Studies of the associations between soft drinks and the risk of cancer showed inconsistent results. No previous published systematic reviews and meta-analysis has investigated a dose–response association between exposure dose and cancer risk or assessed the certainty of currently available evidence. Therefore, we aim to demonstrate the associations and assessed the certainty of the evidence to show our confidence in the associations.We searched Embase, PubMed, Web of Science, and the Cochrane Library from inception to Jun 2022, to include relevant prospective cohort studies. We used a restricted cubic spline model to conduct a dose–response meta-analysis and calculated the absolute effect estimates to present the results. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence.Forty-two articles including on 37 cohorts enrolled 4,518,547 participants were included. With low certainty evidence, increased consumption of sugar-sweetened beverages (SSBs) per 250 mL/day was significantly associated with a 17% greater risk of breast cancer, a 10% greater risk of colorectal cancer, a 30% greater risk of biliary tract cancer, and a 10% greater risk of prostate cancer; increased consumption of artificially sweetened beverages (ASBs)re per 250 mL/day was significantly associated with a 16% greater risk of leukemia; increased consumption of 100% fruit juice per 250 mL/day was significantly associated with a 31% greater risk of overall cancer, 22% greater risk of melanoma, 2% greater risk of squamous cell carcinoma, and 29% greater risk of thyroid cancer. The associations with other specific cancer were no significant. We found linear dose–response associations between consumption of SSBs and the risk of breast and kidney cancer, and between consumption of ASBs and 100% fruit juices and the risk of pancreatic cancer.An increment in consumption of SSBs of 250 mL/day was positively associated with increased risk of breast, colorectal, and biliary tract cancer. Fruit juices consumption was also positively associated with the risk of overall cancer, thyroid cancer, and melanoma. The magnitude of absolute effects, however, was small and mainly based on low or very low certainty of evidence. The association of ASBs consumption with specific cancer risk was uncertain.PROSPERO: CRD42020152223The online version contains supplementary material available at 10.1186/s12966-023-01459-5. The adverse health effects of artificially sweetened beverages (ASBs), sugar-sweetened beverages (SSBs), and 100% fruit juice have received widespread attention from public and scientific communities . SSBs inAlthough the associations between SSBs, ASBs, or 100% fruit juice intake and other conditions such as type 2 diabetes, obesity, and cardiovascular disease have been well-documented , 8, theiThis systematic review and dose–response meta-analysis aimed to comprehensively assess the associations between soft drink, SSBs, ASBs, and 100% fruit juice intake and the risk of specific cancers. We rated the certainty  of evidence and interpreted our findings using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach .We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist  to reporth, 2022. Search terms included ‘beverages AND cancer AND cohort’ Detailed search strategies are provided in Supplementary Table SWe searched Embase, PubMed, Web of Science, and the Cochrane Library from their inception to Jun 20We included prospective cohort studies with participants aged 18 years or older that reported the most adequately adjusted effect estimates (relative risk (RR), hazard ratio (HR), or odds ratio (OR)) with 95% confidence intervals (CIs). Cohort studies that investigate the associations between SSBs , ASBs , or 100% fruit juice (studies that reported 100% fruit juice or fruit juice assessed separately from soft drinks) intake, and the risks of overall cancer or a specific cancer were included. We also included abstracts if the results of the multivariate analysis were reported. We excluded studies that involved patients with any type of cancer at baseline; that were cross sectional and case–control studies; and that included more than 20% of participants with chronic illness at the baseline. We only included data with the latest publication or longest follow-up and most informative with more relevant data on exposure and outcomes, when multiple studies from the same cohort and with same outcomes. There was no upper limit on the age of participants or restriction to publication status. Detailed definitions of exposure are presented in Supplementary Table SWe used EndNote X9 to manage the initial searched records; after removing duplicate records, the remaining records were imported to Rayyan, an online literature management platform , for titWe performed two-rounds of calibration exercises using a pre-designed standard data collection form to ensure agreement among the reviewers. Subsequently, two reviewers (MTL and HHL) extracted the data and assessed the risk of bias in duplication. Disagreements were resolved by consensus. The data of interest included the name of the cohort, year of publication, country where cohort was conducted, duration of follow-up, sample size at baseline, age, sex, number of participants within each exposure category, person-years, number of events, effect estimates, and 95% CIs.To assess the risk of bias of included individual cohort, we used a modified version of the Newcastle–Ottawa Scale that include seven questions , 24. We We used GRADE approach to assess the certainty of evidence for each cancer outcome and categorised evidence certainty as high, moderate, low, or very low . AccordiTo calculate the absolute effect, we used the population risk from the Global cancer statistics (GLOBOCAN) as the baseline risk for each specific cancer . We calc/day increase in SSBs, ASBs, 100% fruit juices, or total soft drink intake. For studies reporting effect estimates as HRs, we assumed that the HRs were approximately equal to the RRs [We conducted a dose–response analysis as suggested by Greenland and Orsini as the primary analysis , 28. We  the RRs . For ana the RRs , 28. TheWe compared the highest category with the lowest category of exposure by performing a random effect meta-analysis as a sensitivity analysis.I2 statistic [P values of the interaction test (P interaction). P interaction ≤ 0.05 was considered to have statistically significant subgroup difference. We also conducted sensitivity analysis by excluding studies reported SSBs that including 100% fruit juices. Review Manager 5.4  and Stata 15.1  were used for all statistical analyses.Statistical heterogeneity among the included studies was examined using Cochrane’s Q test and quantified using the tatistic . When 10tatistic . For theOur search yielded 142,60 records, after screening of titles and abstracts, 134 full-texts were reviewed for eligibility. Finally, 42 articles including on 37 cohorts with 4,518,547 participants were eligible , a 10% greater risk of colorectal cancer , a 30% risk of biliary tract cancer , and a 10% risk of prostate cancer . An increment of 250 mL/day in SSB intake was not significantly associated with the risk of overall, endometrial, esophagus, gastric, hepatocellular, kidney, oral, ovarian, pancreatic, larynx or pharynx cancer, or leukemia, Multiple myeloma, non-Hodgkin lymphoma  , all cancer , prostate cancer , and pancreatic cancer .There was a linear dose–response association between SSBs consumption and the risk of breast and kidney cancer (ly) Fig. . We obseP interaction = 0.006), and studies with shorter follow-up durations showed stronger association than those with longer follow-up durations (P interaction = 0.03). There were no significant subgroup effects in terms of age, sex, duration of follow-up, or risk of bias for other types of cancer.Subgroup analyses . All 11 studies were included in the highest category versus lowest comparison. We did not find any statistically significant differences between ASB consumption per 250 mL/day and the risk of other types of cancer   and 22% risk of melanoma , 2% risk of squamous cell carcinoma , and 28% risk of thyroid cancer RR = 1.28, 95% CI: 1.08 to 1.53; absolute risk difference 1 more per 1000 persons)    Fig. . We obse18) Fig. .We did not find any a statistically significant subgroup effect for any factors.Five articles focused on the relationship between total soft drink consumption and cancer risk. All five articles were included in the dose–response meta-analysis and the highest category versus lowest category meta-analysis. An intake of total soft drink per 250 mL/day was only associated with the risk of hepatocellular carcinoma  . Dose–response meta-analyses showed that with low to moderate certainty evidence, an SSBs intake increase of 250 mL per day might result in 8 more per 1000 persons for breast cancer, 2 more per 1000 persons for colorectal cancer, and 1 more per 1000 persons for biliary tract cancer; ASBs intake increase of 250 mL per day might result in 1 more per 1000 persons in leukemia; and 100% fruit juices intake increase of 250 mL per day might result in 52 more per 1000 persons in overall cancer, 1 more per 1000 persons in melanoma and thyroid cancer each. Subgroup analyses showed that increased SSB consumption of a 250 mL/day in participants from Asia and Europe had a stronger association with the risk of pancreatic cancer than those from the USA, and studies with shorter follow-up duration showed stronger association than those with longer follow-up duration. We found linear dose–response associations between the consumption of SSBs and the risk of breast and kidney cancer, and between the consumption of ASBs and 100% fruit juices and the risk of pancreatic cancer. For SSBs consumption and the risk of colorectal, overall, prostate, and pancreatic cancer, as well as 100% fruit juice intake and the risk of prostate cancer, we observed non-linear dose–response associations.Our findings confirm or refute several previously published systematic reviews. The results of our study on colorectal cancer differ from those of previous systematic reviews and meta-analysis. Schwingshackl and colleagues  found thOur systematic review has several strengths. Our review is the first to address the dose–response associations between SSBs, ASBs, 100% fruit juices, or total soft drink consumption and specific cancer risk. We focused not only on meta-analysis of highest versus lowest comparison but also dose–response meta-analysis, which provides the most convincing evidence for the associations between SSBs, ASBs, 100% fruit juices, or total soft drink and health outcomes. We conducted of this systematic review and meta-analysis according PRISMA checklist to ensure higher reporting quality  and we eLimitations also existed in this systematic review. First, our review included prospective cohort studies, which are observational studies that are prone to confounding. Second, our study identified 42 studies that focused on 22 types of cancer, of these, 11 types of cancer only included one studies, which may make the results of our analyses that focused on above 11 types of cancer insufficiently informative and relative lower power of the analyses. More cohort studies are needed to further investigate the associations between soft drinks and the risk of cancers, and more randomised controlled trials are needed to confirm the adverse health effects of soft drinks. Third, the dietary information was assessed mainly based on questionnaire in included cohorts, which might result in recall bias. Fourth, servings are usually different depending on the country, in our study, we used a median intake of 250 mL/serving, which could be underestimating the intake of SSBs, ASBs, and 100% fruit juices. Fifth, dietary exposure is prone to be correlated with other potentially confounding factors, however, among eligible studies, there was a lack of adequate adjustment for potential confounders , which is a major source of potential bias .SSBs usually contain 1 to 12 percent sugar, which may result in adverse health effects . ConsumpWe demonstrated that an increment of 250 mL/day in SSB intake was positively associated with risk of breast, colorectal and biliary tract cancers, but the evidence was graded as being of low certainty. The consumption of 100% fruit juices was also positively associated with overall cancer and thyroid cancer risk, and the risk of melanoma. The association of ASBs consumption with specific cancer risk was uncertain except for leukemia. More targeted intervention, action-oriented research, and public education of the above factors may be appropriate.Additional file 1. Supplementary material is available at QJMED online.


We investigated the association of several air pollution measures with postmenopausal breast cancer (BCa) risk.2, from 2007 and 2010 for PM10, and from 2010 for PM2.5, NOX, PM2.5–10 and PM2.5 absorbance. Information on BCa risk factors was collected at baseline. Cox proportional hazards regression was used to evaluate the associations of year-specific and cumulative average exposures with BCa risk, overall and with 2-year exposure lag, while adjusting for BCa risk factors.This study included 155,235 postmenopausal women (of which 6146 with BCa) from UK Biobank. Cancer diagnoses were ascertained through the linkage to the UK National Health Service Central Registers. Annual exposure averages were available from 2005, 2006, 2007, and 2010 for NO10 in 2007 and cumulative average PM10 were positively associated with BCa risk . Compared to women with low exposure, women with higher 2007 PM10 and cumulative average PM10 had greater BCa risk . No significant associations were found for any other exposure measures. In the analysis with 2-year exposure lag, both 2007 PM 10 and cumulative average PM10 were positively associated with BCa risk .PM10 and cumulative average PM10 with postmenopausal BCa risk.Our findings suggest a positive association of 2007 PMThe online version contains supplementary material available at 10.1186/s13058-023-01681-w. Established breast cancer risk factors explain only 30–50% of breast cancer cases –5, and p2) are of interest with respect to breast carcinogenesis. PM, including fine inhalable particles of ≤ 2.5 µm in diameter (PM2.5) and inhalable particles ≤ 10 µm in diameter (PM10), have biological properties relevant to breast carcinogenesis and other chronic diseases  = 3.1 years) for breast cancer cases and 10.7 years (SD = 2.0 years) for cancer-free women. The average follow-up time calculated for analyses of exposures measured in 2010, was 4.9 years (standard deviation [SD] = 2.9 years) for breast cancer cases and 9.8 years (SD = 1.6 years) for cancer-free women. The distribution of air pollution measures , and as quartiles , and as quartiles   , and as quartiles    , and as quartiles    of breast cancer cases) had a 2010 PM10 concentration greater than the 2007 PM10 cutoff concentration for the 4th quartile (23.5 μg/m3).While we found significant associations of 2007 PM2.5, PM2.5 absorbance, or PMcoarse 2.5–10 with breast cancer risk in any of the analyses performed, consistent with the previous studies in postmenopausal women, though some studies that were not limited to postmenopausal women reported some associations [3) increase of PM2.5  [2.5 levels in this study were slightly higher than in our sample (10.8 [SD = 3.5] vs. 9.95 [SD = 1.04]) and the analyses were not stratified by menopausal status. Finally, PM2.5, PM2.5 absorbance and PM coarse 2.5–10 were only measured in 2010 and not 2007. Therefore, the same reasons for why PM10 in 2010 was not associated with breast cancer risk could potentially also explain the null associations for these other PM measures.We found no associations of PMciations , 28, 29.0, 1.03) . However10 lagged exposure with postmenopausal breast cancer. We found stronger associations when we included only breast cancer cases diagnosed two years as well as only those diagnosed 5 years after exposure to PM10 in 2007; thus, our findings provide further evidence that earlier exposures to higher concentrations of PM10 may be more relevant with respect to breast cancer etiology. Even though the confidence intervals for the estimates in overall analysis have some overlap with those in 2-year analysis, this overlap becomes less apparent with 5-year exposure lag further demonstrating that earlier exposures might be more relevant and that the observed differences in the strengths of association is unlikely to be the result of just random variation. However, we found a weaker effect of 2-year or 5-year lagged exposure for PM10 cumulative average compared to the effect of exposure for PM10 cumulative average without exposure lag, which could be potentially explained by declining PM10 concentrations over time combined with a reduction in the number of breast cancer cases included in these lagged analyses. Finally, we could not examine the associations with 7- and 10-year lag in the exposure as this would result in significant reduction of the number of breast cancer cases  for 7-year lagged analysis and down to as few as 70 cases for 10-year lagged analysis), which would not be informative.To our best knowledge, no other study looked at associations of PM10 with breast cancer risk are consistent with previous studies indicating relevant biological pathways as a possible explanation for potential effects of PM on breast cancer risk which could lead to tumor development. The biological effects of exposure to PMs could result from systemic inflammation, oxidative stress, and epigenetic changes that lead to formation of DNA adducts, disruption of DNA repair, induction of carcinogen-activating enzymes, and DNA methylation of tumor suppressor genes in breast tissue [Our findings of significant association of PMt tissue , 75–85. t tissue –88.2 and NOx exposures reported mixed findings. Six of the 12 studies that investigated the association of NO2 with breast cancer risk reported significant positive associations [2 stratified by menopausal status, with positive associations found in postmenopausal women [. Two of the four studies that investigated the association of NOx with breast cancer risk [2 and NOx in the air, these two air pollutants may represent a marker of exposure to a mixture of components with carcinogenetic properties, such as PAHs, benzene, metals and other chemicals, possibly acting on breast tissues [Contrary to our hypothesis, we found a marginal association of NOx with breast cancer risk when only invasive cancers were included in analyses. Studies that assessed NOciations , 37. Of al women , 37, 89.cer risk , 26, 30 cer risk , 30. Howcer risk  includedcer risk , 36, 90. tissues , 61. Som tissues .While our findings of suggestive inverse associations of NOx with breast cancer risk are puzzling, they could potentially be the result of residual confounding, for example, by mammographic breast density, a well-established breast cancer risk factor, as some studies reported inverse associations of NOx with high breast density . Informa10 and NO2 levels, Table Our study is the largest study to date to investigate the association of air pollution with breast cancer among postmenopausal women. The study utilized a population-based prospective cohort with a rigorously defined protocol, rigorous ascertainment of the endpoints through continuous linkages to the national registries, and well-validated methods for assessing air pollution. This study has a few limitations. Information on covariates was used from baseline assessment only; however, the correlations with the values available from follow-up assessments were high (as described in Covariate information section) and thus, use of baseline risk factor data is unlikely to introduce misclassification. We were also unable to investigate associations by breast cancer subtypes, such as estrogen receptor (ER)-positive versus ER-negative, because the information was not recorded within the UK Biobank. Further, exposures to air pollutants were estimated based on a single residential address at baseline; therefore, we cannot rule out potential exposure misclassification caused by outside activities performed away from home or change of residence. However, recent studies suggest very small contribution of commuting to total weekly exposure and demonstrate that omitting commute does not significantly underestimate health effects as compared with the model combining home and work , 94. Any10 with postmenopausal breast cancer risk. Our findings contribute to the limited evidence on the association of air pollution with the risk of breast cancer in postmenopausal women. More studies in diverse populations, including Black women and other racial/ethnic minorities, are needed to confirm our results and to elucidate the potential biological mechanisms underlying the observed associations.We found a significant association of exposure to PMAdditional file 1: Table 1. Summary of the follow-up times and breast cancer case inclusions in different models for associations of air pollution measures with breast cancer risk. Table 2. Correlation between 2010 air pollution measures. Table 3. Characteristics of the study participants at baseline, by the quartiles of 2005 Nitrogen dioxidelevels. Table 4. Associations of 5-year lagged air pollution exposure with breast cancer risk. Table 5. Association of air pollution measures with invasive breast cancer risk


BRCA1 and BRCA2 pathogenic variants account for 90% of hereditary breast malignancies, incurring a lifetime breast cancer risk of 85% and 40–45% respectively, in affected individuals. Well-resourced health care settings offer genetic counselling and genetic screening for susceptible individuals, followed by intense breast cancer surveillance programmes for those identified at high risk of breast cancer. Such high standards of care are not available in countries with limited resources. This study assessed breast cancer surveillance behaviors among a cohort of BRCA positive Sri Lankan women.BRCA1 and BRCA2 genes from 2015 to 2022 at the Human Genetics Unit, Faculty of Medicine, University of Colombo was carried out followed by telephone interviews of the respondents. Patients who were not contactable, deceased, undergone bilateral mastectomy and males were excluded from the interview component of the study. Standard descriptive statistics were used to analyze the data using SPSS statistics version 25.A retrospective case review of all patients diagnosed with pathogenic variants in Only 25 patients were diagnosed during the study period:14/25 women responded . 71.4% (10/14) had performed breast self-examination during the preceding month; 35.7% (5/14) had a clinical breast examination (CBE), and 50% (7/14) had undergone a screening/diagnostic mammogram during the last one year. 28.5% (4/14) had undergone both mammography and CBE; 21.45% (3/14) mammogram only, 7.1% (1/14) had CBE only. 42.8%(6/14) had not undergone any surveillance. None had dual screening with mammogram and MRI. 85.71% (12/14) women expressed willingness to participate in a regular screening programme if made available.BRCA1/2 positive women in our study had not undergone annual imaging-based surveillance by mammography or MRI, and none had undergone annual dual screening with mammography and MRI, indicating inadequate breast cancer surveillance in this high-risk group.Fifty percent of  BRCA1 and BRCA2 genes, responsible for nearly 90% of hereditary breast cancers [BRCA1 and BRCA2 genes are considered a high-risk category for breast cancer having a lifetime risk of developing a breast malignancy of 85% and 40–45%, respectively [Genetic predisposition accounts for 5–10% of all breast cancers , primariectively . High riBRCA 1/2 positive women, National Institute of Health (NICE), UK guidelines recommend offering annual surveillance MRI from 30–49 years and annual mammographic surveillance from the age of 40–69 years [In well-resourced countries, genetic counseling and screening are offered to susceptible individuals identified through family or clinical history , 5 High-69 years , 8, highHowever, in limited resourced settings, particularly in low and lower-middle-income regions of Asia, opportunities for mammographic breast cancer screening are much less. The number of mammography units per one million women aged 50 to 69 years is reported as low as 0 in Bhutan, and 2.81 in Sri Lanka to 32.6 in Mongolia, compared to high-income (HI) countries such as, 127.6 in Singapore and 227.3 in Japan . NeverthSri Lanka's age-standardized breast cancer rates have risen from 18.4 per 100,000 in 2005 to 33.5 in 2019 . Free heAlthough low in number, state sector mammographic facilities are established across all provinces in Sri Lanka, primarily focusing on diagnostic services . While aBRCA variant carriers, giving options for annual multimodality surveillance referring to guidelines from HI countries, they lack guidance on resource-adaptive implementation [High-risk women in Sri Lanka access opportunistic screening including mammographic facilities, similar to average-risk women. There are no dedicated national programs prioritizing their surveillance. No systematic high-risk women identification or registry exists. Although updated national guidelines acknowledge the need for intensified screening for entation . Only a BRCA1 or BRCA2 pathogenic variants. Our aim was to understand high-risk women's behaviors in the backdrop of limited-resource opportunistic screening in countries like Sri Lanka. This knowledge can guide better resource allocation, prioritize high-risk groups, and spark discussions on the necessity for more detailed guidelines and proactive referral systems.In this context, our study assessed breast cancer surveillance behaviors among a cohort of Sri Lankan women genetically predisposed to breast cancer with BRCA1 and BRCA2 genes from 2015 to 2022 period at the Human Genetics Unit (HGU), Faculty of Medicine, University of Colombo.A cross sectional observational study was carried out in a cohort of patients diagnosed with pathogenic variants in The HGU serves as the principal National Referral Center for offering genetic counselling and genetic testing in Sri Lanka, and receives referrals from the state and private sector from all over the country , 19 The BRCA1 and BRCA2 genes during the study period. Patients who had consented to undergo genetic testing and whose test reports were either BRCA1 or BRCA2 positive were selected from the de-identified database of the HGU using the patient registration numbers and their detailed clinic records were retrieved. Subsequently patients were contacted by telephone . Patients who were not contactable, deceased, undergone bilateral mastectomy, and male patients were excluded from the relevant interview components of the study.The study population included all patients diagnosed with pathogenic variants in Ethical clearance was taken from the Ethics Review Committee, Faculty of Medicine, University of Colombo. Informed written consent for willingness to be contacted, and willingness to contribute one’s information from clinical records/databases for research purposes, is normally obtained from the patients during the pre-test counselling session prior to genetic testing. Further informed verbal consent was taken for this particular study when the patients were contacted over the phone. Patients were given the option to have more time to consider their willingness to participate in the study. Consenting patients were given the opportunity to decide on a preferable time to be contacted for data collection and a second phone call was made at their preferred time. Data was collected only by the authors (investigators). A simulated practice session was held prior to data collection to avoid/minimize any confusion or emotional trauma to the patient. Only the information that was not in the medical records, such as current income, screening behaviours, and details that had to be verified such as incomplete data fields were gathered at the telephone interview to reduce patient exhaustion. Family history was retrieved from the detailed pedigree documented in the clinic records to avoid emotional trauma in recalling family cancer history.Data was collected from the HGU database, the clinic records and by telephone interview according to a pretested data collection form for each patient and entered into a database. Indication for referral, family history and medical information were collected from HGU records. Current socio demographic data, perceived risk of breast cancer, information on breast self-awareness and breast screening behaviors and willingness to attend a screening programme were inquired during the telephone interview.Breast self-awareness was assessed by asking if participants observe their breasts in the mirror to check if they look normal, and by inquiring if they would consider seeking further assessment by a doctor or healthcare worker, to rule out breast cancer, if the following symptoms/signs were noted by the participant: nipple discharge , change in size or shape of a breast, skin irritation such as redness, thickening or dimpling of the skin, swollen lymph nodes in the armpit, nipple problems such as pain or redness, swelling of a breast and breast pain occurring with the menstrual cycle. Practice of Self-Breast Examination was checked for the frequency, and inquiring who trained the patient on the technique. Screening behaviors with CBE, mammography and MRI were checked for frequency of attendance for individual modalities, and if participants had received surveillance by multiple screening tools such as dual screening by mammography and MRI.Strong family history was defined as per recommendations made by 2019 updated NICE guidance, UK [BRCA1 or BRCA2 positive from 2015 to 2022. Their ages and indications for genetic screening are shown in Table A total of 25 patients, belonging to 23 families were diagnosed as 14/25 (56%) had family history of breast/ovarian cancer: 9/14 (64.2%) of this group had strong family history of breast or ovarian cancer, and 55.5% (5/9) individuals with strong family history had had a genetic diagnosis made after developing at least one personal breast/ovarian cancer, while one patient  with strong family history received a genetic diagnosis after developing the second personal breast/ovarian cancer.BRCA1/2 positive at least one year before data collection.Only 14/25 (56%) participated in the telephone interviews, as 6/25 (24%) were deceased due to advanced breast/ovarian cancer, 3/25(12%) were not contactable and two  were excluded as one patient had undergone bilateral therapeutic mastectomy and one was excluded due to male gender. Only one  of the deceased patients had a strong family history of breast/ovarian cancer. One of the non-contactable patients had metastatic breast cancer at the time of genetic referral. All 14 participants were diagnosed as Details of the patients who participated in the telephone interviews are shown in Table BRCA positive woman developing breast cancer; 78% (11/14) said that they do not know, and the remaining 3/14 (21.4%) expressed figures between 1- 25%.The majority  were aware that they are at increased risk of breast cancer compared to the rest of the population. However, none of the 14 respondents knew the actual lifetime risk of a Breast self-awareness, SBE practices and breast screening practices and behaviours related to CBE, mammography and MRI are shown in Table Nine out of the twelve (75%) women who had performed BSE at some point of time in their lives were trained by healthcare staff and the others  had self-learnt the procedure.Annual Surveillance pattern relevant to the past one-year period is shown in Fig. Even when surveillance within the past two years was considered, none underwent screening MRI, neither as a single modality nor in combination with other modalities; 35.7% (5/14) had undergone dual surveillance with CBE and mammography, and 28.5% (4/14) had undergone mammogram only. 35.7% (5/14) had not undergone either CBE, mammogram, or MRI during the last two years.n = 7;refer Table Out of the 7 women who had not had a mammogram within the last one year  were done free of charge in the state sector while 2/7 (28.6%) were done in the private sector.85.71% (12/14) women expressed willingness to participate if a regular screening programme was made available. One woman said it is not required for her as she was already being followed up by private consultation and another woman did not respond to this question.BRCA1/2 genes during the study period at HGU. Considering that only a limited number of centers offer genetic testing services in Sri Lanka and given that over 3000 new cases of breast cancer are diagnosed annually in the country, with an increasing incidence rate [This study revealed that only 25 cases were diagnosed with germline pathogenic variants in the nce rate , the numObstacles such as the high cost of genetic testing, a lack of awareness about genetic services, and concerns about discrimination following genetic diagnosis have been identified as challenges to risk reduction in hereditary breast/ovarian cancer, particularly among low-income and minority populations with low rates of attendance for genetic counseling and testing, such as in the United States . AffordaThe majority of patients with a strong family history in our cohort were referred for genetic testing after developing at least one personal breast or ovarian cancer. This raises the question of whether these individuals would have benefited had they been referred for early genetic testing or cancer surveillance based on family history, before developing personal cancer. Although this study did not specifically investigate whether the breast cancers in these patients were detected early through opportunistic breast screening or diagnosed after the onset of signs and symptoms, it underscores the importance of emphasizing family history assessment at the primary care level for the early identification of pre-symptomatic high-risk individuals. The importance of family history as the starting point of genetic risk assessment has reached international consensus .Failure to suspect an underlying genetic predisposition on the part of the clinicians may also result due to lack of clear guidelines for early identification & prompt referral of high-risk groups for genetic evaluation. The current Sri Lankan National Guideline on Cancer Early Detection and Referral Pathways of Common cancers for Primary Care Physicians, as outlined by the National Cancer Control Programme (NCCP), gives criteria for referral to genetic consultation, including criteria for identifying high-risk pre-symptomatic individuals based on family history . HoweverBRCA-positive women been recognized in Sri Lanka [Despite the need for more intense breast cancer screening for ri Lanka , we obseBRCA positive women and their untested first-degree relatives starting at 30 years of age (or 10 years before the age of diagnosis of the first degree relative) [We were unable to find similar regional or prior local studies discussing surveillance care received by women at high risk. Like Sri Lanka, India underscores prioritizing cancer screening to risk groups, however, no national guideline exits . Breast elative) , neverthBRCA positive individuals at HGU before reverting them to referring physicians, attendance for screening with CBE or mammography may not be ensured as there is no system for patient registration for sending reminders at least for hereditary breast cancer or high-risk groups. It is also observed that Sri Lanka cancer incidence and mortality data based on National Cancer Registry does not describe family history details for breast cancer [This study did not delve into the reasons behind these women not undergoing surveillance. However, we note that although post-test counselling is received once by all t cancer . DevelopIt is worth noting that the majority of study participants perceived themselves to be at a higher risk of developing breast cancer compared to the normal population. Furthermore, they expressed a willingness to participate in regular screening programs. It is also noteworthy that despite limited mammographic facilities in the country compared to high-income countries in the region, all patients in this study resided within 25 km of a state sector mammographic facility. These factors may suggest the potential for successful participation in a cancer surveillance program if offered. It is also important to highlight that although the majority were aware of being placed at an increased risk compared to the general population, most women were unaware of the actual magnitude of their lifetime risk of developing breast cancer, this could have been due to recall bias. The relationship between perceived risk and attendance at mammography screening programs has been reported with varying outcomes based on differing levels of risk perception . ConsideThe primary limitation of this study is the small sample size, which raises a query about the underlying reasons for low case numbers of the genetic diagnosis in Sri Lanka, as discussed. Additionally, due to the small sample size, it was not feasible to estimate associations between practices and behaviors with socio-demographic factors as originally planned. Furthermore, reliance on telephone interviews to inquire about health behaviors is a notable limitation which introduces the possibility of recall bias and likely respondent exhaustion due to prolonged interviews, potentially impacting the reliability and validity of the results. To address these limitations, several measures were implemented. These included pre-interview training and piloting sessions, the collection of existing data from HGU records before conducting interviews to establish context and rapport with respondents, and scheduling interviews at times preferred by participants. It is important to note that this study did not assess cancer prevention strategies within the study group. Nevertheless, it is worth mentioning that none of the patients had undergone prophylactic mastectomy of the unaffected breast(s).BRCA1/2 gene-positive women had not received annual imaging-based surveillance by mammography or MRI, and none had undergone dual screening with mammography and MRI. This preliminary investigation, conducted in the context of Sri Lanka, raises a critical concern regarding the adequacy of breast cancer surveillance for genetically predisposed women in resource-constrained South Asian countries.In this study, we found that fifty percent of These findings underscore the need to develop locally adapted public health strategies that identify high-risk, individuals and provide them with regular coordinated surveillance. Given the limitations of resource-constrained settings, priority should be given to leveraging available opportunistic breast cancer screening services to ensure equitable care for this high-risk group.


African American (AA) women navigate the world with multiple intersecting marginalized identities. Accordingly, AA women have higher cumulative stress burden or allostatic load (AL) compared to other women. Studies suggest that AA women with a college degree or higher have lower AL than AA women with less than a high school diploma. We examined the joint effect of educational attainment and AL status with long-term risk of cancer mortality, and whether education moderated the association between AL and cancer mortality.We performed a retrospective analysis among 4,677 AA women within the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2010 with follow-up data through December 31, 2019. We fit weighted Cox proportional hazards models to estimate adjusted hazard ratios (aHRs) of cancer death between educational attainment/AL .AA women with less than a high school diploma living with high AL had nearly a 3-fold increased risk  of cancer death compared to AA college graduates living with low AL. However, after adjusting for age, this effect attenuated . AA women with high AL had 2.3-fold increased risk of cancer death  when compared to AA with low AL, specifically among women with high school diploma or equivalent and without history of cancer.Our findings suggest that high allostatic load is associated with a higher risk of cancer mortality among AA women with lower educational attainment, while no such association was observed among AA women with higher educational attainment. Thus, educational attainment plays a modifying role in the relationship between allostatic load and the risk of cancer death for AA women. Higher education can bring several benefits, including improved access to medical care and enhanced medical literacy, which in turn may help mitigate the adverse impact of AL and the heightened risk of cancer mortality among AA women.The online version contains supplementary material available at 10.1186/s12905-023-02529-3. Chronic stress has been linked to worse health outcomes for various diseases, from atherosclerosis and hypertension to depression to hypertension , 2. The Geronimus et al. suggested that systemic stress from cumulative socioeconomic disadvantage and political marginalization contribute greatly to the early and disproportionate health deterioration of African Americans (AA) [Allostatic load (AL) measures the cumulative burden of chronic stress on physiological systems. Chronic stress can result from major life events, but more importantly, is the summative effect of ordinary, everyday stressors such as poor sleep, a lack of exercise, and a lack of access to healthy food . A crossans (AA) .Upchurch et al., observed that AA women reported higher levels of discrimination, perceived stress, and hostility, all of which will increase allostatic load [Moore et al. found that AA women had the highest age-adjusted mean allostatic load scores at the end of 30 years compared to others in their same age group [Multiple studies have illuminated that AA men and women consistently have the highest allostatic load scores, compared to those of the same age in other racial groups –12. AA wtic load . In a crge group . Considege group , 17.Williams et al. found that AA women with lower educational attainment had a higher allostatic load [Furthermore, tic load . Therefotic load , 16, 17.N = 95,359). Patients were excluded if they reported current pregnancy or were less than 18 years of age , were missing AL biomarkers or not linked via NDI . This resulted in a final analytic sample of NHANES participants aged 18 and older, corresponding to a total of 41,218 participants over a 22- year study period, of which 4,677 identified as AA women , a representative sample of non-institutionalized US residents linked with the National Center for Health Statistics (NCHS) 2019 National Death Index (NDI) file. The NHANES program oversamples those aged 60 and older, Latinx and non-Hispanic (NH)-Black  individuals, and weighted analysis generates generalizable estimates [ age N = 2,791, weThe Institutional Review Boards considered this study exempt from review because of the use of secondary, publicly available, and de-identified data.Williams et al. (2022), to determine our variables of interest [This study mirrored methods of our investigative team’s prior work, interest . We examinterest  less thas et al. 022, to dinterest  some colinterest  college interest . Due to Geronimus et al. (2006) and Moore et al. (2021) taxonomies [AL has been defined using varying components, although most incorporate biomarker measures from three different categories, including physiologic functioning, which incorporates cardiovascular, metabolic, and immune systems . While txonomies , 15. AL xonomies , 23. To xonomies , 25 or bet al. 20 taxonomixonomies .After categorizing NHANES participants based on the distribution of AL components and their self-reported educational attainment, we created a variable examining the intersection of AL and educational attainment. This variable was categorized into eight levels;  college Our primary outcome of interest was the time to cancer death. Deaths attributed to malignant neoplasms (ICD-10 019–043) were included as cancer-related deaths. Our primary outcome of interest was time to cancer-related death. Follow-up data for this analysis was available through December 31, 2019, based on NDI-NHANES publicly available linkages. The primary determination of mortality for eligible NHANES participants is based upon matching survey records to the NDI although additional redundant sources are also incorporated, including the Social Security Administration, the Centers for Medicare and Medicaid Services, data collection, NCHS’ follow- up surveys , and ascertainment of death certificates.We included other variables as covariates based on their consideration as potential confounders, or their possible effect on education, cumulative stress, and cancer outcomes based on prior studies. These variables included NHANES baseline survey completion period , family poverty-to-income ratio (PIR), current smoking status, any self-reported history of cancer, congestive heart failure, and ever heart attack. PIR was calculated as the ratio of total family income to poverty threshold values by NHANES investigators . ParticiPrimary analyses were conducted using NHANES-generated sampling statistical strata, clusters, and weights as designated and described in detail within the NHANES methodology handbook . NHANES 16. Individuals were censored at the time of their event, death, or end of follow-up . Models were sequentially adjusted first for age, then with age, poverty to income ratio, and smoking status.For descriptive statistics we presented categorical variables as weighted row percentages and continuous variables as mean and associated 95% confidence intervals using appropriate SAS survey weighted procedures including PROC SURVEYFREQ, SURVEYMEANS, and SURVEYREG accordingly . Mean suMultiplicative interactions of AL and educational attainment were examined by introducing an interaction term within our model and presenting the corresponding p-value for this association. P-values ≤ 0.05 were considered statistically significant. Additionally, we conducted all the time-to-cancer death event survival analyses by allostatic load status , stratified by educational attainment. Estimates were presented from our survey-weighted Cox proportional hazard models as hazard ratios (HRs) and associated 95% confidence intervals (CIs). We conducted two sets of sensitivity analyses. We repeated all survival analyses using un-weighted Cox proportional hazard models and thus treating NHANES participants as a simple random sample. In addition, we examined the relationships between the joint effect of education with allostatic load on cancer death risk, and the moderated effect of education on the relationship between allostatic load and cancer death risk while excluding NHANES participants with a history of cancer. All statistical analyses were performed using SAS .Among 4,677  AA women, the average age of participants was 42.71 years (Standard Error (SE) = 0.33) and the median follow-up time was 15.90 years (Q1-Q3 = 11.48–21.88)  of dying from cancer compared to college graduates living with low allostatic load . Similarly, among those with a high school diploma or equivalent, there was over a 3.5-fold increase in risk of cancer death in those with high allostatic load compared to those with a low allostatic load . However, when adjusted for age, the risk of cancer death was attenuated for both the less than high school degree and high school diploma or equivalent groups . Lastly, among participants with college graduate degree or more, those with high allostatic load had a nearly 2-fold increase in cancer death compared to those with low allostatic load . This effect, too, was similarly attenuated when adjusted for age . No other statistically significant associations between educational attainment groups and allostatic load status with risk of cancer death were found when stratified by educational attainment.Supplemental Table We conducted sensitivity analysis treating NHANES participants as simple random sample in an unweighted analysis to examine the joint effect  and moderated effects of educational attainment on the relationship between high allostatic load and risk of cancer death. We observed similar effect measures as main analysis; most noticeably when limited to AA women with less than high school education, those with high allostatic load had 3-fold  increased risk of cancer death compared to AA women with low AL , a 2.3-fold increased risk when accounting for age , and 2.3-fold increased risk when fully adjusted  when compared to their counterparts with low allostatic load . Further, because of our use of publicly available NDI-linked NHANES data we were unable to disentangle cancer-specific  mortality. There may be other factors in play between the time of the survey and interview and the time they passed from cancer. Another limitation is in the initial collection of the educational data, wherein there was limited disaggregation for those with at least a baccalaureate degree or higher. Our inability to analyze whether differences at the baccalaureate versus the postgraduate levels forced us to make incomplete inferences about educational attainment, AL, and cancer mortality. However, some strengths of our study include using a nationally representative sample. This allows us to generalize our findings better. Further, this is one of the first studies to look at AL and the risk of cancer death, specifically among AA women.Previous studies have shown that increased allostatic load is associated with increased risk of cancer death. In our study higher educational attainment modified and reduced the risk of cancer mortality for African American women. However, the role of educational attainment on AL differences in cancer mortality among AA women were significantly attenuated once adjusted for age. Our findings reveal the benefits associated with higher education, such as increased access to medical care and better medical literacy improve but do not fully explain AA women’s risk of cancer mortality. Further research is needed to better understand the factors affecting AA women’s lives that may contribute to higher rates of cancer specific mortality and the potential mediating role of AL.Below is the link to the electronic supplementary material.Supplemental Table 1: Unweighted Cox proportional hazard models for the association between educational attainment and allostatic load status with risk of cancer death presented as hazard ratios (HRs) and associated 95% confidence intervals (CIs), among 4,677 non-Hispanic Black women participants with 241 cancer-related deaths.Supplemental Table 2: Excluding 180 NHANES participants with history of cancer survey, weighted Cox proportional hazard models presented as Hazard Ratios (HR) and 95% Confidence Intervals (CI) for the association between educational attainment/allostatic load and risk of cancer death, among 4,484  NHANES participants with 204  cancer-related deaths.


In female mammals, the development and regulation of the reproductive system and non-reproductive system are significantly influenced by estrogens (oestrogens). In addition, lipid metabolism is another physiological role of estrogens. Estrogens act through different types of receptors to introduce signals to the target cell by affecting many estrogen response elements. Breast cancer is considered mostly a hormone-dependent disease. Approximately 70% of breast cancers express progesterone receptors and/or estrogen receptors, and they are a good marker for cancer prognosis. This review will discuss estrogen metabolism and the interaction of estrogen metabolites with breast cancer. The carcinogenic role of estrogen is discussed in light of both conventional and atypical cancers susceptible to hormones, such as prostate, endometrial, and lung cancer, as we examine how estrogen contributes to the formation and activation of breast cancer. In addition, this review will discuss other factors that can be associated with estrogen-driven breast cancer. In adhttps://app.biorender.com/biorender-templates/t-5db2fd9f9688420082acf5d3-estrogen-receptor-signaling.BioRender (2021). Estrogen Receptor Signaling. Retrieved from 2In premenopausal women, estrogens are synthesized primarily in theca cells in the ovaries, placenta, and corpus luteum. A noteworthy quantity of estrogens can also be created by non-gonad organs, like the liver, skin, brain, and heart. The synthesis process ends with the conversion of androgens to estrogens in granulosa cells by the aromatase enzyme as illustrated in 3Estrogens are metabolized via hydroxylation and conjugation. Hydroxylation is achieved by cytochrome P450 enzymes such as CYP1A1 and CYP3A4, while conjugation is performed by estrogen sulfotransferases (sulfation) and UDP-glucuronyltransferases (glucuronidation). Moreover, estradiol is dehydrogenated by 17β-hydroxysteroid dehydrogenase into the less common estrogen estrone as shown in 3.12-hydroxylation is the main hydroxylation pathway. CYP1A1 and CYP1B1; cytochrome P-450 enzymes which are expressed in breast and liver tissues are major phase I enzymes . C2 hydr3.2In liver microsomes, the 4 hydroxylations of estradiol primary start with the CYP3A4/3A5 enzyme . 4-Hydro3.3In the 16-hydroxylation pathway, 16α-hydroxyestrone is the main product. 16α-hydroxyestrone showed a potential tumor stimulation by catalyzing unprogrammed DNA synthesis and promoting independent growth in mammary epithelial cells ,33. Some4Estrogens are found in both males and females; they are usually present at higher levels in women during reproductive age. They control the improvement of women's secondary sexual characteristics, such as breasts, and are elaborated in the thickening of the endometrium and other features of regulating the menstrual cycle. In men, estrogen regulates specific functions of the reproductive system essential to sperm maturation ,37. Estr5+ T lymphocytes contributes to the high survival rates of the patient, and this shows It is more clearly in patients who have ER-negative compared with patients with ER-positive . F. F120]. 8.1.4anti-Mullerian hormone (AMH) which could suggest PCOS is the original factor responsible for the increased breast cancer risk occurring in women with high levels of (AMH), not the increase in the hormone itself [Polycystic ovarian syndrome (PCOS) is the most common metabolic disease occurring in women at the age of reproduction. Women with the condition are more prone to cardiovascular manifestations as well as insulin resistance, but it also affects fertility, hormone balance, and ovulation . PCOS doe itself ,132. Thee itself .8.2Breast cancer is the most common malignancy among women regardless of their ethnic groups with a considerable difference in the incidence between populations . For ins8.3Weight and body mass index (BMI) can affect breast cancer by the high amounts of aromatase enzymes due to the high content of adipose tissue . It has 8.4Proteobacteria, families Micrococcaceae, Caulobacteraceae, Rhodobacteraceae, Nocordioidaceae, and Methylobacteriaceae, and genus Propionicimonas compared to benign healthy breast tissue, even with different types of breast cancer like HER2, Luminal A, Luminal B, ER+ the type of microbiome was diverse and different [S. pyogenes [Bacillus, Enterobacteriaceae, Staphylococcus, and Escherichia coli (a member of the Enterobacteriaceae family) and Staphylococcus epidermidis rising [Dysbiosis was found to make an impact on the effectiveness of chemotherapy drugs and prefer the environment of tumor development, suggesting an association between gut dysbiosis and the progression of cancers, autoimmune disorders of the gut, or inflammatory diseases. Even with the presence of some skeptical concerns about whether breast cancer development is due to this dysbiosis or the natural selection of microorganisms that can survive in a carcinogenic environment with special nutritional requirements , a diverifferent . A shiftpyogenes . To supps rising . Fernánds rising . The guts rising ,159. Thes rising . Anothers rising . Many bas rising .8.5Breast cancer in active or passive smokers can't be negligible knowing that this tobacco smoke included a lot of carcinogens of breast tissue, especially mammary cells. The enzyme N-acetyltransferase 2 (NAT2) was found to play a role in the detoxification and eradication of tobacco smoke chemicals so genetic polymorphisms of this enzyme gene will play a role to determine whether you are a fast or slow acetylators. Moreover, being a slow acetylators with a long history of smoking increases the risk for breast cancer development two times. The onset of smoking was found to increase the risk, like young age or long history of smoking before the first term of pregnancy . Jones e8.6Several reviews support the idea that oral contraceptives increase BC risk especially, in up five years of use or before the first pregnancy ,168. A s8.7Most women with breast cancer are in a premenopausal state and a wide range of patients are hormone receptor-positive. Therefore, the use of blockers for this hormonal receptor was the way of treatment for a long time like Tamoxifen, but in the last years with the appearance of aromatase inhibitors, the directions are more toward using aromatase inhibitors, especially with gonadotropin-releasing hormone (GnRH) agonists showed to have a promising effect on the treatment of hormone receptor-positive particularly in premenopausal women . The adj8.8One of the postmenopausal complications in women is the complaining of genital changes like vaginal atrophy and symptoms of hot flashes due to changes in the hormonal balance mainly of estrogen in their body at that period of their life. Accordingly, the availability of synthetic topical estragon analog to relieve genital symptoms only showed no link to increases in the risk of heart disease or cancer risk in general . So the 8.9Hormonal replacement therapy showed effective outcomes in the treatment of menopausal symptoms in women like hot flashes . A Neste9The variety of estrogen concentrations during pregnancy among pregnant women is explained by the impact of numerous exogenous variables on estrogen levels in the intrauterine period. In comparison to estrogen during the intrauterine period, when levels are ten times higher, the adult lifetime estrogen level is often significantly lower. Furthermore, estrogen is one of the key players in the development of breast cancer. Trichopoulos put up a theory that claims that the risk of breast cancer starts even before conception, or in utero ,194.To calculate the chance of getting breast cancer later in life, many studies employed indirect indicators of estrogen levels during pregnancy. Some of these indicated factors, such as greater mother age and having twins, have been linked to an increased risk of breast cancer after pregnancy, while others, such as maternal smoking, have been linked to a decreased chance of developing breast cancer in later life . Even thHowever, other research revealed that conditions including pre-preeclampsia and twins will secrete less potent forms of estrogen-like E3 and E4, and even in rare cases, may lower intrauterine estrogen . For the10Fibroadenoma of the breast is common among all ages with a peak incidence during the second and third decades occurring in 25% of females ,204. HisThe clinical assessment of fibroadenomas involves clinical examination  imaging, and non-surgical tissue biopsy (triple test) . It is uAs mentioned earlier, the fibroadenoma is a biphasic breast lesion in which both epithelial and stromal components of the terminal ductal unit proliferate . The priThe estrogen receptor (ER)-α is the traditional mediator of the response to estradiol. Although ER-α is mostly expressed by epithelial cells in fibroadenoma, its expression by stromal cells remains controversial. According to a recent investigation, only the ER-β isoforms were detected in the stromal cells of adult human mammary glands. Recent studies revealed that ER-β activates a heterogeneous fibroblast population with different lifespans in the stroma of fibroadenomas. In fibroadenomas, ER-β-related myofibroblastic differentiation of fibroblasts may influence matrix remodeling and inhibition of the sclerotic involution .In young premenopausal women, the incidence and development of fibroadenoma are dependent on their reproductive history and the presence of ovarian hormones. In addition, environmental factors may affect endogenous estrogen levels and cause hormonal dysfunction, and menstrual fluctuations, which may increase the risk of fibroadenoma, and some lifestyle factors with antiestrogenic effects may reduce the risk of fibroadenoma. Also, early pregnancy appears to prepare the breast for lactation, while estrogens and other circulating hormones stimulate the fast proliferation of epithelial breast tissue, followed by hormonally driven mammary epithelium differentiation. This early differentiation could prevent epithelial cells from developing fibroadenoma, which is caused by estrogen-dependent hyperplasic processes. Even while the preventive effects of OCPs containing >50 mcg estrogen (but not for progestogen-only OCPs) were suggested, the current studies showed that the incidence of fibroadenoma is not higher in women who use oral contraceptives for longer periods. Likewise, severe stress, which can raise endogenous estrogen levels, was considered another possibility in this aspect. However, further research is needed to determine the involvement of psychological illnesses in the occurrence of fibroadenoma .1111.1204. This disease progresses with premenopausal age and is most noticeable in women in their forties. While fibrocystic changes regress during the postmenopausal period. The pathophysiology of fibrocystic changes is determined by estrogen dominance and progesterone deficiency, which results in connective tissue hyperproliferation and fibrosis and is followed by facultative epithelial proliferation. Likewise, the risk of breast cancer is increased two to fourfold in these patients [Fibrocystic changes refer to several clinical and histological abnormalities in the female mammary gland. Some of these should be viewed as a disorder of physiological development, maturation, and involution rather than a disease. Moreover, fibrocystic changes are common in around 50% of all women over the age of 30 patients . ProlifeOne of the key pathophysiological issues in fibrocystic breast diseases is the prevalence of elevated estrogen concentration throughout the menstrual cycle . Likewis11.2The clinical assessment of fibrocystic changes involves clinical examination  imaging, and fine-needle aspiration . Benign 11.3Gallicchio et al. showed weakly relationship between breast cancer and ESR1 variations and one of the four ESR2 variants investigated in 1438 Caucasian women with benign breast disease . Obesity1212.1The terminal duct lobular unit (TDLU) is formed when normal breast ducts come to an end. The duct terminates in lobules made up of acini, which are tiny glandular structures. Inner luminal epithelial cells and outer luminal myoepithelial cells make up the bilayer that lines the ductal-lobular systems . The TDLIn breast tissue, atypical ductal hyperplasia is a pathogenic condition. Atypical Ductal Hyperplasia (ADH) is generally discovered by chance on needle biopsy specimens taken in response to aberrant mammography findings. Because atypical ductal hyperplasia is associated with an increased risk of breast cancer, it is classified as a "high-risk" lesion rather than a "precursor" lesion. The difference is that breast cancer associated with ADH can occur anywhere in the breasts, not just in the ADH area. The true incidence of ADH is unknown because most cases are discovered by chance. Once discovered, it is known to raise the risk of breast cancer by about fivefold . It is c12.1.1Estrogen is thought to play a role in the pathophysiology of breast cancer by promoting normal growth of the breast epithelium through the estrogen receptor's mechanism of absorption into the cell . As mentThese clinical findings, along with previous research on ER expression in other benign breast epitheliums, suggest that ER expression in atypical hyperplasia could be a predictor of breast cancer risk in the future. The researchers wanted to look at ER expression in atypical hyperplasia and see if there were any links to age at biopsy, the reason for biopsy, type of atypia, number of atypical foci, involution status, and family history, as well as see if there was any link between ER expression in atypia and subsequent breast cancer risk . A large12.2Carcinoma In Situ (CIS) of the breast is a heterogeneous collection of lesions that covers a broad range of clinical and histological changes. Biologically; CIS can range from biologically aggressive lesions with a high chance of progressing to invasive carcinoma to lesions with very low malignant potential. There are two forms of CIS, ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). CIS is common, and it is expected that roughly 20% to almost a third of all women will get it during their lives .12.2.1DCIS is an early, localized stage of breast cancer . It acco12.2.2This form of breast cancer starts in lobules and terminal ducts and is more common and more frequent than this incident would seem to suggest. When the tumor invades, it often does so in an odd way that enables one to recognize the likelihood of such an origin even though it is hard to trace it after some experience. Furthermore, it is frequently possible to find peripheral areas where lobular carcinomatosis in situ is still clearly visible in the completely infiltrative form. Thus, out of these same 300 examples, 5 had a very distinct pattern, 2 had one that was only moderately developed, and 5 had one that was certainly there but was insufficient .12.3Invasive ductal carcinoma (IDC) is a highly malignant subtype of breast cancer that belongs to the classification of epithelial tumors. It is the general designation for nonspecific invasive carcinoma that belongs to the epithelial tumors classification group. IDC is the most frequent kind of breast cancer in women, and it is also the main cause of cancer-related death . The mos13Granulosa cell tumors (GCT) and thecoma are called estrogen-producing tumors. Researchers found that there is a relationship between these tumors and an increased risk of breast cancer . With th14241. There are already identifiable risk factors such as constitutional, environmental, hormonal , and genetic  factors. In 75% of cases, the clinical manifestation is a painless hard and fixed nodule in the subareolar region, with nipple commitment occurring earlier than in women [Male breast cancer is a rare type of cancer that accounts for fewer than 1% of all malignancies in men and 1% of all breast cancers. However, the incidence of the disease is increasing, reaching 15% in some patient groups throughout their lives . It is min women . The mosin women . The conin women . Also, ain women .15Estrogen homeostasis and tissue-specific exposure to estrogen and its metabolites are influenced by genetic and environmental variables. Uncertainty exists regarding the relative impact of the changing serum estrogen levels linked to the menstrual cycle in premenopausal women and the more constant levels in postmenopausal women on the total lifetime exposure to estrogen. When considered collectively, the body of evidence is consistent with the idea that estrogen and its metabolites are connected to both the beginning and advancement of breast cancer, albeit these connections are complicated. Recent findings from sizable clinical trials of selective estrogen receptor modulators provide more proof of the link between estrogen and the risk of breast cancer. Tamoxifen's antiestrogenic impact lowered the incidence of breast cancer in healthy premenopausal and postmenopausal women who were at higher risk for the condition, while raloxifene did the same for postmenopausal women who had osteoporosis. Although a link between estrogen exposure and the risk of breast cancer has been shown in some populations of women, the risk for a given woman cannot be precisely predicted. Breast density on mammography, serum estrogen concentrations, and bone mineral density are a few clinical indicators of estrogen exposure that may help determine a woman's risk of breast cancer. Composite risk assessments based on these and other risk variables, such as family and reproductive histories, may help us better understand the role of estrogen in the pathogenesis of breast cancer and provide a more accurate evaluation of risk for specific women.Conceptualization: MSA and RMA. Study design, data collection, and data analysis: KA, SA and AK. Writing-Original draft preparation: KA, AK, SA, AMA, SAS, RAB, SFA, AMA, and SHB. Writing- Reviewing and Editing the final manuscript: RMZ and MSA. All authors reviewed, contributed, and approved the final manuscript version.None.Many of the factors highlighted in the review should be considered by researchers studying the impact of estrogens on breast cancer disease (BCa).Data will be made available on request.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Platelet count (PLT) is associated positively with lung cancer risk but has a more complex association with body mass index (BMI), positive only in women (mainly never smokers) and inverse in men (mainly ever smokers), raising the question whether platelets interact with obesity in relation to lung cancer risk. Prospective associations of platelet size (an index of platelet maturity and activity) with lung cancer risk are unclear.2), dichotomising platelet parameters at ≥ median (sex-specific), and multiplicative interactions with BMI . We examined heterogeneity according to smoking status  and antiaggregant/anticoagulant use (no/yes).We examined the associations of PLT, mean platelet volume (MPV), and platelet distribution width (PDW)  with lung cancer risk in UK Biobank men and women using multivariable Cox proportional hazards models adjusted for BMI and covariates. We calculated Relative Excess Risk from Interaction (RERI) with obese : 1.09–1.20) and women  but interacted inversely with BMI only in men . Only in men, MPV was associated inversely with lung cancer risk  and interacted positively with BMI , while PDW was associated positively , with no evidence for interactions. The associations with PLT were consistent by smoking status, but MPV was associated inversely only in current smokers and PDW positively only in never/former smokers. The interactions with BMI were retained for at least eight years of follow-up and were consistent by smoking status but were attenuated in antiaggregant/anticoagulant users.In men, PLT was associated positively and MPV inversely with lung cancer risk and these associations appeared hindered by obesity. In women, only PLT was associated positively, with little evidence for interaction with obesity.The online version contains supplementary material available at 10.1186/s12931-023-02561-9. Platelets can promote carcinogenesis by releasing growth and angiogenic factors and extracellular vesicles, which induce changes in stromal and tumour cells . The lunAlthough general obesity, as reflected in body mass index (BMI), is associated with higher risk of venous thromboembolism , BMI shoPLT is only one aspect of platelet pathology and does not provide information about platelet functionality, while platelet size could be indicative of platelet activity, as thrombotic conditions are associated with large mean platelet volume (MPV)  and largIn this study, we used data from the UK Biobank cohort to investigate the prospective associations of PLT, MPV, and PDW with lung cancer risk and their interactions with obesity in men and women.UK Biobank includes half a million participants registered with the National Health Service, which were aged 40 to 70 years at recruitment (years 2006 to 2010) and were living within 40 km of an assessment centre in England, Scotland, and Wales . In thisCancer cases in UK Biobank are ascertained based on linkage to the national cancer registry of the United Kingdom. The outcome of interest was first primary lung cancer diagnosed after recruitment, defined with code C34 from the 10th version of the International Statistical Classification of Diseases (ICD10) and malignant behaviour , defined as in . Follow-9/L) was measured directly, while MPV (fL) and PDW (%) were derived from scatter plots and histograms of platelet size on Beckman Coulter LH750 automated analysers. We log-transformed all platelet parameters, to mitigate right-skewness of the distributions.Blood samples were collected at recruitment in EDTA (ethylenediaminetetraacetic acid) vacutainers, throughout the day (irrespective of fasting status) and were analysed within 24 h of blood draw . PLT  on a standardised continuous scale  after log-transformation), interpreting hazard ratios (HR) per one SD increase. We examined men and women separately, due to the pronounced sex differences in the associations of obesity with platelet parameters . We exam2; overweight BMI = 25 to < 30 kg/m2; obese BMI = 30 to < 45 kg/m2) and used the data augmentation method of Lunn and McNeil [We explored heterogeneity in groups according to BMI :To evaluate additive interactions, we calculated the Relative Excess Risk from Interaction (RERI)  in fullynlcom in STATA-13 [We obtained confidence intervals and p-values for RERI with the delta method applied in function STATA-13 .To evaluate multiplicative interactions between platelet parameters and BMI on a continuous scale, we used the Wald test for the corresponding interaction term, examining each platelet-BMI pair in a separate model with adjustment for covariates.We used STATA-13 for the statistical analyses and R version 4.1.3  for dataWe obtained HRs and 95% confidence intervals (CI) from delayed-entry Cox proportional hazards models, which account for left-truncation and are conditional on surviving cancer-free to cohort recruitment. We used age as the underlying time scale, with origin at the date of birth, entry time at the date at recruitment, and exit time at the earliest of the date of diagnosis of the first primary incident cancer, or death, or last complete follow-up. We stratified all models by age at recruitment (five-year categories), region of the assessment centre, and for women, a combined variable reflecting menopausal status and hormone replacement therapy (HRT) use (defined similarly to ), with fTo confirm correlations between platelet parameters in this study, we calculated partial Pearson correlation coefficients adjusted for all covariates, except region of the assessment centre, and using age, Townsend deprivation index, time of blood collection, and fasting time as continuous variables, and smoking with categories never, former, and current smoker.To examine the influence of adjustment on the observed associations and interactions, we used models stratified by age only and models additionally adjusted only for smoking status and intensity. To examine the potential influence of reverse causality, we excluded participants with less than two years and less than eight years of follow-up and lagged the entry date with two or eight years, correspondingly, to condition on surviving cancer free to later than recruitment.Last, we examined the consistency of our findings in groups according to smoking status , as smoking can affect platelet parameters , and accDuring a mean follow-up of 10.4 years, 1620 lung cancers were ascertained in 192,355 men and 1495 lung cancers were ascertained in 218,761 women (Table obese = 0.002) . PDW was associated weakly positively with lung cancer risk also only in men .PLT was associated positively with lung cancer risk in men  and women , more specifically in normal weight and overweight and not in obese participants, but with clear evidence for heterogeneity between BMI categories only in men  and less for women, and there was a matching inverse multiplicative interaction only in men  . High-PDW was associated positively with lung cancer risk for BMI < 30 kg/m2 also only in men, but with no evidence for additive or multiplicative interactions.High-PLT was associated positively with lung cancer risk for BMI < 30 kg/mThe positive associations of PLT with lung cancer risk in men and women were stronger in the age-stratified unadjusted model and were partly attenuated after adjustment for smoking status and intensity, but with no material influence of additional stratification and adjustment for covariates Fig. . The posThe inverse association of MPV with lung cancer risk in men was influenced little by adjustment for smoking or covariates but was partly attenuated after 8 years of follow-up and in antiaggregant/anticoagulant users and was observed only in current smokers  and not in never or former smokers Fig. . On the The inverse interactions of PLT with BMI and the positive interactions of MPV with BMI were partly attenuated after adjustment for smoking but with no material influence of additional adjustment for covariates and were largely retained for at least 8 years of follow-up Fig. . They reAntiaggregant/anticoagulant users had higher lung cancer risk compared to non-users, independent of PLT, BMI, and covariates, but more prominently in men  than in women .In this study, PLT was associated positively with lung cancer risk in women and men but showed consistent inverse additive and multiplicative interactions with BMI only in men. Also only in men, MPV was associated inversely with lung cancer risk and showed positive additive and multiplicative interactions with BMI, while PDW was associated weakly positively, with no evidence for interactions with obesity.Our findings corroborate previous prospective studies reporting positive associations of PLT with lung cancer risk within the year prior to diagnosis , 27 and A plausible mechanism linking PLT to lung cancer development would be an inflammation-related platelet increase, as platelets are involved in immuno-inflammatory responses  and PLT Notably, the inverse association of MPV with lung cancer risk in men was observed in the same BMI categories  as the positive association with PLT. This is consistent with the inverse correlation between PLT and MPV, which we have previously shown in UK Biobank for a restricted dataset excluding participants with cardiometabolic conditions  and haveAlthough MPV and PDW are associated positively with each other in UK Biobank  , which cThe associations of platelet parameters with lung cancer risk and their interactions with obesity showed sex differences, as previously did the associations of platelet parameters with obesity in UK Biobank . This maDespite the detailed adjustment for smoking status and intensity, some residual confounding from smoking may have remained in the positive association of PLT with lung cancer risk, as PLT is higher in smokers . We did Although there is interest in using aspirin for lung cancer prevention , it woulA major strength of our study is the prospective cohort design with available platelet measurements and a sizable number of incident lung cancer cases, which permitted examining cross-classifications. Anthropometric measurements, performed by trained personnel and according to standardised protocols, avoided bias from self-reporting. Information for major lifestyle factors (including smoking intensity and time since quit) and drug use permitted adjustment and minimisation of confounding.A clear limitation of our study is the lack of information about platelet activation or about blood clotting factors, so we were unable to assess platelet function and thrombosis. We were also unable to examine thrombopoiesis and platelet maturity. Our project did not have access to the information for air pollution available in UK Biobank, as examining this was beyond the scope of our project but merits investigation in future studies because air pollution is associated with platelet activation , as wellIn men, PLT was associated positively and MPV inversely with lung cancer risk and obesity appeared to hinder these associations, possibly via platelet destruction due to obesity related liver fibrosis for PLT and via oestrogen related platelet activation for MPV. In women, only PLT was associated positively with lung cancer risk, with little evidence for interaction with obesity.Additional file 1: Table S1. Flow chart of study participants. Table S2. Characteristics of study participants.