Impact of contralateral prophylactic mastectomy on survival outcomes in patients with unilateral breast cancer: A systematic review and meta-analysis

Objective: To synthesize contemporary evidence of the impact of contralateral prophylactic mastectomy (CPM) on survival outcomes in patients with unilateral breast cancer (UBC). Methods: PubMed, EMBASE and Scopus databases were searched for observational studies published up to November 15, 2023. Random-effects model was used to obtain pooled effect estimates that were reported as hazards ratio (HR) with 95% confidence intervals (CI). The outcomes of interest were overall survival (OS), breast cancer-specific survival (BCSS), recurrence free survival (RFS) and risk of contralateral breast cancer (CBC). Results: Twenty-one studies were included. Most studies had a retrospective design. CPM was associated with significant improvement of OS (HR 0.80, 95% CI: 0.75, 0.85), BCCS (HR 0.82, 95% CI: 0.74, 0.90), and RFS (HR 0.72, 95% CI: 0.60, 0.86) and significantly reduced risk of CBC (HR 0.05, 95% CI: 0.03, 0.09) in patients with UBC. No evidence of publication bias was detected. Conclusion: Our results provide strong evidence supporting the positive impact of CPM on survival outcomes in patients with UBC. Further research and long-term follow-up studies are warranted to validate these findings.


INTRODUCTION
Breast cancer is the most prevalent female cancer, with about 2.3 million new cases reported worldwide the year 2000 and documented that CPM was linked to a significant increase in the OS of recipients when compared to non-recipients. 8CPM was also found to be associated with lower risks of breast cancer specific mortality and risk of CBC.With the publication of more contemporary data, there is a pressing need for an updated and comprehensive review of the recent studies.Understanding the impact of CPM on survival outcomes is crucial, as it directly informs treatment decisions and influences the evolving landscape of breast cancer care.The current review aimed to fill the existing gap by conducting a thorough literature search and synthesizing data from relevant contemporary studies to critically assess whether CPM confers a survival benefit in cases of UBC.

Databases searched and search strategy:
An extensive and systematic search was done in PubMed, Embase, and Scopus databases.We used a combination of keywords, and the search was confined to studies published up to November 15, 2023.Manual search of reference lists and relevant review articles was done as well.Inclusion and exclusion criteria: Studies of female patients with UBC, specifically examining the correlation between CPM in the apparently healthy breast, and reporting various outcomes such as OS, BCSS, recurrence-free survival (RFS), and the risk of CBC were included.The selected studies were required to include control subjects under surveillance without any surgical or non-surgical intervention in the contralateral breast.English-language, peer-reviewed observational studies (cohort studies and case-control studies), and randomized controlled trials were eligible for inclusion.To ensure the reliability of reported effect sizes in the included studies, we considered only those studies that provided adjusted effect sizes for the specified outcomes.This was done to mitigate bias in the reported associations.
We excluded studies published before the year 2000, studies where the control group underwent any form of surgical intervention or radiotherapy in the contralateral breast, and studies reporting unadjusted effect sizes.Case reports, letters, reviews, and conference abstracts were also excluded.Study screening and final selection: After obtaining the initial set of studies from the search across the database's, duplicated studies were removed.Two researchers from our team independently conducted a review of the remaining studies.In the initial screening phase, titles and abstracts of each study were assessed to determine their potential relevance to the research question.Studies meeting predefined criteria were selected for further evaluation.In the subsequent stage, a detailed assessment of the full texts of the selected studies was carried out to determine their eligibility for inclusion.Any discrepancies or disagreements regarding study inclusion were resolved through discussions among the study authors.The meta-analysis adhered to the PRISMA guidelines. 9We registered the study protocol in PROSPERO, a prospective register for systematic reviews (Registration number [CRD42023484810]).

Statistical analysis, including data extraction and quality assessment:
Data from the final set of studies were extracted independently by two authors, using

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a standardized data extraction Form.In cases of any disparities, discussions were done to reach a consensus.The Newcastle-Ottawa Scale (NOS) assessed potential bias in the included studies. 10Pooled effect sizes were reported as hazard ratios (HR) with 95% confidence intervals (CI).A random-effects model was used for all analyses to account for the variations in the baseline characteristics.Publication bias was assessed by funnel plots and Egger's test. 11P< 0.05 was statistically significant.

RESULTS
Search of the databases identified 281 studies (Fig. 1).After eliminating 33 duplicate papers, 248 unique studies underwent an initial screening based on titles and abstracts, leading to the exclusion of 210 studies, not meeting the predetermined criteria.Full texts examination of the remaining 38 studies led to the exclusion of an additional 17 studies.At the end, 21 studies were incorporated in our meta-analysis.  Suppentary Table-I provides details of the included studies.All, except one, were retrospective cohort studies.Most were conducted in the United States (n=12), followed by China (n=4) and Netherlands (n=2).One study each was done in Canada, United Kingdom, and Australia (Supplementary Table-I).The included studies reported data of a total of 10,47,497 patients of them, 9,32,779 underwent unilateral mastectomy only, and 1,14,718 underwent additional contralateral mastectomy.A total of 19 studies, out of 21, reported on the stage of tumour and all of them had patients with stage one or two tumour.
Eleven studies had reported on the grade of the tumour: seven had patient with grade three or four tumour and remaining four had patients with grade one or two tumour (Supplementary Table-I).Three studies had patients with triple negative tumour.Out of seven studies that reported HER-2 status, all were negative.There were 13 studies with most patients with hormonal receptor-positive (HR+) tumour and two studies had patients with HR-tumour.The follow up period varied among the studies and ranged from 35 months (roughly three years) to 17.3 years (Supplementary Table-I).NOS score of 13 studies was eight (out of a maximum attainable score of nine) and NOS of another eight studies was seven.The average NOS score of the included studies was 7.6, indicating that the studies were of acceptable quality.

Overall survival (OS):
Patients who underwent CPM had significantly improved OS (HR 0.80, 95% CI: 0.75, 0.85; N=20, I 2 =70.1%) (Fig. 2), with no evidence of publication bias, as confirmed by funnel plots and the Egger's test (p=0.58)(Supplementary Fig. 1).The subgroup analysis showed that patients with early stage (Stage-I or II) tumour had better OS with CPM.CPM was associated with improved OS (Table-I), irrespective of the tumour grade.However, the association with improved OS was found only in HR+ patients, and not in HR-or triple negative patients (Table -

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bias on Egger's test (p=0.77)(Supplementary Fig. 2).
The subgroup analysis showed that patients with early-stage (Stage-I or II) and low-grade (Grade-1 or 2) tumours exhibited improved BCSS with CPM.
Additionally, CPM was associated with better BCSS in HR+ patients, and triple negative patients (Table-I).However, this association with improved BCSS was not observed in patients with high-grade (Grade-2 or 3) tumours or HR-negative tumours (Table-I).For some of the performed analyses, the number of studies were few and therefore, statistical significance may not have been achieved, even if there was one.
There was no evidence of publication bias, either on egger's test (p=0.32)or on inspection of funnel plot (Supplementary Fig. 4).The subgroup analysis revealed that this association was present in all subgroups, for which data were available from individual studies (Table-I).

DISCUSSION
The findings of our meta-analysis provide compelling evidence supporting the favourable outcomes associated with CPM among women diagnosed with UBC.CPM was associated with significantly improved OS, BCSS, RFS, and lower risk of CBC.Our findings are similar to the previous two reviews on this issue. 7,8A review by Jia et al. revealed that CPM correlated with a decreased risk of CBC, underscoring the preventive nature of this surgical intervention.Moreover, the review highlighted a significant increase in both OS and BCSS among patients opting for CPM compared to those receiving no intervention on the contralateral breast.A study by Fayanju et al that included 14 studies showed a significantly higher OS in CPM patients compared to patients who did not undergo the surgery. 8Moreover, CPM was associated with lower

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Supplementary Table - This risk reduction may contribute to an improved OS rate.The decision to undergo CPM is often influenced by psychological factors, including anxiety and fear of cancer recurrence. 33,34For some women, the removal of the contralateral breast might alleviate psychological distress associated with the constant fear of developing a new cancer in the unaffected breast. 34he resulting reduction in psychological burden may positively impact overall well-being and contribute to a better quality of life, indirectly influencing OS, and contributing to an improved BCSS.UBC patients who opt for CPM possibly reduce the burden of dealing with bilateral disease.Bilateral involvement can complicate treatment approaches and present additional challenges, associated with managing two separate breast cancers.In such cases, opting for CPM may potentially lead to improved disease-specific outcomes.
There is limited data on the practice of conducting CPM.Available data is mostly from developed settings.A recent systematic review 4 documented that in the USA, between 2004 and 2012, there was a nearly three-fold rise in CPM rates across all age groups, with the most substantial increase observed among women under 40 years old.CPM rates exhibited an inverse correlation with age, ranging from 3% in patients aged 70 or older to 30% in those aged 20 to 29.Factors significantly associated with opting for CPM included tumor type, particularly lobular histology, hormone receptor-positive (ER+/PR+) cancer, Caucasian ethnicity, and possessing private insurance.The primary motivations for undergoing CPM were to mitigate mortality risk and eliminate the potential of contralateral breast cancer occurrence.Increased societal attention toward breast cancer prevention, screening, and genetic testing may contribute to an overestimation of contralateral breast cancer risk among patients.Moreover, the review highlights the influential role of surgeons' opinions in patients' decisions regarding CPM.
In addition to exploring the impact of contralateral prophylactic mastectomy (CPM) on survival outcomes, a retrospective study by Fei et al. 35 , investigated the influence of a single esketamine intravenous (IV) injection on the recovery of breast cancer patients following modified radical mastectomy.The findings revealed that esketamine significantly improved the quality of early recovery.This suggests that esketamine, known for its anesthetic and analgesic properties, could be a beneficial adjunct in perioperative care, enhancing the immediate postoperative experience of mastectomy patients.While our primary focus remains on CPM's impact on survival, acknowledging such studies is essential, as they contribute valuable insights into optimizing the holistic care of breast cancer patients during the immediate postoperative period.
Limitations: Our analysis has some limitation which should be considered while interpreting the findings.The included studies exhibited considerable variations in sample sizes, population characteristics, tumour features, and follow-up durations, potentially introducing heterogeneity.Most of the studies in our review were retrospective.Therefore, there is a risk that essential confounders were not systematically collected or adjusted for.This may have introduced a potential bias in the observed associations.
While we specifically included studies reporting adjusted effect sizes, there were discrepancies in the variables adjusted for among the different studies, introducing some heterogeneity in the reported strength of associations.Additionally, most of the studies were conducted in limited geographical settings, potentially constraining the external generalizability and broader applicability of the findings.Finally, individual studies also differed in their surgical approaches to mastectomy, potentially influencing the outcomes.

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Fig. 1 :
Fig.1: Selection process of studies included in the review.

Fig. 2 :
Fig.2: Association between contralateral prophylactic mastectomy and overall survival in subjects with unilateral breast cancer.

Fig. 3 :
Fig.3: Association between contralateral prophylactic mastectomy and breast cancer specific survival in subjects with unilateral breast cancer.

Fig. 4 :Fig. 5 :
Fig.4: Association between contralateral prophylactic mastectomy and recurrence free survival in subjects with unilateral breast cancer.

Table - I
: Findings of the subgroup analysis.
I: Characteristics of the studies included in the meta-analysis.