Secondary Risk-Reducing Strategies for Contralateral Breast Cancer in BRCA1/2 Variant Carriers: A Systematic Review and Meta-analysis

Abstract

Introduction

Breast cancer poses significant challenges, especially the increased risk of contralateral breast cancer (CBC) in BRCA1/2 variant carriers. This study systematically reviews and analyzes the effectiveness of secondary risk-reducing strategies for CBC in BRCA1/2 carriers.

Methods

A systematic review and meta-analysis were conducted from January 2000 to December 2023, including RCTs, cohort, or case–control studies involving BRCA carriers with unilateral breast cancer. Random-effects models were used for odds ratios (ORs) on CBC incidence and hazard ratios (HRs) for overall survival (OS), with bias assessed via the Newcastle–Ottawa Scale.

Results

A total of 23,840 participants from 26 studies were included. Secondary risk-reducing interventions reduced CBC incidence by 38% [OR 0.62, 95% confidence interval (CI) 0.57–0.68] and improved OS by 45% (HR 0.55, 95% CI 0.46–0.67). Subgroup analyses showed differences by BRCA type, menopausal status, and treatment duration. For BRCA1 carriers, chemotherapy was most effective, while, for BRCA2, it was endocrine therapy. Postmenopausal interventions reduced CBC by 47% (OR 0.53, 95% CI 0.40–0.71), while premenopausal carriers saw a 34% reduction (OR 0.66, 95% CI 0.53–0.82). Tamoxifen’s effect diminished over time.

Conclusion

Secondary prophylaxis reduces CBC and improves OS in BRCA1/2 carriers, with variations by genetic and physiological factors. These findings underscore the need for personalized strategies, considering menopausal status and treatment duration.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-024-03054-x.

Key Summary Points

Why carry out this study?

Individuals with BRCA1/2 variants who have a history of unilateral breast cancer are at a substantially increased risk of developing contralateral breast cancer (CBC), with BRCA1 carriers facing up to a 40% risk and BRCA2 carriers a 26% risk.

Current secondary prophylactic interventions for reducing CBC risk in BRCA1/2 carriers lack comprehensive synthesized evidence, especially when considering genetic and menopausal differences, creating an unmet need for personalized strategies.

This study aimed to systematically review and assess the effectiveness of secondary prophylactic strategies (e.g., mastectomy, chemotherapy, endocrine therapy) for reducing CBC incidence and improving overall survival in BRCA1/2 carriers, while considering variations in genetic variants and menopausal status.

What was learned from the study?

The study found that secondary prophylactic interventions significantly reduced CBC incidence by 38% and improved overall survival by 45%, with differences observed based on genetic variant, menopausal status, and treatment duration.

Prophylactic strategies, including chemotherapy and endocrine therapy, showed variant-specific effectiveness, with chemotherapy being more beneficial for BRCA1 carriers and endocrine therapy for BRCA2 carriers.

Postmenopausal women had a higher protective benefit compared to premenopausal women.

These findings advocate for more personalized prophylactic interventions based on genetic and physiological factors.

Introduction

Breast cancer, a multifaceted disease with complex etiology, remains one of the leading causes of cancer-related mortality among women globally [1]. The annual incidence of contralateral breast cancer (CBC) among individuals who have previously had breast cancer is estimated to be 0.5% per year [2, 3]. This risk is strongly impacted by characteristics such as germline mutation status [4], racial or ethnic background [5], age at initial diagnosis [6], and menopausal status [7–10]. The risk of developing CBC is much higher in individuals with a history of unilateral breast cancer who are pathogenic variant BRCA1/2 carriers [11]. The actual long-term risk, though, can vary based on several factors, including the patient’s age at initial breast cancer diagnosis and overall survival. This emphasizes the necessity of secondary prophylaxis. Survivors with pathogenic BRCA1/2 variants face a significantly elevated risk of CBC. For BRCA1 carriers, the estimated 20-year risk of CBC is approximately 40%, while, for BRCA2 carriers, it is about 26% [8]. While the actual long-term risk varies based on factors like the patient’s age at diagnosis and survival, this elevated risk underscores the importance of implementing secondary risk-reducing strategies.

Various secondary prophylaxis measures have been suggested to decrease the incidence of CBC. These include contralateral risk-reducing mastectomy (CRRM), pharmaceutical prevention using selective estrogen receptor modulators or aromatase inhibitors, lifestyle changes, and regular monitoring [12]. The NCCN Guidelines for Breast Cancer (version 3.2022) recommend chemotherapy and endocrine therapy primarily as adjuvant treatments to prevent distant metastasis in early breast cancer [13]. While these therapies are used to reduce the risk of recurrence in the treated breast, retrospective studies have observed a secondary benefit of reducing the risk of CBC, particularly in patients who are carriers of BRCA1/2 variants [13, 14]. Research has demonstrated that CRRM can decrease the likelihood of CBC by as much as 95% [15], rendering it a highly efficacious yet significantly invasive alternative. Pharmacological therapies and lifestyle adjustments provide less intrusive options; however, their effectiveness varies and necessitates additional research [16, 17]. The use of advanced monitoring techniques, such as regular imaging, allows for early identification opportunities. However, the effects of this on long-term results are still being studied.

Existing reviews to date have not systematically synthesized the effectiveness of secondary risk-reducing interventions for patients with BRCA1/2 mutations with unilateral breast cancer history, nor fully summarized the heterogeneities of intervention effectiveness among patients with different types of BRCA variants and menopausal status at diagnosis. For example, one review highlighted the variability in intervention outcomes but did not delve deeply into the specificities of different BRCA variants or consider the impact of menopausal status [18]. Another review offered some insights into the overall effectiveness of these interventions but stopped short of a detailed examination of subgroup variations based on genetic and menopausal differences [19]. Such insufficient synthesized evidence may hinder precision medicine for patients with breast cancer with BRCA variants. Although past studies have synthesized findings for premenopausal cohorts to prevent premature death, they have left a gap in research concerning postmenopausal women [20]. With medical advancements pushing the boundaries of life expectancy, it becomes increasingly important to consider deaths from breast cancer in postmenopausal women as premature. These deaths represent a substantial loss of potential life years, particularly as this group is more likely to be diagnosed at later stages when treatment options are limited [21]. The lack of focused reviews on postmenopausal women in studies of breast cancer interventions fails to fully recognize the effectiveness of these treatments, leading to a knowledge gap regarding their long-term outcomes and potential for improving life quality in this population. Therefore, including patients of different types characterized by carrier status, menopausal status, etc., would provide a path for enhancing precision in treatment and contribute to healthcare equity by providing tailored and effective interventions for all patient groups, including those often underrepresented in research.

In light of these research gaps, this study aims to systematically review and analyze whether secondary risk-reducing strategies for CBC in individuals with BRCA1/2 mutations is effective, compared with no prophylaxis (or standard surveillance) in terms of CBC incidence and overall survival. Whether effectiveness differs by different carriers, menopausal status and treatment duration were also explored. This study is expected to provide insights into precision medicine through comprehensive synthesized epidemiological evidence, and health technology assessment through the estimation of parameters for evaluating the cost-effectiveness of secondary risk-reducing interventions for CBC.

Methods

Search Strategy

We conducted this systematic review and meta-analysis following the guideline of the Cochrane Handbook for Systematic Reviews of Interventions (version 6.4). Reporting adhered to the standards set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [22].

Multiple databases were searched, including PubMed, Cochrane Library, Embase, OVID Emcare, and Web of Science. The search was conducted from 14 to 31 December 2023, concentrating on keywords related to treatment for patients diagnosed with unilateral breast cancer and preventive measures against CBC in those with BRCA mutations. The search terms included "BRCA", "mutation", "variant", "contralateral risk-reducing mastectomy", "CBC", "contralateral prophylactic interventions", "hereditary breast and ovarian cancers", etc. Reference lists of identified studies were hand-searched to capture additional pertinent studies not initially retrieved through database searching. An update of the search was conducted on June 15, 2024 to include the most updated studies in the field. The specific search terms for each database are detailed in Supplementary Materials Table S2.

Criteria for Inclusion and Exclusion

Studies were included in the further screening stages if they met the following criteria: (1) randomized controlled trials, case–control studies, or cohort studies; (2) involving patients with BRCA variants and confirmed unilateral breast cancer diagnoses; (3) including risk-reducing interventions, including but not limited to CRRM, bilateral oophorectomy, chemotherapy, oral contraceptives, salipingo oophorectomy, radiotherapy, and combination therapy; (4) reporting CBC risk reduction, or CBC-specific, or overall mortality reduction due to the risk-reducing strategies; (5) reporting complete odds ratios (ORs), hazard ratios (HRs), or relative risks (RR), and 95% confidence intervals (CIs). Some interventions, such as chemotherapy and endocrine therapy, were used as adjuvant treatments to improve outcomes in patients with early breast cancer. In this review, we also evaluated their impact on reducing the risk of CBC.

We excluded studies that did not align with our research objectives, both in terms of content and study type. Specifically, studies focusing on the attitudes, decision-making, and screening method practices among BRCA1/2 carriers were excluded from our analysis. Additionally, review articles, editorials, and conference abstracts were also excluded, as they do not provide original research data. Moreover, studies with a sample size of fewer than 30 participants were excluded, as such small cohorts may not provide sufficient scope for a comprehensive analysis. We limited our review to publications in English to ensure consistency and clarity in data interpretation.

Four reviewers (YJ, TL, YYG, and XM) independently evaluated the titles and abstracts of the identified studies at the stage of the screening process. Discrepancies encountered were resolved through discussion among YJ, TL, YYG, XM, and the senior reviewers SJ, WKM, and YG.

Data Extraction

After the screening process, data from the eligible studies were extracted by four reviewers (YJ, TL, YYG, and XM). Data were extracted on: (1) the characteristics of the study, including the first author's name, year of publication, study locations, characteristics of design, including study design (whether retrospective, prospective, cohort, or case–control, sample size of participants, sample size in exposure and controlled groups, types of interventions, and the mean duration of follow-up; and (2) the characteristics of outcomes, e.g., study-specific estimates of ORs or RRs for CBC risk, and HRs for CBC-specific or overall mortality for BRCA carriers undergoing risk-reducing interventions, compared to those without any risk-reducing interventions.

When a single study reported multiple datasets that met our criteria, we considered these as separate sub-studies for our analysis. We established the distinction among these sub-studies based on the type of BRCA variant, the timing of cancer diagnosis, the type of intervention, and the intervention's duration. Each sub-study received a specific identifier, denoted by lowercase letters (a, b, c, etc.), as referenced in Supplementary Materials Tables S3, S4. We adopted a combination of descriptive and narrative synthesis to summarize the characteristics of the included studies, such as the study's location, year, and type. All results for analysis were directly extracted from the included sub-studies, ensuring our analysis was grounded in the original study data.

Quality Assessments

The Newcastle–Ottawa Scale (NOS) was employed to evaluate the quality of included nonrandomized studies, especially case–control studies and cohort studies [23]. In this systematic review and meta-analysis, the NOS assessed three critical areas of the included studies: selection of the study groups (maximum 4 stars), comparability (maximum 2 stars), and ascertainment of outcomes/exposure (maximum 3 stars). Each study was scored based on these categories, with a potential maximum of nine stars [23]. Studies achieving a score higher than 7 were classified as high quality, indicating robust research methodology, while those receiving 7 or fewer points were categorized as lower quality, reflecting possible methodological limitations [24]. This scoring process was performed independently by the reviewers JY, TL, YYG, and XM. Any differences in the assessment were reconciled through a discussion that included the senior authors, SJ, WKM, and YG, ensuring a consistent evaluation of the studies' quality.

Statistical Analysis

We carried out separate meta-analyses based on BRCA variants, intervention types, diagnosis time (i.e., premenopausal and postmenopausal) and intervention duration. The findings from these analyses were instrumental in understanding the differential impacts of interventions and BRCA variants on cancer outcomes.

We calculated 95% CIs for the pooled rates of CBC risk and mortality if not reported. RRs were transformed into ORs based on the raw data from the studies for CBC risk reduction.

The statistical heterogeneity among the studies was evaluated by the Q statistic (including p value and I²). When heterogeneity was not significant (p ≥ 0.05), we utilized fixed-effects models (Mantel–Haenszel method) [25] for pooled outcomes’ estimates. In contrast, significant heterogeneity (p < 0.05) prompted the use of random-effects models (DerSimonian and Laird method) [26]. Additionally, the potential publication bias was examined through funnel plots.

Subgroup analyses were performed to evaluate the heterogeneity in relative effectiveness of risk-reducing strategies for different variant types, and synthesize the evidence within each group. The statistical heterogeneity among the effectiveness of different interventions in specific to BRCA1 or BRCA2 was tested by meta-regression analysis. We also compared the heterogeneity in the effectiveness for patients with premenopausal and postmenopausal primary breast cancer diagnosis. We excluded studies with missing data regarding the subgroups.

All statistical procedures were conducted using the “metan” package in STATA (version 18.0, StataCorp, College Station, TX, USA).

Sensitivity Analysis

A sensitivity analysis was conducted to evaluate the robustness of the pooled effect estimates when modifying the composition of included studies. We initially incorporated all study types in our pooled estimation. Subsequently, case–control studies were excluded due to quality concerns. We then calculated the difference between the initial and revised estimates excluding case–control studies to detect any significant changes in the effect estimates that could suggest an influence of study design on the results [27].

Ethics Statement

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

Our initial search across databases and through manual effort identified 1079 records. A total of 883 records were selected for further eligibility screening after excluding 196 duplicates. Studies (n = 857) with no relevant content and study type were further excluded. Finally, 26 unique studies were selected and included in this study for further analysis (Fig. 1).

Fig. 1.

Flowchart of search results

Description of Included Studies

The extracted information from the 26 studies is summarized in Table 1, including 18 cohort studies and 7 case–control studies. All the studies originated from high-income countries. The sample sizes of the included studies range from 144 to over 3000 patients. The risk-reducing interventions included chemotherapy (e.g. anthracyclines and cyclophosphamide), endocrine therapy (e.g. tamoxifen and aromatase inhibitors), radiotherapy, and risk-reducing surgeries such as oophorectomy and mastectomy.

Table 1.

Narrative synthesis of selected studies

References	Study country	Study purpose	Study design	Participants	Sample size	Intervention	Outcome measurements
Akdeniz et al. [43]	Netherlands	Assessing chemotherapy's CBC risk effect on BRCA1/2 carriers	Cohort study	BRCA1/2 carriers with PBC	1090 BRCA1, 568 BRCA2	Chemotherapy (CMF, anthracyclines and taxanes), endocrine therapy(tamoxifen), radiotherapy	OR of incidence
Drooger et al. [44]	Netherlands	Evaluating adjuvant radiotherapy's impact on CBC risk in BRCA1/2 carriers, focus on < 40 years	Cohort study	BRCA1/2 carriers with PBC	691	Chemotherapy, endocrine therapy (tamoxifen), salpingo-oophorectomy, post-mastectomy radiotherapy	OR of incidence
Kotsopoulos et al. [45]	17 countries	Exploring oophorectomy's impact on CBC risk among BRCA1/2 mutation women	Cohort study	BRCA1/2 carriers with PBC	2303	Oophorectomy	OR of incidence
Metcalfe et al. [46]	North America	CBC risk estimation in BRCA1/2 carriers post BC diagnosis	Cohort study	BRCA1/2 carriers with PBC	491	Oophorectomy, chemotherapy, radiotherapy, endocrine therapy (tamoxifen)	OR of incidence
Phillips et al. [47]	Europe, Australia, New Zealand, USA, Canada	Evaluating tamoxifen’s effectiveness in reducing CBC risk after BC	Cohort study	BRCA1/2 carriers with PBC	1,583 BRCA1, 881 BRCA2	Endocrine therapy (tamoxifen)	OR of incidence
Shubeck et al. [28]	United States	Comparing outcomes in BRCA carriers undergoing BCS versus mastectomy	Cohort study	BRCA1/2 carriers with PBC	395	CRRM	OR of incidence
Barele et al. [48]	12 countries	Examining if adjuvant RT for PBC heightens CBC risk in BRCA1/2-associated patients with BC	Cohort study	BRCA1/2 carriers with PBC	3602	Radiotherapy, chemotherapy, endocrine therapy	OR of incidence
Ahmed et al. [49]	United States	Analyzing outcomes and survival in patients with BRCA1/2 + variants treated with accelerated partial breast irradiation	Cohort study	BRCA1/2 carriers with PBC	341	Radiotherapy	OR of incidence
Kiely et al. [50]	Australia and New Zealand	Determining the prevalence and predictors of CRRM in high familial risk women	Cohort study	BRCA1/2 carriers with PBC	1018	Adjuvant chemotherapy, RRSO, CRRM	OR of incidence
Metcalfe et al. [14]	North America	Estimating CBC risk in BRCA1/2 carriers; assessing risk modification by host, family history, and treatment factors	Cohort study	BRCA1/2 carriers with PBC	498 BRCA1, 300 BRCA2, 12 with both mutations	Oophorectomy, chemotherapy, radiotherapy, endocrine therapy (tamoxifen)	OR of incidence
Shafaee et al. [31]	United States	Investigating if AI reduce CBC risk in BRCA carriers	Cohort study	BRCA1/2 carriers with PBC	53 BRCA1, 94 BRCA2	BSO, Endocrine therapy (tamoxifen, AI, tamoxifen + AI)	HR of mortality
Evron et al. [38]	Israel	Assessing contralateral breast irradiation's role in early BC-treated BRCA carriers who decline contralateral mastectomy	Phase II, multicenter, two-arm comparative trial	BRCA1/2 carriers with PBC	162	Prophylactic irradiation	HR of mortality
Heemskerk-Gerritsen et al. [51]	The Netherlands	Examining CRRM's efficacy on overall survival in BRCA1/2 carriers with PBC history	Cohort study	BRCA1/2 carriers with PBC	193 BRCA1, 49 BRCA2	CRRM	HR of mortality
Makhnoon et al. [52]	United States	Evaluating CRRM overall survival (OS) in BRCA1/2 pathogenic variant carriers with unilateral BC	Cohort study	BRCA1/2 carriers with PBC	144	CRRM	HR of mortality
Shubeck et al. [28]	United States	Comparing outcomes in modern BRCA carriers undergoing BCS versus mastectomy	Cohort study	BRCA1/2 carriers with PBC	395	CRRM	HR of mortality
Evans et al. [53]	UK	Assessing whether CRRM improves overall survival in BRCA1/2 carriers	Cohort study	BRCA1/2 carriers with PBC	698	RRBSO, CRRM + RRBSO	HR of mortality
Soenderstrup et al. [54]	Denmark	Estimating OS and DFS based on tumor characteristics and treatment in patients with BC with post-surgery BRCA1/2 mutations	Cohort study	BRCA1/2 carriers with PBC	141 BRCA1, 97 BRCA2	CRRM	HR of mortality
Huang et al. [55]	China	Comparing prognostic impact of BCT and mastectomy in BRCA1/2 carriers and noncarriers with BC	Cohort study	BRCA1/2 carriers with PBC	490	CRRM	HR of mortality
Figueiredo et al. [56]	United States, Denmark	Investigating the impact of OC and PMH use on CBC risk in the WECARE Study	Case–control	BRCA1/2 carriers with PBC	109 BRCA1, 72 BRCA2	Oral contraceptives	OR of incidence
Gronwald et al. [57]	North America, Poland, plus 8 others countries (total 10)	Examining if tamoxifen treatment for primary BC reduces risk of subsequent contralateral cancers in BRCA1/2 carriers	Case–control	BRCA1/2 carriers with PBC	1504	Endocrine therapy (tamoxifen)	OR of incidence
Gronwald et al. [58]	10 countries	Refining the understanding of tamoxifen's protective effect, evaluating its magnitude separately for BRCA1 and BRCA2 carriers	Case–control	BRCA1/2 carriers with PBC	848 BRCA1, 188 BRCA2	Endocrine therapy (tamoxifen)	OR of incidence
Reding et al. [59]	United States and Denmark	Evaluating the effects of chemotherapy and tamoxifen on CBC risk in BC cases, considering BRCA1/2 status	Case–control	BRCA1/2 carriers with PBC	210	Endocrine therapy (tamoxifen)	OR of incidence
Narod et al. [60]	Canada	Estimating tamoxifen's protective effect against contralateral BC in BRCA1/2 carriers	Case–control	BRCA1/2 carriers with PBC	593	Endocrine therapy (tamoxifen)	OR of incidence
Pierce et al. [61]	United States, Canada, Isreal	Comparing outcomes of breast-conserving surgery and radiotherapy in BRCA1/2 carriers with BC to matched sporadic controls	Case–control	BRCA1/2 carriers with PBC	123 BRCA1, 37 BRCA2	Endocrine therapy (tamoxifen)	HR of mortality
Reiner et al. [62]	Denmark and the United States	Investigating how radiotherapy and genetic variants in ATM, BRCA1/2, and CHEK2 genes affect cumulative CBC risk	Case–control	BRCA1/2 carriers with PBC	2107	Radiotherapy	OR of incidence
Sprundel et al. [63]	The Netherlands	Estimate the efficacy of CRRM in reducing the CBC risk and overall mortality among women with pathogenic BRCA1 or BRCA2 variants and a personal history of unilateral invasive breast cancer	Cohort study	BRCA1/2 carriers with PBC	115 BRCA, 33 BRCA2	CRRM	HR of mortality

AI aromatase inhibitors, BC breast cancer, BCT breast-conserving therapy, BCS breast-conserving surgery, BSO bilateral salpingo-oophorectomy, CBC contralateral breast cancer, CRRM contralateral risk-reducing mastectomy, HR hazard ratio, OC oral contraceptive, OR odds ratio, OS overall survival, PBC primary breast cancer, PMH post-menopausal hormone, RR relative risk, RRBSO risk-reducing bilateral salpingo-oophorectomy, RRSO risk-reducing salpingo-oophorectomy, RT radiation treatment, PBC primary breast cancer, WECARE Women’s Environment, Cancer and Radiation Epidemiology

Risk-Reducing Interventions in CBC Risk and Mortality

A total of 17 of the 26 studies investigated the risk of CBC in BRCA carriers who received risk-reducing interventions relative to standard surveillance. Subgroup analysis by different risk-reducing interventions is presented in Table 2, indicating varying levels of heterogeneity in effectiveness for CBC risk and mortality reduction. Overall, there was a significant decrease in CBC risk with risk-reducing interventions (OR 0.62, 95% CI 0.57–0.68). CRRM (OR 0.16, 95% CI 0.05–0.95, n = 1 study) [28], endocrine therapy (OR 0.54, 95% CI 0.49–0.60, n = 12 studies) and prophylactic contralateral irradiation (OR 0.20, 95% CI 0.05–0.88, n = 1 study) were relatively more effective than other therapies, for example, chemotherapy (OR 0.61, 95% CI 0.51, 0.73, n = 9 studies) and combined therapy (OR 0.60, 95% CI 0.38–0.97, n = 4 studies). Oral contraceptives (OR 0.98, 95% CI 0.54–1.78, n = 1 study) and ipsilateral adjuvant radiotherapy (OR 1.14, 95% CI 1.00–1.29, n = 4 studies) had weak or no protective effects compared to other interventions. Significant heterogeneity were observed among studies investigating the impact of chemotherapy on CBC incidence (I² = 56.20%), while there was low heterogeneity among the studies investigating the impact of other interventions on CBC incidence (I² < 50%).

Table 2.

Subgroup analysis for different risk-reducing interventions

Subgroup	OR/HR (95% CI)	I2 Value	p value	Number of studies
CBC risk
Chemotherapy	0.61 (0.51–0.73)	56.20%	< 0.000	9
Endocrine therapy	0.54 (0.49–0.6)	30.90%	0.01	12
Ipsilateral adjuvant radiotherapy	1.14 (1.0–1.29)	15.40%	0.285	4
Prophylactic contralateral irradiation	0.02 (0.05–0.88)	0.00%	< 0.000	1
Bilateral oophorectomy	0.66 (0.54–0.8)	45.20%	0.010	7
Combination therapy	0.60 (0.38–0.97)	33.20%	0.174	3
CRRM	0.16 (0.05–0.95)	0.00%	0.528	1
Oral contraceptive	0.98 (0.54–1.78)	5.80%	0.364	1
Overall	0.62 (0.57–0.68)	58.10%	< 0.000	–
Overall mortality
CRRM	0.59 (0.46–0.76)	0.00%	0.897	9
Bilateral oophorectomy	0.61 (0.32–1.17)	11.10%	0.325	2
Combination therapy	0.16 (0.06–0.43)	0.00%	< 0.000	1
Overall	0.55 (0.44–0.70)	0.00%	0.497	–
CBC-specific mortality
CRRM	0.51 (0.31–0.83)	0.00%	0.744	3
Bilateral oophorectomy	0.74 (0.29–1.89)	0.00%	< 0.000	1
Overall	0.55 (0.36–0.85)	0.00%	0.783	–

The p values presented in this table represent the significance level of heterogeneity between the studies, as indicated by the I² statistic

CBC contralateral breast cancer, CI confidence interval, CRRM contralateral risk-reducing mastectomy, HR hazard ratio, OR odds ratio

A total of 9 of the 26 studies investigated overall mortality in BRCA carriers who received risk-reducing interventions relative to standard surveillance. Overall, there was a significant reduction in mortality with risk-reducing interventions (HR 0.55, 95% CI 0.44–0.70). Combined therapy (HR 0.16, 95% CI 0.06–0.43, n = 1 study) and CRRM (HR 0.59, 95% CI 0.46–0.76, n = 9 studies) were the most effective. The impact of bilateral oophorectomy was not statistically significant (HR 0.61, 95% CI 0.32–1.17, n = 2 studies), as presented in Figure S1 in the Supplementary Materials.

There was also a significant reduction in CBC-specific mortality with risk-reducing interventions (HR 0.55, 95% CI 0.36, 0.85), as detailed in Figure S2. Again, CRRM was the most effective intervention (HR 0.51, 95% CI 0.31–0.83, n = 3 studies), and the impact of bilateral oophorectomy was not statistically significant (HR 0.74, 95% CI 0.29–1.89, n = 1 study). Heterogeneity across the studies was not significant (I² < 50%).

Risk-Reducing Interventions and Carriers’ Characteristics

BRCA1 Carriers

Nine studies examine the effectiveness of risk-reducing interventions in CBC risk reduction for BRCA1 carriers, as depicted in Table 3 and Supplementary Materials Figure S3. Overall, there was a significant decrease in CBC risk with risk-reducing interventions for BRCA1 carriers (OR 0.64, 95% CI 0.53–0.76). Chemotherapy (OR 0.50, 95% CI 0.33–0.78, n = 5 studies) was the most effective intervention compared with other interventions. Endocrine therapy also demonstrated a notable protective effect (OR 0.56, 95% CI 0.45–0.70, n = 7 studies). Bilateral oophorectomy showed a slightly decreased protective effect against CBC risk that was not statistically significant (OR 0.59, 95% CI 0.31–1.41, n = 2 studies). Radiotherapy (OR 1.16, 95% CI 0.94–1.42, n = 4 studies) and oral contraceptive (OR 1.40, 95% CI 0.62–3.18), did not demonstrate protective effects against CBC risk.

Table 3.

Effectiveness of risk-reducing interventions in BRCA1 carriers

Interventions	OR (95% CI)	I2 value (%)	p value
Chemotherapy	0.50 (0.33–0.78)	69.10	0.002
Endocrine therapy	0.56 (0.45–0.70)	57.50	0.002
Ipsilateral adjuvant radiotherapy	1.16 (0.94–1.42)	0.00	0.823
Bilateral oophorectomy	0.59 (0.31–1.14)	74.80	0.019
Oral contraceptive	1.40 (0.62–3.18)	6.30	0.301
Overall	0.64 (0.53–0.76)	69.8	< 0.000

The p values presented in this table represent the significance level of heterogeneity between the studies, as indicated by the I² statistic

CI confidence interval, OR odds ratio

A meta-regression analysis was conducted to explore the heterogeneity in the effectiveness of different interventions for BRCA1 carriers. The analysis revealed significant between-study heterogeneity, with a coefficient for intervention type of − 0.164 (95% CI − 0.314 to − 0.013, p = 0.034) as shown in Supplementary Materials Figure S4. This indicates that the effectiveness of different interventions varied significantly across studies.

BRCA2 Carriers

Ten studies assessed the effectiveness of various risk-reducing interventions for BRCA2 carriers, as shown in Table 4 and Supplementary Materials Figure S5. Overall, there was a significant decrease in CBC risk with risk-reducing interventions for BRCA2 carriers (OR 0.59, 95% CI 0.48, 0.72). Endocrine therapy was the most effective intervention (OR 0.47, 95% CI 0.37–0.60, n = 8 studies). Both chemotherapy and bilateral oophorectomy showed similar effectiveness in reducing CBC risk, however chemotherapy's effect was statistically significant (OR 0.62, 95% CI 0.46–0.85, n = 5 studies), but bilateral oophorectomy had a wider confidence interval (OR 0.62, 95% CI 0.35–1.10, n = 3 studies). Similar to BRCA1 carriers, radiotherapy in BRCA2 carriers did not provide risk-reducing benefits (OR 1.05, 95% CI 0.64–1.75, n = 4 studies).

Table 4.

Effectiveness of risk-reducing interventions in BRCA2 carriers

Interventions	OR (95% CI)	I2 value (%)	p value
Chemotherapy	0.62 (0.46–0.85)	0.00	0.482
Endocrine therapy	0.47 (0.37–0.60)	34.60	0.085
Ipsilateral adjuvant radiotherapy	1.05 (0.63–1.75)	59.70	0.059
Bilateral oophorectomy	0.62 (0.35–1.10)	0.00	0.774
Oral contraceptive	0.65 (0.28–1.53)	0.00	0.504
Overall	0.59 (0.48–0.72)	51.00	< 0.000

The p values presented in this table represent the significance level of heterogeneity (p) between the studies, as indicated by the I² statistic

CI confidence interval, OR odds ratio

Notably, endocrine therapy had a greater protective effect in BRCA2 carriers than in those with BRCA1 variants (OR 0.46, 95% CI 0.38–0.55 in BRCA2 versus OR 0.57, 95% CI 0.50–0.66 in BRCA1), as detailed in Supplementary Materials Figure S6.

A meta-regression analysis was performed to assess the heterogeneity in the effectiveness of various interventions for BRCA2 carriers. The results demonstrated significant between-study heterogeneity, with a coefficient for intervention type of − 0.136 (95% CI − 0.245 to − 0.027, p = 0.016) as showed in Supplementary Materials Figure S7. This highlights that the effectiveness of different interventions varied significantly across studies.

Premenopausal and Postmenopausal

Heterogeneity was found across studies of different menoposal status, as shown in Table 5 and Supplementary Materials Figure S8. In postmenopausal BRCA carriers, interventions had a higher protective effect against CBC risk (OR 0.53, 95% CI 0.40–0.71, n = 3 studies). Conversely, the protective effect was slightly lower in premenopausal carriers (OR 0.66, 95% CI 0.53–0.82, n = 5 studies).

Table 5.

Effectiveness of risk-reducing interventions in pre or postmenopausal

Menopausal status	OR (95% CI)	I2 value (%)	p value
Pre-menopasual	0.95 (0.81–1.11)	0.00	0.845
Post-menopasual	0.49 (0.36–0.66)	0.00	0.909
Overall	0.79 (0.67–0.94)	28.4	0.000

The p values presented in this table represent the significance level of heterogeneity between the studies, as indicated by the I² statistic

CI confidence interval, OR odds ratio

Tamoxifen Usage Duration

The efficacy of tamoxifen as an endocrine risk-reducing intervention varies with the duration of use (Table 6 and Supplementary Materials Figure S9). For a 1-year duration, a substantial decrease in CBC risk was observed (OR 0.36; 95% CI 0.24–0.55). However, this protective effect was slightly less pronounced with tamoxifen use for 1–4 years (OR 0.52; 95% CI 0.38–0.72). When the duration extended beyond 5 years, the effectiveness further decreased (OR 0.73; 95% CI 0.48–1.11). The meta-regression analysis, as shown in Supplementary Materials Figure S10, further indicated that with increasing duration of tamoxifen use, the protective effect may diminish over time.

Table 6.

Tamoxifen usage duration and CBC risk reduction

Tamoxifen usage duration	OR (95% CI)	I2 value (%)	p value
1 year	0.36 (0.24–0.55)	0.00	0.944
1–4 years	0.52 (0.38–0.72)	0.00	0.835
Over 4 years	0.73 (0.48–1.11)	18.90	0.296
Overall	0.52 (0.42–0.65)	0.00	0.446

The p values presented in this table represent the significance level of heterogeneity between the studies, as indicated by the I² statistic

CBC contralateral breast cancer, CI confidence interval, OR odds ratio

Risk of Bias of Studies

The risk of bias for the studies has been summarized in Table 7. Seven studies attained the maximum score of nine stars, denoting a particularly high quality. In contrast, six studies with seven or fewer stars, indicating a relatively lower quality. In addition, Fig. 2 provides a visual illustration of the distribution of bias risk levels within the three domains of Selection, Comparability, and Exposure/Outcome. Two studies had a relatively higher level of risk of bias in Exposure/Outcome, while other 23 studies had a medium or low risk of bias in Exposure/Outcome. All 25 studies had a medium or low risk of bias in the domain Selection and Comparability.

Table 7.

Bias assessment outcomes based on the Newcastle–Ottawa Scale

Study and publication years	Selection				Comparability	Exposure/outcome			Risk of bias
Akdeniz et al. (2022)	*	*	*		**	*	*	*	Low
Drooger et al. (2015)	*	*	*	*	**	*	*	*	Low
Kotsopoulos et al. (2019)	*	*	*	*	**	*	*	*	Low
Metcalfe et al. (2004)	*	*	*	*	**	*	*	*	Low
Phillips et al. (2013)	*	*		*	**		*	*	High
Shubeck et al. (2022)	*	*	*		*	*	*	*	High
Barele et al. (2023)	*	*	*	*	*	*	*	*	Low
Ahmed et al. (2019)	*	*		*	**	*	*	*	Low
Kiely et (2010)	*	*	*	*	**	*	*	*	Low
Metcalfe et al. (2011)	*	*		*	**	*	*	*	Low
Shafaee et al. (2022)	*	*		*	**	*	*	*	Low
Evron et al. (2019)	*	*	*	*	*	*	*	*	Low
Heemskerk-Gerritsen et al. (2015)	*	*	*	*	**	*	*	*	Low
Makhnoon et al. (2022)	*		*	*	**	*	*	*	Low
Shubeck et al. (2022)	*		*	*	**	*	*	*	Low
Soenderstrup et al. (2018)	*		*	*	**	*	*	*	Low
Huang et al. (2020)	*	*	*	*	*	*	*	*	Low
Figueiredo et al. (2010)	*	*	*	*	*	*	*	*	Low
Gronwald et al. (2014)	*	*	*	*	*	*	*	*	Low
Gronwald et al. (2006)	*	*		*	*	*	*	*	High
Reding et al. (2010)	*	*	*	*	*	*			High
Narod et al. (2000)	*	*	*	*	**	*	*		Low
Pierce et al. (2006)	*	*		*	*	*	*		High
Reiner et al. (2020)	*	*	*	*	*			*	High
Sprundel et al. (2005)	*	*	*	*	**	*	*	*	Low

Stars are awarded based on the Newcastle–Ottawa Scale (NOS) for risk of bias, with up to four stars for Selection, two for Comparability, and three for Outcome or Exposure. Studies scoring the maximum in each category are considered to have a low risk of bias

Fig. 2.

Distribution of the risk of bias across studies

Sensitivity Analysis

The sensitivity analysis assessing the effect on CBC risk of excluding case–control studies on our meta-analysis estimates is presented in Table 8. The effect sizes were minimally affected by excluding case–control studies. Specifically, the effect size estimate for BRCA1/2 variants was reduced by 0.056, and the estimates for BRCA1 and BRCA2 individually showed a decrease of 0.015. Effect size changes for the assessed interventions did not surpass 0.07, indicating that the meta-analysis estimates were stable and reliable.

Table 8.

Sensitivity analysis of effectiveness change with exclusion of case–control studies

	OR	OR after remove case–control studies	Difference
All variants	0.64	0.69	− 0.06
BRCA1	0.64	0.65	− 0.02
BRCA2	0.59	0.61	− 0.02
Interventions
Radiotherapy	1.16	1.15	0.01
Endocrine	0.56	0.55	0.01
Chemotherapy	0.64	0.62	0.02
Bilateral oophorectomy	0.80	0.73	0.07
CRRM	0.16	0.21	− 0.05
Combination intervention	0.62	0.68	− 0.06

CRRM contralateral risk-reducing mastectomy, OR odds ratio

Discussion

This was an updated and comprehensive study systematically reviewing the effectiveness of current secondary risk-reducing interventions for CBC in patients with BRCA1/2 variants carriers and a breast cancer history. Our meta-analysis summarized the effectiveness of these interventions on CBC risk reduction and overall survival improvement. The results of our analysis indicated that these secondary risk-reducing measures were significantly effective, leading to a near 40% reduction in CBC risk and over a 50% improvement in both overall survival and CBC-specific survival rates. We also highlighted that such risk reduction varied by variants, menopausal status at diagnosis, and treatment duration. These findings collectively demonstrate the potential for tailored secondary interventions to improve life expectancy for patients with breast cancer with BRCA variants.

The genetic landscape of breast cancer susceptibility has been increasingly clarified through large-scale studies. In breast cancer cases, these frequencies are significantly higher, with BRCA1 occurring in 1 in 101 cases and BRCA2 in 1 in 68 cases. In the general population, BRCA mutations occur with notable frequency. For example, BRCA2 has a prevalence of around 0.25% (1 in 400) [29]. In certain populations, such as Ashkenazi Jewish individuals, the prevalence of these variants can reach 1 in 40 [30]. Carriers of these variants face a substantially higher risk of developing cancers. Specifically, the risk of CBC within 10 years for BRCA1 and BRCA2 carriers is between 20 and 30%, and this risk increases to 40–50% over 20 years, markedly higher than in the general population [31, 32]. The high incidence of associated cancers underscores the critical need for preventive strategies for BRCA carriers, such as the secondary risk-reducing interventions in the context of this study. Furthermore, we noticed the difference between BRCA1 and BRCA2 carriers in terms of their genetic predisposition risk and response to risk-reducing interventions. When receiving risk-reducing interventions, BRCA1 carriers showed a 36% reduction in CBC risk, while BRCA2 carriers experienced a 41% reduction. This heterogeneity highlights the necessity of individualized risk-reducing strategies tailored to the specific variant in the spirit of precision medicine.

To conduct individualized risk-reducing strategies, we need to understand the heterogeneity between different BRCA types in the interventional context. BRCA2 carriers may potentially experience a reduction in risk due to oral contraceptives (35%), while, for BRCA1 carriers, oral contraceptives show no protective effects (OR 1.40). The difference between BRCA1 and BRCA2 carriers and among different interventions is partly rooted by variations in estrogen receptor (ER) status. Breast cancers associated with BRCA1 mutations are typically ER-negative [33], whereas most BRCA2-related breast cancers tend to be ER-positive [34]. This difference in ER status is associated with different response rates to hormonal therapies [35, 36]. Therefore, these findings suggest that the integration of BRCA types into the medical decision-making process for risk-reducing interventions is crucial.

Our study indicates a decreasing trend of tamoxifen efficacy in reducing CBC risk among BRCA carriers who were ER-positive. Specifically, a 1-year usage of tamoxifen was associated with a 64% reduction in CBC risk. However, this benefit diminished to 48% with a duration of 1–5 years, and further reduced to 27% when the use of tamoxifen extended beyond 5 years. This trend of diminishing efficacy stands in contrast to the finding of Gierach et al. (2016), who suggested an increasing trend of tamoxifen efficacy in reducing CBC risk among the general patients with breast cancer. This divergence may be because of the distinct response of BRCA carriers to tamoxifen compared to the general patients with breast cancer. This evidence emphasize the importance of differentiating BRCA carriers from the general patients with breast cancer. This differentiation also reinforces the individualized preventive strategy for BRCA carriers to implement precision medicine [37].

We also noticed heterogeneity between different interventional contexts to reduce cancer risk for each BRCA subgroup. Specifically, for BRCA1 carriers, chemotherapy had the greatest protective effect (50%) compared to other interventions, such as endocrine therapy (40%). For BRCA2 carriers, endocrine therapy was the most effective for BRCA2 carriers (a 53% CBC risk reduction) compared to other interventions. The heterogeneity between interventions provides clinical implications that, for different BRCA subgroups, the most effective interventions should be considered to provide a tailored preventive strategy.

In our review of risk-reducing interventions, we identified important differences in how radiotherapy is used to address CBC risk. Ipsilateral radiotherapy, typically given to the treated breast or chest wall after surgery, did not show any significant effect on reducing CBC risk, which is consistent with its primary role of preventing local recurrence. On the other hand, contralateral prophylactic irradiation has been examined as a strategy for lowering CBC risk specifically in BRCA1/2 mutation carriers. For instance, the study by Evron et al. [38] found that prophylactic irradiation of the contralateral breast significantly reduced CBC incidence by around 80% among BRCA mutation carriers. However, it is important to note that this short-term risk reduction may be due to the elimination of pre-existing small tumors rather than long-term prevention. Additionally, the small sample size and limited follow-up (median 58 months) suggest that further long-term studies are needed to confirm its effectiveness, as the overall risk between groups was similar at 120 months. Despite these limitations, these findings highlight the distinct purposes of ipsilateral radiotherapy and contralateral prophylactic irradiation. While the former is critical for local control, the latter offers a promising approach to reducing CBC risk in high-risk patients. Acknowledging these differences in clinical practice could allow for more personalized prevention strategies, particularly for BRCA mutation carriers who might not opt for contralateral mastectomy.

In our review of risk-reducing interventions, we identified important differences in how radiotherapy is used to address CBC risk. Ipsilateral radiotherapy, typically given to the treated breast or chest wall after surgery, did not show any significant effect on reducing CBC risk, which is consistent with its primary role of preventing local recurrence. On the other hand, contralateral prophylactic irradiation has been examined as a strategy for lowering CBC risk specifically in BRCA1/2 mutation carriers. For instance, the study by Evron et al. [37] found that prophylactic irradiation of the contralateral breast significantly reduced CBC incidence by around 80% among BRCA mutation carriers. These findings highlight the distinct purposes of ipsilateral radiotherapy and contralateral prophylactic irradiation. While the former is critical for local control, the latter offers a promising approach to reducing CBC risk in high-risk patients. Acknowledging these differences in clinical practice could allow for more personalized prevention strategies, particularly for BRCA mutation carriers who might not opt for contralateral mastectomy.

In addition to BRCA types, this study also observed heterogeneities when comparing premenopausal and postmenopausal patients. Notably, interventions for postmenopausal women benefited more from the risk-reducing interventions, showing a 47% reduction in CBC risk compared to a 34% reduction for premenopausal women. This may first of all be confounded by the selections of the interventions by doctors and patients. Second, these varied effects imply that menopausal status at the time of diagnosis could be a critical factor influencing the response to interventions. It is plausible that the physiological changes accompanying menopause might modify the response to preventive interventions. The hormonal milieu in premenopausal carriers is significantly higher than that in postmenopausal carriers, which potentially leads to lower response rates to various interventions. Therefore, in contrast to previous research focusing on preventing premature death in premenopausal women [20, 39], our study emphasizes the critical need to include postmenopausal women in breast cancer research. This inclusion is crucial for implementing better health equity between patients of different menopause status, which motivates the modification of the current clinical guidelines to incorporate menopausal status in an individualized interventions strategy.

It has been found that the uptake rate of risk-reducing intervention largely depends on the time of receiving genetic testing. Previous studies highlighted the association between the genetic testing and risk-reducing intervention, noting a higher propensity for women with early genetic testing to receive risk-reducing interventions [40, 41], which leads to better health outcomes. This underscores the significant reliance of preventive strategies on early genetic testing. From an economic perspective, the better health outcome may improve the cost-effectiveness of genetic testing, which is in debate of covering genetic testing by the publicly funded health insurance. The fact that the timing of genetic testing affects the uptake rate of risk-reducing interventions implies that future economic evaluations of genetic testing should consider the time of patients receiving genetic testing.

Limitations

Our study's insights into secondary risk-reducing interventions for BRCA1/2 carriers, while informative, are subject to several limitations. First, the patients in the included studies were predominantly from high-income countries. We are concerned that the results and conclusions of this study might not be able to be generalized to patients from low- and middle-income countries (LMICs). Since we notice the significant unmet need of patients from LMICs [42], we call for future medical studies focusing on the efficacy of interventions in LMICs. Second, we noticed that the included studies in our review did not simultaneously report BRCA status and ER status—which limited our ability to conduct evidence synthesis with higher preciseness. This is possibly due to the clinical application of personalized interventions based on both genetic and ER status is still in its infancy, thereby very limited real-world evidence has been generated. Third, data for some interventions, such as oral contraceptives and tamoxifen use for less than 1 year, were limited to a small number of studies. Specifically, the data for tamoxifen use under 1 year were derived from a single study involving 137 patients. This restricts the strength of conclusions drawn for this subgroup and introduces potential bias in our meta-regression analysis. We acknowledge this as a limitation and emphasize the need for further studies with more comprehensive data on different tamoxifen usage durations. Fourth, studies may be confounded by other factors and were inconsistent in terms of the range of confounders used as control variables when estimating ORs, RRs, or HRs. In addition, several studies did not provide sufficient data to adjust for survival bias or left censoring, particularly for CRRM and BSO. Some patients underwent CBC or BSO several years after their initial diagnosis, which may have introduced survival bias. Many studies also lacked adjustments for tumor stage and ER status. As a result, the mortality-related findings should be interpreted with caution, and future research should address these limitations with more detailed data and adjustments. Furthermore, although the included studies had extended follow-up periods, the long-term effects of chemotherapy on CBC risk beyond those durations remain uncertain and require further investigation to fully understand its impact over time.

Conclusion

We conducted a meta-analysis to provide a synthesized evidence on the effectiveness of secondary risk-reducing interventions in preventing contralateral breast cancer for BRCA1/2 carriers. While we observed a substantial reduction in breast cancer risk and mortality rate, the preventive effects varied by genetic variant, menopausal status, and treatment duration.

These results highlight the importance of precision medicine in contralateral breast cancer prophylaxis, advocating for tailored preventive strategies engaging individual genetic and physiological characteristics. This study also provides insights into disease modeling and HTA studies that evaluate the health economics of risk-reducing interventions in patients with BRCA variants following breast cancer.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Conceptualization: Yuanyuan Gu and Wai-kit Ming; methodology: Jing Yu, Taoran Liu, Shan Jiang, Yangyang Gao and Xinyang Ma; formal analysis: Jing Yu, Shan Jiang, Taoran Liu, Yangyang Gao, Xinyang Ma; resources: Yuanyuan Gu and Wai-kit Ming; writing—original draft preparation: Jing Yu, Taoran Liu, Shan Jiang, Yangyang Gao and Xinyang Ma; writing—review and editing: Jing Yu, Shan Jiang, Taoran Liu, Yangyang Gao, Xinyang Ma, Ginenus Fekadu, Yunqiu Xia, Bonny Parkinson, Yuanyuan Gu and Wai-kit Ming; visualization: Jing Yu, Taoran Liu and Yangyang Gao, All authors have read and agreed to the published version of the manuscript.

Funding

Open access funding provided by City University of Hong Kong Library’s agreement with Springer Nature. No funding or sponsorship was received for the publication of this article.

Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Jing Yu, Taoran Liu, Yangyang Gao, Xinyang Ma, Ginenus Fekadu, Yunqiu Xia, Bonny Parkinson, Yuanyuan Gu and Wai-kit Ming declare that they have no conflicts of interest related to this manuscript. Shan Jiang is an Editorial Board member of Advances in Therapy. He was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.