Although cholesterol has been hypothesized to promote cancer development through several potential pathways, its role in the risk of developing hormonally driven cancer is controversial. This literature review summarizes evidence from the highest quality studies to examine the consistency and strength of the relationship between serum cholesterol parameters and incidence of hormonally driven cancer. Articles were identified using EMBASE. Longitudinal observational studies published between January 2000 and December 2020 were considered for inclusion. The endpoint of interest was incident prostate, ovary, breast, endometrium, and uterine cancers. In total, 2732 reports were identified and screened; 41 studies were included in the review. No associations were found for ovarian cancer. Most endometrial cancer studies were null. The majority (76.9%) of studies reported no association between cholesterol and prostate cancer. Data on breast cancer were conflicting, associations limited, and effect sizes modest. Our results do not provide evidence for a clear association between cholesterol and different types of incident, hormonally driven reproductive cancers. Future studies should investigate the impact of lipid‐lowering therapy. A literature review summarizing evidence from studies examining the consistency and strength of the relationship between serum cholesterol parameters and incidence of hormonally driven cancer was conducted. The endpoint of interest was incident prostate, ovary, breast, endometrium, and uterine cancers. In total, 2372 reports were identified and screened; 41 studies were included in the review. Overall, our results do not provide evidence for a clear association between cholesterol and different types of incident, hormonally driven cancers. Further studies are needed to assess the role of cholesterol in the development of other cancer types.2We conducted a literature review to find studies that assessed the association between serum cholesterol levels and the development of hormonally driven reproductive cancers in humans.2.1Studies reporting on adults (≥18 years of age) in the general population who were at risk of developing hormonally driven cancers (and without the cancer of interest at baseline) were included. Studies enrolling both those <18 years old and adults (≥18 years old) were included if >80% of the population were adults, or if separate data were presented for adults. Studies enrolling patients who already had cancer at the start of the study were excluded. The exposure of interest was high serum cholesterol levels versus low serum cholesterol levels. High versus low cholesterol could be assessed incrementally (tertiles and quartiles) or using a single cutoff point. Cholesterol measurements of interest included total cholesterol, high‐density lipoprotein cholesterol (HDL‐C), and low‐density lipoprotein cholesterol (LDL‐C). Outcomes of interest were the incidences of breast, endometrial, or ovarian cancer (for women) and the incidence of prostate cancer (for men). Studies reporting on the risk of testicular cancer in men or cervical cancer in women were excluded, since hormone levels have not been previously associated with the incidence of these cancers. Observational studies designed to assess the temporal association between cholesterol and cancer development were considered, including cohort, case‐cohort, nested case–control, and Mendelian randomization studies. Both prospective and retrospective study designs were considered. Published systematic literature reviews and/or meta‐analyses of studies with relevant designs, as noted above, were also included. The following study designs were excluded: case control studies, case series, and case reports. Interventional studies  were excluded, due to additional effects that may be independent from lipid lowering. All articles and abstracts reviewed were required to be in English. Non‐English papers (even if the abstract was in English) were excluded.2.2We searched the EMBASE electronic bibliographic database from January 1, 2000, through to December 14, 2020. In addition, we searched congress abstracts listed in EMBASE over a 2‐year period . A full‐text screen was performed on the references identified from the title and abstract screening. Systematic reviews and meta‐analyses were identified during the first pass, and manual bibliographic searching was conducted to identify any additional relevant studies. The search criteria are provided in Table 2.3p values.The identified reports, based on the above eligibility criteria, were screened in a two‐step process:  title/ab33.1A flow diagram of the screening results is shown in Figure 3.2n = 2118; 43 cases) reported a positive association between higher total cholesterol and an increased risk of prostate cancer .In total, 17 longitudinal studies reporting on the incidence of prostate cancer met the inclusion criteria, including cohorts from Korea, Scandinavia, Western Europe, the USA, and the UK Table . A summaOnly three studies assessed the association between LDL‐C and incidence of prostate cancer.Lastly, the association between low HDL‐C levels and prostate cancer was reported in seven studies3.3Three Mendelian randomization studies assessing the association between circulating lipids and prostate cancer were identified Table .48, 43.4The literature review identified 17 records reporting on the association between serum cholesterol levels and risk of breast cancer, including cohorts from Austria, Denmark, France, Korea, Italy, Norway, Sweden, and the USA Table . A summaptrend 0.96) after model adjustment for age and treatment  or per 1 SD increase (HR [95% CI]: 0.96 [0.89–1.03]) and breast cancer risk.n = 9738; 326 cases) reported that the relative risk of breast cancer had no significant trends over quartiles of total cholesterol levels in perimenopausal/postmenopausal women ; furthermore, total cholesterol did not affect breast cancer risk in premenopausal women .The effect of total serum cholesterol levels on incident breast cancer risk varied among the studies identified. An analysis of the Women's Health Study cohort, including 15,602 women aged ≥45 years and without cardiovascular disease, use of hormone replacement therapy, or use of lipid‐lowering therapies at baseline, demonstrated no association between quartiles of total cholesterol  of the National Institute of Health‐American Association of Retired Persons (NIH‐AARP) Diet and Health Study reported a consistent positive association between elevated cholesterol (self‐reported) and overall risk of breast cancer (HR [95% CI]: 1.13 [1.04–1.23]), which was maintained in a normal BMI subgroup.n = 38,823; 708 cases), an inverse association between total serum cholesterol was reported for those with cholesterol in the highest quartile (>6.82 mmol/L) compared with the lowest quartile (<5.24 mmol/L) and postmenopausal breast cancer . However, it should be noted that no association was reported among overweight and obese women.ptrend 0.04).In comparison, a positive association between serum total cholesterol levels and risk of breast cancer was reported in three studies.ptrend 0.1); interestingly, the same study reported that total cholesterol and HDL‐C were associated with breast cancer risk .p = 0.84); the results were not modified when assessed by menopausal status.ptrend 0.02); no significant association was observed in the premenopausal cohort.ptrend 0.05; postmenopausal: per one unit increment in HDL‐C, HR [95% CI]: 0.53 [0.28–1.01], ptrend 0.05).ptrend 0.03), which strengthened when excluding users of hormone therapy .In total, 12 studies reported on the association between HDL‐C levels and breast cancer. A prospective study evaluating the association of breast cancer with lipid biomarkers in participants from the Women's Health Study reported no association between HDL‐C levels and breast cancer risk .Four Mendelian randomization studies were identified that evaluated the association between circulating lipids and breast cancer Table .49, 6p = 0.02 and 1.09 (1.02–1.18); p = 0.020, respectively. The other two studies found no association between genetically predicted LDL‐C and breast cancer.p = 0.004) but not for ER‐ breast cancer (p = 0.577).PCSK9 genetic variants known to result in elevated LDL‐C levels were associated with increased breast cancer risk overall .Four studies reported the association between genetically predicted increase in LDL‐C and breast cancer.p = 4.93 × 10−4 and 1.12 [1.08–1.16]; p = 1.7 × 10−9), respectively.p = 0.037).Similar to the LDL‐C findings, half of the studies examining the relationship between HDL‐C and breast cancer observed a significant association.3.6The risk of endometrial cancer has risen substantially over the years, mainly due to increases in BMI.ptrend 0.731). However, when the association was analyzed according to the National Cholesterol and Education Program thresholds for high cholesterol, <6.50 versus ≥6.50 mmol/L, instead of quartiles, the association no longer remained.For the lipoproteins of interest, four of the five studies reported associations between the risk of endometrial cancer by total cholesterol, LDL‐C, and HDL‐C,ptrend 0.0003); however, after further adjustment for sex steroid hormones and other obesity‐related hormones, the observed association between HDL‐C and endometrial cancer was no longer significant (ptrend 0.09).Of the four studies that assessed the relationship between HDL‐C levels and incidence of endometrial cancer, only one reported an association.3.7n = 188,578p = 0.036); however, this finding was not significant after adjusting for multiple comparisons.One record reporting on a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between circulating lipids  and endometrial cancer risk was identified.3.8n = 24,208; 115 cases) reported no association between quartiles of total cholesterol, LDL‐C, and HDL‐C with ovarian cancer risk.n = 27,394; 808 cases) showed no association between circulating levels of total cholesterol, LDL‐C, and HDL‐C with risk of ovarian cancer (assessed by quartiles).Only two studies evaluated the relationship between circulating cholesterol levels and ovarian cancer.There were no Mendelian randomization studies for ovarian cancer located in the literature.4The aim of our study was to summarize the association between serum cholesterol levels and incidence of hormonally driven cancers, with a focus on epidemiological studies with designs supporting the highest level of causal evidence. We identified 41 longitudinal or Mendelian randomization studies reporting on the association between circulating cholesterol levels and risk of prostate, breast, endometrial, or ovarian cancers. These results provide evidence for a complex association between cholesterol and different types of incident hormonally driven reproductive cancers. Even among the same types of cancer and serum cholesterol measures, often studies reported conflicting results and overall failed to convey evidence of an effect of plasma lipids.p‐value was non‐significant after adjusting for multiple comparisons.Thus far, the evidence reviewed does not support an association between serum cholesterol variables  and incident ovarian cancer. Additionally, there were no observed associations between endometrial cancer and serum cholesterol variables among the longitudinal studies. However, the single Mendelian randomization study examining this relationship found that higher genetically predicted levels of HDL‐C and lower genetically predicted levels of LDL‐C were associated with incident endometrial cancer. The association with HDL‐C is likely spurious as the confidence interval for the comparison with HDL included 1 [estimate 1.07 (1.00–1.14)] and the Similarly, the evidence reviewed does not support an association between cholesterol and prostate cancer. Most of the longitudinal studies and all the Mendelian randomization studies assessing the relationship between cholesterol and prostate cancer found no association. In the few studies reporting an association, the direction is inconsistent. Two publications reported an association between higher levels of total cholesterol and an increased risk of prostate cancerFinally, the association between cholesterol levels and breast cancer requires further research. Interestingly, our summary of longitudinal studies indicates a potential effect of lower HDL levels and increased breast cancer risk in some subgroups . To examine these relationships often requires a large sample size and statistical evaluation of the interaction. These variables were not handled consistently across these studies. For example, menopausal status is often treated as a confounding variableThe limitations of this study include the inability to account for potential differences in risk factors related to cholesterol across geographic and ethnic populations. The data were not pooled for meta‐analysis due to the wide variety of populations, study designs, and serum cholesterol parameters included in the studies. Studies in this review were not formally assessed with a quality tool, but common weaknesses across included studies are insufficient sampling, short follow‐up time, and potential misclassification, such as pre‐clinical bias. In cases of pre‐clinical bias, undiagnosed cancer may already be affecting serum cholesterol as the cancer may utilize cholesterol for cell replication and therefore result in decreased serum levels. This could result in a mistaken association between low serum cholesterol and cancer diagnosis. The strengths of this analysis include the robustness of the review of studies and selection of those with the strongest epidemiologic study designs.In summary, these results show no clear signal between serum cholesterol  and incident, hormonally driven cancer. The apparent lack of a role for cholesterol in the risk of developing the hormonally driven cancers in the studies included in this review may be related to confounders, modifiers, or the design of such studies (limitations discussed above) that prevent clear patterns of association from emerging. While serum cholesterol levels do not necessarily reflect the status of intracellular cholesterol trafficking, these cells are reliant on circulating cholesterol for cancer development and growth. This need may be particularly elevated for malignant and fast‐growing tumors and for steroid hormone‐dependent cancers.Thus, additional research into the role of cellular cholesterol is warranted. In addition, we would suggest conducting a rigorous life course epidemiologic study examining both the genetic and longitudinal association between serum lipids  and cancer risk. Such a study would help to elucidate biological and behavioral processes that operate in combination across an individual's life that influence cancer risk, accounting for multiple confounders such as diet, exercise, and use of lipid‐lowering therapy.Dana J. Murdock: Conceptualization ; formal analysis ; methodology ; writing – original draft ; writing – review and editing . Robert Sanchez: Conceptualization ; formal analysis ; methodology ; writing – original draft ; writing – review and editing . Kusha A Mohammadi: Conceptualization ; formal analysis ; methodology ; writing – review and editing . Sergio Fazio: Conceptualization ; formal analysis ; methodology ; writing – review and editing . Gregory P. Geba: Conceptualization ; formal analysis ; methodology ; writing – review and editing .This analysis was funded by Regeneron Pharmaceuticals, Inc.All authors are employees of and stockholders in Regeneron Pharmaceuticals, Inc.Appendix S1Click here for additional data file.


Lung and breast cancer are important in the working-age population both in terms of incidence and costs. The study aims were to estimate the 10-year risk of lung and breast cancer by occupation and smoking status and to create easy to use age-, and sex-specific 10-year risk charts.New lung and breast cancer cases between 2010 and 2014 from all 5 cancer registries of Western Switzerland, matched with the Swiss National Cohort were used. The 10-year risks of lung and breast cancer by occupational category were estimated. For lung cancer, estimates were additionally stratified by smoking status using data on smoking prevalence from the 2007 Swiss Health Survey.The risks of lung and breast cancer increased with age and were the highest for current smokers. Men in elementary professions had a higher 10-year risk of developing lung cancer compared to men in intermediate and managerial professions. Women in intermediate professions had a higher 10-year risk of developing lung cancer compared to elementary and managerial professions. However, women in managerial professions had the highest risk of developing breast cancer.The 10-year risk of lung and breast cancer differs substantially between occupational categories. Smoking creates greater changes in 10-year risk than occupation for both sexes. The 10-year risk is interesting for both patients and professionals to inform choices related to cancer risk, such as screening and health behaviors. The risk charts can also be used as public health indicators and to inform policies to protect workers. Lung cancer, in men and women, and breast cancer, in women, are important in the working-age population both in terms of incidence and costs . In SwitAssociations of lifestyle-related factors with cancer risk have been explored in the literature, but accurate estimates of the cancer burden associated with occupations is lacking. Assessing the effect of occupation on cancer risk is challenging due to data availability and quality, particularly on measurements and levels of exposures, and information on employment. Burden estimates are only available for a few countries and are not directly comparable –5. OccupAccounting for smoking patterns is key to understanding the burden of occupational cancer. Smoking prevalence varies by occupation due to, for example, sociodemographic and employment-related factors . PreviouTo our knowledge, there is scarce evidence on the association of occupation with cancers in Switzerland , 10. OneOur first aim was therefore to estimate the age-, and sex-specific cumulative 10-year risk of both lung cancer, in men and women, and breast cancer, in women, in Western Switzerland, by occupation, and, for lung cancer, also by smoking status. Our second aim was to create easy to interpret risk charts for lung and breast cancer using the previously calculated risk estimates.New lung and breast cancer cases registered by all five cancer registries in Western Switzerland  between 2010 and 2014 were used. Information on occupation and vital status were retrieved from the Swiss National Cohort (SNC) and were matched with the data from the cancer registries. The SNC covers an estimated 98.6% of the population and is based on data from the 1990 and 2000 federal censuses . SmokingParticipants were eligible for the study if they were of working and transitional to retirement age (18 to 65 years at study entry) and were permanent residents of one of the Western Swiss cantons. In addition, they had to be included into the SNC either on December 4, 1990 (the date of the 1990 census) or on December 5, 2000 (the date of the 2000 census) and have information on occupation. End of follow-up was at the earliest date of: death, emigration, 85th birthday, or end of the study .Lung cancer, in men and women, and breast cancer, in women, were the two primary outcomes. Only incident primary malignant cancers were considered and were identified based on the data from the cancer registries, coded using the International Classification of Diseases for Oncology (ICD-O), 3rd edition: C33–C34 for lung cancer and C50 for breast cancer. Using probabilistic linkage, the Institute of Social and Preventive Medicine of the University of Bern linked the registries' data with SNC data. Almost all lung and breast cancer could be linked with the SNC data (94.4%).Occupational status was categorized using the International Standard Classification of Occupations version 1988 (ISCO-88). This classification was used in the 1990 and 2000 censuses and coded using four-digit codes by the Swiss Federal Statistical Office. Based on this information, the following three categories were constructed: workers in (A) agriculture, industry, crafts, and elementary professions; (B) intermediate professions, administrative employees, personal service and personnel; and (C) managerial, intellectual or scientific professions. In this study, category A was labeled as “elementary professions,” category B as “intermediate professions,” and category C as “managerial professions” .Sex-, age-, and time-period specific prevalence of never, former, and current smoking in Switzerland were used to compute risks. To estimate the risk of lung cancer by smoking status, national smoking prevalence data stratified by age and sex were used. Smoking status was defined as a categorical variable: never smokers, former smokers, and current smokers, based on the questions “Do you currently smoke?” and “Have you ever smoked regularly for more than 6 months?” in the 2007 SHS. Using the 2007 survey provides the most recent prevalence estimates before cancer diagnosis.The 10-year risks of lung and breast cancer at age 35, 45, 55, 65, and 75 between the years 2010 to 2014, by occupation, were estimated following the studies by Bruder et al. and Woloshin et al. using the formulas below , 24. TheAge-, sex-, cause-specific lung cancer risk = all men of a specific age and occupation who were diagnosed with lung cancer between 2010 and 2014 divided by the total number of men of that age in the population and occupation between 2010 and 2014.The Swiss Health Survey was used to compute the prevalence of each smoking strata by age, sex, and time. The relative risk (RR) of lung cancer associated with current and former smoking compared to never smoking was used: RR = 6.57 for current smokers below 60 years of age, 9.62 for current smokers between 60 and 69, 9.07 for current smokers 70 years or over, and 4.30 for former smokers of all ages .For any given age group and sex:For any given age group and sex:To estimate 10-year risk for the age group starting at age X, accumulate the risks for age X until X+9.Using the calculated 10-year risk estimates, risk charts for lung and breast cancer, by age group, occupational status, and smoking status were created in the following way: the charts see –3 show tIn total, 3,090 men and 2,102 women were diagnosed with lung cancer and 7,045 women were diagnosed with breast cancer in the period 2010–2014 and were included in the study . Most meThe risk chart for lung cancer in women is shown in Charts were created to estimate the sex-specific 10-year risk of both lung cancer, in men and women, and breast cancer, in women, in Western Switzerland, by occupation, and, for lung cancer, by smoking status. To the best of our knowledge, these are the first estimates of 10-year risk of developing lung or breast cancer taking occupational status into account. Results showed an overall increasing risk of lung and breast cancer by age group. Men in elementary and women in intermediate professions had the highest risk of developing lung cancer. Women in managerial professions had the highest risk of developing breast cancer. Smoking status creates greater change in 10-year risk than occupational status for both sexes. In addition, 10-year risk of lung cancer remains higher in men than women in Western Switzerland. In women, 10-year risk is higher for breast than lung cancer, except for current smokers.The association between occupation and cancer can be direct through occupational exposures, but the occupational categories can also be viewed as a descriptor of socioeconomic status . StudiesA main strength of this study was the use of high-quality and exhaustive data from five cancer registries in Switzerland, with information on all cases of lung and breast cancer . This alThis study also has some limitations. First, more personalized risk estimates, taking other disease-specific and synergistic effects between risk factors into account, would be even more useful for reliable estimates. Non-occupational risk factors such as diet, physical activity, weight, socioeconomic status, and air pollution could be interesting to include in the calculations , 12. In The 10-year risk charts are useful for both patients and professionals to inform choices related to cancer risk, such as screening and health behaviors. The charts clearly show the magnitude related to certain risk factors, in this case smoking, which could facilitate health professionals in consultations about smoking cessation and informed health decision making . The risThis is the first study that estimates the 10-year risk of developing lung or breast cancer by occupational status in Switzerland. Results indicate that men in elementary professions and women in intermediate professions have the highest risk of developing lung cancer. Women in the managerial professions have the highest risk of developing breast cancer.Estimating an individual's probability of developing cancer in the next 10 years, i.e., the cumulative 10-year risk, is informative and easily understood by both individuals and health professionals , 24. Howbernadette.vanderlinden@unifr.ch.The datasets presented in this article are not readily available because due to the nature of this research, study participants could not agree for their data to be shared publicly. Supporting data is therefore not available in accordance with ethical and legal requirements. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by Swissethics have approved the creation and use of this database for this project (N° de ref CER-VD 2018-02077). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.BL, NB, AC, and IG: conceptualization, validation, and methodology. NB: data curation. BL: formal analysis and writing—original draft preparation. NB, PA, YB, J-LB, EF, SG, IK, MM, ER, AC, and IG: writing—review and editing. All authors have read and agreed to the published version of the manuscript.