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Background: To evaluate the use of stereotactic body radiation therapy (SBRT) for spine metastases and the associated factors in Australia. Methods: The Victorian Radiotherapy Minimum Dataset, which captures all episodes of radiotherapy delivered in the state of Victoria, was accessed to evaluate the patterns and trends of SBRT for spine metastases. The primary outcome was SBRT use and associated factors. Results: There were 6244 patients who received 8861 courses of radiotherapy for spine metastases between 2012 and 2017. Of these, 277 (3%) courses were SBRT, which increased from 0.4% in 2012 to 5% in 2017 (P-trend < 0.001). There was a higher proportion of SBRT use in patients with prostate cancer (6%) and melanoma (4%) compared to other cancers (2–3%) (p < 0.001). Patients from the highest socioeconomic quintiles (5%) were more likely to be treated with SBRT compared to patients from the lowest socioeconomic quintiles (3%) (p < 0.001). There was a higher proportion of SBRT use in private radiotherapy centres (6%) compared to public radiotherapy centres (1%) (p < 0.001). No spine SBRT was delivered in regional centres. In multivariate analyses, the year of treatment, age, primary cancers and radiotherapy centres were independently associated with SBRT use. Conclusion: This is the first Australian population-based study quantifying the increasing use of spine SBRT; however, the overall use of spine SBRT remains low. We anticipate an ongoing increase in spine SBRT, as spine SBRT gradually becomes the standard-of-care treatment for painful spine metastases. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the patterns of use of different radiation therapy (RT) fractionation for multiple myeloma (MM) bone disease. Methods: This is a population‐based cohort of patients with MM who had RT between 2012 and 2017 as captured in the statewide Victorian Radiotherapy Minimum Data Set in Australia. Data linkage was performed to identify subsets of RT delivered within 3 months of death. RT fractionation was classified into four groups: single‐fraction (SFRT), 2–5, 6–10, and > 10 fractions. Changes in RT fractionation use over time were evaluated with the Cochran–Armitage test for trend. Factors associated with RT fractionation were evaluated using multivariate logistic regressions. Results: Nine hundred and sixty‐seven courses of RT were delivered in 623 patients. The proportion of SFRT, 2–5, 6–10 and > 10 fractions RT was 18%, 47%, 28%, and 7%, respectively. There was an increase in the use of 2–5 fractions, from 48% in 2012 to 60% in 2017 (p‐trend <.001), with corresponding decrease in the use of 6–10 fractions, from 26% in 2012 to 20% in 2017 (p‐trend =.003). Nine percent (40/430) of RT courses at private institutions were SFRT, compared to 25% (135/537) in public institutions (p <.001). In multivariate analyses, treatment in private institution was the strongest predictor of multifraction RT use. SFRT use was more common closer to the end of life–18%, 14%, and 33% of RT within 2–3, 1–2, < 1 month of death, respectively. Conclusion: There is increasing use of shorter course RT (2–5 fractions) for MM over time. SFRT use remains low, with large variation in practice. [ABSTRACT FROM AUTHOR]

Increased implementation of proven prevention strategies is required to combat rising breast cancer incidence. We assessed use of risk reducing medication (RRMed) by Australian women at elevated breast cancer risk. Only 2.4% had ever used RRMed. Higher breast cancer risk was statistically significantly associated with use of RRMed (OR 1.82, 95%CI: 1.08–3.07, p = 0.02 for ≥30% lifetime risk compared with 16%–29% lifetime risk), but parity, education level and family history of breast cancer were not. Breast cancer prevention medications are underutilised. Efforts are needed to incorporate breast cancer risk assessment and risk management discussions into routine health assessments for women. • Risk-reducing medication is infrequently used by Australian women at increased risk of breast cancer. • Higher breast cancer risk is associated with greater uptake of risk reducing medication, but not with adherence. • Routine breast cancer risk assessment may increase risk reducing medication use. [ABSTRACT FROM AUTHOR]

Background: Self-reported physical activity is inaccurate, yet few investigators attempt to adjust for measurement error when estimating risks for health outcomes. We estimated what the association between self-reported physical activity and colorectal cancer risk would be if physical activity had been assessed using accelerometry instead.Methods: We conducted a validation study in which 235 Australian adults completed a telephone-administered International Physical Activity Questionnaire (IPAQ), and wore an accelerometer (Actigraph GT3X+) for 7 days. Using accelerometer-assessed physical activity as the criterion measure, we calculated validity coefficients and attenuation factors using a structural equation model adjusted for age, sex, education and body mass index. We then used a regression calibration approach to apply the attenuation factors to data from the Melbourne Collaborative Cohort Study (MCCS) to compute bias-adjusted hazard ratios (HR) and 95% confidence intervals (CI).Results: Average daily minutes of physical activity from the short form of the International Physical Activity Questionnaire (IPAQ-short) were substantially higher than accelerometer-measured duration (55 versus 32 min). The validity coefficient (0.32; 95% CI: 0.20, 0.43) and attenuation factor (0.20; 95% CI: 0.12, 0.28) were low. The HRs for colorectal cancer risk for high (75th percentile; 411 min/week) versus low (25th percentile; 62 min/week) levels of self-reported physical activity were 0.95 (95% CI: 0.87, 1.05) before and 0.78 (95% CI: 0.47, 1.28) after bias adjustment.Conclusions: Over-estimation of physical activity by the IPAQ-short substantially attenuates the association between physical activity and colorectal cancer risk, suggesting that the protective effect of physical activity has been previously underestimated. [ABSTRACT FROM AUTHOR]

Background and Aims: In Australia, as in many countries, alcohol consumption increased dramatically during the second half of the 20th century, with increased availability of alcohol, relaxation of attitudes towards drinking and shifting roles and opportunities for women as facilitating factors. We sought to investigate drinking trends by gender and birth cohort in Australia during this period. Design Retrospective cohort study. Setting, Participants and Measurements: Using the usual frequency and quantity of beverage‐specific alcohol intake for 10‐year periods from age 20, reported retrospectively from 40 789 participants aged 40–69 years (born 1920–49) at recruitment to the Melbourne Collaborative Cohort Study in 1990–94, we compared trends in alcohol consumption by sex in Australia between 1950 and 1990. Participants' average daily consumption for age decades were transformed to estimated intakes for 1950, 1960, 1970, 1980 and 1990. Findings Alcohol consumption was higher for men than women during each decade. Alcohol consumption increased for both sexes in the 1950s, 1960s and 1970s, and fell after 1980. The rise before 1980 was roughly equal in absolute terms for both sexes, but much greater relative to 1950 for women. Women born during 1930–39 and 1940–49 drank more alcohol during early–middle adulthood (ages 20–40) than women born during 1920–29. In the 1980s, the fall was greater in absolute terms for men, but roughly equal relative to 1950 for both sexes. In both sexes, the decline in drinking in the 1980s for birth‐decade cohorts was roughly in parallel. Conclusions: Specific birth cohorts were influential in the rise in alcohol consumption by Australian women born in 1920–49 after World War II. Much of the convergence with men's drinking after 1980 reflects large reductions in drinking among men. [ABSTRACT FROM AUTHOR]

Introduction: The International Cancer Benchmarking Partnership (ICBP) identified significant international differences in lung cancer survival. Differing levels of comorbid disease across ICBP countries has been suggested as a potential explanation of this variation but, to date, no studies have quantified its impact. This study investigated whether comparable, robust comorbidity scores can be derived from the different routine population-based cancer data sets available in the ICBP jurisdictions and, if so, use them to quantify international variation in comorbidity and determine its influence on outcome.Methods: Linked population-based lung cancer registry and hospital discharge data sets were acquired from nine ICBP jurisdictions in Australia, Canada, Norway and the UK providing a study population of 233 981 individuals. For each person in this cohort Charlson, Elixhauser and inpatient bed day Comorbidity Scores were derived relating to the 4-36 months prior to their lung cancer diagnosis. The scores were then compared to assess their validity and feasibility of use in international survival comparisons.Results: It was feasible to generate the three comorbidity scores for each jurisdiction, which were found to have good content, face and concurrent validity. Predictive validity was limited and there was evidence that the reliability was questionable.Conclusion: The results presented here indicate that interjurisdictional comparability of recorded comorbidity was limited due to probable differences in coding and hospital admission practices in each area. Before the contribution of comorbidity on international differences in cancer survival can be investigated an internationally harmonised comorbidity index is required. [ABSTRACT FROM AUTHOR]

Initially submitted February 1, 2016; accepted for publication August 4, 2016. The ability to classify people according to their underlying genetic susceptibility to a disease is increasing with new knowledge, better family data, and more sophisticated risk prediction models, allowing for more effective prevention and screening. To do so, however, we need to know whether risk associations are the same for people with different genetic susceptibilities. To illustrate one way to estimate such gene-environment interactions, we used prospective data from 3 Australian family cancer cohort studies, 2 enriched for familial risk of breast cancer. There were 288 incident breast cancers in 9,126 participants from 3,222 families. We used Cox proportional hazards models to investigate whether associations of breast cancer with body mass index (BMI; weight (kg)/height (m)2) at age 18-21 years, BMI at baseline, and change in BMI differed according to genetic risk based on lifetime breast cancer risk from birth, as estimated by BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) software, adjusted for age at baseline data collection. Although no interactions were statistically significant, we have demonstrated the power with which gene-environment interactions can be investigated using a cohort enriched for persons with increased genetic risk and a continuous measure of genetic risk based on family history. [ABSTRACT FROM AUTHOR]

Study Question: Do women with ITALIC! BRCA1 or ITALIC! BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration?Summary Answer: Women with a germline mutation in ITALIC! BRCA1 have reduced ovarian reserve as measured by AMH.What Is Known Already: The DNA repair enzymes encoded by ITALIC! BRCA1 and ITALIC! BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan.Study Design, Size, Duration: This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform.Participants/materials, Setting, Methods: Eligible women were from families segregating ITALIC! BRCA1 or ITALIC! BRCA2 mutations and had known mutation status. Participants were aged 25-45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying ITALIC! BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying ITALIC! BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking.Main Results and the Role Of Chance: Mean AMH concentration was negatively associated with age ( ITALIC! P < 0.001). Mutation carriers were younger at blood draw than non-carriers ( ITALIC! P ≤ 0.031). ITALIC! BRCA1 mutation carriers had, on average, 25% (95% CI: 5%-41%, ITALIC! P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11-303, ITALIC! P = 0.02). There was no evidence of an association between AMH concentration and ITALIC! BRCA2 mutation status ( ITALIC! P = 0.94).Limitations, Reasons For Caution: AMH does not directly measure the primordial follicle pool. The clinical implications of the lower AMH concentrations seen in ITALIC! BRCA1 mutation carriers cannot be assessed by this study design.Wider Implications Of the Findings: Women with a germline mutation in ITALIC! BRCA1 may have reduced ovarian reserve. This is consistent with other smaller studies in the literature and has potential implications for fertility and reproductive lifespan.Study Funding/competing Interests: kConFab is supported by a grant from the Australian National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. K.A.P. is an Australian National Breast Cancer Foundation Practitioner Fellow. J.L.H. is a NHMRC Senior Principal Research Fellow. M.H. is a NHMRC Practitioner Fellow. R.A.A. reports personal fees from Roche Diagnostics & Beckman Coulter outside the submitted work and C.S. reports other earnings from Melbourne IVF outside the submitted work. The remaining authors have nothing to declare and no conflicts of interest. [ABSTRACT FROM AUTHOR]

Adding to the limited literature on the subject, this letter to the editor focuses on the trend in the use of stereotactic radiation therapy for metastatic renal cell carcinoma. [ABSTRACT FROM AUTHOR]

The article presents a study to estimate the prevalence of the use of cancer risk-reducing measures among BRCA1 and BRCA2 mutation carriers in Australia. Results of the study suggest that there is potential scope to increase the uptake of cancer risk-reducing measures among Australian BRCA1 and BRCA2 mutation carriers. Findings encourage future study of the factors contributing to low uptake in the country and changes to policy and practice to reduce cancer incidence.

Background: A previous Australian population-based breast cancer case-control study found indirect evidence that control participation, although high, was not random. We hypothesized that unaffected sisters may provide a more appropriate comparison group than unrelated population controls.Methods: Three population-based case-control-family studies of breast cancer in women of white European origin were carried out by the Australian, Ontario and Northern California sites of the Breast Cancer Family Registry. We compared risk factors between 3643 cases, 2444 of their unaffected sisters and 2877 population controls and conducted separate case-control analyses based on population and sister controls using unconditional multivariable logistic regression.Results: Compared with sister controls, population controls were more highly educated, had an earlier age at menarche, fewer births, their first birth at a later age and their last birth more recently. The established breast cancer associations detected using sister controls, but not detected using population controls, were decreasing risk with each of later age at menarche, more births, younger age at first birth and greater time since last birth.Conclusions: Since participation of population controls might be unintentionally related to some risk factors, we hypothesize that sister controls could provide more valid relative risk estimates and be recruited at lower cost. Given declining study participation by population controls, this contention is highly relevant to epidemiologic research. [ABSTRACT FROM AUTHOR]

Background To improve melanoma early detection, tools to predict personal risk based on genetic information (polygenic risk scores, PRS) have been developed, but require external validation. Methods We analysed invasive melanoma incidence in UK Biobank (UKB; n = 395,647; 1,651 cases) and the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4,765; 303 cases). Three PRS were evaluated: 68 genetic variants (SNPs) at 54 loci from a 2020 meta-analysis (PRS68); 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50); 45 SNPs at 21 loci known pre-2020 (PRS45). 10-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment. Results All PRS were strongly associated with melanoma incidence, including after adjustment for age, sex, ethnicity, and ease of tanning. Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in UKB (ratio expected/observed cases E/O=0.65, 95% confidence interval 0.62-0.68) and MCCS (E/O=0.65, 0.57-0.73). For UKB, this was reduced by PRS-adjustment, e.g. PRS50-adjusted risks E/O=0.91 (0.87-0.95). Discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (deltaAUC 0.07-0.1, p < 0.0001), and higher than for PRS45-adjusted risks (deltaAUC 0.02-0.04, p < 0.001). Conclusions A PRS derived from a larger, more diverse meta-analysis improves melanoma risk prediction compared to an earlier PRS. Re-calibration of absolute risks may be necessary for application to specific populations. Key messages A genetic score can improve prediction of melanoma risk and might help tailor melanoma prevention and early detection strategies to different risk levels. [ABSTRACT FROM AUTHOR]

Simple Summary: It is well established that women who carry pathogenic CHEK2 variants have about a 3-fold increased risk of developing breast cancer. CHEK2 is now commonly included in genetic tests for breast cancer predisposition and increasingly used to inform the clinical management of women who are identified to carry pathogenic variants. Important information for counselling these women includes knowing how breast cancer risk, due to having a pathogenic variant in CHEK2, changes over a woman's lifetime. This information is currently not well established. By conducting a population-based case-control-family study of pathogenic CHEK2 variants we aimed to provide this information and estimated the penetrance (age-specific cumulative risk) of breast cancer to be 18% (95% CI 11–30%) to age 60 years and 33% (95% CI 21–48%) to age 80 years. These findings provide new and important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2. Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2. [ABSTRACT FROM AUTHOR]

Background: The use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced breast cancer risk, but it is not known if this association extends to women at familial or genetic risk. We examined the association between regular NSAID use and breast cancer risk using a large cohort of women selected for breast cancer family history, including 1054 BRCA1 or BRCA2 mutation carriers.Methods: We analyzed a prospective cohort (N = 5606) and a larger combined, retrospective and prospective, cohort (N = 8233) of women who were aged 18 to 79 years, enrolled before June 30, 2011, with follow-up questionnaire data on medication history. The prospective cohort was further restricted to women without breast cancer when medication history was asked by questionnaire. Women were recruited from seven study centers in the United States, Canada, and Australia. Associations were estimated using multivariable Cox proportional hazards regression models adjusted for demographics, lifestyle factors, family history, and other medication use. Women were classified as regular or non-regular users of aspirin, COX-2 inhibitors, ibuprofen and other NSAIDs, and acetaminophen (control) based on self-report at follow-up of ever using the medication for at least twice a week for ≥1 month prior to breast cancer diagnosis. The main outcome was incident invasive breast cancer, based on self- or relative-report (81% confirmed pathologically).Results: From fully adjusted analyses, regular aspirin use was associated with a 39% and 37% reduced risk of breast cancer in the prospective (HR = 0.61; 95% CI = 0.33-1.14) and combined cohorts (HR = 0.63; 95% CI = 0.57-0.71), respectively. Regular use of COX-2 inhibitors was associated with a 61% and 71% reduced risk of breast cancer (prospective HR = 0.39; 95% CI = 0.15-0.97; combined HR = 0.29; 95% CI = 0.23-0.38). Other NSAIDs and acetaminophen were not associated with breast cancer risk in either cohort. Associations were not modified by familial risk, and consistent patterns were found by BRCA1 and BRCA2 carrier status, estrogen receptor status, and attained age.Conclusion: Regular use of aspirin and COX-2 inhibitors might reduce breast cancer risk for women at familial or genetic risk. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the use of single-fraction palliative radiation therapy (SFRT) for the management of bone metastases (BM) in Victoria, Australia.Methods and Materials: This is a population-based cohort of patients with cancer who received radiation therapy for BM between 2012 and 2017 as captured in the Victorian Radiotherapy Minimum Data Set. The primary outcome was proportion of SFRT use. The Cochrane-Armitage test for trend was used to evaluate changes in practice over time. Multivariable logistic regression was used to assess factors associated with SFRT use.Results: Of the 18,158 courses of radiation therapy for BM delivered to a total of 10,956 patients, 17% were SFRT. There was no significant change in SFRT use over time, from 18% in 2012 to 19% in 2017 (P = .07). SFRT was less commonly given to the skull (4%) and spine (14%), compared with the shoulder (37%) and ribs (53%). Patients with lung cancer (21%) were most likely to receive SFRT, followed by those with prostate cancers (18%) and gastrointestinal cancers (16%). Patients from regional/remote areas were more likely to have SFRT compared with those in major cities (22% vs 16%, P < .001). Patients treated in public institutions were more likely to have SFRT compared with those treated in private institutions (22% vs 10%, P < .001). In multivariable analyses, increasing age, lung cancer, higher socioeconomic status, residence in regional/ remote areas, and being treated in public institutions were factors independently associated with increased likelihood of receiving SFRT.Conclusions: SFRT appears underused for BM in Australia over time, with variation in practice by patient, tumor, sociodemographic, geographical, and institutional provider factors. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the adoption of the Royal Australian and New Zealand College of Radiologists Choosing Wisely (CW) radiation oncology recommendations before and after the release of the recommendations.Methods and Materials: The Victorian Radiotherapy Minimum Data Set captures details of radiation therapy delivered in the state of Victoria, Australia. This study included the following 3 groups of patients relevant to 3 of the 5 CW recommendations: women who received a diagnosis of early-stage breast cancer at age ≥50 years who had breast radiation therapy (excluding nodal irradiation), patients with cancer who had palliative bone radiation therapy (excluding those with primary bone malignancies), and patients with cancer who had stereotactic radiation therapy to the brain (excluding those with primary malignancies of the central nervous system). The outcomes of interest were use of hypofractionated breast radiation therapy (<25 fractions), use of long-course palliative bone radiation therapy (>10 fractions), and use of adjuvant whole brain radiation therapy within 1 month of stereotactic radiation therapy. The Cochrane-Armitage test was used to evaluate changes in practice over time.Results: Among the 8204 patients who had breast radiation therapy, there was an increase in hypofractionation use from 42% in 2013 to 82% in 2017 (P < .001). The progressive increase in hypofractionation use was observed across institutions. Of the 15,634 courses of palliative bone radiation therapy delivered, only 1279 (8%) were >10 fractions, and this decreased from 10% in 2013 to 5% in 2017 (P < .001). Of the 1049 patients who received stereotactic radiation therapy for brain metastases, only 2% had adjuvant whole brain radiation therapy, and this decreased from 4% in 2013 to 0.7% in 2017 (P = .02).Conclusions: There was a significant change in radiation oncology practice in Australia between 2013 and 2017, in line with the CW recommendations. However, some of the recommendations need to be revised to reflect the rapidly evolving evidence in radiation oncology. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on abortion as a risk factor for Australian women with breast cancer.

Study Design: A retrospective cohort study.Objective: The aim of this study was to determine the fusion rate using recombinant human bone morphogenetic protein (rhBMP) in spinal surgery and to estimate the risk of cancer subsequent to their use.Summary Of Background Data: rhBMP may obviate the need for iliac crest bone graft harvest and provides similar or higher fusion rates than autologous bone graft. Recently, there are concerns that rhBMPs may either cause cancer or accelerate progression.Methods: Patients were treated by 2 spine surgeons between 2002 and 2012. Inclusion criteria were patients who resided in the state of Victoria, Australia, undergoing lumbar fusion (anterior, lateral, posterior, and posterolateral) with rhBMP [either rhBMP-2 (Infuse) or rhBMP-7 (OP-1)]. Exclusion criteria were patients who reported having an invasive cancer diagnosis before the spinal fusion procedure. The occurrence of incident cancers was obtained from record linkage to the Victorian Cancer Registry.Results: A total of 527 patients were included in the cohort, with a mean follow-up of 4.4 years (1.8-11.5). Patients received Infuse in 77% of cases and OP-1 in 23%. The mean Infuse does was 10.2  mg (2.5-48.0) and 3.3  mg (1.7-6.6) for OP-1. There was no significant difference in fusion rates between Infuse (90.1%) and OP-1 (91.9%) (P = 0.42). The overall success of interbody fusion with rhBMP was 93.5% at 12 months. Twenty-seven patients were diagnosed with an invasive cancer since treatment (20 Infuse and 7 OP-1 patients). Comparing the observed numbers in our study cohort with those expected on the basis of the Victorian population's age and sex-specific rates, we observed that the study cohort was not at a significantly increased risk of cancer. The standardized incidence ratio for cancer overall (of any type) was 0.84 [95% confidence interval (95% CI) 0.56-1.21].Conclusion: Off-label use of rhBMP provided high fusion rates with no evidence of a significantly increased risk of cancer.Level Of Evidence: 4. [ABSTRACT FROM AUTHOR]

Self-rated health (SRH) is a subjective indicator of overall health based on a single questionnaire item. Previous evidence found that it is a strong predictor of mortality, although the underlying mechanism is poorly understood. Epigenetic age is an objective, emerging biomarker of health, estimated using DNA methylation data at hundreds of sites across the genome. This study aimed to assess the overlap and interaction between SRH and epigenetic ageing in predicting mortality risk. We used DNA methylation data from 1059 participants in the Melbourne Collaborative Cohort Study (mean age: 69 years) to calculate three age-adjusted measures of epigenetic ageing: GrimAge, PhenoAge, and DunedinPACE. SRH was assessed using a five-category questionnaire item ("excellent, very good, good, fair, poor"). Cox models were used to assess the associations of SRH, epigenetic ageing, and their interaction, with all-cause mortality over up to 17 years of follow-up (N deaths  = 345). The association of SRH with mortality per category increase was HR = 1.29; 95%CI: 1.14-1.46. The association was slightly attenuated after adjusting for all three epigenetic ageing measures (HR = 1.25, 95%CI: 1.10-1.41). A strong gradient was observed in the association of GrimAge (P interaction  = 0.006) and DunedinPACE (P interaction  = 0.002) with mortality across worsening SRH strata. For example, the association between DunedinPACE and mortality in participants with "excellent" SRH was HR = 1.02, 95%CI: 0.73-1.43 and for "fair/poor" HR = 1.72, 95%CI: 1.35-2.20. SRH and epigenetic ageing were synergistic risk factors of mortality in our study. These findings suggest that consideration of subjective and objective factors may improve general health assessment, which has implications for the ongoing development of molecular markers of ageing., (© 2024. The Author(s).)

Objectives: It was previously estimated that 1814 (1.6 % of incident cancers) were attributable to physical inactivity in Australia in 2010, when only three sites were considered. We estimated the burden of cancer due to physical inactivity in Australia for 13 sites., Design: The population attributable fraction estimated site-specific cancer cases attributable to physical inactivity for 13 cancers. The potential impact fraction was used to estimate cancers that could have been prevented in 2015 if Australian adults had increased their physical activity by a modest amount in 2004-05., Methods: We used 2004-05 national physical activity prevalence data, 2015 national cancer incidence data, and contemporary relative-risk estimates for physical inactivity and cancer. We assumed a 10-year latency period., Results: An estimated 6361 of the cancers observed in 2015 were attributable to physical inactivity, representing 4.8 % of all cancers diagnosed. If Australian adults had increased their physical activity by one category in 2004-05, 2564 cases (1.9 % of all cancers) could have been prevented in 2015., Conclusions: More than three times as many cancers are attributable to physical inactivity than previously reported. Physical activity promotion should be a central component of cancer prevention programmes in Australia., Competing Interests: Declaration of interest statement None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Glioma accounts for approximately 80% of malignant adult brain cancer and its most common subtype, glioblastoma, has one of the lowest 5-year cancer survivals. Fifty risk-associated variants within 34 glioma genetic risk regions have been found by genome-wide association studies (GWAS) with a sex difference reported for 8q24.21 region. We conducted an Australian GWAS by glioma subtype and sex., Methods: We analyzed genome-wide data from the Australian Genomics and Clinical Outcomes of Glioma (AGOG) consortium for 7 573 692 single nucleotide polymorphisms (SNPs) for 560 glioma cases and 2237 controls of European ancestry. Cases were classified as glioblastoma, non-glioblastoma, astrocytoma or oligodendroglioma. Logistic regression analysis was used to assess the associations of SNPs with glioma risk by subtype and by sex., Results: We replicated the previously reported glioma risk associations in the regions of 2q33.3 C2orf80, 2q37.3 D2HGDH, 5p15.33 TERT, 7p11.2 EGFR, 8q24.21 CCDC26, 9p21.3 CDKN2BAS, 11q21 MAML2, 11q23.3 PHLDB1, 15q24.2 ETFA, 16p13.3 RHBDF1, 16p13.3 LMF1, 17p13.1 TP53, 20q13.33 RTEL, and 20q13.33 GMEB2 (P < .05). We also replicated the previously reported sex difference at 8q24.21 CCDC26 (P = .0024) with the association being nominally significant for both sexes (P < .05)., Conclusions: Our study supports a stronger female risk association for the region 8q24.21 CCDC26 and highlights the importance of analyzing glioma GWAS by sex. A better understanding of sex differences could provide biological insight into the cause of glioma with implications for prevention, risk prediction and treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: While remaining incurable, median overall survival for MM now exceeds 5 years. Yet few studies have investigated how modifiable lifestyle factors influence survival. We investigate whether adiposity, diet, alcohol, or smoking are associated with MM-related fatality., Research Design and Methods: We recruited 760 incident cases of MM via cancer registries in two Australian states during 2010-2016. Participants returned questionnaires on health and lifestyle. Follow-up ended in 2020. Flexible parametric survival models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for lifestyle exposures and risk of all-cause and MM-specific fatality., Results: Higher pre-diagnosis Alternative Healthy Eating Index (AHEI) scores were associated with reduced MM-specific fatality (per 10-unit score, HR = 0.84, 95%CI = 0.70-0.99). Pre-diagnosis alcohol consumption was inversely associated with MM-specific fatality, compared with nondrinkers (0.1-20 g per day, HR = 0.59, 95%CI = 0.39-0.90; >20 g per day, HR = 0.67, 95%CI = 0.40-1.13). Tobacco smoking was associated with increased all-cause fatality compared with never smoking (former smokers: HR = 1.44, 95%CI = 1.10-1.88; current smokers: HR = 1.30, 95%CI = 0.80-2.10). There was no association between pre-enrollment body mass index (BMI) and MM-specific or all-cause fatality., Conclusions: Our findings support established recommendations for healthy diets and against smoking. Higher quality diet, as measured by the AHEI, may improve survival post diagnosis with MM.

Aim: To evaluate the patterns of use of different radiation therapy (RT) fractionation for multiple myeloma (MM) bone disease., Methods: This is a population-based cohort of patients with MM who had RT between 2012 and 2017 as captured in the statewide Victorian Radiotherapy Minimum Data Set in Australia. Data linkage was performed to identify subsets of RT delivered within 3 months of death. RT fractionation was classified into four groups: single-fraction (SFRT), 2-5, 6-10, and > 10 fractions. Changes in RT fractionation use over time were evaluated with the Cochran-Armitage test for trend. Factors associated with RT fractionation were evaluated using multivariate logistic regressions., Results: Nine hundred and sixty-seven courses of RT were delivered in 623 patients. The proportion of SFRT, 2-5, 6-10 and > 10 fractions RT was 18%, 47%, 28%, and 7%, respectively. There was an increase in the use of 2-5 fractions, from 48% in 2012 to 60% in 2017 (p-trend < .001), with corresponding decrease in the use of 6-10 fractions, from 26% in 2012 to 20% in 2017 (p-trend = .003). Nine percent (40/430) of RT courses at private institutions were SFRT, compared to 25% (135/537) in public institutions (p < .001). In multivariate analyses, treatment in private institution was the strongest predictor of multifraction RT use. SFRT use was more common closer to the end of life-18%, 14%, and 33% of RT within 2-3, 1-2, < 1 month of death, respectively., Conclusion: There is increasing use of shorter course RT (2-5 fractions) for MM over time. SFRT use remains low, with large variation in practice., (© 2022 The Authors. Asia-Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Background: Previous studies suggest that polygenic risk scores (PRSs) may improve melanoma risk stratification. However, there has been limited independent validation of PRS-based risk prediction, particularly assessment of calibration (comparing predicted to observed risks)., Objectives: To evaluate PRS-based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry., Methods: We analysed invasive melanoma incidence in the UK Biobank (UKB; n = 395 647, 1651 cases) and a case-cohort nested within the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4765, 303 cases). Three PRSs were evaluated: 68 single-nucleotide polymorphisms (SNPs) at 54 loci from a 2020 meta-analysis (PRS68), 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50) and 45 SNPs at 21 loci known in 2018 (PRS45). Ten-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment., Results: Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in the UKB [ratio of expected/observed cases: E/O = 0·65, 95% confidence interval (CI) 0·62-0·68] and MCCS (E/O = 0·63, 95% CI 0·56-0·72). For UKB, calibration was improved by PRS adjustment, with PRS50-adjusted risks E/O = 0·91, 95% CI 0·87-0·95. The discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (Δ area under the curve 0·07-0·10, P < 0·0001), and higher than for PRS45-adjusted risks (Δ area under the curve 0·02-0·04, P < 0·001)., Conclusions: A PRS derived from a larger, more diverse meta-analysis improves risk prediction compared with an earlier PRS, and might help tailor melanoma prevention and early detection strategies to different risk levels. Recalibration of absolute risks may be necessary for application to specific populations., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Introduction: To evaluate the pattern of use of single-fraction conformal radiation therapy (SF-RT) and advanced radiation therapy techniques (ART), including stereotactic body radiation therapy (SBRT), for management of bone metastases (BM) in a population-based cohort of Australian men with prostate cancer (PCa) PATIENT AND METHODS: We reviewed men with metastatic PCa who received RT for BM between 2012 and 2017 as captured in the statewide Victorian Radiotherapy Minimum Data Set (VRMDS). The primary outcomes were: proportion of RT courses using SF-RT and ART. The Cochrane-Armitage test for trend was used to evaluate the changing pattern of SF-RT and ART over time. Multivariate analyses were used to identify factors associated with the primary outcomes RESULTS: Of the 4,324 courses of palliative RT for BM, 767 (17.7%) were SF-RT, and 615 (14.2%) were ART. There was no evidence of change in SF-RT use over time (P-trend=0.13). In multivariate analyses, increasing age at RT, site of BM (rib, shoulder, pelvis, and extremities), patients' area of residence (regional and remote), and treatment in public and metropolitan centres were associated with increased likelihood of SF-RT use. There was marked increase in ART use from 0.2% in 2012 to 24% in 2017 (11% intensity modulated RT, 13% SBRT) (P-trend<0.001). In multivariate analyses, younger age at RT, site of BM (rib and pelvis), higher socioeconomic status, and treatment in private and metropolitan centres were associated with increased likelihood of ART use., Conclusion: SF-RT continues to be a clear minority of RT schedules employed in management of BM in PCa, and the adoption of SF-RT use should be encouraged in men with limited prognosis. There has been increasing use of ART, especially SBRT, for BM in PCa over time, and we expect this will continue to increase in the era of metastatic-directed treatment for PCa., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To ascertain which of the Alternative Healthy Eating Index (AHEI) 2010, Dietary Inflammatory Index (DII®) and Mediterranean Diet Score (MDS) best predicted BMI and waist-to-hip circumference ratio (WHR)., Design: Body size was measured at baseline (1990-1994) and in 2003-2007. Diet was assessed at baseline using a FFQ, along with age, sex, socio-economic status, smoking, alcohol drinking, physical activity and country of birth. Regression coefficients and 95 % CI for the association of baseline dietary scores with follow-up BMI and WHR were generated using multivariable linear regression, adjusting for baseline body size, confounders and energy intake., Setting: Population-based cohort in Melbourne, Australia., Participants: Included were data from 11 030 men and 16 774 women aged 40-69 years at baseline., Results: Median (IQR) follow-up was 11·6 (10·7-12·8) years. BMI and WHR at follow-up were associated with baseline DII® (Q5 v. Q1 (BMI 0·41, 95 % CI 0·21, 0·61) and WHR 0·009, 95 % CI 0·006, 0·013)) and AHEI (Q5 v. Q1 (BMI -0·51, 95 % CI -0·68, -0·35) and WHR -0·011, 95 % CI -0·013, -0·008)). WHR, but not BMI, at follow-up was associated with baseline MDS (Group 3 most Mediterranean v. G1 (BMI -0·05, 95 % CI -0·23, 0·13) and WHR -0·004, 95 % CI -0·007, -0·001)). Based on Akaike's Information Criterion and Bayesian Information Criterion statistics, AHEI was a stronger predictor of body size than the other diet scores., Conclusions: Poor quality or pro-inflammatory diets predicted overall and central obesity. The AHEI may provide the best way to assess the obesogenic potential of diet.

Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (P homogeneity = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Conservative management, specifically with active surveillance (AS), has emerged as the preferred approach for low-risk prostate cancer (LRPC). We evaluated the trend for conservative management (ie, no active treatment within 12mo of diagnosis) for LRPC in an Australian population-based cohort of men captured in the Prostate Cancer Outcomes Registry Victoria (PCOR-Vic). Of the 3201 men diagnosed with LRPC between January 2009 and December 2016, 60% (1928/3201) had conservative management, and 52% (1664/3201) were documented to be on AS. There was an increase in conservative management from 52% in 2009 to 73% in 2016 (p<0.001), largely attributable to an increase in AS from 33% in 2009 to 67% in 2016 (p<0.001). When stratified by age group, the increase in conservative management was more pronounced among younger patients: from 37% to 66% for men aged <60yr versus from 72% to 86% for men aged ≥70yr. In multivariable analyses, increasing age, lower prostate-specific antigen and clinical category, lower socioeconomic status, and being diagnosed in public metropolitan institutions were all independently associated with a greater likelihood of conservative management. Identification of sociodemographic and institutional variations in practice allows for targeted strategies to improve management for men with LRPC. PATIENT SUMMARY: We looked at the uptake of conservative management (no active treatment within 12 mo of diagnosis) over time in an Australian population-based cohort of men with low-risk prostate cancer. The proportion of men with low-risk prostate cancer managed conservatively increased from 52% in 2009 to 73% in 2016. The increase in the uptake of conservative management for low-risk prostate cancer in Australia is concordant with international guidelines and other international population-based studies., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Effective cardiovascular disease (CVD) prevention relies on timely identification and intervention for individuals at risk. Conventional formula-based techniques have been demonstrated to over- or under-predict the risk of CVD in the Australian population. This study assessed the ability of machine learning models to predict CVD mortality risk in the Australian population and compare performance with the well-established Framingham model. Data is drawn from three Australian cohort studies: the North West Adelaide Health Study (NWAHS), the Australian Diabetes, Obesity, and Lifestyle study, and the Melbourne Collaborative Cohort Study (MCCS). Four machine learning models for predicting 15-year CVD mortality risk were developed and compared to the 2008 Framingham model. Machine learning models performed significantly better compared to the Framingham model when applied to the three Australian cohorts. Machine learning based models improved prediction by 2.7% to 5.2% across three Australian cohorts. In an aggregated cohort, machine learning models improved prediction by up to 5.1% (area-under-curve (AUC) 0.852, 95% CI 0.837-0.867). Net reclassification improvement (NRI) was up to 26% with machine learning models. Machine learning based models also showed improved performance when stratified by sex and diabetes status. Results suggest a potential for improving CVD risk prediction in the Australian population using machine learning models.

Guidelines endorse the use of chemoprevention for breast cancer risk reduction. This study examined the barriers and facilitators to chemoprevention use for Australian women at increased risk of breast cancer, and their clinicians. Surveys, based on the Theoretical Domains Framework, were mailed to 1,113 women at ≥16% lifetime risk of breast cancer who were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer cohort study (kConFab), and their 524 treating clinicians. Seven hundred twenty-five women (65%) and 221 (42%) clinicians responded. Only 10 (1.4%) kConFab women had ever taken chemoprevention. Three hundred seventy-eight (52%) kConFab women, two (3%) breast surgeons, and 51 (35%) family physicians were not aware of chemoprevention. For women, the strongest barriers to chemoprevention were side effects (31%) and inadequate information (23%), which operate in the Theoretical Domains Framework domains of "beliefs about consequences" and "knowledge," respectively. Strongest facilitators related to tamoxifen's long-term efficacy (35%, "knowledge," "beliefs about consequences," and "goals" domains), staying healthy for family (13%, "social role" and "goals" domains), and abnormal breast biopsy (13%, "environmental context" domain). The strongest barrier for family physicians was insufficient knowledge (45%, "knowledge" domain) and for breast surgeons was medication side effects (40%, "beliefs about consequences" domain). The strongest facilitators for both clinician groups related to clear guidelines, strong family history, and better tools to select patients ("environmental context and resources" domain). Clinician knowledge and resources, and beliefs about the side-effect consequences of chemoprevention, are key domains that could be targeted to potentially enhance uptake. PREVENTION RELEVANCE: Despite its efficacy in reducing breast cancer incidence, chemoprevention is underutilised. This survey study of Australian women and their clinicians used behavioural change theory to identify modifiable barriers to chemoprevention uptake, and to suggest interventions such as policy change, educational resources and public campaigns, that may increase awareness and use. See related Spotlight by Vogel, p. 1 ., (©2020 American Association for Cancer Research.)

Background: This study examined why women and doctors screen for ovarian cancer (OC) contrary to guidelines., Methods: Surveys, based on the Theoretical Domains Framework, were sent to women in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer and family physicians and gynecologists who organized their screening., Results: Of 1264 Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer women, 832 (65.8%) responded. In the past 2 years, 126 (15.1%) had screened. Most of these (n = 101, 80.2%) would continue even if their doctor told them it is ineffective. For women, key OC screening motivators operated in the domains of social role and goals (staying healthy for family, 93.9%), emotion and reinforcement (peace of mind, 93.1%), and beliefs about capabilities (tests are easy to have, 91.9%). Of 531 clinicians 252 (47.5%) responded; a minority (family physicians 45.8%, gynecologists 16.7%) thought OC screening was useful. For gynecologists, the main motivators of OC screening operated in the domains of environmental context (lack of other screening options, 27.6%), and emotion (patient peace of mind, 17.2%; difficulty discontinuing screening, 13.8%). For family physicians,, the strongest motivators were in the domains of social influence (women ask for these tests, 20.7%), goals (a chance these tests will detect cancer early, 16.4%), emotion (patient peace of mind, 13.8%), and environmental context (no other OC screening options, 11.2%)., Conclusion: Reasons for OC screening are mostly patient driven. Clinician knowledge and practice are discordant. Motivators of OC screening encompass several domains, which could be targeted in interventions to reduce inappropriate OC screening., (© The Author(s) 2020. Published by Oxford University Press.)

Men with prostate cancer experience side effects for which a supportive social environment may be beneficial. We examined the association between four measures of social connectedness and mortality after a prostate cancer diagnosis. Male participants in the Melbourne Collaborative Cohort Study in 1990-1994, who developed incident prostate cancer and attended follow-up in 2003-2007, were eligible for the study. Information on social connectedness, collected at follow-up, included (i) living arrangement; (ii) frequency of visits to friends/relatives and (iii) from friends/relatives; (iv) weekly hours of social activities. A total of 1,421 prostate cancer cases was observed (338 all-cause deaths, 113 from prostate cancer), including 867 after follow-up (150 all-cause deaths, 55 from prostate cancer) and 554 before follow-up (188 all-cause deaths, 58 from prostate cancer). Cox models stratified by tumour Gleason score and stage, and sequentially adjusted for socioeconomic, health- and lifestyle-related confounders, were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between social connectedness and all-cause mortality after prostate cancer. Men who reported living alone before diagnosis had higher overall mortality (HR = 1.6, 95% CI: 1.0-2.5), after adjustment for socioeconomic, health and lifestyle confounders. Lower mortality was observed for men with more social activities (p-trend = 0.07), but not in comprehensively adjusted models. Consistent with these findings, men living alone after prostate cancer diagnosis had higher mortality (HR = 1.3, 95% CI: 0.9-1.9). Lower mortality was observed with increasing socializing hours in the age-adjusted model (p-trend = 0.06) but not after more comprehensive adjustment. Our findings suggest that living with someone, but not other aspects of social connectedness, may be associated with decreased mortality for men with prostate cancer., (© 2019 UICC.)

Interval breast cancers (those diagnosed between recommended mammography screens) generally have poorer outcomes and are more common among women with dense breasts. We aimed to develop a risk model for interval breast cancer. We conducted a nested case-control study within the Melbourne Collaborative Cohort Study involving 168 interval breast cancer patients and 498 matched control subjects. We measured breast density using the CUMULUS software. We recorded first-degree family history by questionnaire, measured body mass index (BMI) and calculated age-adjusted breast tissue aging, a novel measure of exposure to estrogen and progesterone based on the Pike model. We fitted conditional logistic regression to estimate odds ratio (OR) or odds ratio per adjusted standard deviation (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). The stronger risk associations were for unadjusted percent breast density (OPERA = 1.99; AUC = 0.66), more so after adjusting for age and BMI (OPERA = 2.26; AUC = 0.70), and for family history (OR = 2.70; AUC = 0.56). When the latter two factors and their multiplicative interactions with age-adjusted breast tissue aging (p = 0.01 and 0.02, respectively) were fitted, the AUC was 0.73 (95% CI 0.69-0.77), equivalent to a ninefold interquartile risk ratio. In summary, compared with using dense breasts alone, risk discrimination for interval breast cancers could be doubled by instead using breast density, BMI, family history and hormonal exposure. This would also give women with dense breasts, and their physicians, more information about the major consequence of having dense breasts-an increased risk of developing an interval breast cancer., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Funded by the European Commission Horizon 2020 programme, the Lifepath research consortium aimed to investigate the effects of socioeconomic inequalities on the biology of healthy aging. The main research questions included the impact of inequalities on health, the role of behavioral and other risk factors, the underlying biological mechanisms, the efficacy of selected policies, and the general implications of our findings for theories and policies. The project adopted a life-course and comparative approach, considering lifetime effects from childhood and adulthood, and pooled data on up to 1.7 million participants of longitudinal cohort studies from Europe, USA, and Australia. These data showed that socioeconomic circumstances predicted mortality and functional decline as strongly as established risk factors currently targeted by global prevention programmes. Analyses also looked at socioeconomically patterned biological markers, allostatic load, and DNA methylation using richly phenotyped cohorts, unraveling their association with aging processes across the life-course. Lifepath studies suggest that socioeconomic circumstances are embedded in our biology from the outset-i.e., disadvantage influences biological systems from molecules to organs. Our findings have important implications for policy, suggesting that (a) intervening on unfavorable socioeconomic conditions is complementary and as important as targeting well-known risk factors, such as tobacco and alcohol consumption, low fruit and vegetable intake, obesity and a sedentary lifestyle, and that (b) effects of preventive interventions in early life integrate interventions in adulthood. The report has an executive summary that refers to the different sections of the main paper., (Copyright © 2020 Vineis, Avendano-Pabon, Barros, Bartley, Carmeli, Carra, Chadeau-Hyam, Costa, Delpierre, D'Errico, Fraga, Giles, Goldberg, Kelly-Irving, Kivimaki, Lepage, Lang, Layte, MacGuire, Mackenbach, Marmot, McCrory, Milne, Muennig, Nusselder, Petrovic, Polidoro, Ricceri, Robinson, Stringhini and Zins.)

The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%-56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Our aim was to estimate how long-term mortality following breast cancer diagnosis depends on age at diagnosis, tumor estrogen receptor (ER) status, and the time already survived. We used the population-based Australian Breast Cancer Family Study which followed-up 1,196 women enrolled during 1992-1999 when aged <60 years at diagnosis with a first primary invasive breast cancer, over-sampled for younger ages at diagnosis, for whom tumor pathology features and ER status were measured. There were 375 deaths (median follow-up = 15.7; range = 0.8-21.4, years). We estimated the mortality hazard as a function of time since diagnosis using a flexible parametric survival analysis with ER status a time-dependent covariate. For women with ER-negative tumors compared with those with ER-positive tumors, 5-year mortality was initially higher (p < 0.001), similar if they survived to 5 years (p = 0.4), and lower if they survived to 10 years (p = 0.02). The estimated mortality hazard for ER-negative disease peaked at ~3 years post-diagnosis, thereafter declined with time, and at 7 years post-diagnosis became lower than that for ER-positive disease. This pattern was more pronounced for women diagnosed at younger ages. Mortality was also associated with lymph node count (hazard ratio (HR) per 10 nodes = 2.52 [95% CI:2.11-3.01]) and tumor grade (HR per grade = 1.62 [95% CI:1.34-1.96]). The risk of death following a breast cancer diagnosis differs substantially and qualitatively with diagnosis age, ER status and time survived. For women who survive >7 years, those with ER-negative disease will on average live longer, and more so if younger at diagnosis., (© 2019 UICC.)

DNA methylation-based biological age (DNAm age), as well as genome-wide average DNA methylation, have been reported to predict breast cancer risk. We aimed to investigate the associations between these DNA methylation-based risk factors and 18 conventional breast cancer risk factors for disease-free women. A sample of 479 individuals from the Australian Mammographic Density Twins and Sisters was used for discovery, a sample of 3354 individuals from the Melbourne Collaborative Cohort Study was used for replication, and meta-analyses pooling results from the two studies were conducted. DNAm age based on three epigenetic clocks (Hannum, Horvath and Levine) and genome-wide average DNA methylation were calculated using the HumanMethylation 450 K BeadChip assay data. The DNAm age measures were positively associated with body mass index (BMI), smoking, alcohol drinking and age at menarche (all nominal P < 0.05). Genome-wide average DNA methylation was negatively associated with smoking and number of live births, and positively associated with age at first live birth (all nominal P < 0.05). The association of DNAm age with BMI was also evident in within-twin-pair analyses that control for familial factors. This study suggests that some lifestyle and hormonal risk factors are associated with these DNA methylation-based breast cancer risk factors, and the observed associations are unlikely to be due to familial confounding but are likely causal. DNA methylation-based risk factors could interplay with conventional risk factors in modifying breast cancer risk.

Age- and body mass index (BMI)-adjusted mammographic density is one of the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie inter-individual variation in mammographic density. We aimed to investigate the association between breast cancer risk-predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, nondense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed-effect meta-analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome-wide significant (p < 10 -7 ) association for any mammographic density measure from the meta-analysis, or from the cohort-specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all p > 0.05/299 = 1.7 × 10 -4 ). In summary, our study did not find evidence for associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk., (© 2019 UICC.)

Introduction: Physical activity may affect health via DNA methylation. The epigenetic influences of sedentary behaviors such as television viewing are unknown. We performed a genomewide study of DNA methylation in peripheral blood in relation to physical activity and television viewing time., Methods: DNA methylation was measured using the Illumina Infinium HumanMethylation450K BeadChip array in blood samples collected at baseline (N = 5513) and follow-up (N = 1249) from participants in the Melbourne Collaborative Cohort Study. At baseline, times per week of leisure-time physical activity were self-reported. At follow-up, the International Physical Activity Questionnaire was used to assess MET-hours per week of total and leisure-time physical activity and hours per day of television viewing time. Linear mixed models were used to assess associations between physical activity and television viewing measures and DNA methylation at individual CpG sites, adjusted for potential confounders and batch effects., Results: At follow-up, total physical activity was associated with DNA methylation at cg10266336 (P = 6.0 × 10), annotated to the SAA2 gene. Weaker evidence of associations (P < 1.0 × 10) were observed for an additional 14 CpG sites with total physical activity, for 7 CpG sites with leisure-time physical activity, and for 9 CpG sites with television viewing time. Changes in leisure-time physical activity between baseline and follow-up were associated with methylation changes (P < 0.05) at four of the seven CpG sites with weaker evidence of cross-sectional associations with leisure-time physical activity., Conclusion: Physical activity and television viewing may be associated with blood DNA methylation, a potential pathway to chronic disease development. Further research using accelerometer data and larger sample sizes is warranted.

Background: Several studies have reported DNA methylation in blood to be associated with body mass index (BMI), but few have investigated causal aspects of the association. We used a twin family design to assess this association at two life points and applied a novel analytical approach to appraise the evidence for causality., Methods: The methylation profile of DNA from peripheral blood was measured for 479 Australian women from 130 twin families. Linear regression was used to estimate the associations of DNA methylation at ~410,000 cytosine-guanine dinucleotides (CpGs), and of the average DNA methylation at ~20,000 genes, with current BMI, BMI at age 18-21 years, and the change between the two (BMI change). A novel regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess causation., Results: At a 5% false discovery rate, nine, six and 12 CpGs at 24 loci were associated with current BMI, BMI at age 18-21 years and BMI change, respectively. The average DNA methylation of the BHLHE40 and SOCS3 loci was associated with current BMI, and of the PHGDH locus with BMI change. From the ICE FALCON analyses with BMI as the predictor and DNA methylation as the outcome, a woman's DNA methylation level was associated with her co-twin's BMI, and the association disappeared after conditioning on her own BMI, consistent with BMI causing DNA methylation. To the contrary, using DNA methylation as the predictor and BMI as the outcome, a woman's BMI was not associated with her co-twin's DNA methylation level, consistent with DNA methylation not causing BMI., Conclusion: For middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with current BMI, BMI at age 18-21 years and BMI change. Our study suggests that BMI has a causal effect on peripheral blood DNA methylation.

Dietary intakes of B vitamins and other components involved in one-carbon metabolism, which is necessary for DNA replication, DNA repair, and regulation of gene expression, may be associated with carcinogenesis. We investigated associations between intakes of 11 nutrients (thiamine, riboflavin, niacin, pantothenic acid, vitamin B6, biotin, folate, vitamin B12, methionine, choline, and betaine) and gastric cancer risk. A total of 159 incident gastric cancer cases were identified from the Melbourne Collaborative Cohort Study (N = 41,513) and matched with 159 controls on year of birth, sex, and country of birth using incidence density sampling. Dietary intakes of nutrients were estimated at baseline (1990-1994) using a 121-item food frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression models adjusting for Helicobacter pylori infection, and other potential confounders. We observed a positive association between intake of niacin and overall gastric cancer risk (OR = 1.33, 95%CI: 1.01-1.75 per SD increment). For thiamine, heterogeneity by subtype (cardia and non-cardia) was found (P het  = 0.05), with weak evidence of an inverse association with cardia cancer risk. Our results do not support increasing intakes of B vitamins or other nutrients involved in one-carbon metabolism to reduce gastric cancer risk in a well-nourished population.

Background: The association between body mass index (BMI) and risk of breast cancer depends on time of life, but it is unknown whether this association depends on a woman's familial risk., Methods: We conducted a prospective study of a cohort enriched for familial risk consisting of 16,035 women from 6701 families in the Breast Cancer Family Registry and the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer followed for up to 20 years (mean 10.5 years). There were 896 incident breast cancers (mean age at diagnosis 55.7 years). We used Cox regression to model BMI risk associations as a function of menopausal status, age, and underlying familial risk based on pedigree data using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), all measured at baseline., Results: The strength and direction of the BMI risk association depended on baseline menopausal status (P < 0.001); after adjusting for menopausal status, the association did not depend on age at baseline (P = 0.6). In terms of absolute risk, the negative association with BMI for premenopausal women has a much smaller influence than the positive association with BMI for postmenopausal women. Women at higher familial risk have a much larger difference in absolute risk depending on their BMI than women at lower familial risk., Conclusions: The greater a woman's familial risk, the greater the influence of BMI on her absolute postmenopausal breast cancer risk. Given that age-adjusted BMI is correlated across adulthood, maintaining a healthy weight throughout adult life is particularly important for women with a family history of breast cancer.

Background: Physical activity reduces the risk of colorectal cancer (CRC), but the relevant evidence derives primarily from self-reported recreational and occupational activity. Less is known about the contribution of other domains of physical activity, such as transport and household. We examined associations between domain-specific physical activities and CRC risk within the Melbourne Collaborative Cohort Study., Methods: Analyses included 23,586 participants who were free from invasive colorectal cancer and had completed the International Physical Activity Questionnaire-Long Form at follow-up 2 (2003-2007). Cox regression, with age as the time metric, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ordinal categories of each physical activity domain., Results: Adjusted HRs for the highest versus the lowest categories of physical activity were 0.71 (95% CI: 0.51-0.98; p trend  = 0.03) for recreational activity; 0.80 (95% CI: 0.49-1.28; p trend  = 0.38) for occupational activity; 0.90 (95% CI: 0.68-1.19; p trend  = 0.20) for transport activity; and 1.07 (95% CI: 0.82-1.40; p trend  = 0.46) for household activity., Conclusions: Recreational activity was associated with reduced CRC risk. A non-significant, inverse association was observed for occupational activity, whereas no association was found for transport or household domains.

Background: Folate and other one-carbon metabolism nutrients are essential to enable DNA methylation to occur, but the extent to which their dietary intake influences methylation in adulthood is unclear., Objective: We assessed associations between dietary intake of these nutrients and DNA methylation in peripheral blood, overall and at specific genomic locations., Design: We conducted a cross-sectional study using baseline data and samples from 5186 adult participants in the Melbourne Collaborative Cohort Study (MCCS). Nutrient intake was estimated from a food-frequency questionnaire. DNA methylation was measured by using the Illumina Infinium HumanMethylation450 BeadChip array (HM450K). We assessed associations of intakes of folate, riboflavin, vitamins B-6 and B-12, methionine, choline, and betaine with methylation at individual cytosine-guanine dinucleotides (CpGs), and with median (genome-wide) methylation across all CpGs, CpGs in gene bodies, and CpGs in gene promoters. We also assessed associations with methylation at long interspersed nuclear element 1 (LINE-1), satellite 2 (Sat2), and Arthrobacter luteus restriction endonuclease (Alu) repetitive elements for a subset of participants. We used linear mixed regression, adjusting for age, sex, country of birth, smoking, energy intake from food, alcohol intake, Mediterranean diet score, and batch effects to assess log-linear associations with dietary intake of each nutrient. In secondary analyses, we assessed associations with low or high intakes defined by extreme quintiles., Results: No evidence of log-linear association was observed at P < 10-7 between the intake of one-carbon metabolism nutrients and methylation at individual CpGs. Low intake of riboflavin was associated with higher methylation at CpG cg21230392 in the first exon of PROM1 (P = 5.0 × 10-8). No consistent evidence of association was observed with genome-wide or repetitive element measures of methylation., Conclusion: Our findings suggest that dietary intake of one-carbon metabolism nutrients in adulthood, as measured by a food-frequency questionnaire, has little association with blood DNA methylation. An association with low intake of riboflavin requires replication in independent cohorts. This study was registered at http://www.clinicaltrials.gov as NCT03227003.

Background: Management advice for women with lobular carcinoma in situ (LCIS) is hampered by the lack of accurate personalised risk estimates for subsequent invasive breast cancer (BC). Prospective validation of the only tool that estimates individual BC risk for a woman with LCIS, the International Breast Cancer Intervention Study Risk Evaluation Tool (IBIS-RET), is lacking., Methods: Using population-based cancer registry data for 732 women with LCIS, the calibration and discrimination accuracy of IBIS-RET Version 7.2 were assessed., Results: The mean observed 10-year risk of invasive BC was 14.1% (95% CI:11.3%-17.5%). IBIS-RET overestimated invasive BC risk (p = 0.0003) and demonstrated poor discriminatory accuracy (AUC 0.54, 95% CI: 0.48 - 0.62)., Conclusions: Clinicians should understand that IBIS-RET Version 7.2 may overestimate 10-year invasive BC risk for Australian women with LCIS. The newer IBIS-RET Version 8.0, released September 2017, includes mammographic density and may perform better, but validation is needed.

Objective: To test the hypothesis that more frequent consumption of sugar-sweetened soft drinks would be associated with increased risk of obesity-related cancers. Associations for artificially sweetened soft drinks were assessed for comparison., Design: Prospective cohort study with cancers identified by linkage to cancer registries. At baseline, participants completed a 121-item FFQ including separate questions about the number of times in the past year they had consumed sugar-sweetened or artificially sweetened soft drinks. Anthropometric measurements, including waist circumference, were taken and questions about smoking, leisure-time physical activity and intake of alcoholic beverages were completed., Setting: The Melbourne Collaborative Cohort Study (MCCS) is a prospective cohort study which recruited 41 514 men and women aged 40-69 years between 1990 and 1994. A second wave of data collection occurred in 2003-2007., Subjects: Data for 35 593 participants who developed 3283 incident obesity-related cancers were included in the main analysis., Results: Increasing frequency of consumption of both sugar-sweetened and artificially sweetened soft drinks was associated with greater waist circumference at baseline. For sugar-sweetened soft drinks, the hazard ratio (HR) for obesity-related cancers increased as frequency of consumption increased (HR for consumption >1/d v. 1/d v. <1/month=1·00; 95 % CI 0·79, 1·27; P-trend=0·61)., Conclusions: Our results add to the justification to minimise intake of sugar-sweetened soft drinks.

Purpose: To compare breast cancer prognosis in BRCA1 and BRCA2 mutation carriers with that in patients with sporadic disease., Patients and Methods: An international population-based cohort study was conducted in Canada, the United States, and Australia of 3,220 women with incident breast cancer diagnosed between 1995 and 2000 and observed prospectively. Ninety-three had BRCA1 mutations; 71, BRCA2 mutations; one, both mutations; 1,550, sporadic breast cancer; and 1,505, familial breast cancer (without known BRCA1 or BRCA2 mutation). Distant recurrence and death were analyzed., Results: Mean age at diagnosis was 45.3 years; mean follow-up was 7.9 years. Risks of distant recurrence and death did not differ significantly between BRCA1 mutation carriers and those with sporadic disease in univariable and multivariable analyses. Risk of distant recurrence was higher for BRCA2 mutation carriers compared with those with sporadic disease in univariable analysis (hazard ratio [HR], 1.63; 95% CI, 1.02 to 2.60; P = .04). Risk of death was also higher in BRCA2 carriers in univariable analysis (HR, 1.81; 95% CI, 1.15 to 2.86; P = .01). After adjustment for age, tumor stage and grade, nodal status, hormone receptors, and year of diagnosis, no differences were observed for distant recurrence (HR, 1.00; 95% CI, 0.62 to 1.61; P = 1.00) or death (HR, 1.12; 95% CI, 0.70 to 1.79; P = .64)., Conclusion: Outcomes of BRCA1 mutation carriers were similar to those of patients with sporadic breast cancer. Worse outcomes in BRCA2 mutation carriers in univariable analysis seem to reflect the presence of more adverse tumor characteristics in these carriers. Similar outcomes were identified in BRCA2 carriers and those with sporadic disease in multivariable analyses.

Few studies have considered the joint association of body mass index (BMI) and physical activity, two modifiable factors, with all-cause mortality after breast cancer diagnosis. Women diagnosed with invasive breast cancer (n = 4,153) between 1991 and 2000 were enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. During a median follow-up of 7.8 years, 725 deaths occurred. Baseline questionnaires assessed moderate and vigorous recreational physical activity and BMI prior to diagnosis. Associations with all-cause mortality were assessed using Cox proportional hazards regression, adjusting for established prognostic factors. Compared with no physical activity, any recreational activity during the 3 years prior to diagnosis was associated with a 34% lower risk of death [hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.51-0.85] for women with estrogen receptor (ER)-positive tumors, but not those with ER-negative tumors; this association did not appear to differ by race/ethnicity or BMI. Lifetime physical activity was not associated with all-cause mortality. BMI was positively associated with all-cause mortality for women diagnosed at age > or =50 years with ER-positive tumors (compared with normal-weight women, HR for overweight = 1.39, 95% CI: 0.90-2.15; HR for obese = 1.77, 95% CI: 1.11-2.82). BMI associations did not appear to differ by race/ethnicity. Our findings suggest that physical activity and BMI exert independent effects on overall mortality after breast cancer.

Objective: To estimate the association between measures of socio-economic status (SES) and breast cancer (BC) survival for young, urban Australian women., Methods: We used a population-based sample of 1,029 women followed prospectively for a median of 7.9 years. SES was defined by education and area of residence. Hazard ratios (HRs) associated with SES measures were estimated for (i) distant recurrence (DR) and (ii) all-cause mortality as end-points., Results: HRs for area of residence were not significantly different from unity, with or without adjustment for age at diagnosis and education level. The univariable HR estimate of DR for women with university education compared with women with incomplete high school education was 1.51 (95% CI = 1.08 - 2.13, p = 0.02), which reduced to 1.20 (95% CI = 0.85 - 1.72, p = 0.3) after adjusting for age at diagnosis and area of residence. Adjusting for prognostic factors differentially distributed across SES groups did not substantially alter the association between survival and SES., Conclusions: Among young, urban Australian women there is no association between SES and BC survival., Implications: This lack of estimates of association may be partly attributed to universal access to adequate breast cancer care in urban areas., (© 2010 The Authors. Journal Compilation © 2010 Public Health Association of Australia.)

Although having a family history of breast cancer is a well established breast cancer risk factor, it is not known whether it influences mortality after breast cancer diagnosis. We studied 4,153 women with first primary incident invasive breast cancer diagnosed between 1991 and 2000, and enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. Cases were oversampled for younger age at diagnosis and/or family history of breast cancer. Carriers of germline mutations in BRCA1 or BRCA2 were excluded. Cases and their relatives completed structured questionnaires assessing breast cancer risk factors and family history of cancer. Cases were followed for a median of 6.5 years, during which 725 deaths occurred. Cox proportional hazards regression was used to evaluate associations between family history of breast cancer at the time of diagnosis and risk of all-cause mortality after breast cancer diagnosis, adjusting for established prognostic factors. The hazard ratios for all-cause mortality were 0.98 (95% confidence interval [CI] = 0.84-1.15) for having at least one first- or second-degree relative with breast cancer, and 0.85 (95% CI = 0.70-1.02) for having at least one first-degree relative with breast cancer, compared with having no such family history. Estimates did not vary appreciably when stratified by case or tumor characteristics. In conclusion, family history of breast cancer is not associated with all-cause mortality after breast cancer diagnosis for women without a known germline mutation in BRCA1 or BRCA2. Therefore, clinical management should not depend on family history of breast cancer.