Breast-conserving surgery (BCS) is a standard surgical treatment for early-stage breast cancer. The primary goal of BCS is to obtain complete tumor excision because positive resection margins are found to be associated with an increased risk of local recurrence.Using multivariable analysis, this study found that selective use of preoperative MRI was associated with a lower risk of positive resection margins (involved margins > 4 mm) after BCS for patients with screen-detected invasive breast cancer .The study results suggest that selective use of preoperative MRI for women with screen-detected invasive breast cancer promises to minimize the risk of positive resection margins after BCS. Future studies should focus on the prognostic impact of the study findings and investigate the cost-effectiveness of preoperative breast MRI for surgical planning.


There is a correlation between rs1042838 (PGR) and waist-to-hip ratio (WHR) in women with gigantomastia-AC genotype correlates with lower WHR and CC with higher WHR. There were no correlations between the onset of gigantomastia, the age of menarche and the length of the menstrual cycle, and rs1042838, rs749292 and rs7172156. We did not find differences in the SNP of PGR (rs1042838) between women with gigantomastia and controls. However, our findings showed more frequent G allele in CYP19A1 (rs749292) in women with gigantomastia.The role of estrogen, progesterone, their receptors and aromatase in the development of the breast is well documented. In this study we examined the association of genetic variants of progesterone receptor (PGR) and aromatase (CYP19A1) genes with gigantomastia risk. We conducted a case-control study among 124 women: 60 with gigantomastia and 64 controls. We examined the single nucleotide polymorphisms (SNPs) for CYP19A1 (rs749292 and rs7172156) and PGR (rs1042838). Our results showed that allele G in rs749292 (CYP19A1) increased the risk of gigantomastia, but not significantly ( Breast hypertrophy, also known as gigantomastia, is a rare condition characterized by excessive breast growth. Physical and psychological symptoms are criteria for the diagnosis, rather than the volume of excessive breast tissue ,2,3. DueThe aim of this study was to identify genetic risk factors for breast hypertrophy among genes for aromatase (CYP19A1) and progesterone receptor (PGR), examining their single nucleotide polymorphisms (SNPs) (CYP19A1: rs749292 and rs7172156 and PGR: rs1042838). A rationale for choosing these polymorphisms was based on previous studies suggesting a possible role of aromatase in the development of this condition and on the basis of the literature review ,12,16. C2), pregnancy-related gigantomastia, any abnormalities in breast, history of breast malignancy, only aesthetic reasons for breast reduction, and reductions less than 1000 g per breast. Removed tissues were routinely sent for histological examination.The study involved 124 participants (Caucasian women), including 60 patients who underwent breast reduction due to juvenile/idiopathic gigantomastia in two Plastic Surgery Centers located in different regions of Poland  . The aveAmong Medical University students , 64 women were recruited as control. All women declared their breast cup sizes from A to D and had no history of breast cancer.The study consisted of a clinical questionnaire concerning demographic data, history of breast hypertrophy, family history of gigantomastia and a genetic investigation.® SNP Genotyping Assays . Reactions were carried out using the AriaMx Real-Time PCR thermocycler  in 96-well plates, in a volume of 20 μL, according to manufacturer’s instructions.DNA was isolated from buccal cells using a commercial kit for isolation of genomic DNA, Sherlock AX, A&A Biotechnology, Gdynia, Poland according to manufacturer’s instructions. The resulting nucleic acid was suspended in TE buffer and stored at −20 °C for further analysis. The SNPs located at the genes for aromatase  and progesterone receptor  were evaluated. The G>A  A–0.400216), G>A , and the C>A  SNPs were determined using TaqMan2 for the history of breast hypertrophy in mother, grandmother, ANOVA for breast volume and waist-to-hip ratio (WHR), and Kruskall-Wallis test for the age of the onset of gigantomastia, the age of menarche and the length of the menstrual cycle. In case of significant ANOVA results, we used Scheffe’s test to ascertain which pairs of means are significant.Logistic regression was used to evaluate the relationship between the genetic variant and the risk of gigantomastia Four genetic models were considered: dominant—GG vs. AA + AG (or CC vs. AA + AC), recessive—AA vs. AG + GG (or AA vs. AC + CC), over-dominant—AG vs. AA + GG (or AC vs. AA + CC), multiplicative . To avoid the increase of type I error due to multiple comparisons, we chose the best model before calculating the OR for each model . We alsop < 0.05 was accepted. All statistical analyses were performed using the STATISTICA package .A significance level of The protocol for the study was approved by the local ethics committee of the Medical University of Lodz, RNN/06/18/KE.p = 0.09). Also allele A of aromatase rs7172156 (CYP19A1) increased the risk of gigantomastia  (p = 0.0028), but its frequency in women with gigantomastia was similar to the populational (p = 0.269). There were no differences in the minor alleles’ frequency between the groups in rs1042838 PGR (gigantomastia 17.5% vs. controls 14.06% vs. EU population 16.31%) and in rs749292 CYP19A1(gigantomastia 48.33% vs. controls 59.38% vs. EU population 44.12%).As shown in  = 0.15) . Allele 2 = 1.248, p = 0.54; grandmothers—χ2 = 2.95, p = 0.23). Anthropometric variables did not correlate with CYP19A1 SNPs. None of the gene variants correlated with breast volume , but we found a correlation between PGR rs1042838 and WHR. Scheffe test indicated that the difference is related to differences between genotypes AC (lower WHR) and CC (higher WHR)  . There wThe etiology of juvenile/idiopathic gigantomastia is unknown and examination of this issue seems to be important as it could help to answer questions about the possible risk of breast cancer and other sex-hormone dependent cancers in these women as well as provide a basis for pharmacotherapy of this disease. Kusano et al. 2006) found that for lean women larger breast size was associated with a higher risk of breast cancer and Eriksson et al. 2012) showed that two single nucleotide polymorphisms, which had previously been associated with breast cancer risk, are also associated with breast size ,20. Ther06 found  showed tThere are two functional PGR polymorphisms: PROGINS and +331G/A. PROGINS is a haplotype of three genetic variations in complete linkage disequilibrium: Val660Leu substitution (rs1042838), silent-His770His (rs1042839) and a HS-1/PV Alu insertion. It has a frequency of 0.12–0.16 among Caucasians and reduces the activity of progesterone receptors ,22. TherWe also analyzed two clinically significant polymorphisms of the aromatase gene (rs7172156 and rs749292 in CYP19A1). Their inclusion in our analysis was based on the study which reported that the minor alleles of rs749292 were positively and the minor alleles of rs7172156 were inversely associated with daily 17β-estradiol. Moreover, the rs749292 minor alleles were inversely associated with absolute mammographic density-lean women with rs749292 minor alleles had lower risk for high absolute mammographic density, while lean women with rs7172156 minor homozygous genotype had risk for high absolute mammographic density . In theiThere are some limitations to the study. First, the study cohort is small, resulting in low statistical power for detection of associations. However, the limited sample size in this study has some justifications. Most of all, gigantomastia is not a common condition  and, considering its diagnosis is based on physical symptoms, it creates a rather heterogenous group of disorders. To overcome this problem, we imposed rigorous inclusion criteria—we included only women with juvenile or idiopathic gigantomastia . An additional criterion that limited the number of participants was resection weight of at least one kilogram per breast. These criteria helped to recruit a rather homogenous group of women with gigantomastia. Applying such standards resulted in a small number of participants so we included patients from another center where such surgeries are often performed and where an accurate recruitment for the project was secured. To further increase the number of patients meeting these criteria, more centers should be included and a multicenter project could be established. Secondly, we included only white women from two regions of the country, which does not allow for generalization. The results are preliminary and provide rationale for further studies examining PGR and CYP19 polymorphisms in women with gigantomastia, e.g., also including intron 4 (TTTA)n repeat and TCT deletion/insertion polymorphisms .Another methodological aspect that should be commented on is the rationale for choosing female students as a control group, as their age is lower than in the case of women with gigantomastia. However, age-matching did not seem to be relevant as age does not influence gene polymorphism and, with high probability, the controls did not include women who will develop juvenile or idiopathic gigantomastia, as the mean age of gigantomastia onset in our participants was 14.6 years, much lower than the controls’ mean age.To conclude, we did not find significant differences in the single nucleotide polymorphisms (SNPs) of genes for aromatase  and progesterone receptor  between women with gigantomastia and controls. However, we observed that allele G in rs749292 (CYP19A1) increased the risk of gigantomastia. We found a correlation between A allele of rs1042838 in PGR  and lower WHR in women with gigantomastia, which may suggest that women with this condition and lower WHR may be at higher risk of endometrial cancer. Further multicenter studies on larger samples are needed to establish the etiology of gigantomastia and the risk of sex-hormone dependent cancers in these women.


N-palmitoylglycine) were positively associated (OR per 1 SD = 1.29 to 1.32), and one (3-methylxanthine) was inversely associated with CRC risk . We did not replicate findings from two earlier prospective studies of 250 cases each after adjusting for multiple comparisons. Large pooled prospective analyses are warranted to confirm or refute these findings and to discover and replicate metabolites associated with colorectal cancer risk.Untargeted metabolomic studies have identified potential biomarkers of colorectal cancer risk, but evidence is still limited and broadly inconsistent. Among 39,239 Cancer Prevention Study II Nutrition cohort participants who provided a blood sample between 1998–2001, 517 newly diagnosed colorectal cancers were identified through 30 June 2015. In this nested case–control study, controls were matched 1:1 to cases on age, sex, race and date of blood draw. Mass spectroscopy-based metabolomic analyses of pre-diagnostic plasma identified 886 named metabolites, after quality control exclusions. Conditional logistic regression models estimated multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) for 1 standard deviation (SD) increase in each metabolite with risk of colorectal cancer. Six metabolites were associated with colorectal cancer risk at a false discovery rate < 0.20. These metabolites were of several classes, including cofactors and vitamins, nucleotides, xenobiotics, lipids and amino acids. Five metabolites  and  Colorectal cancer (CRC) is a multi-factorial disease with many established lifestyle and behavioral risk factors, including smoking, diet, pharmacologic agents, and several variables related to energy balance and metabolism  ,2,3. MetThe use of metabolomic methods to identify candidate biomarkers of CRC risk is still a new area of research, with fewParticipant characteristics are provided in N-palmitoylglycine, an acyl glycine; guanidinoacetate, an amino acid involved in creatine metabolism; and 2’-O-methylcytidine, a nucleotide involved in pyrimidine metabolism. The ORs for each metabolite with CRC risk were similar between minimally adjusted  and multivariable-adjusted models; therefore, only multivariable-adjusted models are presented. 3-Methylxanthine was inversely associated with risk; all other metabolites were associated with an increased CRC risk. O-methylcytidine changed least . Results using categorical variables (based on quartile distribution) are also presented. Associations of all 886 metabolites with CRC risk are provided in O-methylcytidine (pinteraction = 0.04) .Only one of these six metabolites had a statistically significant interaction with sex, with a stronger association observed in men than women for 2’- = 0.04) . When stn = 0.04). None ofIn this study of 517 colorectal cancer cases and 517 matched controls, six metabolites among 886 identified were moderately associated with colorectal cancer risk at the FDR < 0.20. These metabolites covered a range of metabolite classes, including amino acids, fatty acids, cofactors, nucleotides and xenobiotics. Only one metabolite association differed by sex, and sex-specific associations were generally of the same magnitude, albeit with varying precision. p = 0.015, FDR = 0.39; p = 0.050, FDR = 0.61; not shown). In the Shanghai Men’s and Women’s Health Study cohorts (SMHS and SWHS) including 250 cases and 250 controls, 35 of the 618 annotated metabolites were statistically significantly associated with CRC risk using FDR < 0.05 to define significance, of which nine metabolites were independently associated with risk  and 7 unknown subsite. Controls were incidence-density matched 1:1 to cases on sex, race/ethnicity, age at blood draw (± 6 months) and date of blood draw (± 30 days).Metabolomic profiling was conducted by Metabolon, Inc.  using untargeted, ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) ,23. Brien = 27) and those with a technical intraclass correlation coefficient (ICC) that was missing (n = 74) or <0.50 (n = 76) were excluded from the analyses, leaving 886 named metabolites with an average CV% 0.29 (interquartile range 0.18–0.35) and ICC 0.82 (interquartile range 0.74–0.92).Colorectal cancer cases and controls were analyzed in the same batch in a blinded fashion. Replicate quality control samples from 29 study participants were included with the study samples and used to assess intra- and inter-batch variation in the metabolite measurements. A total of 1063 named metabolites were measured. Metabolites which were undetectable in >90% of the samples , smoking, recreational physical activity, alcohol drinking, non-steroidal anti-inflammatory drug use, American Cancer Society diet guidelines score , ; regional [tumors that extend through the bowel wall to adjacent tissue or regional lymph nodes (n = 225 cases)] and distant metastases (n = 53). The Wald p value for heterogeneity by tumor site and stage was estimated from an unconditional nominal polytomous logistic regression model using the model-based variance–covariance matrix estimate [Associations were considered statistically significant if the false discovery rate (FDR)  adjusted studies ,27 to alestimate . Analyseestimate , and SAS


MC1R] gene) in a study randomizing (like the flip of a coin) 600 diverse primary care patients to a MC1R test offer or usual care. We found that testing did not improve sun protection and skin cancer screening, nor did it lead worry to increase. However, groups less aware of their skin cancer risk, including those who thought their risk was “unlikely” at the start of the study, showed significant improvements in sun protection at three months. In conclusion, testing might be very helpful for certain people who have the most to learn about their risk, who may become motivated to protect themselves from the damaging effects of the sun as a result of skin cancer genetic testing.Genetic information is publicly available but research examining the best use of such information has not engaged diverse members of the public. We examined public reactions to melanoma genetic testing (using the melanocortin-1 receptor [MC1R) gene melanoma risk variants in the general population, we examined genomic testing of MC1R for skin cancer risk in a randomized controlled trial in Albuquerque, New Mexico primary care. Participants were 48% Hispanic and were randomized 5:1 to a MC1R test invitation or usual care. We assessed 3 month sun protection, skin cancer screening, and skin cancer worry outcomes associated with testing, and key effect moderators . Our findings indicate that the primary outcomes were unchanged by the MC1R test offer, test acceptance, and level of risk feedback. Moderator analyses showed that those with lower risk perception, and those with skin that readily tans, significantly increased their sun protection in response to higher than average risk feedback. Risk feedback did not prompt cancer worry, and average risk feedback did not erode existing sun protection. This study paves the way for the development of tailored strategies to address low skin cancer risk awareness in this understudied context of public health genomics.Public availability of genetic information is increasing; thus, efforts to improve diversity in basic and translational research in genomics is a top priority. Given the increasing U.S. incidence and mortality of melanoma, and the prevalence of common melanocortin-1 receptor ( Costs for sequencing have been decreasing rapidly [Genetic information regarding health risk, and cancer risk specifically, is available through multiple sources—both within and outside of the U.S. medical and public health systems, and there are relatively high levels of public awareness concerning this availability . Genetic rapidly . Despite rapidly , that ar rapidly . AdditioMelanoma is the 5th most common cancer in the U.S., and its incidence has tripled in the last four decades _ENREF_1 ,13,14,15MC1R) gene encodes a protein that signals the production of melanins. MC1R exhibits great genetic variability, and a large proportion of individuals of European ancestry, including Hispanics, carry at least one MC1R risk variant [MC1R variants is a robust marker of increased risk of melanoma and keratinocyte skin cancers [MC1R variants and skin cancer are stronger in individuals with “sun-resistant” phenotypic characteristics  than in those with “sun-sensitive” characteristics  [MC1R variants  ranges from 1.2 to 8.9% and approaches 40% when summed across variants [MC1R genotype conveys information about inherited skin cancer risk for a broad spectrum of individuals, including Hispanics. Most (50–70%) of the general population of European ancestry and 50% of Hispanics have at least one risk variant at MC1R [MC1R variants a potential novel route to motivate sun protection and skin cancer screening in the general population. In New Mexico, specifically, those who identify as Hispanic derive from mating between Native Americans  and Europeans and Africans, who arrived over the past 400 years. Recent studies indicate that the majority of ancestry is European (mean = 71%), followed by Native American (27%) and African (2%) [MC1R variants in Europe (26–28), many New Mexican Hispanics today carry MC1R variants.The melanocortin-1 receptor  ,27. The variants ; this pr at MC1R ,28, even at MC1R ,33, makican (2%) ,35,36. GMC1R for skin cancer risk may promote behavior change across ethnically and racially diverse populations [MC1R test offer and completion. Our research questions were as follows. First, what are the 3 month outcomes  associated with the receipt of higher (compared to average) risk MC1R feedback? We also examined outcomes associated with receiving a MC1R test offer  and accepting that offer (compared to declining the offer). Second, were there significant moderators of the relationship between the receipt of higher vs. average genetic risk findings and the 3 month outcomes ? Potential moderators included participant health literacy, perceived importance of genetic information, cancer risk perceptions, demographics, and skin cancer risk factors, all of which may influence behavioral and psychosocial outcomes associated with skin cancer genetic testing [Genomic testing of ulations , especiaulations ,41,42,43ulations , yet theulations  is extreulations . This raulations . We exam testing ,53,54,55Bilingual Project Assistants (PAs) approached primary care patients in University of New Mexico (UNM) outpatient primary care clinics with SOMBRA study invitation flyers (English and Spanish) and National Cancer Institute skin cancer information for diverse skin types (available in English and Spanish versions: “Anyone can get skin cancer”) . PatientMC1R testing or usual care (control group), balanced across Hispanic vs. non-Hispanic ethnicities. Overall, 600 participants enrolled in the RCT and completed the baseline assessment; 499 were randomized to the MC1R testing offer; and 101 were randomized to usual care. Usual care participants did not receive an invitation to log on to the study website. All participants received National Cancer Institute skin cancer information brochures about skin cancer risk in diverse skin types (available in both English and Spanish) [Patients who were eligible completed a one-minute screening survey that assessed perceived importance in learning about genes and health risks, skin cancer risk perceptions, and demographics. Refusers were asked their reasons for study refusal. Those willing to participate completed the informed consent and baseline assessment and were then randomized 5:1 to an invitation to consider Spanish) . See FigMC1R testing and then register their decision to participate in testing. Patients without internet access were offered the opportunity to view the website via paper format. Participants who chose testing were mailed a kit to obtain their DNA, and if they so desired, provided a saliva sample for genetic testing. Those participants who sent in their sample received a report with their results in the form of genetic risk feedback stating that they were at either average risk, based on the presence of no MC1R variants associated with melanoma risk, or higher risk, based on the presence of at least one MC1R variant associated with risk of developing melanoma [MC1R testing as a courtesy after completion of the final 3 month follow-up outcome assessment, and 57 of 101 usual care participants requested it.Those randomized to the intervention arm were invited to log onto the study website  to read melanoma . The desmelanoma . Particimelanoma . PrimarySun protection: The frequency of use of five sun protective behaviors while in the sun—sunscreen, shade-seeking, hats, protective clothing, and sunglasses—were reported at baseline and again at the 3 month follow-up. Participants rated each behavior on a 5-point frequency scale ranging from 1 = Never to 5 = Always . We calcSkin cancer screening: At the baseline assessment, we assessed whether participants had ever had their skin checked for skin cancer (from head to toe) by a healthcare professional. At the 3 month follow-up, they were asked whether they had received skin cancer screening since they had started the study.Cancer worry: Worry items were drawn from Lerman and colleagues  on 4-poiMC1R test offer . Second, among those who received the test offer, we examined the outcomes associated with accepting that offer (vs. declining that offer). Test offer acceptance was defined as logging on to the website and requesting a test kit. Declining the test offer included those who actively declined the test offer on the study website, as well as those who did not log on to the website at all. Third, of those who completed testing by accepting the test offer, we tested the outcomes associated with the receipt of higher (vs. average) risk test results. See We examined three predictors. First, we explored the outcomes associated with the receipt of an p-values for hypotheses testing, to avoid the problem of multiple comparisons.We included participant health literacy, perceived importance of genetic information, cancer risk perceptions, demographics, and skin cancer risk factors in the models as potential effect moderators. Health literacy was assessed with three items: (1) level of confidence in filling out medical forms independently, (2) frequency of needed assistance reading hospital materials, and (3) frequency of problems learning about medical conditions because of difficulty reading hospital materials . These items have _ENREF_133 good sensitivity across diverse literacy levels ,61. ModePerceived importance in learning about ones’ genes and associated health risks was assessed  . Perceivt-tests and Chi-square tests, for continuous and categorical variables, respectively. The general framework for analysis was generalized regression modeling, regressing 3 month outcomes on predictors  and adjusting for baseline. For our first research question, the 3 month outcomes were compared across MC1R test offer , test acceptance (compared to declined), and receipt of higher (compared to average risk results). Models were fitted both with and without adjustment for baseline characteristics that differed based on attrition status. For our second research question, another series of regression models were used to assess moderator effects with the receipt of higher, compared to average, risk test results on 3 month outcomes, separately. For these models, the baseline outcome, potential moderator , test results, and interaction of moderator and test results were included. Eta-squared (η2) in a regression model is the ratio of the variance explained by a parameter of interest. The interaction term was the parameter of interest, with η2 reported as a measure of standardized effect sizes for continuous outcomes and standardized odds ratios for the binary skin exam outcome. This strategy of using standardized effect sizes and then probing non-trivial associations, rather than merely relying on p-values, reduced the risk of inflated family-wise error rate when investigating a large number of potential moderators [2 in multiple regression, values of 0.02, 0.13, and 0.26 were considered small, medium, and large effect sizes, respectively. For interaction odds ratios (iOR) with standardized variables and rare outcomes, values of 1.68, 3.47, and 6.71 were considered small, medium, and large effects [Sun protection and cancer worry were treated as continuous 3 month outcomes, and skin cancer screening as a dichotomous outcome. Attrition between the baseline and 3 month follow-up was described; completers were compared to non-completers based on baseline characteristics. Differences by attrition were tested via a series of independent sample derators . For η2 less likely to participate in the study than patients who gave another scale response; these psychosocial factors remained significant predictors of study participation after adjustment for ethnicity and education [As reported previously , 1998 prducation .n = 494, 82%) completed a 3 month follow-up. Participants who were not retained at the 3 month follow-up were more likely to be Hispanic , have lower educational attainment (p < 0.01) or income (p < 0.01), have no family history of cancer , have responded “don’t know” to absolute perceived risk , and have rated their risk as “unlikely” at baseline . Overall, those who completed the study were predominantly female (79%), white (72%), had at least some college education (80%), and were 53 years of age . Baseline levels of sun protection, skin screening, and cancer worry were unrelated to the study completion status. Baseline characteristics both overall and by study completion status are shown in Of the 600 study participants, 79% were female, 48% Hispanic, 71% white, and 77% had more than a high school education. Most  of participants had sun protection scores less than 15 across the five behaviors; the mean score was 17 , which translates to somewhere between “sometimes” and “often.” However, only one third (37%) of the participants had ever received skin cancer screening, and skin cancer worry was extremely low .Most participants reported little to no change in all outcomes between the baseline and 3 month follow-up. For example, the median sun protection change score was zero , and only 5% of participants had a change score of more than five points in either direction. Similarly, only 10% of participants who had never had skin screening received one in the study time period, and cancer worry scores increased slightly, by 0.03 points on average. In models adjusted for baseline outcomes only, the predictors  were not significantly associated with sun protection, skin cancer screening, or cancer worry at 3 months . The basMC1R risk feedback (higher vs. average risk) on outcomes; however, some of these effects stood apart with small but significant effect sizes. See Most moderators had no significant interaction effects with level of 2 = 0.03; p = 0.01) and perceived risk  were significant moderators of the effect of risk feedback on sun protection. The same risk perception item had a non-trivial effect size  for moderation of risk feedback level on cancer worry. These moderations effects are depicted in MC1R feedback reported significantly greater improvement in sun protection (p = 0.02) than those who received average risk MC1R feedback. For participants who believed they were unlikely to develop skin cancer at baseline, those with higher risk feedback had significantly greater improvement in sun protection (p = 0.04), compared to those who received average risk feedback. These associations did not hold for participants who reported that their skin did not tan or who reported at baseline a high likelihood of skin cancer risk. Though the stratified results for risk perception were not significant for cancer worry, the same pattern held . Different patterns of moderators were seen for the effect of MC1R risk feedback level on the skin cancer screening outcome. Educational attainment, history of sunburn, and family skin cancer history stood apart as potential moderators after controlling for skin screening history, based on effect sizes. First, among those who had never received prior skin cancer screening, higher risk feedback was associated with skin cancer screening completion at 3 months among those with lower educational attainment . Cell sizes were too small to make similar inference for participants who had previously screened. Second, regardless of their skin cancer screening history, among those who had no history of sunburn, receipt of average risk results predicted 3 month skin cancer screening . Third, the family history effect was complex. Among those who had never been screened, only those with a family history of skin cancer and higher risk MC1R, or those with no family history of skin cancer and average risk MC1R, completed any screening at follow up. Among those who had never been screened, none of the participants who received only higher risk feedback, or had a family history of skin cancer, reported screening at the follow up time period .Tannability . Further, selection for youth in secondary schools and universities to heighten awareness of skin cancer is a promising area for future research. This may include large portions of the general population who tan and/or do not use adequate sun protection . In the MC1R testing, we had relatively small samples of those who received feedback. While this limited the statistical power to test moderation on risk feedback (higher versus average risk), our study design allowed for examination of behavioral and psychosocial outcomes critical to real-world use of skin cancer genetic testing feedback, where those who follow through with testing may differ significantly from those who do not. Future use of larger samples will also allow for further examination of moderators, such as differences in educational attainment. These important influences on behavior may not be measurable in study designs where all participants recruited are already interested in pursuing genetic testing. Our exceptionally high recruitment rates (86% of eligible primary care patients) were a study strength, along with the careful measurement of interest in, and completion of, testing; most (88%) who visited the website to consider testing went ahead and ordered a test kit [The current study has limitations as well as strengths. First, we assessed primary care patients in only one area of the country, which already had a generally high prevalence of practicing sun protection, which reduces generalizability. Second, we relied on self-reported sun protection, although self-report has been found to be a valid indicator of objective sun protection usage . Future test kit . RecruitMC1R testing feedback on behavioral outcomes, including sun protection and skin cancer screening, and similarly did not find any increase in skin cancer worry, an important and promising finding. However, we identified moderators with relatively large effect sizes, including low risk perceptions, which suggest targets for the deployment of tailored strategies, using skin cancer genetic testing in diverse subpopulations that may be most readily impacted by risk feedback.Efforts to improve diversity in genomic research, both basic and translational, are a top priority . The cur


Germ-line mutation in BRCA (BReast CAncer gene) 1 or BRCA2 are found in 3–4% of all women with breast cancer. These patients have a significant increased risk of breast and ovarian cancer. They are often younger when diagnosed with the mutation, and the possible breast cancer they get is often aggressive with inferior outcome. There are risk reducing strategies, and the most powerful strategy is risk reducing surgery, both risk reducing bilateral mastectomy (RRM) and risk reducing bilateral salpino-oophorectomy (PBSO). This review is meant to address breast surgery in patients with germline BRCA mutation. The guidelines and techniques applied is under continuous change and it is important for the clinicians to be well informed to provide the patient with the information needed for them to make an informed decision on what risk strategy to choose. •Patients with germ-line mutation in BRCA1 or BRCA2 have a significant increased risk of breast and ovarian cancer.•There are different risk reducing strategies and the most powerful strategy is risk-reducing surgery, both risk reducing bilateral mastectomy and risk reducing bilateral salpingo-oophorectomy.•Guidelines and techniques for the risk reducing surgery of the breast are under continuous change and improvement.•Breast conserving therapy is not associated with worse survival and is a good option for a BRCA mutation carrier diagnosed with breast cancer. Risk-reducing mastectomy can be performed in a later setting.•The management of BRCA mutation carriers, both affected and unaffected, should be performed in a multidisciplinary team. Physicians need to be systematically educated and updated on the most recent literature. There iThis review is meant to address BRCA mutation carriers, both unaffected and affected carriers, with a focus on breast cancer and surgery of the breast. There are many different strategies on how to approach these patients and it is important that they are well informed and prepared for proper surveillance, treatment, and follow-up. The information present in the review is based upon extensive review of the literature with “BRCA” and “surgery” as search terms. More than 1500 publications answered to these search terms. A selection was made on publications covering BRCA and surgery from an oncological breast surgeon's perspective.1.2https://www.breastcancer.org/risk/factors/genetics).There are other high penetrance gene mutations associated with breast cancer, but BRCA1 and BRCA2 are best elucidated . Other h1.3A specific predisposing gene is identified in <30% of the patients where there is a family history of breast cancer . The bio22.1Women with BRCA1 mutation are recommended prophylactic bilateral salpingo-oophorectomy (PBSO) at the age between 35 and 40. Women with BRCA2 mutation are recommended the same procedure at a later age, preferably between 40 and 45 . The ben2.2PBSO renders an anticipated early menopause which has unfortunate physical and psychological consequences ,40). Pre. Pre40])3Bilateral risk-reducing mastectomy (RRM) is the most effective approach to reduce risk of breast cancer in patients with genetically caused breast cancer. The expected benefit of prophylactic mastectomy in women with BRCA mutation who have not had their breast cancer (unaffected carriers) differs by age at the time of the procedure being done . The proThe effect of contralateral RRM in women with BRCA mutation diagnosed with breast cancer is debated. There are six studies with similar results all suggesting contralateral RRM has positive impact on survival . In oneWomen undergoing RRM may experience great discomfort. It has been reported that as many as 69% experience pain after the procedure, up to 71% experience discomfort in the breast, 85% has reported reduced sexual sensation, and enjoyment of sex was reduced in 75% of the patients . These r4https://ccge.medschl.cam.ac.uk/boadicea/), BRCAPRO (https://projects.iq.harvard.edu/bayesmendel/brcapro), Myriad , the Tyrer-Cuzick Model Breast Cancer Risk Evaluation Tool (https://ibis.ikonopedia.com/) )= 0.147) . Decreas= 0.147) ,86). Wom= 0.147) ,88). Thi= 0.147) .6.2For the general population pregnancy after a breast cancer diagnosis is not associated with inferior outcome compared to matched non-pregnant controls . The saf7Surveillance is a reasonable alternative to risk reducing surgery in selected women . Risk re8BRCA1 and 2 mutations  like tamoxifen and aromatase inhibitors (Ais). This treatment significantly reduces breast cancer risk beyond the active treatment period . Studiestations ,101). Th. ThBRCA1tations  are not aware of having a BRCA mutation prior to surgery 104). This influence the choice of surgery being performed (p = 0.017) but will not influence the risk of ipsilateral breast cancer recurrence (p = 0.765) or the risk of contralateral breast cancer (p = 0.69) . This in). In a s1010.1In sporadic breast cancer breast conserving therapy (BCT) has the same survival data as mastectomy if it is combined with adjuvant radiotherapy ,111). So. So111])BCT requires adjuvant radiotherapy to reduce risk of local recurrence. There are different opinions on the safety of adjuvant radiation therapy and the risk of contralateral breast cancer. BRCA mutation involves mutation and malfunction of the DNA damage repair pathways. DNA damage is the same mechanism applied when treating the patient with adjuvant radiotherapy. Therefore, it has been argued that there is an increased risk of radiation induced contralateral breast cancer. This was evaluated in a study of 247 patients who experienced contralateral breast cancer, 169 received radiotherapy and 78 did not. Conclusion from this study was that compared to patients with sporadic breast cancer women with BRCA mutation had an increased risk of developing a radiation induced contralateral breast cancer . OthersConclusively BCT is not contraindicated in female with BRCA mutation who experience primary breast cancer, however ipsilateral therapeutic mastectomy and contralateral RRM should be discussed with the patient considering the increased risk of contralateral breast cancer compared to those with sporadic cancers, and that there is a risk of ipsilateral primary event even though the latter does not seem to be different between women with or without BRCA mutation . All the10.2There are different approaches to prophylactic surgical procedure both when it comes to time of surgery, number of surgeries, the order of the different surgical procedure, and how the surgical procedures should be performed. The approach to the surgical strategy differs between unaffected and affected women with BRCA. In BRCA carriers not diagnosed with breast cancer a combined approach with concurrent PBSO and bilateral prophylactic mastectomy (RRM) is preferred . The com10.2.1RRM can be performed both with and without primary reconstruction. There is an increased risk of complications and a possible second surgical procedure in patients having primary reconstruction compared to a simple mastectomy . ImmediaAn example of an implant-based approach is the nipple-sparing bilateral prophylactic mastectomy and immediate reconstruction with TiLoop®Bra mesh. This is a procedure where the implant, which is covered by a mesh, is placed subcutaneously D, and is10.2.2As an alternative to implant-based reconstruction, the reconstruction can be done based on autologous tissue. Trans rectus abdominis myocutaneous flap (TRAM) is the most common technique  Fig. 3)Fig. 3). Indications for autologous based reconstruction over implant-based reconstruction is above all patient preference. It is more often used in unilateral reconstructions because of the amount of abdominal tissue needed to reconstruct both breasts. Therefore, it might be a challenge in BRCA mutation carriers who need bilateral reconstruction. A woman with enough abdominal bulk is more suited for this procedure but obesity is a relative contraindication. Other relative contraindications are prior abdominal surgery, prior abdominal contouring procedures like liposuction and abdominoplasty, smoking history less than a month before surgery, and if the patients suffer from a hypercoagulable state . There aThere are alternative donor sites for both pedicle and free flap. Latissimus dorsal pedicle flap is an option, but this procedure is often combined with an implant-based reconstruction or a breast conserving therapy to fill the defect breast volume . The latA single institutional study of 238 patients compared implant-based versus autologous reconstruction, 89.5% had implant-based and the rest had autologous based. Women who underwent autologous based reconstruction were more satisfied than those who had implant-based reconstruction . This isIn cases where the PBSO is combined with the bilateral RRM and primary reconstruction based on autologous tissue it is important to be well prepared. If the PBSO is performed through a laparoscopic technique, it is important to place the ports where they will not interfere with the donor site. PBSO is then performed as the first part of the procedure followed by bilateral RRM and breast reconstruction with for instance DIEP (deep inferior epigastric perforator flaps). This one-step procedure is shown to be safe, feasible and well accepted . The comRemodeling of a breast by autologous fat grafting (lipofilling) is a popular technique for breast reconstruction but its oncological safety is debated . It was 10.2.3Preservation of the nipple is positive correlated with psychosocial and sexual well-being . The saf1111.1Prophylactic mastectomy and primary reconstruction require good planning, both in cancer patients and in non-affected high-risk patients. It is shown that a multidisciplinary model of trained and committed members is favorable for timing and outcome of surgery . A nipplSurgical management and prevention of breast cancer is under continuous change and improvement. It is important to at all time have trained personnel and well-qualified centers .11.2RRM is the most powerful prevention of breast cancer in BRCA mutation carriers, with a 90–95% reduction rate ,170. TheComplications vary according to type of surgery, but there are as with all type of surgery, patient related factors like diabetes, body mass index and smoking . There ahttps://www.bcna.org.au/resource/breconda). This is valid for all patients in need of a reconstruction, not just women with BRCA mutation [There are online tools which are shown to be of great value for patients in the decision of which reconstruction to choose . In. In175])13Age is no limit for surgery. In a retrospective study where patients over 70 years were tested and found to be BRCA mutation carriers, 16% of patients without prior cancer had a risk-reducing mastectomy .14Another important question is if women without BRCA mutations should be advised or accepted for RRM if they request the procedure. Bilateral mastectomy will not provide any survival benefit and is associated with worsened body image and quality of life. In addition there are more re-do surgeries and more complications compared to breast conserving therapy on the affected side . The hig15Evaluation of the cost-effectiveness is challenging considering the psychological stress of experiencing a breast cancer diagnosis. It has been suggested that the long-term health-care costs can be reduced by performance of risk-reducing surgeries in BRCA positive patients, both PBSO and RRM,186). Gu. Gu186])16Molecular profiling of breast cancer initiated in the millennium change, revealed the heterogeneity of breast cancer, and separated it into molecular subtypes of specific clinical implication including different prognosis and different response to treatment . This ha17There are guidelines as to which patients to test for BRCA mutation and when is the appropriate timing. It is important that the patients are offered genetic counseling parallel to the testing. Surveillance with breast MRI and mammography may be a good option for some patients. RRM should be discussed with the patient and the surgical method should be discussed in a multidisciplinary team prior to the discussion with the patient. It is mandatory that the choice of surgical procedure is based upon informed consent from the patient. BCT is safe for BRCA positive patients who are diagnosed with breast cancer, and this may be the best immediate option. A RRM can safely be performed later. If the woman is prepared and surgery will not delay further treatment of the breast cancer, a bilateral mastectomy may be suggested, therapeutic on the affected side and prophylactic RRM on the contralateral side. Bilateral RRM is a good option for unaffected women with BRCA mutation. NSM is considered safe and should be offered to the patient if it is technically possible. In a BRCA mutation carrier diagnosed with breast cancer the choice of surgery should be influenced by the age of the woman and her situation according to family planning.The review does not need ethical approval since it is a review of the literature and individual patients are not mentioned.The author has no funding for this review. She is employed in a surgical department and have written the manuscript parallel to her clinical work.The author has written the manuscript by herself. The head of the department has read through the manuscript but have not made any changes.Name of the registry:Unique Identifying number or registration ID:Hyperlink to your specific registration (must be publicly accessible and will be checked):Not relevant for this review.The author takes full responsibility for the content of the manuscript.Not commissioned, externally peer reviewed.The author has written the manuscript alone.The author confirms no conflict of interest.


Breast cancer (BrCa) is a heterogeneous disease with multiple intrinsic tumor subtypes evidenced by the joint expression of molecular tumor markers. Data from epidemiologic studies provide evidence supporting differential effects of oral contraceptives on risk of developing the distinct subtypes of breast cancer; while some studies suggest increased risk, others show its lack. Toward this objective, we conducted meta-analysis of case-control trials devoted to this topic. The results of our study suggest that the oral contraceptive use has different effects on the risk of developing the various molecular breast cancer subtypes.p = 0.002), as well as of ER−BrCa . There was also a significant reduction in the risk of ER+BrCa  and a slight reduction in the risk of HER2+BrCa  after taking OCs. Meta-analysis indicated that OC use has different impacts on risk of breast cancer subtypes defined by receptor status. The identified differences between individual subtypes of breast cancer may reflect different mechanisms of carcinogenesis.We conducted a systematic review and meta-analysis to investigate the effect of oral contraceptives (OCs) on risk of breast cancer (BrCa) by status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). We searched the MEDLINE (PubMed), Embase and the Cochrane Library database and bibliographies of pertinent articles published up to 2020. Therein, we identified nineteen eligible case-control studies which provided data by breast cancer subtypes: ER-positive (ER+), ER-negative (ER−), HER2-positive (HER2+) and Triplet-negative (TN). Summary risk estimates (pooled OR [pOR]) and 95% confidence intervals (CIs) were calculated using fixed/random effects models. The summary meta-analysis showed that over-use of OCs led to significant increased risk of TNBrCa (OR = 1.37, 95% CI; 1.13 to 1.67,  Breast cancer (BrCa) is the most commonly diagnosed malignant neoplasm in women, most often originating in the epithelial tissue of the mammary gland. In 2020, 2,261,419 new cases were estimated, accounting for 11.7% of all cancer cases, and causing 684,996 deaths worldwide. BrCa death rates were significantly higher in developed countries compared to developing countries  ,4.BrCa is a heterogeneous disease with multiple intrinsic tumor subtypes evidenced by the joint expression of molecular tumor markers such as estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor 2  and a proliferation index Ki67), based on their presence or absence; together with tumor size, tumor grade and nodal status . Subtype7, based The most common group of BrCa is ER-positive (ER+). This includes the two subgroups, luminal A and luminal B, occurring in about 60% of all cancers ,8. The lThe distinct group of BrCa is of the ER-negative (ER−) subtype. Its characteristic morphological features are: infiltrative margin, high grade, lymphoid stroma, central fibrosis/necrosis, and comedo-type necrosis. It is worth pointing out that the most invasive cancers (20–25%) are of the ER−/PgR− subgroup associated with a lower endocrine therapy sensitivity score , and somThere are more and more reports showing the existence of a unique BrCa subtype with an ER−/PgR+ phenotype (about 3%), with different molecular and clinical characteristics. This subtype is characterized by a low result of hormone sensitivity and a tendency of early relapse and worse overall survival ,16,17. HHER2-positive BrCa, defined as ER−/PgR−/HER2+, accounts for 10% to 34% of all invasive breast cancers. It stands out because of its tendency to grow and spread more aggressively. It is associated with shorter disease-free status and overall survival ,23,24. TAlthough differences in the etiology of the respective breast cancer subtypes are not fully understood, there are many risk factors, among others: reproductive, genetic, lifestyle, BrCa in family history, carrier of the mutation, age of menarche, parity, age at first birth, breastfeeding, or exogenous hormone use ,28,29. IThe relationship between oral contraceptive (OC) taking and the risk of breast cancer has also been extensively researched. Findings suggest that OC use is associated with a moderately increased breast cancer risk in the general population ,33,34,35Data from epidemiologic studies provide evidence supporting differential effects of oral contraceptives on risk of developing the distinct subtypes of breast cancer; while some studies suggest increased risk, others show its lack. Toward this objective, we conducted meta-analysis of case-control trials devoted to this topic.This systematic review with meta-analysis was designed according to PRISMA  guidelines ,37 to deWe included publications written in English, based on case-control studies , providing information about the association between oral contraceptive use and breast cancer by ER, PR or HER2 status, and the data contained therein were sufficient to calculate the odds ratio (OR) and the 95% confidence interval (CI). The exclusion criteria were as follows: insufficient data for calculating desired parameters, the results were reported as graphics; duplicate reports; and reviews or case only studies.The following data were extracted for each study: (i) clinical and methodological study characteristics such as last name of first author, publication year, country in origin, years of data collection, number of participants in case and control subgroups; (ii) information on use of OC in individual subgroups: whenever/never, duration, age at first use, and years since last use prior to diagnosis; (iii) in the original studies, different definitions and combinations of subgroup used; in our analysis, we grouped subtypes into the following four categories: ER-positive (regardless of their PR/HER2 status), ER-negative (regardless of their PR status), HER2-positive (absence of ER/PR), and Triplet-negative (absence of ER/PR/HER2).The Newcastle–Ottawa Scale (NOS) score was employed to evaluate methodological quality of included studies. With this tool, each study was assessed in three separate categories: selection of cases and controls, comparability of cases and controls on the basis of the design or analysis, and ascertainment of exposure. A maximum score was 9, of which 0–3, 4–6, and 7–9 scores were considered as low, fair, and high quality .The distribution of cases and controls at risk, ORs and 95% CI were separately identified by receptor status and for oral contraceptive use (ever or never) and by age of first use of OCs, duration of OC use, and years since last use of OCs prior to diagnosis, when data were available. We calculated the summary risk estimates and 95% CIs and plotted forest plots using random-effects models (DerSimonian–Laird method) for the association between ever oral contraceptives use and breast cancer by receptor status. The results indicated that the taking of OCs may have a high probability of increase in risk if OR was above 1, compared with non-use of OCs .2 statistic and p values associated with Q statistics. I2 statistic indicates the percentage of total variability explained by heterogeneity, and values of ≤25%, ‘25%–75%’, and ≥75% are arbitrarily considered as indicative of low, moderate, and high heterogeneity, respectively [Heterogeneity among articles was estimated by engaging the Iectively .To explain the possible presence of publication bias, Begg’s test  and Egger’s test (a linear regression method) were applied ,42. We aSearches of electronic databases allowed the identification of four hundred and forty-three (443) citations. Subsequently, three hundred forty-six (346) items were excluded on the basis of title and/or abstracts. In turn, ninety-seven (97) articles with potentially significant case-control works were identified and submitted for full-text assessment. Of these, seventy-eight (78) papers contained duplicate publications, or included insufficient data for calculating the desired parameters, or for other reasons, did not meet all the inclusion criteria. Finally, nineteen articles were included in the systematic review and meta-analysis. A detailed review of selection procedure is shown in The quality of the analyzed studies as assessed on the basis of the Newcastle–Ottawa Scale (NOS) ranged between 4–8, and the average score was 6.74 for included studies. Furthermore, 12 (63.16%) were considered high quality studies (NOS ≥ 7 points).Thirteen (13) case-control studies were conducted in North, three (3) in Asia, and one each in Australia, and Europe, while one pooled study was conducted in the United States, Canada, Australia and Korea. The studies involved a total of 246,152 persons, including 31,250 cases of breast cancer and 214,902 people as control. Six studies exclusively included premenopausal women ,48,49,50The present meta-analysis was conducted on the basis of data from nineteen case-control studies assessing the effect of oral contraceptives on the risk of individual molecular subtypes of BrCa. Characteristics of selected works are shown in p = 0.026, I2 = 66.59% (p = 0.529) and Egger’s (p = 0.384) test assessments ; or for ≥ 25 years . The Begg’s test indicated no evidence of publication bias for age ≥ 25 years (p = 0.117); the result for age < 25 years was inaccessible, whereas the Egger’s test reported lack of publication bias for age < 25 years (p = 0.305); however, the result of the test was significant (p = 0.008) for age ≥ 25 years [p = 0.798. Analysis based on data from three studies ,57,61 di25 years . Multivap = 0.124, I2 = 82.41%); and use of OC for less than five years lowered the risk of cancer. This last result was statistically significant: OR = 0.93, 95% CI: 0.87 to 1.00, p = 0.042, I2 = 53.09%. A comparison of OC use for more than five years and less than five years showed that the risk of developing ER+BrCa was similar: OR = 0.99, 95% CI: 0.91 to 1.08, p = 0.791. No evidence of publication bias was recorded for the duration of OC use, according to Begg’s and Egger’s tests .Finally, we examined whether the risk of developing ER+BrCa differs between premenopausal and postmenopausal women. It turned out that the risk was increased in premenopausal women, but the results were not statistically significant: OR = 1.07, 95% CI: 0.85 to 1.34, p = 0.019, I2 = 75.49% (p = 0.929) and Egger’s (p = 0.927) tests indicate the lack of evidence of publication bias  subtype was assessed on the basis of 11 studies ,59,60,62= 75.49% . The resion bias . p = 0.373, I2 = 94.39%. In addition, OC self-administration for <5 years induced a non-significant risk of this cancer subtype developing: OR = 1.14, 95% CI: 0.93 to 1.40, p = 0.201, I2 = 79.46. On the other hand, the comparison of these two groups showed a significantly higher risk of ER−BrCa in the case of OC use for more than five years: OR = 1.14, 95% CI: 1.01 to 1.27, p = 0.031. Results of Begg’s test were inaccessible for variable ≥ 5 years, while that for the covariate < 5 years suggested the possibility of a publication bias (p = 0.041). In turn, Egger’s test did not indicate publication bias for both covariates, ≥5 years (p = 0.230) and <5 years (p = 0.436). When comparing these groups, both the Begg’s (p = 0.005) and Egger’s tests (p = 0.000) showed the possibility of a publication bias; however, all publications in the funnel plot were placed inside the funnel ; and for the variable ≥ 5 years . Beeg’s test indicated no evidence of publication bias for variables of cessation of OC use <5 years, (p = 0.117) and ≥5 years (p = 0.117) before diagnosis. Data from Egger’s test indicate publication bias for both covariates: < 5 years (p = 0.022) and ≥ 5 years, p = 0.018 , z = −1.28, p = 0.2022.The meta-analysis of the risk of ER−BrCa subtype depending on the period of discontinuation taking of OC before diagnosis was based on four studies ,48,52,60 = 0.018 . Multivap = 0.850. No significant publication bias was detected by the Egger’s test (p = 0.258).In addition, the risk of developing ER−BrCa has been shown to be similar in premenopausal and postmenopausal women: OR = 1.05, 95% CI: 0.62 to 1.79, p = 0.561, I2 = 26.62%  subtype included eight trials, and was based on data from 12,704 participants  ,55,58,61= 26.62% . Both teectively .p = 0.447, I2 = 19.01%. Results of the Egger’s and Begg’s tests did not reveal publication bias: p = 0.327 and p = 0.109, respectively. Moreover, the use of OC for less than five years was associated with a clear, albeit non-significant, reduction in the risk of HER+BrCa: OR = 0.88, 95% CI: 0.62 to 1.25, p = 0.480, I2 = 58.34%. Both tests were insignificant for publication bias: Begg’s test: p = 0.497, and Egger’s test: p = 0.855. Additionally, the risk of developing HER2+BrCa was slightly increased when using OC for more than five years, but the results were not statistically significant: OR = 1.14, 95% CI: 0.84 to 1.54, p = 0.412. No evidence of publication bias was recorded for the duration of OC use, according to Begg’s (p = 0.174) and Egger’s tests (p = 0.605)  . Multivap = 0.555, I2 = 0.00%. In turn, discontinuation of OC intake ≥ 5 years before diagnosis indicated a higher, but non-significant HER+BrCa subtype risk: OR = 1.12, 95% CI: 0.90 to 1.40, p = 0.295, I2 = 0.00%. Results of Begg’s test and Egger’s test showed a lack of evidence of publication bias for the variable < 5 years: p = 0.602, and p = 0.485, respectively; the results for the variable ≥ 5 years also demonstrated absence of evidence of publication bias: p = 0.602 and p = 0.840, respectively.  and Egger’s tests (p = 0.781).Moreover, the risk of breast cancer was slightly lower, although not statistically significant, in premenopausal women: OR = 0.79, 95% CI: 0.58 to 1.06, p = 0.002, I2 = 75.03% (p = 0.532 and p = 0.914 (We assessed the changes in the risk of triplet-negative breast cancer (TNBrCa) after the use of oral contraceptives based on data from ten case-control studies involving 180,419 women  ,60,61,63= 75.03% . Begg’s  = 0.914 .p = 0.005, I2 = 0.00%. Begg’s test (p = 0.117) and Egger’s test (p = 0.269) indicated no evidence of publication bias. In turn, starting of OC use at age ≥ 25 years was associated with slight increase in risk: OR = 1.03, 95% CI: 0.86 to 1.23, p = 0.758, I2 = 0.00%. Begg’s and Egger’s tests demonstrated the lack of publication bias: p = 0.602 and p = 0.966, respectively  and Egger’s tests (p = 0.091) showed no evidence of publication bias. In contrast, taking OC < 5 years also led to an increased, albeit insignificant, risk of TNBrCa: OR = 1.16, 95% CI: 0.95 to 1.40, p = 0.146, I2 = 51.10%. Begg’s and Egger’s tests also demonstrated no evidence of publication bias: p = 0.189 and p = 0.199, respectively. Additionally, the comparison of these two groups showed that the use of OC for more than five years significantly increased risk of TNBrCa subtype: OR = 1.27, 95% CI: 1.12 to 1.42, p = 0.000. No significant publication bias was detected by the Begg’s (p = 0.851) and the Egger’s tests (p = 0.974),,. Multivap = 0.043, I2 = 71.09%) for last use < 5 years. The results of Begg’s test were inaccessible, while Egger’s test revealed no evidence of publication bias (p = 0.581). An increase in the risk of the cancer subtype was also observed, but was statistically insignificant regarding last OC use ≥ 5 years before diagnosis . Herein, the results of the Begg’s test were unavailable, while the Egger’s test indicated no evidence of publication bias (p = 0.248)  . Multivap = 0.489. No significant publication bias was detected by the Egger’s test (p = 0.279).In addition, the risk of breast cancer was slightly lower, although not statistically sig-nificant, in premenopausal women: OR = 0.90, 95% CI: 0.67 to 1.21, Consistent with our results, the summary meta-analysis showed that ever-use of OC significantly increased the risk of TNBrCa, as well as of ER−BrCa. There was also a significant reduction in the risk of ER+BrCa and a slight reduction in the risk of HER2+BrCa after OC taking. This may indicate a protective OC effect in some molecular subtypes of BrCa. Furthermore, the initiation of OC use under the age of 25 years was associated with a significantly increased risk of TNBrCa and a non-significant reduction in the risk of ER+BrCa. In turn, the starting of OC use at the age of over 25 years resulted in a slight increase in the risk of TNBrCa and a slight reduction in the risk of ER+BrCa. Duration of OC use longer than five years was found to lead to a significant increase in risk of TNBrCa, and to an insignificant increase in risk of ER−BrCa and a slightly increased risk of HER2+ OC. In contrast, taking OC for less than five years led to an increased, albeit insignificant, risk of TNBrCa, as well as risks of ER−BrCa. Our work demonstrated that a shorter period of OC use was associated with a statistically significant reduction in the risk of ER+BrCa, and also with a clear, albeit non-significant, reduction in the risk of HER2+BrCa. p = 0.04.The results of our study showed that the last use of OC in the period less than five years before diagnosis was associated with a statistically significant increase in risk of both TNBrCa and ER−BrCa, and with a slightly higher, statistically insignificant risk of HER2+BrCa. Moreover, we noted a non-significant reduction in risk of ER+BrCa. In turn, discontinuation of OC more than five years before diagnosis was associated with a statistically significant increase in ER−BrCa risk, and with a higher but non-significant risk of both TNBrCa and HER+BrCa, and a marginal increase in ER+BrCa. The only meta-analysis related to the above issue looked at the effect of oral hormonal contraception on the risk of TNBrCa. In this, Li et al.  showed tp = 0.036); as well as with the use of OC for more than five years . On the other hand, the use of OC before the age of 25 reduced the risk of BrCa: OR = 0.91, 95% CI: 0.83 to 1.00, p = 0.052 [p = 0.036 [In the previous article, we compiled, also using meta-analyzes, data from 79 case-control studies from 1960–2010. According to the results of the statistical analysis, there was an increased risk of BrCa with the use of OC before the first full-term pregnancy (OR = 1.14, 95% CI: 1.01 to 1.28,  = 0.052 . Our sec = 0.036 .The exact causes of the increased risk of ER-negative breast cancer with estrogen use have not yet been identified. The fact that estrogen promotes tumorogenesis of this subtype provides evidence that the presently observed effects occur via the influence of estrogens on the physiology of the tissues of the tumor-bearing host, rather than on the tumor cells themselves. One of the mechanisms by which the use of OC affects BrCa in women is the growth and angiogenesis of the tumor in the mammary gland caused by estrogen and ER positivity. A recent publication of Gupta et al. has proposed a second mechanism whereby estrogen promotes the growth of ER-negative breast cancer by systematically enhancing angiogenesis and stromal cell recruitment . In the Great caution should be exercised in drawing final conclusions from our meta-analysis, as there were various limitations in conducting it. The value of the results may have been influenced by limiting the search results to works in English only. As a result of such a limitation, it was not possible to reach all the research related to the topic of our work. Secondly, retrospectively, self-reporting of use of oral contraceptives poses a risk of providing inaccurate data, and therefore the possibility of mistakes made in the recruitment to the control groups. Thirdly, there exists a possibility of errors occurring when cases are similar to the controls selected for the research, depending on the use of the OC. Fourthly, there is no available information on the type of oral contraceptive used, and also a possible source of bias is that the definition of “ever” for OC use is not unified, meaning that women are exposed to OC at various periods limited to the start and end of self-administration of pills. This may lead to misclassifications regarding the peak incidence of most cancers in old age with a long interval from last or first OC use, or the use of various hormone preparations in a woman’s life.Additionally, a sensitivity analysis was performed to assess whether excluding any of the studies would significantly affect the meta-analysis result. The exclusion of any study did not affect the results of the meta-analysis of HER2 positive and triple negative breast cancer subtypes. However, in the case of the ER-positive breast cancer subtype, the exclusion of the Cotterchio , Gaudet The results of our study suggest that the use of oral contraceptives has different effects on the risk of developing the various molecular breast cancer subtypes; however, given that associations between them are still poorly understood, further research is required.


According to the literature, women with BCIS have a higher risk of developing subsequent invasive breast cancer; conflicting information has been reported regarding their potential risk for a subsequent invasive non-breast cancer.Even though breast cancer Data from 1,082 women, whose first-ever cancer diagnosis was primary BCIS between 2003 and 2015 and were living in the canton of Zurich, were used. Standardized incidence ratios (SIRs) were calculated to compare the risk of an invasive breast or non-breast cancer among women with a primary BCIS with the corresponding risk of the adult female population. SIRs were calculated overall and by patient and tumor characteristics. To investigate potential risk factors  for a subsequent invasive breast or non-breast cancer we used Cox proportional hazards regression models.BCIS patients had 6.85 times [95% confidence interval (CI): 5.52–8.41] higher risk of being diagnosed with invasive breast cancer compared to the general population. They additionally faced 1.57 times (95% CI: 1.12–2.12) higher risk of an invasive non-breast cancer. The SIRs were higher for women < 50-years old for both invasive breast and non-breast cancer at BCIS diagnosis. Age ≥ 70-years old at BCIS diagnosis was statistically significantly associated with a subsequent invasive non-breast cancer diagnosis.BCIS patients had a higher risk of being diagnosed with invasive breast and non-breast cancer compared to the general population. Age 70 years or older at BCIS diagnosis was the only risk factor statistically significantly associated with a subsequent invasive non-breast cancer. Our results support the increased risk for subsequent cancers in BCIS patients reported in the literature. Future studies should establish the risk factors for subsequent cancers, highlight the need for intensive monitoring in this population, and help distinguish BCIS patients who could benefit from systemic therapy to prevent distant cancers. Generally, BCIS is considered a non-obligatory precursor or a potential risk factor for invasive breast cancer, depending on the morphological subtype. Women with BCIS rarely report symptoms, and the majority of in situ tumors are detected through organized or opportunistic mammographic screening attendance  (Even though BCIS incidence has been increasing in the past decades –5 and itctively) , 14.Furthermore, the findings regarding the risk of BCIS patients for subsequent invasive cancer in sites other than the breast are contradicting. A previous Swiss study including data from the Canton of Vaud did not report an increased risk for invasive cancer in sites other than the breast  comparedWe aimed to investigate the risk for a subsequent invasive cancer (breast and non-breast) in BCIS patients in the Canton of Zurich, where no organized mammographic screening program exists. To the best of our knowledge, this is the first study to report on the risk for subsequent invasive cancer after BCIS diagnosis in the German-speaking region of Switzerland.in situ. Cases with ICD-O-3 morphological code 8520/2 were categorized as lobular carcinoma in situ, and cancers with ICD-O-3 morphological code 8522/2 as unspecified cancers in situ. We excluded from our analyses patients diagnosed with a recorded cancer before the BCIS, patients diagnosed with Paget disease of the breast, and patients for whom invasive breast cancer was diagnosed simultaneously with the BCIS. Patients with unknown laterality of BCIS and those diagnosed with bilateral BCIS were also excluded from our analyses.We used data from women whose first-ever cancer diagnosis was primary BCIS  and occurred between 2003 and 2015 (hereafter referred to as primary BCIS). The data were obtained from the Cancer Registry of the Cantons of Zurich, Zug, Schaffhausen, and Schwyz. A recent publication demonstrated that the data quality from the Cancer Registry was acceptable based on four widely used data quality indicators  . When looking at the risk of invasive breast cancer, patients treated with double mastectomy (n=3) for their primary BCIS were excluded from the analyses given their very low risk for subsequent invasive breast cancer. However, these patients were retained when looking at the subsequent risk of invasive non-breast cancer.Our outcomes of interest were invasive breast cancer diagnosis  and invasive non-breast cancer diagnosis . The latter tumors  were included in our analyses as invasive non-breast tumors due to their malignant behavior according to ICD-O-3. Thus, patients diagnosed with a second primary Time at risk for an invasive cancer was assumed to begin 3 months after primary BCIS and lasted until the date of an invasive cancer diagnosis, date of emigration, date of death or end of follow-up (31st December 2016), whichever came first. Thus, patients with less than 3 months of follow-up after their primary BCIS diagnosis were excluded from our analysis. We obtained patients’ vital status from the Citizen Services Departments of the Canton of Zurich. Our final study population included 1,082 patients with primary BCIS diagnosis .Given the different treatment schemes for BCIS patients, we only focused on the first available treatment after BCIS diagnosis. Treatment options were grouped into four categories as follows: breast-conserving surgery , mastectomy or surgery not otherwise specified (NOS), radiotherapy, hormonal therapy, or other therapies, and unknown.popEpi package in R (Standardized incidence ratios (SIRs) were calculated to compare the risk of invasive breast or non-breast cancer among women with primary BCIS with the corresponding risk of primary invasive breast or primary invasive non-breast tumor in the adult female population of the canton of Zurich. The observed number of invasive breast or non-breast cancers was counted among the index cohort by year and age group at diagnosis . The expected number of invasive cancers was estimated among the comparison cohort by multiplying the person-time of follow-up with the corresponding age- and period-specific incidence rates. Ninety-five percent of confidence intervals (CIs) for the SIRs were estimated by assuming Poisson distribution for the observed cases and using Wald's normal-approximation [age in R ]. Stratisurvival package in R  and significance levels were set at alpha = 0.05.Description of the study population and baseline characteristics are shown in The overall age-standardized incidence rate (ASR) for primary invasive breast cancer in the adult female population of the Canton of Zurich during our study period (2003–2016) was 104.2 per 100,000 person-years. The corresponding ASR for primary invasive non-breast cancer  was 195.7 per 100,000 person-years.The results of the risk for subsequent invasive breast cancer after BCIS diagnosis compared to the risk of the general adult female population of Zurich for primary invasive breast cancer are shown in Regarding the risk for invasive non-breast cancer, after 6,371 person-years, BCIS patients had 1.57 (95% CI: 1.12–2.12) times higher risk of being diagnosed with invasive non-breast cancer, compared to the risk of primary invasive non-breast cancer in the general adult female population of Zurich. Women diagnosed with BCIS before the age of 50 had higher SIR  for invasive non-breast cancer; however, the CI of the SIR were overlapping with those of other age groups. The risk did not vary considerably by morphological subtype, laterality, treatment of the initial BCIS, or time-period of the BCIS diagnosis Table 2.vs. 2010–2015), or age at diagnosis of the primary BCIS diagnosis were seen with either invasive breast or non-breast cancer risk. Sensitivity analyses excluding women with less than 6 months of follow-up did not alter our results (data not shown).The association between sociodemographic and tumor characteristics and risk for a subsequent invasive (breast or non-breast) cancer is shown in In our study, we observed an increased risk of a subsequent invasive breast or non-breast cancer diagnosis in BCIS patients compared to the general adult female population of Zurich. Older age at primary BCIS diagnosis was associated with the risk of a subsequent invasive non-breast cancer, but not with subsequent invasive breast cancer.in situ tumors compared to regions with organized screening programs). Some studies looking at the SIRs in regions where organized mammographic screening programs have been implemented suggest that the SIRs are high before and during the implementation of the screening programs, but start decreasing long after implementation   .in situ lesions in our study population had progressed to higher grade before detection. Our previous findings suggest that one-third of the breast cancer in situ lesions in the Canton of Zurich were of high grade  was statistically significantly associated with a subsequent invasive non-breast cancer, but not with a subsequent invasive breast cancer diagnosis in the univariate Cox models. The lack of statistically significant associations with the majority of the factors investigated in this study could suggest that basic primary tumor or patient characteristics might not be strongly associated with subsequent invasive cancers after an initial BCIS diagnosis. Some studies in the literature also failed to detect such associations. However, larger studies have reported associations of younger age at diagnosis of the initial BCIS, race, or family history for breast cancer with subsequent cancer risk , 12, 20.Our study had several strengths. Given the high registry coverage in the Canton of Zurich, we are confident that we capture almost all incident cancer cases in the canton . Additioin situ cancer registration is mandatory , we cannot exclude the possibility that some women in our study might have previously had an in situ cancer of another site that was not registered, and thus, they should have been excluded from our analyses. However, since the most frequent in situ cancers are registered by the cancer registry, a very low number of women might be falsely included in our analyses, if any at all.However, this study also had some limitations. Information on potential risk factors such as family history for breast cancer, genetic polymorphisms, parity, and age at first full-term pregnancy that have been associated with invasive cancer risk in previous studies was not available. Additionally, due to the small number of subsequent invasive breast cancer cases, we could not investigate separately the risk of ipsilateral vs. contralateral invasive breast cancer. As with most studies focusing on outcomes in cancer patients, the intensive monitoring of patients after their initial BCIS diagnosis, may have increased the probability of detecting the invasive cancer  in them. Women included in our study might have attended opportunistic mammographic screening for different reasons , which could differentiate them from the general population. Unfortunately, the lack of information on the reasons for screening attendance and family history for breast cancer did not allow us to explore this further. Finally, since not all In summary, BCIS patients in the canton of Zurich faced approximately 6.9 times higher risk of invasive breast cancer compared to the general population. They additionally faced 1.6 times higher risk of invasive cancer in sites other than the breast. Of all the potential risk factors for a subsequent invasive (breast or non-breast) cancer tested, only age equal to or greater than 70 years old at BCIS diagnosis was statistically significantly associated with a subsequent invasive non-breast cancer diagnosis. Our results support the increased risk for subsequent cancers in BCIS patients reported in the literature. Future studies should establish the risk factors for subsequent cancers, highlight the need for intensive monitoring in this population, and help distinguish BCIS patients who could benefit from systemic therapy to prevent distant cancers.The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author upon reasonable request.Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Conception and design: NK and SR. Data acquisition: ML, DK, and MW. Analyzing the data: NK, KM, and GP. Interpretation of the data: NK and SR. Drafting the manuscript: NK. Critically revising the manuscript: NK, KM, GP, ML, DK, MW, and SR. All authors contributed to the article and approved the submitted version.This work was supported by Krebsforschung Schweiz under Grant KFS-4114-02-2017 to SR. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Screening of breast cancer in asymptomatic women is important to evaluate for early diagnosis. In China ultrasound is a more frequently used method than mammography for the detection of breast cancer. The objectives of the study were to provide evidence and assessment of parenchymal patterns of ultrasonography for breast cancer detection among Chinese women.Breast ultrasound examinations including the parenchymatous pattern of cytopathological confirmed breast cancer (n = 541) and age-matched cytopathological not confirmed breast cancer (n = 849) women were retrospectively reviewed by seven sonographer physicians. According to compositions of ducts, the thickness of the breast, diameter of ducts, fat lobules, and fibro glandular tissues, the breast parenchymatous pattern was categorized into heterogeneous (high percentage of fatty tissues), ductal (the inner diameters of ducts > 50% of the thick mass of the breast), mixed (the inner diameters of ducts was 50% of the thick mass of the breast), and fibrous categories (a dense classification of the breast).p < 0.0001, OR = 3.972) and fibrous categories  were higher among women who have cytopathological confirmed breast cancer than those who have not cytopathological confirmed breast cancer. The heterogeneous category was high-risk ultrasonographic examination category followed by the fibrous category. Agreements between sonographer physicians for categories of ultrasonic examinations were fair to good (Cohen’s k = 0.591).Heterogeneous (Breast cancer risk in Chinese asymptomatic women differ according to the ultrasonographic breast parenchymal pattern.Level of Evidence: III.Technical efficacy stage: 2. Breast cancer is the most common in Chinese women , 2. ScreGenetic and environmental factors affect breast parenchymatous tissue structure and there is a correlation between breast parenchymatous tissue structure and the risk of breast cancer in any individual woman . TherefoMammography is an established imaging method for breast cancer screening because it has accuracy but has low sensitivity . This isThe objectives of retrospective analysis of cross-sectional study were to provide evidence and assessment of breast parenchymal patterns of ultrasonography for breast cancer detection among Chinese women considering those of women with cytopathology confirmed breast cancer as a reference standard.Women who underwent ultrasound examinations for breast cancer screening were included in the analyses.Women who underwent breast cancer surgeries, estrogen replacement therapy, and have incomplete data in the institutional records were excluded from the study.In a lateral or supine position with raised arms, fully exposed breasts, and axillae conditions of women, ultrasound examinations were performed. EPIQ 5 , M8 , and iU22  ultrasound devices were preferred to examine women. Linear array probes for 5–13 MHz, 6.6–13 MHz, and 7.5–10 MHz respectively were used. All examinations were performed by seven sonographer physicians (minimum 3-years experiences of institutes). Multi-angle and multi-plane ultrasound scans were performed for bilateral breasts and axillae. Two mutually orthogonal planes were used for confirmation of all lesions. The characteristics of the breast parenchyma and ultrasound images of all lesions were recorded. The images were taken at the same location in each breast.Ultrasound-guided core biopsies were performed using an 18 G needle  . Core biBreast tissue histopathology was performed by pathologists (minimum 3-years of experience of institutes). The diagnosis of breast cancer was confirmed by breast tissue histopathology.The thickness of the breast, ducts, fat lobules, and fibro glandular tissues were examined by ultrasonography. According to compositions of ducts, the thickness of the breast, diameter of ducts, fat lobules, and fibro glandular tissues, the breast parenchymatous pattern was categorized into 4 types: heterogeneous category: the inner diameters of ducts were less than 50% of a thick mass of the breast, the hypo-echoic fatty mass of the breast, less dense iso-echoic fibro glandular tissue, and hypo-echoic ductal ingredients. Ductal category: the inner diameters of ducts was more than 50% of the thick mass of the breast, hypo-echoic ductal ingredients in the mesh structure. Mixed category: the inner diameters of ducts was 50% of the thick mass of the breast, iso-echoic fibro glandular tissue, and hypo-echoic ductal ingredients. Fibrous category: the inner diameters of ducts was less than 50% of the thick mass of the breast, dense iso-echoic fibro glandular tissue, and less hypo-echoic ductal ingredients . The difp < 0.05, odds ratio (OR) with 95% of confidence interval (Cl). Cohen’s k was evaluated for agreements among sonographer physicians. Values were 0 ≤ k ≥ 0.4: poor agreement, 0.41 ≤ k ≥ 0.75: fair to good agreement, 0.76 ≤ k > 1.0: excellent agreement, k = 1.0: perfect agreement [SPSS 26.0 IBM Corporation, Armonk, NY, USA was used for statistical analyses. One-way analysis of variance (ANOVA) was used for categorical data and the Fischer exact test or Chi-square test of Independence was used for continuous data. All results were considered significant if greement .A total of 6,125 Chinese women have undergone ultrasound examinations at the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China and the Fujian Provincial Hospital, Fuzhou, Fujian, China from 15 April 2015 to 13 May 2019. Three women underwent breast cancer surgeries, two women underwent estrogen replacement therapy, and five women have no complete data in the institutional records. Therefore, data of these women (n = 10) were excluded from the study. Among 6,115 women, 541 women had cytopathological confirmed breast cancer. From 5,574 cytopathological not confirmed breast cancer women, data of 849 age-matched women were randomly selected for the study. The demographical, social, and clinical conditions of women are presented in Table p < 0.0001 for both). However, mixed type and ductal categories were the same among women who have cytopathological confirmed breast cancer and those who have not cytopathological confirmed breast cancer. The breast parenchymatous pattern categories shown in ultrasound examinations are reported in Table Heterogeneous and fibrous categories were higher among women who have cytopathological confirmed breast cancer than those who have not cytopathological confirmed breast cancer (Agreements among sonographer physicians for categories of ultrasonic examinations were fair to good Table .Table 3AThe current study reported that heterogeneous and fibrous categories were high-risk ultrasonographic examination categories for breast cancer. The results of the breast parenchymatous pattern categories of the current study were agreed with those of an available study , retrospThe study reported fair to good agreements among sonographer physicians for categories of ultrasonic examinations. The results of agreements between sonographer physicians for categories of ultrasonic examinations were parallel with those of an available study  and prosThere are several limitations of the study, for example, the correlation between ultrasonographic parenchymatous pattern and mammographic parenchymatous pattern were not discussed. The possible justification is that by adding mammography there was an addition of extra cost on women’s heads. The retrospective nature of the study and lack of prospective study.Breast ultrasound examinations are associated with breast cancer in asymptomatic women. Heterogeneous and fibrous categories of parenchymatous pattern of breast tissues were high-risk ultrasonographic examination categories for breast cancer. The ultrasonographic parenchymatous pattern could be used for screening breast cancer in asymptomatic Chinese women. If questionnaires and ultrasound examinations were performed in the early stage of breast cancer, it is possible to control the spoil of life of women due to breast cancer. The study data have the potential for the basis of breast cancer risk prediction.