The Effect of Breastfeeding Duration and Parity on the Risk of Epithelial Ovarian Cancer: A Systematic Review and Meta-analysis

Review Objectives: We conducted a systematic review and meta-analysis to summarize current evidence regarding the association of parity and duration of breastfeeding with the risk of epithelial ovarian cancer (EOC). Methods: A systematic search of relevant studies published by December 31, 2015 was performed in PubMed and EMBASE. A random-effect model was used to obtain the summary relative risks (RRs) and 95% confidence intervals (CIs). Results: Thirty-two studies had parity categories of 1, 2, and ≥3. The summary RRs for EOC were 0.72 (95% CI, 0.65 to 0.79), 0.57 (95% CI, 0.49 to 0.65), and 0.46 (95% CI, 0.41 to 0.52), respectively. Small to moderate heterogeneity was observed for one birth (p<0.01; Q=59.46; I 2 =47.9%). Fifteen studies had breastfeeding categories of <6 months, 6-12 months, and >13 months. The summary RRs were 0.79 (95% CI, 0.72 to 0.87), 0.72 (95% CI, 0.64 to 0.81), and 0.67 (95% CI, 0.56 to 0.79), respectively. Only small heterogeneity was observed for <6 months of breastfeeding (p=0.17; Q=18.79, I 2 =25.5%). Compared to nulliparous women with no history of breastfeeding, the joint effects of two births and <6 months of breastfeeding resulted in a 0.5-fold reduced risk for EOC. Conclusions: The first birth and breastfeeding for <6 months were associated with significant reductions in EOC risk. Key words: Ovarian neoplasms, Parity, Breast feeding, Reproduction, Risk factors, Meta-analysis Received: June 29, 2016 Accepted: September 8, 2016 Corresponding author: Suekyung Park, MD, PhD 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-740-8338, Fax: +82-2-747-4830 E-mail: [email protected] This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. INTRODUCTION Worldwide, ovarian cancer is the seventh most common cancer in women. Furthermore, it is the sixth leading cause of cancer deaths in women and the second most common cause of death among those with gynecologic cancers 350 to 8%), germ cell tumors (3% to 5%), and other rare types of ovarian cancer Most ovarian cancers are life-threatening and are notorious for having a poor prognosis, as they are usually diagnosed at an advanced stage. Moreover, screening results based on pelvic imaging or tumor markers for early detection remain unsatisfactory Reproductive risk factors for epithelial ovarian cancer (EOC) have been extensively explored in epidemiologic studies. For instance, a pooled analysis of 12 US case-control studies in 1992 showed that parous women and those who had breastfed had a lower risk of EOC Since 1992, many studies from around the world have reported associations of parity and breastfeeding with ovarian cancer. However, findings concerning the protective role of increasing parity and duration of breastfeeding remain inconsistent. For parity, some studies have indicated that the first birth reduces ovarian cancer risk more than subsequent births Therefore, we conducted a systematic review and metaanalysis to summarize the current evidence regarding the association of parity and duration of breastfeeding with EOC risk. The aim of this study was to clarify the threshold for risk reduction among the studies without heterogeneity across the results. An additional aim was to perform a meta-analysis to estimate the joint risk reductions associated with parity and breastfeeding. METHODS Search Strategy We performed a literature search including studies published through December 2015 using the following search terms in the PubMed and EMBASE databases (1) (parity or "number of live births") and (ovary or ovarian) and (cancer or tumor or neoplasm or malignancy) or (2) (breastfeeding or lactation) and (ovary or ovarian) and (cancer or tumor or neoplasm or malignancy). Furthermore, to find any additional published studies, a manual search was performed by checking all references of prior meta-analyses [5,6.8,20-23] and of all the original studies. This systematic review was planned, conducted, and reported in adherence to the standards of quality for reporting meta-analyses Study Selection To be included, studies had to meet the following criteria: (1) the studies were observational (case-control or cohort studies), (2) the exposures of interest were the number of live births and the total duration of breastfeeding, (3) the outcome of interest was EOC, (4) odds ratios (ORs) or relative risk (RR) estimates with 95% confidence intervals (CIs) were reported or sufficient data were present to allow the calculation of these effect measures, and (5) articles were published in the English language. In the case of overlapping data, the study with the largest number of cases was included. As fertility treatments and BRCA mutation effects on EOC may alter the association between parity/breastfeeding and EOC [26], we excluded studies conducted on specific populations, such as BRCA-1 or BRCA-2 mutation carriers or infertile women treated with fertility drugs. The detailed steps of our literature search are shown in Data Extraction Data extraction was conducted independently by two authors. Disagreements were discussed and resolved by consensus. The following data were collected from each study: the first author's last name, publication year, study region and design, study period, participant age, sample size (cases and 351 Parity and Breastfeeding Effects on Ovarian Cancer Risk controls or cohort size), exposure variables (parity or total breastfeeding duration), study-specific adjusted RR or OR with 95% CIs for each exposure category, and factors matched or adjusted for in the design or data analysis. If no adjusted RR or OR was presented, we included crude estimates. If no RRs or ORs were presented in a given study, we calculated them and the 95% CIs according to the raw frequencies presented in the article. The quality of the study was assessed independently by two authors using the 9-star Newcastle-Ottawa Scale (range, 0 to 9 stars) Statistical Analysis The study-specific RRs or ORs with 95% CIs were used to determine the principal outcome. Because the OR closely approximates the RR for rare diseases, the RR can be estimated from a case-control study using the OR as an approximation One study did not provide the required risk estimates for analysis or separate the risk estimates for different categories of parity or breastfeeding duration. For this study, we used the method proposed by Fleiss and Gross [30]. This method allows adjusted effect estimates and CIs to be calculated for any alternative comparison of levels and can help in a dose-response meta-analysis. Briefly, we combined risk estimates obtained through a simple fixed-effects meta-analysis wherein the subjects were divided into unexposed groups (i=0) and exposed groups (i=1, …, n), and estimates (Ri) with lower and upper 95% CIs were available. To obtain the R1+, we meta-analyzed R1, R2, R3, …, Rn using a fixed-effect model. The categories of parity or breastfeeding duration varied across studies; accordingly, the number of studies included in each metaanalysis and the summary RRs in each meta-analysis were different depending upon the number of categories. Statistical heterogeneity among studies was evaluated with the Cochran Q and I-squared statistics 352 with ≤7 stars considered low-quality as per the 9-star Newcastle-Ottawa Scale; and (3) year of publication (<2000, ≥ 2000), respectively. Publication bias was evaluated using the Begg rank correlation and the Egger linear regression test, in which p-vlaue <0.05 were considered representative of statistically significant publication bias From the meta-analyzed result, to calculate the RR for the joint effect of parity and breastfeeding, we applied the log-linear dose-response model proposed by Berlin et al. We configured the following formula for the multivariate linear logit regression of two factors: Logit P=α + β1χ1 + β2χ2; where P is the probability of a particular outcome (EOC risk), α is the intercept from the linear regression equation, β is the regression coefficient multiplied by some value of the predictor, and χ is the risk factor (parity and breastfeeding). Using this equation yields the value of the RR for the joint effects of parity and breastfeeding duration. For example, in the case of a subject who has no risk factors, logit(P) is α. In this case, the probability of EOC is exp(α)=1.0. In the case of a subject with only χ1, logit(P) is α+β1. In the case of a subject with both χ1 and χ2, logit(P) is α+β1+β2. Accordingly, the probability of EOC is exp(β1+β2)=OR1×OR2. Since the category of parity and breastfeeding duration varied across studies, to calculate the RR for the joint effect of parity and breastfeeding, we used the summary RR for parity and breastfeeding duration that contained the largest number of studies. All statistical analyses were performed with Stata version 12.0 (StataCorp., College Station, TX, USA). RESULTS Study Characteristics The characteristics of the 32 studies included with data regarding parity and the 15 studies included with data regarding breastfeeding are shown in Supplemental 353 Parity and Breastfeeding Effects on Ovarian Cancer Risk Africa. For breastfeeding, two cohort studies and 13 case-control studies were included. The included studies were conducted between 1978 and 2008. Of the 15 studies, seven were performed in North America, six in Europe, one in Asia, and one in Australia. Parity and Epithelial Ovarian Cancer Risk Thirty-two studies had parity categories of 1, 2, and ≥3. The summary RRs for the first, second, and third births were 0.72 (95% CI, 0.65 to 0.79), 0.57 (95% CI, 0.49 to 0.65), and 0.46 (95% CI, 0.41 to 0.52), respectively Duration of Breastfeeding and Epithelial Ovarian Cancer Risk Fifteen studies had breastfeeding categories of <6 months, 6-12 months, and ≥13 months. The summary RRs for these categories were 0.79 (95% CI, 0.72 to 0.87), 0.72 (95% CI, 0.64 to 0.81) and 0.67 (95% CI, 0.56 to 0.79), respectively Subgroup Analysis According to Study Design, Study Quality, and Publication Year The results from the subgroup analysis according to study design, study quality, and publication year are shown in Relative Risk for the Joint Effect of Parity and Breastfeeding The RR for the joint effect of parity and breastfeeding, obtained using the summary RR from the analysis of 32 studies with parity categories of 1, 2, and ≥3 and 15 studies with breastfeeding categories of <6 months, 6-12 months, and ≥ 13 months, is shown in DISCUSSION The findings of this meta-analysis indicate that parity and breastfeeding experiences in women can help prevent EOC, which is typically life-threatening and has a poor prognosis. In particular, the first birth and the first six months of breastfeeding had a greater protective effect than did subsequent births and/or additional breastfeeding, although multiparity and additional breastfeeding did provide some additional protection. The risk reduction effect of the first birth on EOC risk was almost 30%, and the combined effect of the first birth and <6 months of breastfeeding was 40%; thus, breastfeeding provided a nearly 10% greater risk reduction. In regards to parity, the EOC risk reduction was highest for the first birth, with some additional protection from the second birth. However, slightly less risk reduction was observed for the third birth Pregnancy and breastfeeding are thought to reduce EOC risk Ho Kyung Sung, et al. 354 by decreasing pituitary gonadotropin levels and inducing anovulation [7,35]. Pregnancy and breastfeeding are expected to decrease the likelihood of spontaneous genetic mutation under the incessant ovulation hypothesis and of the hyperproliferation of inclusion cysts under the gonadotropin hypothesis. However, the observation that multiparity and additional breastfeeding did not provide an equal amount of protection does not provide evidence for either of these hypotheses. Nev- The summary RRs (95% CIs) in each meta-analysis were estimated using a random effect model. 3 Studies with ≥8 stars were considered high-quality as per the 9-star Newcastle-Ottawa Scale. 4 Studies with ≤7 stars were considered low-quality as per the 9-star Newcastle-Ottawa Scale. 355 Parity and Breastfeeding Effects on Ovarian Cancer Risk ertheless, the results of two experimental studies provide biological evidence for the relatively weaker protective effect of additional parity and breastfeeding [36,37]. For instance, high progesterone levels during pregnancy can increase apoptosis, which may clear transformed cells from the ovarian epithelium, meaning that all the accumulated transformed cells are washed fully out by the first pregnancy. Therefore, the first pregnancy provides a stronger protective effect than subsequent pregnancies [36]. In regards to breastfeeding, breastfeeding in the first few months completely inhibits the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone, leading to suppression of ovulation [37]. After a couple of months, ovulatory activity may return, even though breastfeeding continues [37]; thus, a longer duration of breastfeeding does not provide an additional protective effect. Our finding of decreased EOC risk with longer breastfeeding is similar to that reported by prior meta-analyses in 2013 and 2014 [22,23], but differs from that of a meta-analysis of nine case-control studies conducted in developed countries in 2001, in which breastfeeding for ≥12 months was associated with a significant 0.72-fold reduced risk of EOC compared to never having breastfed, while breastfeeding <12 months did not show such an association (OR, 0.95; 95% CI, 0.80 to 1.12) The strength of this meta-analysis is that it included all available studies, and the large number of EOC cases allowed for the investigation of the risk associated with different categories of parity and breastfeeding duration. However, the current study also has several limitations. First, our meta-analysis wa

Spectroscopic Mass and Host-star Metallicity Measurements for Newly Discovered Microlensing Planet OGLE-2018-BLG-0740Lb

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Candidate Brown-dwarf Microlensing Events with Very Short Timescales and Small Angular Einstein Radii

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In this work, we present the analysis of the binary microlensing event OGLE-2018-BLG-0022 that is detected toward the Galactic bulge field. The dense and continuous coverage with the high-quality photometry data from ground-based observations combined with the space-based {\it Spitzer} observations of this long time-scale event enables us to uniquely determine the masses $M_1=0.40 \pm 0.05~M_\odot$ and $M_2=0.13\pm 0.01~M_\odot$ of the individual lens components. Because the lens-source relative parallax and the vector lens-source relative proper motion are unambiguously determined, we can likewise unambiguously predict the astrometric offset between the light centroid of the magnified images (as observed by the {\it Gaia} satellite) and the true position of the source. This prediction can be tested when the individual-epoch {\it Gaia} astrometric measurements are released.Comment: 10 pages, 10 figures, 4 table

SpitzerSpitzer Parallax of OGLE-2018-BLG-0596: A Low-mass-ratio Planet around an M-dwarf

We report the discovery of a $Spitzer$ microlensing planet OGLE-2018-BLG-0596Lb, with preferred planet-host mass ratio $q \sim 2\times10^{-4}$. The planetary signal, which is characterized by a short $(\sim 1~{\rm day})$ "bump" on the rising side of the lensing light curve, was densely covered by ground-based surveys. We find that the signal can be explained by a bright source that fully envelops the planetary caustic, i.e., a "Hollywood" geometry. Combined with the source proper motion measured from $Gaia$, the $Spitzer$ satellite parallax measurement makes it possible to precisely constrain the lens physical parameters. The preferred solution, in which the planet perturbs the minor image due to lensing by the host, yields a Uranus-mass planet with a mass of $M_{\rm p} = 13.9\pm1.6~M_{\oplus}$ orbiting a mid M-dwarf with a mass of $M_{\rm h} = 0.23\pm0.03~M_{\odot}$. There is also a second possible solution that is substantially disfavored but cannot be ruled out, for which the planet perturbs the major image. The latter solution yields $M_{\rm p} = 1.2\pm0.2~M_{\oplus}$ and $M_{\rm h} = 0.15\pm0.02~M_{\odot}$. By combining the microlensing and $Gaia$ data together with a Galactic model, we find in either case that the lens lies on the near side of the Galactic bulge at a distance $D_{\rm L} \sim 6\pm1~{\rm kpc}$. Future adaptive optics observations may decisively resolve the major image/minor image degeneracy.Comment: 34 pages, 8 figures, Submitted to AAS journa

Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma

BACKGROUND: von Hippel-Lindau (VHL) disease is a rare hereditary tumor syndrome caused by VHL gene mutations that is characterized by heterogeneous phenotypes such as benign/malignant tumors of the central nervous system, retina, kidney, adrenal gland, and pancreas. The genotype-phenotype correlation has not been well characterized in the Korean population so far. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Korean VHL patients. METHODS: Thirteen unrelated subjects with VHL mutations were included. Direct sequencing and multiplex ligation-dependent probe amplification were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated. RESULTS: We identified 10 different VHL mutations. The c.160_161delAT frameshift mutation was novel. Missense mutations clustered in 2 domains (α domain in exon 1; β domain in exon 3). The most frequently observed mutation was c.208G > A (p.Glu70Lys). Milder phenotypes were observed in subjects with de novo mutations. Age-specific risk for CNS hemangioblastoma was significantly higher in subjects carrying missense mutations within the HIF-α binding site (P < 0.05). CONCLUSIONS: This study provides insight into the genotype-phenotype correlation in that amino acid substitutions in the HIF-α binding site may predispose patients to age-related risks of CNS hemangioblastoma