Progesterone and Breast Cancer Trabert, Britton; Sherman, Mark E; Kannan, Nagarajan ...
Endocrine reviews,
04/2020, Volume:
41, Issue:
2
Journal Article
Peer reviewed
Open access
Abstract
Synthetic progestogens (progestins) have been linked to increased breast cancer risk; however, the role of endogenous progesterone in breast physiology and carcinogenesis is less clearly ...defined. Mechanistic studies using cell culture, tissue culture, and preclinical models implicate progesterone in breast carcinogenesis. In contrast, limited epidemiologic data generally do not show an association of circulating progesterone levels with risk, and it is unclear whether this reflects methodologic limitations or a truly null relationship. Challenges related to defining the role of progesterone in breast physiology and neoplasia include: complex interactions with estrogens and other hormones (eg, androgens, prolactin, etc.), accounting for timing of blood collections for hormone measurements among cycling women, and limitations of assays to measure progesterone metabolites in blood and progesterone receptor isotypes (PRs) in tissues. Separating the individual effects of estrogens and progesterone is further complicated by the partial dependence of PR transcription on estrogen receptor (ER)α-mediated transcriptional events; indeed, interpreting the integrated interaction of the hormones may be more essential than isolating independent effects. Further, many of the actions of both estrogens and progesterone, particularly in “normal” breast tissues, are driven by paracrine mechanisms in which ligand binding to receptor-positive cells evokes secretion of factors that influence cell division of neighboring receptor-negative cells. Accordingly, blood and tissue levels may differ, and the latter are challenging to measure. Given conflicting data related to the potential role of progesterone in breast cancer etiology and interest in blocking progesterone action to prevent or treat breast cancer, we provide a review of the evidence that links progesterone to breast cancer risk and suggest future directions for filling current gaps in our knowledge.
Graphical Abstract
Graphical Abstract
Ovarian cancer statistics, 2018 Torre, Lindsey A.; Trabert, Britton; DeSantis, Carol E. ...
CA: a cancer journal for clinicians,
July/August 2018, Volume:
68, Issue:
4
Journal Article
Purpose
The link between lipid-stabilizing medications and epithelial ovarian carcinogenesis is incompletely understood. Statins may reduce ovarian cancer risk, but results are inconclusive.
Methods
...We conducted a systematic review and meta-analysis of studies reporting associations between statin use and ovarian cancer risk in PubMed. Summary risk ratios (RRs) and confidence intervals (CIs) were calculated. Subgroup analyses by cancer histotype, statin class (lipo- or hydrophilic) and duration of statin use were conducted. Use of individual statins in populations was assessed to determine population-specific differences in statin types.
Results
Nine studies with 435,237 total women were included (1 randomized controlled trial (RCT); 4 prospective; 4 case–control). Statin use was associated with a reduced risk of ovarian cancer (RR 0.87, 95% CI 0.74–1.03) and risk was significantly reduced in populations with low pravastatin use (RR 0.83, 95% CI 0.70–0.99). Risk estimates varied by statin class (3 studies; lipophilic: RR 0.88, 95% CI 0.69–1.12; hydrophilic: RR 1.06, 95% CI 0.72–1.57) and cancer histotype (3 studies; serous: RR 0.95, 95% CI 0.69–1.30; clear cell: RR 1.17, 95% CI 0.74–1.86). Long-term use was associated with a reduced risk of ovarian cancer (RR 0.77, 95% CI 0.54–1.10) that further reduced when pravastatin use was low (RR 0.68, 95% CI 0.46–1.01). Between-study heterogeneity was high overall and in subgroups (
I
2
> 60%).
Conclusion
Statins may be associated with a reduced risk of ovarian cancer, but the effect likely differs by individual statin, duration of use and cancer histotype. Additional well-powered studies are needed to elucidate important subgroup effects.
Incorporating the ROCA into ovarian cancer screening has been shown to double the number of screen-detected ovarian cancers compared with single-threshold rules.5 In the UKCTOCS, 202 638 ...postmenopausal women aged 50–74 years were randomly assigned in a 1:1:2 ratio to receive either annual multimodal screening (MMS), which included CA125 testing with the ROCA followed by repeat CA125 and TVS as a second line test, TVS alone (ultrasound screening USS), or no screening.6 Consistent with PLCO, results published after a median of 11·1 years of follow-up reported no significant mortality reduction in either screening group (MMS 15% reduction 95% CI –3 to 30 and USS 11% reduction –7 to 27).6 However, the difference in mortality between the screened and unscreened groups appeared to widen with time, and the authors postulated that a delayed mortality benefit might emerge with additional follow-up. There was a shift in the distribution of disease stage at diagnosis with MMS; women in the MMS group had a 24·5% lower incidence of stage IV ovarian cancers and a 47·2% higher incidence of stage I ovarian cancers than women randomly assigned to no screening, but this difference was accompanied by a higher case fatality rate for stage I cancers (14·8% in the MMS group vs 9·4% in the no screening group). ...although some ovarian cancers might have been detected earlier with MMS, the earlier diagnosis was not enough to alter the prognosis of these cancers and did not translate into lives saved. ...alternative approaches to screening that target women at higher risk as opposed to the general population might prove more effective at reducing ovarian cancer deaths and could lessen the harm from false positive screens, as has been exemplified by lung cancer screening.8 Consequently, screening for ovarian cancer remains elusive but is not a lost cause; there is simply much more work to be done.
To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task MET hours/week) are associated with lower cancer risk, describe the shape of the ...dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity.
Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend (
< .05) and 95% CIs (< 1.0).
A total of 755,459 participants (median age, 62 years range, 32-91 years; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types.
Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.
Purpose
Since the 1960s, increasing oral contraceptive (OC) use has mirrored decreasing ovarian cancer incidence. The impact of intrauterine devices (IUDs) on cancer risk is less well established. ...With improved access and increased options, we must consider how changing usage can affect cancer risks.
Methods
Nationally representative data from the National Health and Nutrition Examination Survey (NHANES, 1999–2016) and the National Survey for Family Growth (NSFG, 2006–2017) were used to evaluate contraceptive use over time in premenopausal women (NHANES
n
= 13,179; NSFG
n
= 26,262). Trends were assessed overall and by race, age, pregnancy history, education, and body mass index.
Results
The average annual absolute increase in self-reported IUD use was 0.81% (NSFG), while OC use decreased 0.49% in NSFG and 0.47% in NHANES. This represents a significant decrease in OC use in NSFG annual percent change (APC) − 2.2% (95% CI − 3.4, − 1.0%),
p
< 0.01. Trends in OC use varied somewhat by pregnancy history in NHANES (
p-
interaction = 0.054). In contrast, IUD use increased 6.2% annually (1.4, 11.2%),
p
= 0.03 and varied significantly by pregnancy history (
p-
interaction < 0.01). Nulligravid women increased IUD use 11.0% annually (2.6, 20.1%),
p
= 0.02 compared to women with prior pregnancy at 5.2% (0.4, 10.2%),
p
= 0.04. In 2015–2017, IUD use was 76.5% hormonal (71.1, 81.8%) and 22.9% copper (17.4, 28.3%) with greater hormonal IUD use in obese women 89.4%, (82.9, 95.9%).
Conclusion
Increasing IUD use outpaced declining OC use in premenopausal US women. There may be a resulting decreased gynecologic cancer risk as more women gain access to potentially risk-reducing contraceptives.
Abstract
Background
Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer. The underlying mechanisms, however, remain elusive.
Methods
In a nested ...case–control study of 621 postmenopausal breast cancer case participants and 621 matched control participants, we measured 617 metabolites in prediagnostic serum. We calculated partial Pearson correlations between metabolites and BMI, and then evaluated BMI-associated metabolites (Bonferroni-corrected α level for 617 statistical tests = P < 8.10 × 10-5) in relation to invasive breast cancer. Odds ratios (ORs) of breast cancer comparing the 90th vs 10th percentile (modeled on a continuous basis) were estimated using conditional logistic regression while controlling for breast cancer risk factors, including BMI. Metabolites with the lowest P values (false discovery rate < 0.2) were mutually adjusted for one another to determine those independently associated with breast cancer risk.
Results
Of 67 BMI-associated metabolites, two were independently associated with invasive breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR = 1.65, 95% confidence interval CI = 1.22 to 2.22) and 3-methylglutarylcarnitine (OR = 1.67, 95% CI = 1.21 to 2.30). Four metabolites were independently associated with estrogen receptor–positive (ER+) breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR = 1.84, 95% CI = 1.27 to 2.67), 3-methylglutarylcarnitine (OR = 1.91, 95% CI = 1.23 to 2.96), allo-isoleucine (OR = 1.76, 95% CI = 1.23 to 2.51), and 2-methylbutyrylcarnitine (OR = 1.89, 95% CI = 1.22 to 2.91). In a model without metabolites, each 5 kg/m2 increase in BMI was associated with a 14% higher risk of breast cancer (OR = 1.14, 95% CI = 1.01 to 1.28), but adding 16a-hydroxy-DHEA-3-sulfate and 3-methylglutarylcarnitine weakened this association (OR = 1.06, 95% CI = 0.93 to 1.20), with the logOR attenuating by 57.6% (95% CI = 21.8% to 100.0+%).
Conclusion
These four metabolites may signal metabolic pathways that contribute to breast carcinogenesis and that underlie the association of BMI with increased postmenopausal breast cancer risk. These findings warrant further replication efforts.
Purpose
Daily aspirin use has been shown to reduce risk of colorectal, and possibly other, cancers, but it is unknown if these benefits are consistent across subgroups of people with differing cancer ...risk factors. We investigated whether age, body mass index (BMI), smoking status, physical inactivity, and family history of cancer modify the effect of daily aspirin use on colorectal, ovarian, breast, endometrial and aggressive prostate cancer risk.
Methods
We pooled 423,495 individuals from two prospective, U.S.-based studies: the NIH-AARP Diet and Health Study (1995–2011) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (1993–2009). Using Cox proportional hazards regression, we examined associations between daily aspirin use (≥ 5 days/week) and risk of colorectal, ovarian, breast, endometrial, and aggressive prostate cancer, overall and across strata of risk factors.
Results
Daily aspirin use was associated with a 15% reduction in colorectal cancer risk (hazard ratio HR: 0.85, 95% confidence interval CI 0.80–0.89). Risk reductions were generally consistent across strata of risk factors but attenuated with increasing BMI (
p
-interaction = 0.16). For ovarian cancer, there was no significant association overall (HR: 0.93, 95% CI 0.80–1.08) but reduced risk among obese women (HR: 0.73, 95% CI 0.52–0.98,
p
-interaction = 0.12). Weak or null associations were observed for breast, endometrial, and aggressive prostate cancer, with no strong effect modification observed.
Conclusions
Daily aspirin use appears to reduce colorectal cancer risk regardless of other risk factors, though the potential modifying effect of BMI warrants further investigation and may need to be considered in risk–benefit calculations for aspirin use.
Ovarian cancer is the eighth most common cancer in women worldwide and incidence rates vary markedly by world region. Our study provides a comprehensive overview of ovarian cancer incidence trends ...globally, examining the influence of birth cohort and period of diagnosis on changing risk. We presented current patterns and trends of ovarian cancer incidence until 2012 using data from successive volumes of Cancer Incidence in Five Contents. The incidence of ovarian cancer is highest in northern and eastern European countries and in northern America. Declining trends were observed in most countries with the exception of a few central and eastern Asian countries. Marked declines were seen in Europe and North America for women aged 50–74 where rates have declined up to 2.4% (95% CI: −3.9, −0.9) annually in Denmark (DNK) over the last decade. Additionally, declines in the incidence rate ratio (IRR) were observed for generations born after the 1930s, with an additional strong period effect seen around 2000 in United States and DNK. In contrast, IRRs increased among younger generations born after the 1950s in Japan and Belarus. Overall, the favorable trends in ovarian cancer incidence is likely due to the increase use of oral contraceptive pills, and changes in the prevalence of other reproductive risk and protective factors for ovarian cancer over the years studied. Changes in disease classifications and cancer registry practices may also partially contribute to the variation in ovarian cancer incidence rates. Thus, continuous cancer surveillance is essential to detect the shifting patterns of ovarian cancer.
What's new?
Ovarian cancer burden varies between countries, but an overall decline in incidence rates have been observed in many countries. Here the authors provide an overview of international ovarian cancer trends in 27 countries. They find marked declines in Europe and North America for women aged 50–74, but a marked increase for women born after 1950 in Japan and Belarus. They propose reasons for the divergent trends in different populations, particularly the use of oral contraceptives and changing registration practices.
A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease.
Levels ...of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models.
Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin IL-15, IL-1RA, IL-1β, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval CI = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1β, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking.
Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time.
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