Elsevier

The Breast

Volume 23, Issue 6, December 2014, Pages 721-742
The Breast

Review
Cumulative risk of second primary contralateral breast cancer in BRCA1/BRCA2 mutation carriers with a first breast cancer: A systematic review and meta-analysis

https://doi.org/10.1016/j.breast.2014.10.005Get rights and content

Abstract

BRCA1/2 mutation carriers are at a higher risk of breast cancer and of subsequent contralateral breast cancer (CBC). This study aims to evaluate the evidence of the effect of the BRCA1/2-carriership on CBC cumulative risk in female breast cancer patients.

The literature was searched in Pubmed and Embase up to June 2013 for studies on CBC risk after a first primary invasive breast cancer in female BRCA1/2 mutation carriers. A qualitative synthesis was carried out and the methodological quality of the studies evaluated. Cumulative risks of CBC after 5, 10 and 15 years since the first breast cancer diagnosis were pooled by BRCA1/2 mutation status.

A total number of 20 articles, out of 1324 retrieved through the search, met the inclusion criteria: 18 retrospective and 2 prospective cohort studies. Cumulative risks of up to five studies were pooled. The cumulative 5-years risk of CBC for BRCA1 and BRCA2 mutation carriers was 15% (95% CI: 9.5%–20%) and 9% (95% CI: 5%–14%), respectively. This risk increases with time since diagnosis of the first breast cancer; the 10-years risk increased up to 27% and 19%, respectively. The 5-years cumulative risk was remarkably lower in non-BRCA carriers (3%; 95% CI: 2%–5%) and remained so over subsequent years (5%; 95% CI: 3%–7%).

In conclusion, risk of CBC increases with length of time after the first breast cancer diagnosis in BRCA1/2 mutation carriers. Studies addressing the impact of treatment-related factors and clinical characteristics of the first breast cancer on this risk are warranted.

Introduction

Breast cancer is the most common cancer and cause of cancer-related death in women in Europe and the USA [1], [2], in spite of having one of the highest survival rates amongst all cancers [3], [2]. Thus, the number of women who overcome a breast cancer is considerably increasing along with the number of survivors after the first diagnosis, raising the number of women at risk of developing subsequent cancers. Most of these second cancers occur in the contralateral breast [4], [5]. It is well-known that BRCA mutation carriers are at higher risk of contralateral breast cancer (CBC) than non-carriers [6], [7]; BRCA mutations have been therefore regarded as responsible for this excess risk [8], [9].

A recently published meta-analysis has estimated that BRCA1 and BRCA2 mutation carriers have a 3.5 fold higher relative risk of CBC compared to non-carriers, and that CBC risk increases up to 42% in BRCA1 compared to BRCA2 carriers [10]. This study confirms that CBC risk is greater than the corresponding figure for the general population of breast cancer patients. However, risk of CBC also varies according to the time passed after the first breast cancer diagnosis. For instance, the 10-year cumulative risk of CBC in BRCA mutation carriers with breast cancer varies between 20 and 35%, and may even further differ by age or menopausal status at diagnosis of the first breast cancer, type of treatment and other clinical and pathological factors of the first tumor in the breast [11].

Female BRCA mutation carriers with breast cancer need counselling on their CBC risk so as to undergo specific surveillance programs or immediate prophylactic surgery (ooferoctomy or mastectomy), radiotherapy or drug treatment (tamoxifen, other hormonal agents or chemotherapy) [12]. Several studies have examined the effect of these options on the risk reduction of CBC [10], [13], [14]. To gain insight into the cumulative risk of CBC by time since diagnosis of the first breast cancer may provide a basis for determining optimal CBC surveillance and treatment strategies in these patients.

A large number of studies have evaluated the cumulative risk of CBC after an initial diagnosis of breast cancer in women carrying a BRCA mutation. A previous review that evaluated the evidence of BRCA-associated breast cancer prognosis [11] included some of these studies, and described results of CBC cumulative risks accordingly. According to this review, the estimated 10-year cumulative risk of CBC ranges from 20 to 40%, but this review did not provide a pooled estimate of this risk nor considered all the available studies on this issue. In addition to the above mentioned limitations, this review mostly included retrospective studies, subjected to the well-known selection and information biases that this kind of design entails. Since then, other studies have been published [15], [16], [17] possibly overcoming these methodological drawbacks. The latest review on risk of CBC in BRCA1/BRCA2 mutation carriers [10], did, again, not evaluate cumulative CBC risk over time in women affected with breast cancer and BRCA mutations.

The aim of the present study was to revise the current evidence on the absolute cumulative risk of CBC after a diagnosis of a first primary invasive breast cancer associated with mutations of the BRCA1/2 genes, and to provide for the first time a pooled estimate of this risk.

Section snippets

Search strategy

A search was carried out to find relevant studies and reviews published up to June 2013. The databases used were Pubmed and Embase.

The following MeSH terms related to “BRCA genes”, “breast cancer”, “prognosis”, “multiple primary cancers” and related subcategories were selected: Neoplasms/Multiple Primary, Neoplasms/Second Primary and epidemiology. A number of key words (“second cancers”, “contralateral breast cancer” and “prognosis”) were also used and combined in these databases (Supplemental

Results of the bibliographical search

A total number of 1324 articles were retrieved through the search. Secondary searches in reference lists of selected studies retrieved other 18 studies. Ninety were ruled out because of duplication. 1186 studies were also excluded based on their abstracts or titles, leaving a total of 66 articles for the “in extenso” analysis. Of these, 46 articles were again ruled out for different causes (Fig. 1). The final selection was made up of 20 articles: 18 retrospective studies [15], [16], [24], [25],

Discussion

This systematic review and meta-analysis is the first quantifying the cumulative risk of CBC in breast cancer patients who are BRCA1/2 mutation carriers. Our results suggest an increased cumulative risk of CBC in women with breast cancer and carrying mutations in BRCA1 or BRCA2 genes with this risk increasing as time since diagnosis of the first breast cancer passes. The pooled cumulative risk of CBC since breast cancer diagnosis increases from 15% at 5 years to 27% at 10 years and to 33% at 15

Conclusion

In view of the findings of this study, risk of CBC in BRCA1 and BRCA2 mutation carriers increases with length of time after the first breast cancer diagnosis. The magnitude of this risk emphasizes the importance of prevention and control policies aimed at reducing the incidence of CBC in BRCA1/2 mutation carriers. Despite the consistency of the data in the literature as reflected in our study, some uncertainties remain about how characteristics of women with BRCA mutations and an initial breast

Conflict of interest statement

The authors declare that they have no conflict of interest.

Disclosures

None.

Role of the funding source

This study has been supported by the Spanish Regional Government of Andalucia: Consejería de Economía, Innovación y Ciencia (CTS-3935, CTS-177) and Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía.

Author's contributions

EMM and MJS carried out the review and drafted the manuscript. MJS participated in its coordination. EMM, MJS and BPN participated in the selection of studies and extraction of data. MP provided expert advice, reviewing the paper and the selected studies, and helped in the drafting of the manuscript. EMM and ESC analyzed the data. JE contributed in the critical revision of the paper and of all the selected studies. All authors read and approved the final manuscript.

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