ReviewRisk of second cancers cancer after a first primary breast cancer: A systematic review and meta-analysis
Introduction
Breast cancer represents a major public health issue worldwide. It is the most commonly diagnosed cancer among women, with 1.38 million new cases estimated in 2012 [1]. In Europe, estimates of cancer incidence and mortality in 2012 show that it remains being the most common cancer and cause of cancer-related death in women [2]. Early detection through systematic screening, better access to care, and advances in treatments have been leading to a decline in mortality rates [3], [4]. Thus, as the number of women who overcome a breast cancer is considerably increasing, the likelihood of developing subsequent cancers, i.e. Multiple Primary Tumours (MPT), becomes higher. Subsequent cancers after an initial breast cancer could be attributed either to common risk factors predisposing to both the first and second cancer, such as genetic predisposition or other identified risk factors, or to treatment-related side effects [5].
Several population-based cancer registry studies [6], [7], [8], [9], [10], [11] as well as studies involving several cancer registries [12], [13], have evaluated the risk of developing second primary cancers among women diagnosed with a first primary breast cancer with respect to the general population. Most of these studies were derived from European data [6], [7], [8], [9], [10], [11], [12], [13] and from the National Cancer Institute's Surveillance, Epidemiology (SEER) cancer registries in the United States [14], [15], [16]. However, risk estimates provided by these studies are largely different, with an overall excess risk ranging between 15 and 45% for all cancer sites combined. Risk differences by age groups have also been examined in some of these studies [7], [10], [11], [12], [13], showing that women diagnosed with breast cancer at premenopausal ages were at higher risk of developing a second cancer. In general, second primary cancers of the endometrium, ovary, melanoma, stomach and colon cancer have been reported to occur more frequently [6], [7], [8], [9], [10], although there is no consensus between studies.
Some studies have also provided risk estimates of second cancers according to treatment of the breast cancer, such as radiotherapy [14], [17], [18], [19], [20], chemotherapy and surgery [17], [18], [19], [20] or hormonal therapy [18], [19], [20], to assess how treatment-related factors may influence this risk. However, as information on treatment is not systematically collected in population-based cancer registries, most of these studies reported risk estimates on a limited number of observed cases with information available on primary treatment for breast cancer. For this reason, calendar year and time since diagnosis of the first breast cancer have been used as a proxy for treatment in some studies [6], [9], [12], [17]. However, results reported by these studies are rather inconsistent as some support an increased risk during the first years after the breast cancer diagnosis [6], [12] whilst others report that risk increases or remains high over time [9], [17].
The aim of the current study is to examine the scientific evidence related to the risk of developing a second primary cancer after a breast cancer diagnosis for all sites combined, by age at breast cancer diagnosis and by time since breast cancer diagnosis, and to further combine the results of these studies by using meta-analysis.
Section snippets
Search strategy
A search was carried out to find relevant studies and reviews published up to 30 June 2013 (no starting date was fixed). The databases used were Pubmed and Embase.
The following MeSH terms related to “second cancers” and “multiple primary cancers” and related subcategories were selected: Neoplasms/Multiple Primary, Neoplasms/Second Primary and epidemiology. A number of key words (“second cancers” and “population-based”) were also used and combined in different databases (Table 1). The reference
Results of the bibliographical search
The defined search criteria in Pubmed and Embase retrieved 710 articles (Fig. 1). 16 articles, identified through manual review of reference lists, were added. 61 articles were ruled out because of duplication, leaving a total number of 665 articles for review. Based on the title and abstract we excluded 583 articles for different causes of exclusions. 82 articles were left for the “in extenso” analysis, of which 67 were further excluded: 11 studies did not use IARC/AICR coding rules for MPC,
Discussion
To the best of our knowledge, this systematic review and meta-analysis, conducted with all the studies available, is the first one to assess the risk of second primary cancers among women previously diagnosed with a first primary breast cancer.
Our results show that these women have a 17% increase in the risk of developing a new primary non-breast cancer in comparison with women without cancer of the general population. This excess in risk is likely to be associated with treatment modalities for
Conclusions
In this review we observed varying results on the magnitude of risk for subsequent cancers after a diagnosis of breast cancer that could be explained by various differences between the published studies, either methodological, such as the definition of second cancers, or inherent to the study populations, such as varying breast cancer treatment protocols between the studies and over time. The qualitative analysis of studies included in this review has revealed that these and other variables may
Conflict of interest
The authors declare that they have no conflict of interest.
Role of the funding source
This study has been supported by the Spanish Regional Government of Andalucia: Consejería Economía, Innovación, Ciencia y Empleo, Junta de Andalucia (CTS-3935, CTS-177).
Author's contributions are as follows
EMM, MR and MJS carried out the review and drafted the manuscript. They also conceived of the study. MJS participated in its coordination. EMM, MFF and ESC conducted the data analysis. MFF, MAM and JE and JPA helped to extract the data and reviewed critically all the studies selected. All authors read and approved the final manuscript.
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