Peter Donovan

Long-acting, progestin-based contraceptives and risk of breast, gynecological, and other cancers

Abstract Background Use of long-acting, reversible contraceptives has increased over the past 20 years, but an understanding of how they could influence cancer risk is limited. Methods We conducted a nested case-control study among a national cohort of Australian women (n = 176 601 diagnosed with cancer between 2004 and 2013; 882 999 matched control individuals) to investigate the associations between the levonorgestrel intrauterine system, etonogestrel implants, depot-medroxyprogesterone acetate and cancer risk and compared these results with the oral contraceptive pill. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). Results Levonorgestrel intrauterine system and etonogestrel implant use was associated with breast cancer risk (OR = 1.26, 95% CI = 1.21 to 1.31, and OR = 1.24, 95% CI = 1.17 to 1.32, respectively), but depot-medroxyprogesterone acetate was not, except when used for 5 or more years (OR = 1.23, 95% CI = 0.95 to 1.59). Reduced risks were seen for levonorgestrel intrauterine system (≥1 years of use) in endometrial cancer (OR = 0.80, 95% CI = 0.65 to 0.99), ovarian cancer (OR = 0.71, 95% CI = 0.57 to 0.88), and cervical cancer (OR = 0.62, 95% CI = 0.51 to 0.75); for etonogestrel implant in endometrial cancer (OR = 0.21, 95% CI = 0.13 to 0.34) and ovarian cancer (OR = 0.76, 95% CI = 0.57 to 1.02); and for depot-medroxyprogesterone acetate in endometrial cancer (OR = 0.21, 95% CI = 0.13 to 0.34). Although levonorgestrel intrauterine system, etonogestrel implant and depot-medroxyprogesterone acetate were all associated with increased cancer risk overall, for etonogestrel implant, the risk returned to baseline after cessation, similar to the oral contraceptive pill. We were unable to adjust for all potential confounders, but sensitivity analyses suggested that adjusting for parity, smoking, and obesity would not have materially changed our findings. Conclusion Long-acting, reversible contraceptives have similar cancer associations to the oral contraceptive pill (reduced endometrial and ovarian cancer risks and short-term increased breast cancer risk). This information may be helpful to women and their physicians when discussing contraception options.

Use of an emulated trial to investigate the association between use of nitrogen-based bisphosphonates and risk of epithelial ovarian cancer

Abstract Background Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users. Methods Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004–12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients. Results Of the 313 383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up. Conclusions Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.

Association between antihypertensive medicine use and risk of ovarian cancer in women aged 50 years and older

Epithelial ovarian cancer (EOC) has few modifiable risk factors. There is evidence that some antihypertensive medicines may have cancer preventive and/or therapeutic actions; therefore, we assessed the associations between use of different antihypertensive medicines and risk of specific EOC histotypes. Our nested case-control study of linked administrative health data included 6070 Australian women aged over 50 years diagnosed with EOC from 2004 to 2013, and 30,337 matched controls. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the association between ever use of each antihypertensive medicine group, including beta-adrenergic blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, diuretics, and alpha blockers, and the risk of EOC overall and separately for the serous, endometrioid, mucinous, clear cell and other histotypes. We found that most antihypertensive medicines were not associated with risk of EOC. However, women who used calcium channel blockers had a reduced risk of serous EOC (OR= 0.89, 95 % CI:0.81,0.98) and use of combination thiazide and potassium-sparing diuretics was associated with an increased risk of endometroid EOC (OR= 2.09, 95 % CI:1.15,3.82). Our results provide little support for a chemo-preventive role for most antihypertensives, however, the histotype-specific associations we found warrant further investigation.

Perioperative Beta-Blocker Supply and Survival in Women With Epithelial Ovarian Cancer and a History of Cardiovascular Conditions

PURPOSE Surgery for epithelial ovarian cancer (EOC) may activate stress-inflammatory responses that stimulate tumor growth and increase metastatic growth. Animal and in vitro studies have shown that inhibition of the catecholamine-induced inflammatory response via beta-adrenergic receptor blockade has antitumor potential in EOC. However, observational studies have reported mixed results. We assessed whether beta-blocker (BB) use at the time of primary ovarian cancer surgery was associated with improved survival in a large population-based study. MATERIALS AND METHODS Using linked administrative data, a population-based cohort of 3,844 Australian women age 50 years or older with a history of cardiovascular conditions who underwent surgery for EOC was followed for survival outcomes. The average treatment effect of selective BB (SBB) and nonselective BB (NSBB) supply at the time of surgery on survival was estimated from a causal inference perspective using covariate-balanced inverse probability of treatment weights with flexible parametric survival models that allowed for time-varying survival effects. RESULTS Around the time of surgery, 560 (14.5%) women were supplied a SBB and 67 (1.7%) were supplied a NSBB. At 2 years postsurgery, the survival proportion was 80% (95% CI, 68 to 88) for women dispensed NSBBs at surgery compared with 69% (95% CI, 67 to 70) for women not supplied NSBBs. The survival advantage appeared to extend to at least 8 years postsurgery. No association was observed for women dispensed a SBB around the time of surgery. CONCLUSION Perioperative supply of NSBBs appeared to confer a survival advantage for women age over 50 years with a history of cardiovascular conditions. Long-term clinical trials are required to confirm these findings.

Nitrogen-based Bisphosphonate Use and Ovarian Cancer Risk in Women Aged 50 Years and Older

Abstract Background There are few readily modifiable risk factors for epithelial ovarian cancer; preclinical studies suggest bisphosphonates could have chemopreventive actions. Our study aimed to assess the association between use of nitrogen-based bisphosphonate medicine and risk of epithelial ovarian cancer, overall and by histotype. Methods We conducted a case-control study nested within a large, linked administrative dataset including all Australian women enrolled for Medicare, Australia’s universal health insurance scheme, between July 2002 and December 2013. We included all women with epithelial ovarian cancer diagnosed at age 50 years and older between July 1, 2004, and December 31, 2013 (n = 9367) and randomly selected up to 5 controls per case, individually matched to cases by age, state of residence, area-level socioeconomic status, and remoteness of residence category (n = 46 830). We used prescription records to ascertain use of nitrogen-based bisphosphonates (ever use and duration of use), raloxifene, and other osteoporosis medicines (no nitrogen-based bisphosphonates, strontium and denosumab). We calculated adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression. Results Ever use of nitrogen-based bisphosphonates was associated with a reduced risk of epithelial ovarian cancer compared with no use (OR = 0.81, 95% CI = 0.75 to 0.88). There was a reduced risk of endometrioid (OR = 0.51, 95% CI = 0.33 to 0.79) and serous histotypes (OR = 0.84, 95% CI = 0.75 to 0.93) but no association with the mucinous or clear cell histotypes. Conclusion Use of nitrogen-based bisphosphonates was associated with a reduced risk of endometrioid and serous ovarian cancer. This suggests the potential for use for prevention, although validation of our findings is required.

Exploring estrogen-related mechanisms in ovarian carcinogenesis: association between bone mineral density and ovarian cancer risk in a multivariable Mendelian randomization study

Abstract Background Estrogen may play a role in epithelial ovarian cancer (EOC) carcinogenesis, with effects varying by EOC histotype. Measuring women’s long-term exposure to estrogen is difficult, but bone mineral density (BMD) may be a reasonable proxy of longer-term exposure. We examined this relationship by assessing the association between genetic predisposition for higher BMD and risk of EOC by histotype. Methods We used Mendelian randomization (MR) to assess associations between genetic markers for femoral neck and lumbar spine BMD and each EOC histotype. We used multivariable MR (MVMR) to adjust for probable pleiotropic traits, including body mass index, height, menarcheal age, menopausal age, smoking, alcohol intake, and vitamin D. Results Univariable analyses suggested greater BMD was associated with increased risk of endometrioid EOC (per standard deviation increase; lumbar spine OR = 1.21; 95% CI 0.93,1.57, femoral neck: OR = 1.25; 0.99,1.57), but sensitivity analyses indicated that pleiotropy was likely. Adjustment using MVMR reduced the magnitude of estimates slightly (lumbar spine: OR = 1.13; 95% CI 1.00,1.28, femoral neck: OR = 1.18; 1.03,1.36). Results for lumbar spine BMD and high-grade serous EOC were also suggestive of an association (univariable MR: OR = 1.16; 95% CI 1.03,1.30; MVMR: OR = 1.06; 0.99,1.14). Conclusion Our study found associations between genetic predisposition to higher BMD, a proxy for long-term estrogen exposure, and risk of developing endometroid and high-grade serous EOC cancers. These findings add to existing evidence of the relationship between estrogen and increased risk of EOC for certain histotypes.