The impact of lifestyle and reproductive factors on the risk of a second new primary cancer in the contralateral breast: a systematic review and meta-analysis

The risk of being diagnosed with contralateral breast cancer (CBC) is an important health issue among breast cancer survivors. There is an increasing interest in the effect of lifestyle and reproductive factors on CBC risk, since these factors may partly be modifiable. We performed a systematic review and meta-analysis and aimed to evaluate the impact of lifestyle and reproductive factors on CBC risk in population-based breast cancer studies. The PubMed electronic database was searched up to 2nd November 2019, for relevant publications. Of the included studies, a meta-analysis per lifestyle or reproductive factor was performed. Thirteen out of 784 publications were used for the meta-analysis. Body mass index (≥ 25 vs. < 25 kg/m2; RR = 1.22; 95% CI 1.01–1.47) was associated with increased CBC risk. The estimates for alcohol use (ever vs. never; RR = 1.15; 95% CI 1.02–1.31) and age at primiparity (≥ 25 vs. < 25 years; RR = 1.06; 95% CI 1.02–1.10) also showed an association with increased CBC risk. For parity (≥ 4 vs. nulliparous; RR = 0.56; 95% CI 0.42–0.76) and age at menopause (< 45 vs ≥ 45 years; RR = 0.79; 95% CI 0.67–0.93), results from two studies suggested a decreased CBC risk. We observed no association between CBC and smoking, age at menarche, oral contraceptive use, gravidity, breastfeeding, or menopausal status. Overall, the number of studies per risk factor was limited (n = 2–5). BMI is a modifiable risk factor for CBC. Data on the effect of other modifiable lifestyle and reproductive factors are limited. For better counseling of patients on lifestyle effects, more studies are urgently needed.


Introduction
Over the last decades, the survival rate of breast cancer patients has been improving as a result of earlier diagnosis and better treatment [1,2]. This leads to an increasing number of women who have been previously diagnosed with breast cancer, and are at risk for developing a second new malignancy in the opposite breast over time, i.e., metachronous contralateral breast cancer (CBC). Ten-year cumulative risk of CBC is around 4-5% in the general population [3,4] The risk of being diagnosed with CBC is therefore an important health issue among breast cancer survivors and often a recurring subject during follow-up at the outpatient clinic. This can also be observed from the increasing number of breast cancer survivors choosing for prophylactic removal of the contralateral breast. However, in a majority of the 1 3 women with breast cancer, no survival benefit has been reported following this procedure [5,6].
For this reason, it is important to evaluate the risk of developing CBC in individual breast cancer patients in a tailored fashion to provide them with an accurate followup strategy. Not only genetic and breast cancer treatmentrelated factors, but also lifestyle and reproductive factors should be assessed for this purpose.
Nowadays, there is an increasing interest in the impact of lifestyle and reproductive factors on CBC risk among healthcare professionals and breast cancer survivors, since these factors may partly be modifiable. Current available estimates on lifestyle and reproductive factors need to be combined to get estimates that are based on the highest level of evidence.
We therefore conducted a systematic review with metaanalysis and aimed to evaluate the impact of lifestyle and reproductive factors on metachronous CBC risk in population-based breast cancer cohorts.

Methods
This systematic review with meta-analysis is conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [7].

Literature search
We searched the PubMed electronic database for publications on 2nd November 2019, by using search terms related to CBC in combination with lifestyle or reproductive factors that are potentially associated with CBC risk. More specific, we were interested in the impact of dietary habits, exercise, body mass index (BMI), alcohol use, smoking, age at menarche, oral contraceptive use, gravidity, age at primiparity, parity, breastfeeding, menopausal status, and age at menopause on metachronous CBC risk in population-based studies, i.e., studies with general, unselected breast cancer populations, without any germline mutation being tested on. Metachronous CBC is defined as a second primary breast cancer developed in the contralateral breast over time, from now onwards referred to as CBC.
Metachronous refers to a certain time lapse between the first primary breast cancer (PBC) diagnosis and the CBC diagnosis, but in literature this has not been clearly defined yet; mainly a time lapse of 3-12 months is being used. Our literature search included search terms for second breast cancer, thereby potentially including publications that studied the risks of developing ipsilateral second PBC, along with CBC. However, the literature states that only 5% of the second PBCs developed in the ipsilateral breast [8].
The literature search was limited to publications written in English from 1st January 1990, onwards. A description of the full search strategy is given in Table S1.

Study selection
Two reviewers (MMK, CZAS) identified potentially eligible publications by reading each title and abstract. From the selected publications, the full text was read. Publications were subsequently excluded if they met at least one of the exclusion criteria, which were defined as publications without pooled data (e.g., narrative review, research report, guideline, comment editorial), publications without relative risk (RR) estimates (i.e., no relative risk, odds ratio or hazard ratio) or publications with less than 20 CBC events reported. Further exclusion concerned publications on highrisk breast cancer patients (e.g., BRCA-related breast cancer, familial/hereditary breast cancer), publications on non-invasive CBC, publications on CBC analyzed in the context of recurrent disease or publications on topics not related to the effect of lifestyle or reproductive factors on CBC risk. When in doubt about including a paper (n = 17), a third reviewer was consulted (DA).
In addition, references of the eligible publications were checked for additional records missed by the initial literature search.

Data extraction
The main study characteristics from the included publications were extracted and collected in an overview (Table 1). These study characteristics included the author, year of publication, origin of cancer or hospital registry, study design, date of first PBC diagnosis, selection criteria, number of first PBC and CBC patients, mean/median years of follow-up (including range) and age (including range) of women with first PBC, required time lapse between first PBC and CBC diagnosis, lifestyle and/or reproductive factors of interest, and time of assessment of the risk factor status (e.g., at first PBC or CBC diagnosis).
Additionally, we extracted the relative risk estimates with the corresponding confidence interval (CI) and factors that were adjusted for in the analysis.

Statistical analyses
Relative risk estimates with the corresponding CI were collected, log-transformed, and pooled per lifestyle or reproductive factor. A random-effects model was used for the metaanalyses. If a study did not report an overall risk estimate for a specific factor, subgroup estimates were combined to create an overall risk estimate with the use of a random effects model. The underlying cohort of this study was composed of women with only estrogen receptor-negative first PBC k No definition for metachronous CBC was provided, but the paper focussed on events occurring over time, therefore assumed that the focus was on metachronous CBC events l No definition for metachronous CBC was provided, but from the figures, we observed the first CBC event to appear at least 3 months after first PBC diagnosis Relative risk estimates from univariable and multivariable analyses were analyzed separately. If both an adjusted (i.e., using multivariable risk estimates) and a crude metaanalysis (i.e., using univariable risk estimates) could be conducted for a factor, we only selected the papers eligible for the adjusted meta-analysis.
Subsequently, we evaluated whether there was potential overlap in patients from the different papers. In case of overlap, we selected either the most recent or the most relevant (i.e., on topic) paper.
To examine the continuous effects (trend analysis) of BMI and number of full-term pregnancies (FTP), we used the dose-response method described by Greenland et al. [9]. Results from this analysis were subsequently pooled using a random-effects meta-analysis and the p-value for trend was extracted from the confidence interval of the pooled estimate.
Additionally, we tested for heterogeneity using the I 2 -statistics and reported the p-value for heterogeneity for each lifestyle or reproductive factor in the figures.
We used the METAN package of Stata Statistical Software version 14.0 to conduct the statistical analyses.

Search results and study selection
Our PubMed literature search identified 784 publications, of which 707 met the inclusion criteria (Fig. 1). Based on relevance, 41 of the remaining publications were selected for further review. Hereof, 20 publications were eligible for inclusion after applying the exclusion criteria. No additional publications were found by checking the references of the eligible publications. In addition, seven out of these 20 publications were ineligible for the (adjusted) meta-analyses due to non-preferable risk estimates (i.e., solely reporting univariable risk estimates [10]) or overlap in patients [11][12][13][14][15][16] and were therefore excluded.
From the 13 papers finally used for the meta-analysis, there were between 424-72,096 first PBC and 24-2515 CBC patients available for the analyses. A majority of the studies (9 out of 13) were at least partially performed in the USA.

Meta-analyses
The adjusted estimates for lifestyle and reproductive factors are presented in an overall plot in Figs. 2 and 3, respectively, and per lifestyle or reproductive factor in Supplementary Figs. S1-16.
Heterogeneity will only be reported for risk factor estimates in case of moderate or high heterogeneity (i.e., I 2 > 50%, p < 0.05 as reported in the figures).
There were no data available on the association between dietary habits or physical exercise and CBC risk.

Discussion
In this systematic review and meta-analysis, we studied the impact of lifestyle and reproductive factors on CBC risk in population-based breast cancer cohorts.
We observed a moderately increased CBC risk in women being overweight. Further, alcohol use and older age at  Fig. 2 Forest plot of the overall adjusted meta-analyses per lifestyle factor on the risk of developing contralateral breast cancer in population-based cohorts Npapers = number of papers used for the analy-sis; I 2 = test for heterogeneity; p-value = p-value for heterogeneity: p < 0.05 considered significant; estimate = relative risk estimate combining relative risks, odds ratios, and hazard ratios] Fig. 3 Forest plot of the overall adjusted meta-analyses per reproductive factor on the risk of developing contralateral breast cancer in population-based cohorts Npapers = number of papers used for the analysis; I 2 = test for heterogeneity; p-value = p-value for heterogene-ity: p < 0.05 considered significant; estimate = relative risk estimate combining relative risks, odds ratios, and hazard ratios. yrs years, FTP(s) full-term pregnancy/pregnancies] primiparity were suggestive of increased CBC risk, whereas a high number of full-term pregnancies and younger age at menopause seemed associated with decreased CBC risk. Overall, the number of papers available for the meta-analyses was limited.
We observed high heterogeneity in the meta-analysis concerning BMI. Difference in menopausal status at first PBC diagnosis could have led hereto, since most women of the lower risk outliers [17,21] were pre/perimenopausal as opposed to the other studies [18,19,22] in which the majority of women was postmenopausal at first PBC diagnosis. It is sometimes hypothesized that high BMI in premenopausal women may lead to anovulation and reduction of circulating estrogen and progesterone and thereby reducing PBC risk [30]. Contrarily, in postmenopausal women, a high BMI is observed to be a risk factor for first PBC [31,32], likely due to increasing estrogen concentration through adipose tissue production and reduction of sex hormone-binding globulins [33]. These mechanisms may also be applied to the association between BMI and CBC. Still, literature supporting the inverse association between BMI and premenopausal first PBC is scarce and lacks strong evidence [31,32].
In contrast to the systematic review of Simapivapan et al. [34] in which no conclusive association between alcohol consumption and second PBC was found, we did observe a positive association between alcohol consumption and CBC risk. Simapivapan et al. included the same publications as we did [12,14,16,19,23], but did not exclude the publications of Li et al. [12,14] which we considered to overlap in patient cohort with Knight et al. [24]. Consequently, because of the limited number of available publications, we had to use a dichotomous outcome (i.e., ever vs. never), whereas Simapivapan et al. gave a narrative overview of the frequency and/or period of exposure (e.g., pre or post breast cancer diagnosis) to alcohol consumption.
Despite contradicting evidence relating to the impact of parity on CBC risk, it seems that multiple FTPs are protective for developing a CBC as shown by the trend-analysis for an increasing number of FTPs and subgroup analyses for parity (≥ 4 FTPs vs. nulliparous and ≥ 2 FTPs vs. 1 FTP). The fact that some analyses did not show a significantly decreased CBC risk for parity (≥ 1 FTPs vs. nulliparous and 1-3 FTPs vs. nulliparous) could be explained by a lack of power from small contrast in numbers of FTP and from including a small number of studies (n = 2-3).
Just as for first PBC [35], having multiple full-term pregnancies seemed protective for developing CBC, whereas primiparity at an older age showed an increased risk of CBC. Pregnancy induces terminal differentiation of mammary luminal cells through exposure to human chorionic gonadotrophin (hCG). This results in changing gene expression in the mammary stem cells, becoming more refractory to carcinogenesis through increased DNA repair pathway and apoptosis control. Older age at primiparity delays the formation of this protective 'genomic signature' and extends the exposure time to carcinogens, thereby making the breast more susceptible to carcinogenesis [36]. We assume that the underlying mechanisms for parity and age at primiparity on first PBC risk may apply for CBC as well.
We observed a decreased CBC risk in women with younger age at menopause (i.e., early/premature menopause), but the number of papers was limited (n = 2). Nonetheless, older age at menopause has previously been described as a risk factor for first PBC [37], possibly due to a higher number of menstrual cycles experienced [38], thereby having longer exposure to high estrogen levels [39]. Therefore, it makes sense that a younger age at menopause is associated with a decreased CBC risk. Moreover, first PBC risk increases less for every year older at menopause than for every year younger at menarche, implying that not only the number of menstrual cycles plays a role in the relationship between childbearing years and first PBC risk (and possibly CBC risk) [37] but also the number of reproductive years before the first FTP is even more important. Nonetheless, we did not find any association between age at menarche and CBC risk.
There are several limitations to our study that need to be considered. First, there were only few studies available per studied risk factor (two to five per meta-analysis), underlining that little is known about the impact of lifestyle and reproductive factors on CBC risk. For example, only two publications were included in the meta-analyses for gravidity, subgroups of parity (1-3 or ≥ 4 full-term pregnancies vs. nulliparous), breastfeeding, and age at menopause. In addition, we had to use a dichotomous outcome (i.e., ever vs. never) for the meta-analyses concerning smoking, alcohol use, oral contraceptive use, gravidity, and breastfeeding. The outcomes of these analyses should therefore be interpreted with caution. In addition, the small number of papers that was available per factor inhibited us from being able to inspect the presence of publication bias.
Second, the analyzed data are heterogeneous regarding the timing of assessment of the lifestyle and reproductive factors. All lifestyle factors (BMI, alcohol use, and smoking) were assessed at first PBC diagnosis, whereas most reproductive factors were assessed at or before CBC diagnosis. Factors assessed at first PBC may be useful for risk prediction but are not that helpful for the prediction of risk modification. Although several modifiable factors were included in this meta-analysis, the potential effect of actual changes in lifestyle factors after first PBC diagnosis has not been addressed.
Third, our literature search included search terms for second breast cancer, thereby including publications that studied the risks of developing ipsilateral second breast cancers as well. However, considering that the large majority (95%) of second PBCs is contralateral as compared to ipsilateral [8], we do not expect large risk alterations.
Fourth, we did not perform a quality assessment of the included studies; instead, we applied our own selection criteria (e.g., selecting only papers with a minimum number of events and evaluating the statistical methods that were used). Moreover, we know from literature that quality assessment tools in meta-analyses do not prevent nor resolve potential bias [40,41].
Many breast cancer survivors express their concern on developing breast cancer in the other breast during followup at the outpatient clinic. In a previous meta-analysis, we assessed the impact of genetic and clinical factors (i.e., pathological characteristics and treatment) on CBC risk [42]. For example, breast cancer patients with a positive mutation status (e.g., BRCA1, BRCA2 or CHEK2 c.1100delC) have a two to four times higher relative risk of developing a CBC [42]. The contribution of lifestyle and reproductive factors on CBC risk is compared hereto relatively small. Nonetheless, there is a specific interest from breast cancer survivors in factors that can be modified after first PBC diagnosis (e.g., weight, alcohol use), thereby potentially decreasing the risk of developing a CBC.
To our knowledge, this is the first meta-analysis that studied the impact of multiple lifestyle and reproductive factors on CBC risk, thereby seeking for the best possible evidence on this topic. Healthy BMI seems to be associated with a lower risk of developing a CBC as compared to high BMI. However, we could not prove that losing weight after the first PBC actually has a risk reducing effect on developing a CBC. More research on the impact of weight loss after the first PBC on CBC risk is therefore necessary. Nonetheless, losing weight is considered beneficial for breast cancer patients who are overweight or obese, if not for decreasing CBC risk, then either for other health outcomes. Weight loss intervention programs could be considered as part of the rehabilitation program for breast cancer survivors and have already gained some success in weight loss in breast cancer patients [43,44]. In addition, breast cancer survivors in general may be advised to maintain a healthy lifestyle.
Most importantly, this systematic review and metaanalysis highlighted the current gaps in our knowledge and stressed the importance of further investigations that are needed to improve CBC risk management in breast cancer survivors. The results pointed in a specific direction for alcohol use, number of FTPs, age at primiparity, and age at menopause, but to provide strong conclusions, more research is definitely needed.
Moreover, more research on the impact of modifiable lifestyle factors (e.g., exercise, dietary habits, extent and timing of alcohol use) and known reproductive risk factors for a first PBC (e.g., parity, menopausal status) on CBC risk is necessary to offer breast cancer patients personalized evidence-based CBC risk estimates.