Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.

BACKGROUND: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS: This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS: In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS: A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51381.

Alcohol intake and endogenous sex hormones in women: Meta-analysis of cohort studies and Mendelian randomization.

BACKGROUND: The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes. METHODS: Cross-sectional associations were investigated between self-reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta-analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). RESULTS: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two-sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6-7.6) and free testosterone (7.8%; 4.1-11.5), and an inverse association with SHBG (-8.1%; -11.3% to -4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). CONCLUSIONS: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.

Healthy lifestyle change and all-cause and cancer mortality in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Healthy lifestyles are inversely associated with the risk of noncommunicable diseases, which are leading causes of death. However, few studies have used longitudinal data to assess the impact of changing lifestyle behaviours on all-cause and cancer mortality. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, lifestyle profiles of 308,497 cancer-free adults (71% female) aged 35-70 years at recruitment across nine countries were assessed with baseline and follow-up questionnaires administered on average of 7 years apart. A healthy lifestyle index (HLI), assessed at two time points, combined information on smoking status, alcohol intake, body mass index, and physical activity, and ranged from 0 to 16 units. A change score was calculated as the difference between HLI at baseline and follow-up. Associations between HLI change and all-cause and cancer mortality were modelled with Cox regression, and the impact of changing HLI on accelerating mortality rate was estimated by rate advancement periods (RAP, in years). RESULTS: After the follow-up questionnaire, participants were followed for an average of 9.9 years, with 21,696 deaths (8407 cancer deaths) documented. Compared to participants whose HLIs remained stable (within one unit), improving HLI by more than one unit was inversely associated with all-cause and cancer mortality (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.81, 0.88; and HR: 0.87; 95% CI: 0.82, 0.92; respectively), while worsening HLI by more than one unit was associated with an increase in mortality (all-cause mortality HR: 1.26; 95% CI: 1.20, 1.33; cancer mortality HR: 1.19; 95% CI: 1.09, 1.29). Participants who worsened HLI by more than one advanced their risk of death by 1.62 (1.44, 1.96) years, while participants who improved HLI by the same amount delayed their risk of death by 1.19 (0.65, 2.32) years, compared to those with stable HLI. CONCLUSIONS: Making healthier lifestyle changes during adulthood was inversely associated with all-cause and cancer mortality and delayed risk of death. Conversely, making unhealthier lifestyle changes was positively associated with mortality and an accelerated risk of death.

Associations between transport modes and site-specific cancers: a systematic review and meta-analysis.

BACKGROUND: Physical inactivity is a global public health problem. A practical solution would be to build physical activity into the daily routine by using active modes of transport. Choice of transport mode can influence cancer risk through their effects on levels of physical activity, sedentary time, and environmental pollution. This review synthesizes existing evidence on the associations of specific transport modes with risks of site-specific cancers. METHODS: Relevant literature was searched in PubMed, Embase, and Scopus from 1914 to 17th February 2023. For cancer sites with effect measures available for a specific transport mode from two or more studies, random effects meta-analyses were performed to pool relative risks (RR) comparing the highest vs. lowest activity group as well as per 10 Metabolic Equivalent of Task (MET) hour increment in transport-related physical activity per week (∼150 min of walking or 90 min of cycling). RESULTS: 27 eligible studies (11 cohort, 15 case-control, and 1 case-cohort) were identified, which reported the associations of transport modes with 10 site-specific cancers. In the meta-analysis, 10 MET hour increment in transport-related physical activity per week was associated with a reduction in risk for endometrial cancer (RR: 0.91, 95% CI: 0.83-0.997), colorectal cancer (RR: 0.95, 95% CI: 0.91-0.99) and breast cancer (RR: 0.99, 95% CI: 0.89-0.996). The highest level of walking only or walking and cycling combined modes, compared to the lowest level, were significantly associated with a 12% and 30% reduced risk of breast and endometrial cancers respectively. Cycling, compared to motorized modes, was associated with a lower risk of overall cancer incidence and mortality. CONCLUSION: Active transport appears to reduce cancer risk, but evidence for cancer sites other than colorectum, breast, and endometrium is currently limited.

Ethnic inequities in use of breast conserving surgery and radiation therapy in Aotearoa/New Zealand: which factors contribute?

PURPOSE: Aotearoa/New Zealand (NZ) faces ethnic inequities with respect to breast cancer survival and treatment. This study establishes if there are ethnic differences in (i) type of surgery and (ii) receipt of radiotherapy (RT) following breast conserving surgery (BCS), among women with early-stage breast cancer in NZ. METHODS: This analysis used Te Rehita Mata Utaetae (Breast Cancer Foundation National Register), a prospectively maintained database of breast cancers from 2000 to 2020. Logistic regression models evaluated ethnic differences in type of surgery (mastectomy or BCS) and receipt of RT with sequential adjustment for potential contributing factors. Subgroup analyses by treatment facility type were undertaken. RESULTS: Of the 16,228 women included, 74% were NZ European (NZE), 10.3% were Maori, 9.4% were Asian and 6.2% were Pacific. Over one-third of women with BCS-eligible tumours received mastectomy. Asian women were more likely to receive mastectomy than NZE (OR 1.62; 95% CI 1.39, 1.90) as were wahine Maori in the public system (OR 1.21; 95% CI 1.02, 1.44) but not in the private system (OR 0.78; 95% CI 0.51, 1.21). In women undergoing BCS, compared to NZE, Pacific women overall and wahine Maori in the private system were, respectively, 36 and 38% less likely to receive RT (respective OR 0.64; 95% CI 0.50, 0.83 and 0.62; 95% CI 0.39, 0.98). CONCLUSION: A significant proportion of women with early-stage breast cancer underwent mastectomy and significant ethnic inequities exist. Recently developed NZ Quality Performance Indicators strongly encourage breast conservation and should facilitate more standardized and equitable surgical management of early-stage breast cancer.

BMI and breast cancer risk around age at menopause.

BACKGROUND: A high body mass index (BMI, kg/m2) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology. METHODS: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy. RESULTS: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO. CONCLUSION: The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.

Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.

Body mass index and cancer risk among adults with and without cardiometabolic diseases: evidence from the EPIC and UK Biobank prospective cohort studies.

BACKGROUND: Whether cancer risk associated with a higher body mass index (BMI), a surrogate measure of adiposity, differs among adults with and without cardiovascular diseases (CVD) and/or type 2 diabetes (T2D) is unclear. The primary aim of this study was to evaluate separate and joint associations of BMI and CVD/T2D with the risk of cancer. METHODS: This is an individual participant data meta-analysis of two prospective cohort studies, the UK Biobank (UKB) and the European Prospective Investigation into Cancer and nutrition (EPIC), with a total of 577,343 adults, free of cancer, T2D, and CVD at recruitment. We used Cox proportional hazard regressions to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and incidence of obesity-related cancer and in turn overall cancer with a multiplicative interaction between BMI and the two cardiometabolic diseases (CMD). HRs and 95% CIs for separate and joint associations for categories of overweight/obesity and CMD status were estimated, and additive interaction was quantified through relative excess risk due to interaction (RERI). RESULTS: In the meta-analysis of both cohorts, BMI (per ~ 5 kg/m2) was positively associated with the risk of obesity-related cancer among participants without a CMD (HR: 1.11, 95%CI: 1.07,1.16), among participants with T2D (HR: 1.11, 95% CI: 1.05,1.18), among participants with CVD (HR: 1.17, 95% CI: 1.11,1.24), and suggestively positive among those with both T2D and CVD (HR: 1.09, 95% CI: 0.94,1.25). An additive interaction between obesity (BMI ≥ 30 kg/m2) and CVD with the risk of overall cancer translated into a meta-analytical RERI of 0.28 (95% CI: 0.09-0.47). CONCLUSIONS: Irrespective of CMD status, higher BMI increased the risk of obesity-related cancer among European adults. The additive interaction between obesity and CVD suggests that obesity prevention would translate into a greater cancer risk reduction among population groups with CVD than among the general population.

Receipt of mastectomy and adjuvant radiotherapy following breast conserving surgery (BCS) in New Zealand women with BCS-eligible breast cancer, 2010-2015: an observational study focusing on ethnic differences.

BACKGROUND: Women with early breast cancer who meet guideline-based criteria should be offered breast conserving surgery (BCS) with adjuvant radiotherapy as an alternative to mastectomy. New Zealand (NZ) has documented ethnic disparities in screening access and in breast cancer treatment pathways. This study aimed to determine whether, among BCS-eligible women, rates of receipt of mastectomy or radiotherapy differed by ethnicity and other factors. METHODS: The study assessed management of women with early breast cancer (ductal carcinoma in situ [DCIS] and invasive stages I-IIIA) registered between 2010 and 2015, extracted from the recently consolidated New Zealand Breast Cancer Registry (now Te Rehita Mate Utaetae NZBCF National Breast Cancer Register). Specific criteria were applied to determine women eligible for BCS. Uni- and multivariable analyses were undertaken to examine differences by demographic and clinicopathological factors with a primary focus on ethnicity (Maori, Pacific, Asian, and Other; the latter is defined as NZ European, Other European, and Middle Eastern Latin American and African). RESULTS: Overall 22.2% of 5520 BCS-eligible women were treated with mastectomy, and 91.1% of 3807 women who undertook BCS received adjuvant radiotherapy (93.5% for invasive cancer, and 78.3% for DCIS). Asian ethnicity was associated with a higher mastectomy rate in the invasive cancer group (OR 2.18; 95%CI 1.72-2.75), compared to Other ethnicity, along with older age, symptomatic diagnosis, advanced stage, larger tumour, HER2-positive, and hormone receptor-negative groups. Pacific ethnicity was associated with a lower adjuvant radiotherapy rate, compared to Other ethnicity, in both invasive and DCIS groups, along with older age, symptomatic diagnosis, and lower grade tumour in the invasive group. Both mastectomy and adjuvant radiotherapy rates decreased over time. For those who did not receive radiotherapy, non-referral by a clinician was the most common documented reason (8%), followed by patient decline after being referred (5%). CONCLUSION: Rates of radiotherapy use are high by international standards. Further research is required to understand differences by ethnicity in both rates of mastectomy and lower rates of radiotherapy after BCS for Pacific women, and the reasons for non-referral by clinicians.

A body shape index (ABSI) is associated inversely with post-menopausal progesterone-receptor-negative breast cancer risk in a large European cohort.

BACKGROUND: Associations of body shape with breast cancer risk, independent of body size, are unclear because waist and hip circumferences are correlated strongly positively with body mass index (BMI). METHODS: We evaluated body shape with the allometric "a body shape index" (ABSI) and hip index (HI), which compare waist and hip circumferences, correspondingly, among individuals with the same weight and height. We examined associations of ABSI, HI, and BMI (per one standard deviation increment) with breast cancer overall, and according to menopausal status at baseline, age at diagnosis, and oestrogen and progesterone receptor status (ER+/-PR+/-) in multivariable Cox proportional hazards models using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. RESULTS: During a mean follow-up of 14.0 years, 9011 incident breast cancers were diagnosed among 218,276 women. Although there was little evidence for association of ABSI with breast cancer overall (hazard ratio HR = 0.984; 95% confidence interval: 0.961-1.007), we found borderline inverse associations for post-menopausal women (HR = 0.971; 0.942-1.000; n = 5268 cases) and breast cancers diagnosed at age ≥ 55 years (HR = 0.976; 0.951-1.002; n = 7043) and clear inverse associations for ER + PR- subtypes (HR = 0.894; 0.822-0.971; n = 726) and ER-PR- subtypes (HR = 0.906; 0.835-0.983 n = 759). There were no material associations with HI. BMI was associated strongly positively with breast cancer overall (HR = 1.074; 1.049-1.098), for post-menopausal women (HR = 1.117; 1.085-1.150), for cancers diagnosed at age ≥ 55 years (HR = 1.104; 1.076-1.132), and for ER + PR + subtypes (HR = 1.122; 1.080-1.165; n = 3101), but not for PR- subtypes. CONCLUSIONS: In the EPIC cohort, abdominal obesity evaluated with ABSI was not associated with breast cancer risk overall but was associated inversely with the risk of post-menopausal PR- breast cancer. Our findings require validation in other cohorts and with a larger number of PR- breast cancer cases.

Incidence, trends, and survival of oropharyngeal squamous cell cancer in Aotearoa New Zealand, 2006-2020.

BACKGROUND: An increasing trend of oropharyngeal cancer (OPC) has been reported in several countries with different demographic characteristics, and often attributed to increases in human papillomavirus (HPV) infection. The survival of patients with OPC has steadily improved, especially for those with positive HPV status. This study assessed the incidence, trends, and survival of OPC in Aotearoa New Zealand (NZ) by age at diagnosis, sex and ethnicity. METHODS: The study included all 2109 patients resident in NZ with a primary diagnosis of oropharyngeal squamous cell carcinoma from 2006 to 2020, identified from the National Cancer Registry. We assessed age-standardised incidence rate (ASR), annual percent change (APC) and overall and relative survival rates. RESULTS: The average annual incidence of OPC was 2.2 per 100,000 population. There was a steady increase of 4.9% per year over 15 years. Although the incidence rates were higher in males over the study period, the overall rate of increase was similar in males (4.9%) and in females (4.3%). The incidence was highest in the 50-69-year group (8.8/100,000 population). This age group had an incidence that increased by 7.5% per year to 2018, and then declined. The main increase in rates was seen between the birth cohort of 1946-50 and that of 1956-60. The increase in incidence was seen in Maori and Pakeha/European populations, but no increase was seen in Pacific or Asian populations. The 5-year overall relative survival rate improved from 69% in 2006-13 to 78% in 2014-20. Survival rates were lower in older patients, females, and Maori patients. CONCLUSION: This study confirmed a substantial increase in OPC incidence in NZ, with some evidence to suggest a recent slowing in this increase. Maori and Pakeha/European had the highest incidence, while Pacific and Asian populations showed the lowest rates and no increase over the study period. Survival rates have improved over time, but remained lower in some demographic groups.

Comparison of Cancer Mortality and Incidence Between New Zealand and Australia and Reflection on Differences in Cancer Care: An Ecological Cross-Sectional Study of 2014-2018.

BACKGROUND: Despite many background similarities, New Zealand showed excess cancer deaths compared to Australia in previous studies. This study extends this comparison using the most recent data of 2014-2018. METHODS: This study used publicly available cancer mortality and incidence data of New Zealand Ministry of Health and Australian Institute of Health and Welfare, and resident population data of Statistics New Zealand. Australian cancer mortality and incidence rates were applied to New Zealand population, by site of cancer, year, age and sex, to estimate the expected numbers, which were compared with the New Zealand observed numbers. RESULTS: For total cancers in 2014-2018, New Zealand had 780 excess deaths in women (17.1% of the annual total 4549; 95% confidence interval (CI) 15.8-18.4%), and 281 excess deaths in men (5.5% of the annual total 5105; 95% CI 4.3-6.7%) compared to Australia. The excess was contributed by many major cancers including colorectal, melanoma, and stomach cancer in both sexes; lung, uterine, and breast cancer in women, and prostate cancer in men. New Zealand's total cancer incidences were lower than those expected from Australia's in both women and men: average annual difference of 419 cases (-3.6% of the annual total 11 505; 95% CI -4.5 to -2.8%), and 1485 (-11.7% of the annual total 12 669; 95% CI -12.5 to -10.9%), respectively. Comparing time periods, the excesses in total cancer deaths in women were 15.1% in 2000-07, and 17.5% in 1996-1997; and in men 4.7% in 2000-2007 and 5.6% in 1996-1997. The differences by time period were non-significant. CONCLUSION: Excess mortality from all cancers combined and several common cancers in New Zealand, compared to Australia, persisted in 2014-2018, being similar to excesses in 2000-2007 and 1996-1997. It cannot be explained by differences in incidence, but may be attributable to various aspects of health systems governance and performance.

The association between body fatness and mortality among breast cancer survivors: results from a prospective cohort study.

Evidence linking body fatness to breast cancer (BC) prognosis is limited. While it seems that excess adiposity is associated with poorer BC survival, there is uncertainty over whether weight changes reduce mortality. This study aimed to assess the association between body fatness and weight changes pre- and postdiagnosis and overall mortality and BC-specific mortality among BC survivors. Our study included 13,624 BC survivors from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with a mean follow-up of 8.6 years after diagnosis. Anthropometric data were obtained at recruitment for all cases and at a second assessment during follow-up for a subsample. We measured general obesity using the body mass index (BMI), whereas waist circumference and A Body Shape Index were used as measures of abdominal obesity. The annual weight change was calculated for cases with two weight assessments. The association with overall mortality and BC-specific mortality were based on a multivariable Cox and Fine and Gray models, respectively. We performed Mendelian randomization (MR) analysis to investigate the potential causal association. Five-unit higher BMI prediagnosis was associated with a 10% (95% confidence interval: 5-15%) increase in overall mortality and 7% (0-15%) increase in dying from BC. Women with abdominal obesity demonstrated a 23% (11-37%) increase in overall mortality, independent of the association of BMI. Results related to weight change postdiagnosis suggested a U-shaped relationship with BC-specific mortality, with higher risk associated with losing weight or gaining > 2% of the weight annually. MR analyses were consistent with the identified associations. Our results support the detrimental association of excess body fatness on the survival of women with BC. Substantial weight changes postdiagnosis may be associated with poorer survival.

Associations between food group intakes and circulating insulin-like growth factor-I in the UK Biobank: a cross-sectional analysis.

PURPOSE: Circulating insulin-like growth factor-I (IGF-I) concentrations have been positively associated with risk of several common cancers and inversely associated with risk of bone fractures. Intakes of some foods have been associated with increased circulating IGF-I concentrations; however, evidence remains inconclusive. Our aim was to assess cross-sectional associations of food group intakes with circulating IGF-I concentrations in the UK Biobank. METHODS: At recruitment, the UK Biobank participants reported their intake of commonly consumed foods. From these questions, intakes of total vegetables, fresh fruit, red meat, processed meat, poultry, oily fish, non-oily fish, and cheese were estimated. Serum IGF-I concentrations were measured in blood samples collected at recruitment. After exclusions, a total of 438,453 participants were included in this study. Multivariable linear regression was used to assess the associations of food group intakes with circulating IGF-I concentrations. RESULTS: Compared to never consumers, participants who reported consuming oily fish or non-oily fish ≥ 2 times/week had 1.25 nmol/L (95% confidence interval:1.19-1.31) and 1.16 nmol/L (1.08-1.24) higher IGF-I concentrations, respectively. Participants who reported consuming poultry ≥ 2 times/week had 0.87 nmol/L (0.80-0.94) higher IGF-I concentrations than those who reported never consuming poultry. There were no strong associations between other food groups and IGF-I concentrations. CONCLUSIONS: We found positive associations between oily and non-oily fish intake and circulating IGF-I concentrations. A weaker positive association of IGF-I with poultry intake was also observed. Further research is needed to understand the mechanisms which might explain these associations.

Metabolically Defined Body Size Phenotypes and Risk of Endometrial Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. METHODS: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case-control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH; <1st tertile) and metabolically unhealthy (MU; ≥1st tertile) status among the control participants. These metabolic health definitions were combined with normal weight (NW); body mass index (BMI)<25 kg/m2 or waist circumference (WC)<80 cm or waist-to-hip ratio (WHR)<0.8) and overweight (OW; BMI≥25 kg/m2 or WC≥80 cm or WHR≥0.8) status, generating four phenotype groups for each anthropometric measure: (i) MH/NW, (ii) MH/OW, (iii) MU/NW, and (iv) MU/OW. RESULTS: In a multivariable-adjusted conditional logistic regression model, compared with MH/NW individuals, endometrial cancer risk was higher among those classified as MU/NW [ORWC, 1.48; 95% confidence interval (CI), 1.05-2.10 and ORWHR, 1.68; 95% CI, 1.21-2.35] and MU/OW (ORBMI, 2.38; 95% CI, 1.73-3.27; ORWC, 2.69; 95% CI, 1.92-3.77 and ORWHR, 1.83; 95% CI, 1.32-2.54). MH/OW individuals were also at increased endometrial cancer risk compared with MH/NW individuals (ORWC, 1.94; 95% CI, 1.24-3.04). CONCLUSIONS: Women with metabolic dysfunction appear to have higher risk of endometrial cancer regardless of their body size. However, OW status raises endometrial cancer risk even among women with lower insulin levels, suggesting that obesity-related pathways are relevant for the development of this cancer beyond insulin. IMPACT: Classifying women by metabolic health may be of greater utility in identifying those at higher risk for endometrial cancer than anthropometry per se.

Post-diagnostic beta blocker use and breast cancer-specific mortality: a population-based cohort study.

PURPOSE: Beta blockers (BB) have been associated with improved, worsened, or unchanged breast cancer outcomes in previous studies. This study examines the association between the post-diagnostic use of BBs and death from breast cancer in a large, representative sample of New Zealand (NZ) women with breast cancer. METHODS: Women diagnosed with a first primary breast cancer between 2007 and 2016 were identified from four population-based regional NZ breast cancer registries and linked to national pharmaceutical data, hospital discharges, and death records. The median follow-up time was 4.51 years. Cox proportional hazard models were used to estimate the hazard of breast cancer-specific death (BCD) associated with any post-diagnostic BB use. RESULTS: Of the 14,976 women included in analyses, 21% used a BB after diagnosis. BB use (vs non-use) was associated with a small and nonstatistically significant increased risk of BCD (adjusted hazard ratio: 1.11; 95% CI 0.95-1.29). A statistically significant increased risk confined to short-term use (0-3 months) was seen (HR = 1.40; 1.14-1.73), and this risk steadily decreased with increasing duration of use and became a statistically significant protective effect at 3 + years of use (HR = 0.55; 0.34-0.88). CONCLUSION: Our findings suggest that any increased risk associated with BB use may be driven by risk in the initial few months of use. Long-term BB use may be associated with a reduction in BCD.

Alcohol Intake and Endogenous Hormones in Pre- and Postmenopausal Women: Findings from the UK Biobank.

BACKGROUND: Alcohol intake may influence breast cancer risk in women through hormonal changes, but the evidence to date is inconclusive. We investigated cross-sectional associations between habitual alcohol intake and serum concentrations of testosterone, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and estradiol (premenopausal women only) in UK Biobank. METHODS: We included 30,557 premenopausal and 134,029 postmenopausal women aged between 40 and 69 years when recruited between 2006 and 2010. At their initial assessment visit, habitual alcohol intake was assessed using a touchscreen questionnaire, and serum hormone concentrations were assayed. Multivariable linear regression analysis was performed. RESULTS: Per 10 g/day increment in alcohol intake, testosterone concentration was 3.9% [95% confidence intervals (CI): 3.3%-4.5%] higher in premenopausal women and 2.3% (1.8%-2.7%) higher in postmenopausal women (P heterogeneity < 0.0001); SHBG concentration was 0.7% (0.2%-1.1%) higher in premenopausal women and 2.4% (2.2%-2.6%) lower in postmenopausal women (P heterogeneity < 0.0001); and IGF-1 concentration was 1.9% (1.7%-2.1%) lower in premenopausal women and 0.8% (0.6%-0.9%) lower in postmenopausal women (P heterogeneity < 0.0001). In premenopausal women, there was no significant overall association of alcohol with estradiol but a positive association was observed in the early and mid-luteal phases: 1.9% (95% CI: 0.2%-3.6%) and 2.4% (95% CI: 0.7%-4.2%) higher, respectively. CONCLUSIONS: This study confirms significant but modest associations between alcohol intake and hormones, with evidence of heterogeneity by menopausal status. IMPACT: The findings facilitate better understanding of whether alcohol intake influences hormone concentrations, but further work is necessary to fully understand the mechanisms linking alcohol with cancer risk.

Associations of circulating insulin-like growth factor-I with intake of dietary proteins and other macronutrients.

BACKGROUND & AIMS: Circulating insulin-like growth factor-I (IGF-I) is associated with the risk of several cancers. Dietary protein intake, particularly dairy protein, may increase circulating IGF-I; however, associations with different protein sources, other macronutrients, and fibre are inconclusive. To investigate the associations between intake of protein, macronutrients and their sources, fibre, and alcohol with serum IGF-I concentrations. METHODS: A total of 11,815 participants from UK Biobank who completed ≥4 24-h dietary assessments and had serum IGF-I concentrations measured at baseline were included. Multivariable linear regression was used to assess the cross-sectional associations of macronutrient and fibre intake with circulating IGF-I concentrations. RESULTS: Circulating IGF-I concentrations were positively associated with intake of total protein (per 2.5% higher energy intake: 0.56 nmol/L (95% confidence interval: 0.47, 0.66)), milk protein: 1.20 nmol/L (0.90, 1.51), and yogurt protein: 1.33 nmol/L (0.79, 1.86), but not with cheese protein: -0.07 nmol/L (-0.40, 0.25). IGF-I concentrations were also positively associated with intake of fibre (per 5 g/day higher intake: 0.46 nmol/L (0.35, 0.57)) and starch from wholegrains (Q5 vs. Q1: 1.08 nmol/L (0.77, 1.39)), and inversely associated with alcohol consumption (>40 g/day vs <1 g/day: -1.36 nmol/L (-1.00, -1.71)). CONCLUSIONS: These results show differing associations with IGF-I concentrations depending on the source of dairy protein, with positive associations with milk and yogurt protein intake but no association with cheese protein. The positive association of fibre and starch from wholegrains with IGF-I warrants further investigation.

Physical activity in relation to circulating hormone concentrations in 117,100 men in UK Biobank.

PURPOSE: Physical activity may reduce the risk of some types of cancer in men. Biological mechanisms may involve changes in hormone concentrations; however, this relationship is not well established. Therefore, we aimed to investigate the associations of physical activity with circulating insulin-like growth factor-I (IGF-I), sex hormone-binding globulin (SHBG, which modifies sex hormone activity), and total and free testosterone concentrations, and the extent these associations might be mediated by body mass index (BMI). METHODS: Circulating concentrations of these hormones and anthropometric measurements and self-reported physical activity data were available for 117,100 healthy male UK Biobank participants at recruitment. Objectively measured accelerometer physical activity levels were also collected on average 5.7 years after recruitment in 28,000 men. Geometric means of hormone concentrations were estimated using multivariable-adjusted analysis of variance, with and without adjustment for BMI. RESULTS: The associations between physical activity and hormones were modest and similar for objectively measured (accelerometer) and self-reported physical activity. Compared to men with the lowest objectively measured physical activity, men with high physical activity levels had 14% and 8% higher concentrations of SHBG and total testosterone, respectively, and these differences were attenuated to 6% and 3% following adjustment for BMI. CONCLUSION: Our results suggest that the associations of physical activity with the hormones investigated are, at most, modest; and following adjustment for BMI, the small associations with SHBG and total testosterone were largely attenuated. Therefore, it is unlikely that changes in these circulating hormones explain the associations of physical activity with risk of cancer either independently or via BMI.