Oral contraceptive use is known to correlate with BC risk in some populations. However, evidence for an effect from A1stOC is controversial. The study by Jee et al found that earlier A1stOC could increase BC risk. In contrast, the study by Palmer et al. demonstrated that older age was associated with BC risk, whereas other studies had uncertain results.[28,32–35,37] Furthermore, the association between A1stOC and BC risk is inconsistent among different categorical representations,[29–31,36] and BC subtypes.[31–33] However, no studies have examined the exact dose–response relationship between A1stOC and BC risk before. Our meta-analysis aimed to explore the potential relationship between A1stOC and BC risk.
This meta-analysis, with a total of 686,305 participants, showed a significant association between A1stOC and the risk of BC without significant heterogeneity and publication bias. By pooling nine articles that included 619,644 participants, we showed a linear relationship between A1stOC and BC risk (P = .21for a non-linear trend), and a borderline significant association of 0.7% increase in the BC rate for every 1.0-year increase in A1stOC (i.e., RR: 1.007 [CI: 95%: 1.002–1.013] for each 1.0-year increment). Subgroup analyses showed inconsistent and statistically insignificant consequences when limited to studies of Western countries, low study quality (<7), small sample size (<10,000), short follow-up (<5 years), and all BC subtypes. Sensitivity analyses indicated that our results were stable and reliable after removing each study in turn and omitting studies of adjusted unreported variables.
Four previous meta-analyses indicated that, BC risk was higher for OC users than for non-users.[7–10]
However, our result shows, for the first time, a steeply linear curve for the association of A1stOC and BC risk. Some plausible mechanisms could account for this association. Many studies support a role for OC in BC carcinogenesis, through estrogen and progesterone themselves,[40–42] disrupting endocrine systems, or even stimulating breast tumor stem cells,[44,45] Moreover, OC can increase the metastatic ability of existing BC cells,[9,46–49] and interact with BC through various signaling pathways.[50–52]
Although little or no heterogeneity was seen in most studies of the association between A1stOC and BC risk, we also conducted stratified analyses to explore potential effect modifiers. Among studies with Western countries, low study quality (<7), small sample size (<10,000), short follow-up (<5 years), and all BC subtypes, we found no significant association between A1stOC and BC risk. Considering their limited participants and relatively wide CIs for risk estimates, the failure to detect significant associations was possibly caused by lack of statistical power. Use of OC was not associated with BC risk in women aged 50 to 79 years, however, Dolle et al reported an increased risk of BC in women who were younger than 40 years, with different effects in premenopausal and postmenopausal women. Thus, menstruation status is another potential modifier. Previous meta-analyses indicated that women who use OC are more likely to develop triple-negative BC (TNBC) than non-users, but no similar results were seen in this study. The most likely explanation is that differences in risk factor distributions do not explain differences in incidence rates.
To our knowledge, this is the first meta-analysis of published prospective studies on A1stOC and BC risk to find a positive linear relationship between them. The sample size was sufficiently large (686,305 participants, of whom 8585 had BC), and came from different regions (Europe, North America and Asia). The measure of exposure was consistent in all of the studies. The subgroup analyses show disparate outcomes when they were restricted to studies of Western countries, low study quality (<7), small sample size (<10,000), short follow-up (<5 years), and all BC subtypes by exposure categories: Western/Eastern country, low/high study quality, small/large sample size, short/long follow-up time and TNBC/non-TNBC/HER-2+/ER+. Our sensitivity analysis was stable and reliable when we removed individual studies in turn and omitted studies of adjusted unreported variables.
This study had several limitations. First, 1 study was excluded for the dose–response meta-analysis for having only two exposure categories. Second, as only 3 studies reported BC subtypes,[31–35] no definite result was presented due to lack of available datasets. Third, 2 studies did not report adjusted variables,[34,35] which prevented us from an in-depth analysis of potential confounders and effect modifiers. What's more, a chance of unmeasured or residual confounding remains (e.g., pathological information, that has not been considered in our analysis). Fourth, no study reported OC formulation, frequency of administration or menstrual status at onset, so no associated subgroup analyses were performed. Fifth, the threshold of A1stOC that increases BC risk was not assessed in our study. Finally, our study used summary statistics rather than individual data which could have allowed more precise delineation and controlled potential residual confounding, leading to more accurate and reliable results, which is an important limitation related to the original design of the studies.
The authors gratefully acknowledge Juan Ye for her assistance in study design and statistical analyses. We also thank Marla Brunker, from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.
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