
Breast cancer incidence.
Satisfactiona with decision to have RRM.
Satisfactiona with cosmetic result following breast reconstruction.
aWith reporting and analysis of outcomes based on different follow‐up times from surgery to assessment, and types of breast reconstruction.
Secondary outcomes
Psychological wellbeing assessed by either quality of life, impact on body image, impact on relationships and sexuality using any validated scale reported by study authors.
Early surgical complications (less than 30 days), including infection, bleeding, repeat surgery, death.
Late surgical complications (30 or more days from surgery): i) general: infection, haematoma; ii) related to breast prostheses including rupture, capsular contraction or infection; iii) complications relating to autologous tissue reconstruction such as necrosis, infection, loss of graft.
Breast cancer mortality.
Overall survival.
Where possible, we will report data for long‐term outcomes (i.e. breast cancer mortality, overall survival) in 5‐year intervals.
Search methods for identification of studies
Electronic searches
The original review of this review topic included evidence up to 2016. For this updated review topic, we will review the included and ongoing studies recorded in the earlier version of this review and determine whether studies are eligible in light of the updated inclusion criteria.
In addition, we will search the medical databases using key words such as “high risk”, “history”, “surgery”, “mastectomy”, “risk‐reducing mastectomy”, “radical mastectomy”, “modified radical mastectomy”, “simple mastectomy”, "skin‐sparing mastectomy", "nipple‐sparing mastectomy", and “total mastectomy". The following databases will be searched from 2016 to present.
MEDLINE (via OvidSP) from 14 July 2016 to present (Appendix 1).
EMBASE (via OvidSP) from 14 July 2016 to present (Appendix 2).
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (trialsearch.who.int/) for all prospectively registered and ongoing trials (Appendix 3).
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov/) (Appendix 4).
For the identification of non‐randomised studies of interventions, we will use amended versions of the search strategies for randomised controlled trials but without study filters (Reeves 2022, Chapter 24). Further, we will conduct these searches in MEDLINE and Embase.
Searching other resources
For ongoing studies that have not been published, we will consider approaching the principal investigators, and major co‐operative groups active in this area, to ask for relevant data. For included studies with survival data, we will attempt to contact investigators for updated unpublished survival data.
We will screen the studies in the reference lists of eligible studies or reviews.
Data collection and analysis
Selection of studies
Two review authors (Shweta Srinivasa (SS) and Annabel Goodwin (AG)) will independently examine each title and abstract to determine whether reports may meet our inclusion criteria. We will obtain full‐text reports of studies that appear to meet the inclusion criteria for closer examination, and two authors (SS and AG) will examine each one to determine eligibility. If required, any differences in study selection will be resolved by review with a third author (Melina Willson (MW)).
We will screen references using Covidence and record the selection process in the PRISMA flow diagram. We will record excluded studies in the 'Characteristics of excluded studies' table for those studies that a reader may expect to find in the review.
Data extraction and management
The entire author group will decide upon uniform criteria for the data extraction form before the process begins. Two group members (SS and AG) will independently extract data from each study included in the review and aim to resolve any differences by discussion. One member of the group (MW or Sam Egger (SE)) will help to resolve any disagreements by discussion. Discussion with all authors will be considered if no consensus has been reached. For studies with more than one publication, data will be extracted from all publications but the most recent version of the study will be considered the primary reference. Records relating to the same study participants will be noted and combined under the overall study ID. Data will be entered into RevMan Web 2022. The entire group will then finalise decisions as to the presentation of the data in the review and the 'Characteristics of included studies' tables.
We will collect the following information.
Study design (e.g. prospective cohort design, retrospective cohort design).
For outcomes assessing rare events, such as breast cancer incidence following RRM, or outcomes assessing patient satisfaction or quality of life, we will include data from studies of any trial design.
For surgical complications, we will use data from cohort studies or any study which included all eligible women who underwent RRM within a specific time frame.
Participants: baseline characteristics (e.g. age of participants), high‐risk gene mutations such as BRCA1 and 2, family history of breast cancer, inclusion/exclusion criteria of study, number of participants at baseline and completion and setting.
Interventions and comparators: type of surgery, co‐interventions (e.g. immediate or delayed breast reconstruction, other preventive options such as tamoxifen or RRSO), type and frequency of surveillance offered (e.g. MRI).
Primary and secondary outcomes: definition of each outcome, outcome assessor, measurement tool (e.g. for psychological outcomes, quality of life), and length of follow‐up.
Results: per‐protocol or intention‐to‐treat analysis, withdrawals, loss to follow‐up.
Potential confounders that were statistically adjusted for: strength of family history of breast or ovarian cancer, BRCA gene mutation status, age, number of biopsies and histological status of previous biopsies, socioeconomic status, breastfeeding, oral contraceptive use, use of other preventive options such as premenopausal RRSO or risk‐reducing medication.
Methods used to control for confounders, adjusted or unadjusted effect estimates in non‐randomised studies.
Assessment of risk of bias in included studies
We will use ROBINS‐I for non‐randomised studies (Chapter 25, Sterne 2021). For rare outcomes that are likely to be best assessed from case series, we will use the tool described by Murad 2018.
Two authors (SS and AG) will independently apply the relevant tool and resolve any differences in opinion by discussion or by appeal to a third review author (MW). We will seek clarification from trial authors if the published data provides inadequate information for the review. We will summarise results in both a risk of bias table and a risk of bias summary, and incorporate these findings in the interpretation of the overall body of evidence.
Non‐randomised studies of interventions
We will use the ROBINS‐I tool for cohort and case‐control studies (Chapter 25, Sterne 2021). We will assess risk of bias for all outcomes and time points listed as critical outcomes. We will use the classification of study features outlined in Reeves 2017 to determine study design rather than rely on study labels reported in potentially eligible studies.
We will assess studies based on the following domains.
Pre‐intervention domains
Bias due to confounding: e.g. strength of the family history of breast or ovarian cancer, BRCA (breast cancer gene mutation) status, age, number of biopsies and histological status of previous biopsies, race, socioeconomic status, breastfeeding, oral contraceptive use, use of other preventive options such as tamoxifen or RRSO, and pre‐existence of psychological morbidity for psychological outcomes.
Bias in selection of participants into the study: e.g. is there evidence of a consecutive sample, a clearly defined patient population (e.g. patients at a particular clinic at a particular time period) or some other method to minimise the chance that clinicians preferentially selected patients with favourable outcomes or that patients with better outcomes volunteered (healthy volunteer bias)? Also, matching or restriction to particular subgroups and in their methods of analysis (e.g. the use of stratification or regression modelling).
At‐intervention domain
Bias in classification of interventions.
Post‐intervention domains
Bias due to deviations from intended interventions: e.g. adherence to breast cancer screening for the risk‐reducing mastectomy and comparison arm are measured in an objective way (i.e. medical or surgical records) or determined exclusively by self‐reporting, and reported.
Bias due to missing data: e.g. dropout rates and whether dropouts/withdrawals are sufficiently accounted for.
Bias in measurement of the outcome: e.g. outcomes are assessed in a valid way (e.g. validated pre/post‐instruments for psychosocial measures, medical records for incidence, medical/death records for vital status).
Bias in selection of the reported result.
Incidence of ovarian cancer may affect overall survival for BRCA1/2 carriers in particular. We will record whether risk reducing salpingo‐oophorectomy was performed (ideally from age 40) or not.
Use of surveillance breast MRI +/‐ mammography for comparison groups.
The response options to the signalling questions will be: 'yes', 'probably yes', 'probably no', 'no', and 'no information'. Free text will be used to provide support for each answer, using direct quotations from the text of the study where possible. We will include details of consensus decisions for signalling questions available in the supplemental data to ensure transparency of decision‐making. Responses to signalling questions will provide the basis for domain‐level judgements about risk of bias.
These domain‐level risk of bias judgements include ‘low risk’, ‘moderate risk’, ‘serious risk’, ‘critical risk’, and 'no information' of bias. Importantly, ‘low risk’ corresponds to the risk of bias in a high‐quality randomised trial (Sterne 2021).
To reach an overall risk of bias judgement for each outcome, we will review all domain‐level risk of bias judgements for studies that report this outcome and label it as 'low', 'moderate', 'serious', or 'critical' risk of bias as per the criterion in Table 25.3c (Chapter 25, Sterne 2021). No studies with critical risk of bias will have their data synthesised (Sterne 2021).
Case series
We will use the tool outlined by Murad 2018 for assessing the quality of case series. The tool contains domains relating to selection, ascertainment, causality, and reporting, and includes eight questions.
Measures of treatment effect
We will use the following measures of the effect of treatment.
Time‐to‐event data (e.g. overall survival) will be expressed as a hazard ratio (HR). If HRs and variance are not reported in the trial publications, we will calculate summary statistics indirectly using the methods outlined by Tierney 2007. We will record the use of indirect methods in the notes section of the ‘Characteristics of included studies’ tables and whether the trial publications reported an assessment of the proportional hazard assumption.
Dichotomous outcomes (e.g. all‐cause mortality, breast cancer mortality) will be extracted from the number of participants in each RRM and no surveillance/any surveillance arm who experienced the outcome of interest and the number of participants will be assessed at endpoint, in order to estimate a risk ratio (RR) with 95% confidence interval (CI).
Continuous data (e.g. quality of life) will be expressed as a mean difference (MD) or median (range) if the same scale has been measured with a 95% CI. If studies use different scales to measure quality of life, we will report the treatment effects as a standardised mean difference (SMD) with 95% CIs. SMDs will interpreted using ‘Cohen’s effect sizes’ (Cohen 1988) and also by back‐transforming SMDs to one of the original scales (section 15.5.3.2 of the Cochrane Handbook for Systematic Reviews of Interventions; Higgins 2021).
For non‐randomised trials, as suggested by the Cochrane Handbook for Systematic Reviews of Interventions, if both unadjusted and adjusted intervention effects are reported, preference will be given to the adjusted effects; if multiple adjusted estimates of intervention effect are reported, preference will be given to the one that is judged to minimise the risk of bias due to confounding (guided by Section 25.2.1; Higgins 2021).
Unit of analysis issues
Participants are the unit of analysis in this review. We will review whether participants have been included in more than one study by focusing on the recruitment process of participants and aim not to include individual participants twice to avoid double‐counting.
Dealing with missing data
We will not impute missing outcome data for the primary or secondary outcomes. If data are missing or the included studies only report imputed data, we will contact study authors to request data on the outcomes only among participants who will be assessed. The impact of any missing data will be discussed in the review.
Assessment of heterogeneity
If data are available and it is statistically possible, we will assess heterogeneity using the I2 statistic and interpret it according to the guide reported in the Cochrane Handbook for Systematic Reviews of Interventions:
0% to 40%: might not be important,
30% to 60%: may represent moderate heterogeneity,
50% to 90%: may represent substantial heterogeneity,
75% to 100%: may represent considerable heterogeneity.
If there is evidence of considerable or substantial heterogeneity, we will explore possible sources of heterogeneity and perform sensitivity analysis.
Assessment of reporting biases
If a sufficient number of studies are included in the systematic review and meta‐analysis for any outcome, we will investigate the potential for small‐study effects, such as publication bias using funnel plot asymmetry. Where possible, we will review the protocols of included studies to assess outcome reporting bias.
Data synthesis
If sufficient clinically similar studies are available, we will pool their results in meta‐analyses using RevMan Web.
For time‐to‐event data, we will pool HRs (appropriately adjusted when extracted from non‐randomised studies, if available) using the generic inverse variance facility in RevMan Web 2022.
For dichotomous outcomes, we will calculate the RRs for each study or extract the most appropriately adjusted RRs from non‐randomised studies. RRs will be pooled using the generic inverse variance method.
For continuous outcomes, we will pool the MDs (appropriately adjusted when extracted from non‐randomised studies, if available) between the intervention data at the end of follow‐up if all studies measured the outcome on the same scale, otherwise we will pool standardised MD values. MDs will be pooled using the generic inverse variance method.
We will use random‐effects models for all meta‐analyses (DerSimonian 1986) if possible. In our review, we will report all studies including those at serious risk of bias for an outcome. However, for those outcomes where the overall risk of bias is considered to be 'critical', we will not present the data in a meta‐analysis.
We will present outcome data by comparing risk‐reducing mastectomy interventions (that is, all surgical types) to no surveillance/any surveillance. If there are sufficient outcome data, we will present by different surgical type of mastectomy.
Findings from the previous review (Carbine 2018) make evidently clear the diversity of the review studies and that the statistical pooling of the data may not be possible. For outcomes where numerical data are lacking or have been measured in diverse ways, we will apply the synthesis without meta‐analysis (SWiM) methods such as vote‐counting based on direction of effect as outlined in Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (McKenzie 2019). Following the SWiM guideline (Campbell 2020; McKenzie 2019), we will report information by grouping studies (e.g. by population, outcome, study design), and describing the standardised metrics and any transformations used, synthesis methods, the criteria used to prioritise results for synthesis (e.g. based on study design, risk of bias assessment), and limitation of the synthesis (Campbell 2020).
Subgroup analysis and investigation of heterogeneity
Where sufficient data are available, we will conduct the following subgroup analysis:
satisfaction with decision to have RRM based on high‐risk status either due to presence of high‐risk gene mutations such as BRCA1 or BRCA2 compared to family history alone status;
psychosocial wellbeing based on age at risk‐reducing mastectomy (for example, < 30 years, 30 to 40 years, > 40 years of age);
satisfaction with cosmetic outcome based on length of follow‐up (for example, < 5 years, 5 to 10 years, or > 10 years);
satisfaction with decision to have RRM based on whether there were early or late surgical complications;
satisfaction with cosmetic outcome of breast reconstruction following RRM based on whether there were early or late surgical complications;
incidence and mortality based on type of surgical procedure (subcutaneous and nipple sparing versus others);
satisfaction with RRM based on type of reconstruction (e.g. autologous versus non‐autologous reconstruction with possible revision surgery to maintain cosmesis).
Sensitivity analysis
If possible, we will perform sensitivity analyses for quantifiable effect measures based on risk of bias assessment of the included studies, that is, by removing studies that are at serious risk of bias.
Summary of findings and assessment of the certainty of the evidence
Two authors will assess the certainty of the evidence using the GRADE approach, used GRADEpro GDT software, and will present the review results in summary of findings tables. The GRADE approach incorporates five domains ‐ risk of bias, inconsistency, indirectness, imprecision, and publication bias.
We will present the overall certainty of the evidence for the main outcomes listed below.
Breast cancer incidence.
Satisfaction with decision to have RRM.
Satisfaction with cosmetic result following breast reconstruction.
Psychological wellbeing assessed by either quality of life, impact on body image, impact on relationships and sexuality.
Early surgical complications (less than 30 days), including infection, bleeding, repeat surgery, death.
Late surgical complications (30 or more days from surgery): i) general: infection, haematoma; ii) related to breast prostheses including rupture, capsular contraction or infection; iii) complications relating to autologous tissue reconstruction such as necrosis, infection, loss of graft.
Breast cancer mortality.
What's new
| Date | Event | Description |
|---|---|---|
| 19 September 2024 | Amended | Addition of an Editorial note to inform readers that this protocol will not progress to review stage. |
History
Protocol first published: Issue 9, 2022
Acknowledgements
We wish to thank the following people for their helpful peer review: Cecilia Fabrizio (consumer reviewer), DrPH; Rebecca Seago‐Coyle (consumer reviewer); Theresa Moore (methodological editor), Editorial and Methods Department, Cochrane, London, The National Institute for Health Research Applied Research Collaboration West (NIHR ARC West), University Hospitals Bristol National Health Service Foundation Trust, Bristol, and Population Health Sciences, Bristol Medical School, University of Bristol, UK; Patricia A Ganz (clinical editor), MD, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA; and the external clinical reviewer who wishes to remain anonymous. We would like to thank Peta Skeers for developing the search strategies.
The following people in the Cochrane Breast Cancer Group conducted the editorial process for this article. Sign‐off Editor (final editorial decision): Nicholas Wilcken, The University of Sydney. Managing Editor (selected peer reviewers, collated peer‐reviewer comments, provided editorial guidance to authors): Ava Grace Tan‐Koay, The University of Sydney. Copy Editor (copy‐editing): Luisa M Fernandez Mauleffinch, Cochrane Central Production Service.
Appendices
Appendix 1. MEDLINE (via OvidSP) search strategy
| 1 | exp Mastectomy, Subcutaneous/ or exp Mastectomy, Extended Radical/ or exp Mastectomy, Segmental/ or exp Mastectomy/ or exp Mastectomy, Radical/ or exp Mastectomy, Modified Radical/ or exp Mastectomy, Simple/ |
| 2 | mastectom$.tw. |
| 3 | (simple mastectom$ or total mastectom$).tw. |
| 4 | (skin‐sparing mastectom$ or skin sparing mastectom$).tw. |
| 5 | (nipple‐sparing mastectom$ or nipple sparing mastectom$).tw. |
| 6 | (segmental mastectom$ or partial mastectom$).tw. |
| 7 | (radical mastectom$ or modified radical mastectom$ or extended radical mastectom$).tw. |
| 8 | subcutaneous mastectom$.tw. |
| 9 | exp Mammaplasty/ |
| 10 | mamm?plast$.tw. |
| 11 | or/1‐10 |
| 12 | prophylac$.tw. |
| 13 | prophylaxis.tw. |
| 14 | prevent$.tw. |
| 15 | (risk‐reducing or RRM).tw. |
| 16 | or/12‐15 |
| 17 | 11 and 16 |
| 18 | (prophylactic$ adj (surger$ or resect$ or mastectom$ or mamm?plast$)).tw. |
| 19 | (prevent$ adj (surger$ or resect$ or mastectom$ or mamm?plast$)).tw. |
| 20 | (risk‐reducing adj (surger$ or resect$ or mastectom$ or mamm?plast$)).tw. |
| 21 | exp Prophylactic Mastectomy/ |
| 22 | exp Prophylactic Surgical Procedures/ |
| 23 | or/18‐22 |
| 24 | 17 or 23 |
| 25 | exp Risk Assessment/ |
| 26 | exp Risk Factors/ |
| 27 | exp Medical History Taking/ |
| 28 | Family history.tw. |
| 29 | (lifetime risk adj6 breast cancer).tw. |
| 30 | history of breast cancer.tw. |
| 31 | (famil* adj6 risk).tw. |
| 32 | (famil* adj6 history).tw. |
| 33 | (famil* adj6 breast).tw. |
| 34 | (famil* adj6 breast cancer).tw. |
| 35 | exp FAMILY/ |
| 36 | family.tw. |
| 37 | exp RISK/ |
| 38 | risk.tw. |
| 39 | (35 or 36) and (37 or 38) |
| 40 | or/25‐34,39 |
| 41 | exp Genes, BRCA1/ |
| 42 | exp Genes, BRCA2/ |
| 43 | (BRCA1 or BRCA2).tw. |
| 44 | exp Genetic Predisposition to Disease/ |
| 45 | genetic risk.tw. |
| 46 | exp Germ‐Line Mutation/ |
| 47 | exp Li‐Fraumeni syndrome/ |
| 48 | (Li‐Fraumeni syndrome or Li Fraumeni syndrome).tw. |
| 49 | exp BRCA1 Protein/ |
| 50 | exp BRCA2 Protein/ |
| 51 | (PALB2 adj mutation).tw. |
| 52 | ((Partner and Localizer of BRCA2 gene) adj mutation).tw. |
| 53 | BRCA1 Protein.tw. |
| 54 | BRCA2 Protein.tw. |
| 55 | exp mutation/ |
| 56 | or/41‐54 |
| 57 | 24 and (40 or 56) |
| 58 | animals/ not humans/ |
| 59 | 57 not 58 |
| 60 | remove duplicates from 59 |
Appendix 2. EMBASE (via Ovid SP) search strategy
| 1 | exp partial mastectomy/ or exp subcutaneous mastectomy/ or exp mastectomy/ or exp segmental mastectomy/ or exp simple mastectomy/ or exp radical mastectomy/ or exp modified radical mastectomy/ or exp extended radical mastectomy/ or exp skin‐sparing mastectomy/ or exp nipple‐sparing mastectomy/ |
| 2 | mastectom$.tw. |
| 3 | (simple mastectom$ or total mastectom$).tw. |
| 4 | (skin‐sparing mastectom$ or skin sparing mastectom$).tw. |
| 5 | (nipple‐sparing mastectom$ or nipple sparing mastectom$).tw. |
| 6 | (segmental mastectom$ or partial mastectom$).tw. |
| 7 | (radical mastectom$ or modified radical mastectom$ or extended radical mastectom$).tw. |
| 8 | subcutaneous mastectom$.tw. |
| 9 | exp breast reconstruction/ |
| 10 | mamm?plast$.tw. |
| 11 | or/1‐10 |
| 12 | prophylac$.tw. |
| 13 | prophylaxis.tw. |
| 14 | prevent$.tw. |
| 15 | exp risk reduction/ |
| 16 | (risk‐reducing or RRM).tw. |
| 17 | or/12‐16 |
| 18 | 11 nd 17 |
| 19 | (prophylactic$ adj (surger$ or resect$ or mastectom$ or mamm?plast$)).tw. |
| 20 | (prevent$ adj (surger$ or resect$ or mastectom$ or mamm?plast$)).tw. |
| 21 | (risk‐reducing adj (surger$ or resect$ or mastectom$ or mamm?plast$)).tw. |
| 22 | exp prophylactic mastectomy/ |
| 23 | exp prophylactic surgical procedure/ |
| 24 | or/19‐23 |
| 25 | 18 or 24 |
| 26 | exp risk assessment/ |
| 27 | exp risk factor/ |
| 28 | exp family history/ |
| 29 | Family history.tw. |
| 30 | exp cancer risk/ |
| 31 | (lifetime risk adj6 breast cancer).tw. |
| 32 | history of breast cancer.tw. |
| 33 | (famil* adj6 risk).tw. |
| 34 | (famil* adj6 history).tw. |
| 35 | (famil* adj6 breast).tw. |
| 36 | (famil* adj6 breast cancer).tw. |
| 37 | exp FAMILY/ |
| 38 | family.tw. |
| 39 | exp RISK/ |
| 40 | risk.tw. |
| 41 | (37 or 38) and (39 or 40) |
| 42 | or/26‐36,41 |
| 43 | exp BRCA1 protein/ |
| 44 | exp BRCA2 protein/ |
| 45 | (BRCA1 or BRCA2).tw. |
| 46 | exp genetic predisposition/ |
| 47 | exp genetic risk/ |
| 48 | genetic risk.tw. |
| 49 | exp germline mutation/ |
| 50 | exp Li‐Fraumeni syndrome/ |
| 51 | (Li‐Fraumeni syndrome or Li Fraumeni syndrome).tw. |
| 52 | (PALB2 adj mutation).tw. |
| 53 | ((Partner and Localizer of BRCA2 gene) adj mutation).tw. |
| 54 | BRCA1 Protein.tw. |
| 55 | BRCA2 Protein.tw. |
| 56 | exp mutation/ |
| 57 | or/43‐56 |
| 58 | 25 and (42 or 57) |
| 59 | animals/ not humans/ |
| 60 | 58 not 59 |
| 61 | remove duplicates from 60 |
Appendix 3. WHO ICTRP search strategy
Basic searches
1. risk‐reducing mastectomy or risk reducing mastectomy 2. prophylactic mastectomy 3. mastectomy AND risk 4. (BRCA1 or BRCA2) AND (risk‐reducing mastectomy or risk reducing mastectomy) 5. (BRCA1 or BRCA2) AND prophylactic mastectomy
Advanced searches
1. Condition: Breast cancer or breast neoplasm
Intervention: prophylactic mastectomy OR prophylactic surgery OR prophylactic resection OR prophylactic mammaplasty OR preventative mastectomy OR preventative surgery OR preventative resection OR preventative mammaplasty OR risk‐reducing mastectomy OR risk reducing mastectomy OR risk‐reducing surgery OR risk reducing surgery OR risk‐reducing resection OR risk reducing resection OR risk‐reducing mammaplasty OR risk reducing mammaplasty
Recruitment status: All
2. Condition: BRCA1 or BRCA2
Intervention: prophylactic mastectomy OR prophylactic surgery OR prophylactic resection OR prophylactic mammaplasty OR preventative mastectomy OR preventative surgery OR preventative resection OR preventative mammaplasty OR risk‐reducing mastectomy OR risk reducing mastectomy OR risk‐reducing surgery OR risk reducing surgery OR risk‐reducing resection OR risk reducing resection OR risk‐reducing mammaplasty OR risk reducing mammaplasty
Recruitment status: All
Appendix 4. ClinicalTrials.gov search strategy
Basic searches
1. Other terms: risk‐reducing mastectomy or risk reducing mastectomy or risk‐reducing mastectomies or risk reducing mastectomies
All studies
2. Other terms: prophylactic mastectomy or prophylactic mastectomies
All studies
3. Condition or disease: breast cancer AND risk
Other terms: mastectomy or mastectomies
All studies
4. Condition or disease: BRCA1 or BRCA2
Other terms: risk‐reducing mastectomy or risk reducing mastectomy or risk‐reducing mastectomies or risk reducing mastectomies
All studies
5. Condition or disease: BRCA1 or BRCA2
Other terms: prophylactic mastectomy or prophylactic mastectomies
All studies
Advanced searches
1. Condition or disease: Breast cancer risk
Intervention/treatment: prophylactic mastectomy OR prophylactic surgery OR prophylactic resection OR prophylactic mammaplasty OR preventative mastectomy OR preventative surgery OR preventative resection OR preventative mammaplasty
Recruitment status: All
2. Condition: Breast cancer risk
Intervention/treatment: risk‐reducing mastectomy OR risk reducing mastectomy OR risk‐reducing surgery OR risk reducing surgery OR risk‐reducing resection OR risk reducing resection OR risk‐reducing mammaplasty OR risk reducing mammaplasty
Recruitment status: All
3. Condition or disease: BRCA1 or BRCA2
Intervention/treatment: prophylactic mastectomy OR prophylactic surgery OR prophylactic resection OR prophylactic mammaplasty OR preventative mastectomy OR preventative surgery OR preventative resection OR preventative mammaplasty
Recruitment status: All
4. Condition or disease: BRCA1 or BRCA2
Intervention/treatment: risk‐reducing mastectomy OR risk reducing mastectomy OR risk‐reducing surgery OR risk reducing surgery OR risk‐reducing resection OR risk reducing resection OR risk‐reducing mammaplasty OR risk reducing mammaplasty
Recruitment status: All
Contributions of authors
Draft the protocol: Melina Willson (MW), Shweta Srinivasa (SS), Kaniz Fatema (KF), Liz Lostumbo (LL), Nora Carbine (NC), Sam Egger (SE), Annabel Goodwin (AG).
Sources of support
Internal sources
No sources of support provided
External sources
No sources of support provided
Declarations of interest
Melina Willson (MW): none known. Shweta Srinivasa (SS): none known. Kaniz Fatema (KF): none known. Liz Lostumbo (LL): none known. Nora Carbine (NC): none known. Sam Egger (SE): none known. Annabel Goodwin (AG): Dr Goodwin reports advisory roles for Pfizer (2018) and AstraZeneca (2018) on the topic of mainstream genetic testing for women diagnosed with breast cancer (BRCA1, BRCA2), and importance of genetic counselling for women considering treatment focused genetic testing (PARP inhibitor therapy). Dr Goodwin has received payment from Pfizer (2019) for providing expert testimony on the results of a treatment trial (EMBRACA – PARP inhibitors) and the institution also received in‐kind support for manuscript writing for the same trial (Pfizer 2019, 2020). These roles relate to work outside the scope of the submitted work; this Cochrane protocol covers the prevention of primary breast cancer. MW and AG are part of the Cochrane Breast Cancer editorial team however, they were not involved in the editorial process for this protocol.
Edited (no change to conclusions)
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