Metabolite profiles provide insight into biologic mechanisms contributing to breast cancer development. We explored the association between prediagnostic plasma metabolites (N = 307) and invasive ...breast cancer among postmenopausal women in a nested case-control study within the Nurses' Health Study (N = 1,531 matched pairs).
Plasma metabolites were profiled via LC/MS-MS using samples taken ≥10 years (distant, N = 939 cases) and <10 years (proximate, N = 592 cases) before diagnosis. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) comparing the 90th to 10th percentile of individual metabolite level, using the number of effective tests (NEF) to account for testing multiple correlated hypotheses. Associations of metabolite groups with breast cancer were evaluated using metabolite set enrichment analysis (MSEA) and weighted gene coexpression network analysis (WGCNA), with adjustment for the FDR.
No individual metabolites were significantly associated with breast cancer risk. MSEA showed negative enrichment of cholesteryl esters at the distant timepoint normalized enrichment score (NES) = -2.26; Padj = 0.02. Positive enrichment of triacylglycerols (TAG) with <3 double bonds was observed at both timepoints. TAGs with ≥3 double bonds were inversely associated with breast cancer at the proximate timepoint (NES = -2.91, Padj = 0.03).
Cholesteryl esters measured earlier in disease etiology were inversely associated with breast cancer. TAGs with many double bonds measured closer to diagnosis were inversely associated with breast cancer risk.
The discovered associations between metabolite subclasses and breast cancer risk can expand our understanding of biochemical processes involved in cancer etiology.
People with Phenylketonuria (PKU) who respond to tetrahydrobiopterin (BH4) often decrease dependence on medical food (MF) following increased phenylalanine (phe) tolerance. Responders to BH4 may ...experience a reduction in certain nutrients if not compensated through intact foods or supplements. This study investigated B6, B12, folate, and iron status based on blood levels and dietary intake in patients with PKU responsive to BH4 over 1 year.
Fifty-eight patients with PKU, ages 4-50 years were recruited and initiated on BH4 therapy. Patients were monitored for BH4 response, and nutritional status was recorded at regular intervals over 12 months. The analysis included 33 patients with known BH4 response status and complete nutritional data. Nutrient intake was determined by National Data System for Research (NDSR) analysis of self reported 3 day diet records and compared to Dietary Reference Intakes (DRIs). Blood biomarkers were analyzed by Quest Diagnostics and compared to laboratory reference ranges. Patient laboratory values were compared to controls from the National Health and Examination Survey (NHANES). Differences in nutrient intakes across time points were examined, stratified by age, using nonparametric methods. Statistical analyses were completed with SAS 9.4, with significance set at α = 0.05.
Medical food intake declined among pediatric (p < 0.01) and adult (p = 0.06) BH4 responders over 1 year. Among those < 18 years of age, mean percent of calories obtained from MF declined from 21.3 to 4.7%. In adults, percent calories from MF dropped from 19.5 to 4.0%. Though maintaining laboratory and dietary values within reference ranges, responders < 18 years experienced a significant decline in serum B12 (p = 0.01), dietary folate (p = 0.006), and dietary iron (p = 0.004) over the study.
Although mean dietary and laboratory values for B12, B6, folate, and iron in BH4 responders and non-responders were adequate at baseline and 12-month follow-up, responders experienced a significant decline in serum B12 over 1 year, which may be explained by decreased intake of fortified MF. Both response groups had lower serum B12 than NHANES controls at baseline and 12 months. Results indicate a need to monitor B12 concentrations and consider micronutrient supplementation, with special attention to pediatric patients with PKU.
Purpose
Physical activity is associated with lower breast cancer risk, especially in postmenopausal women. Associations in premenopausal women are less well established.
Methods
We evaluated ...recreational physical activity and breast cancer risk in the Nurses’ Health Study (NHS) and NHSII (187,278 women; n = 12,785 breast cancers; follow-up: NHS = 1986–2016, NHSII = 1989–2017) by menopausal status and estrogen (ER) and progesterone (PR) receptor status. Physical activity was evaluated as updated cumulative average of metabolic equivalent of task (MET)-h/week. Cox proportional hazards models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI).
Results
Recreational physical activity was inversely associated with breast cancer risk in pre- and postmenopausal women. Higher activity levels were associated with lower risk of ER+/PR + breast cancer in both pre- and postmenopausal women (e.g., total recreational activity, ≥ 27 vs < 3 MET-h/week, premenopausal HR = 0.83, 95%CI = (0.70–0.99), postmenopausal HR = 0.86 (0.78–0.95); p
heterogeneity
= 0.97). Results were attenuated with adjustment for current body mass index (BMI) among postmenopausal, but not premenopausal, women (e.g., ≥ 27 vs < 3 MET-h/week, premenopausal HR = 0.83 (0.69–0.98); postmenopausal HR = 0.95 (0.85–1.05); p
heterogeneity
= 0.99). In analyses of moderate-vigorous activity and breast cancer risk, no heterogeneity by menopausal status was observed (p
het
≥ 0.53; e.g., ≥ 27 vs < 3 MET-h/week, ER+/PR+, premenopausal HR = 0.88 (0.69–1.11); postmenopausal HR = 0.71 (0.58–0.88). No associations were observed for ER−/PR− disease.
Conclusions
Recreational physical activity was associated with lower breast cancer risk in both pre- and postmenopausal women, supporting recreational physical activity as an accessible, modifiable exposure associated with reduced breast cancer risk regardless of menopausal status.
Adiposity is consistently positively associated with postmenopausal breast cancer and inversely associated with premenopausal breast cancer risk, though the reasons for this difference remain ...unclear.
In this nested case-control study of 1649 breast cancer cases and 1649 matched controls from the Nurses' Health Study (NHS) and the NHSII, we selected lipid and polar metabolites correlated with BMI, waist circumference, weight change since age 18, or derived fat mass, and developed a metabolomic score for each measure using LASSO regression. Logistic regression was used to investigate the association between this score and breast cancer risk, adjusted for risk factors and stratified by menopausal status at blood draw and diagnosis.
Metabolite scores developed among only premenopausal or postmenopausal women were highly correlated with scores developed in all women (r = 0.93-0.96). Higher metabolomic adiposity scores were generally inversely related to breast cancer risk among premenopausal women. Among postmenopausal women, significant positive trends with risk were observed (e.g., metabolomic waist circumference score OR Q4 vs. Q1 = 1.47, 95% CI = 1.03-2.08, P-trend = 0.01).
Though the same metabolites represented adiposity in pre- and postmenopausal women, breast cancer risk associations differed suggesting that metabolic dysregulation may have a differential association with pre- vs. postmenopausal breast cancer.
PURPOSEWe evaluated the incidence, timing, and risk factors for second primary non-breast cancers (SPNBC) among young breast cancer (BC) survivors.METHODSThis study included participants of the Young ...Women's BC Study (YWS) who were diagnosed with stage 0-III BC between 2006 and 2016 and age 40 or younger at diagnosis (N = 1,230). Patient characteristics, treatment information, and clinical events were collected via serial surveys. Tumor and treatment data were obtained from medical record review. Five- and 10-year risks of SPNBCs were estimated via the cumulative incidence function, considering death, metastasis, or second primary BC as competing events. Fine and Gray subdistribution hazard models estimated subdistribution hazard ratios (sHRs) and 95% confidence intervals (CI) for SPNBC risk based on risk factors including demographics, germline genetics, primary BC characteristics, and treatments.RESULTSAmong 1,230 women, over a median follow-up of 10.1 years, 47 patients (4%) developed an SPNBC. Types of malignancy included melanoma (n = 10), thyroid (n = 10), ovarian (n = 4), sarcoma (n = 4), uterine (n = 3), rectal (n = 3), bladder (n = 2), cervical (n = 2), head/neck (n = 2), lung (n = 2), lymphoma (n = 2), pancreatic (n = 2), and renal (n = 1). Five and 10-year cumulative incidence were 1.4% and 3.2%, respectively. Median time between primary BC and SPNBC was 7.3 years. No patient factors, primary tumor characteristics, or treatments were statistically significantly associated with SPNBC in univariable or multivariable models.CONCLUSIONIn this population, five-year cumulative incidence was higher than that reported among healthy women under 50 years of age, highlighting the importance of long-term surveillance for new non-breast cancers in young adult BC survivors.
Expression of human paracrine hormones stanniocalcin 1 (STC1) and stanniocalcin 2 (STC2) may potentiate late breast cancer recurrence. We tested the hypothesis that expression of STC1 and STC2 in ...primary breast tumors is more strongly associated with late versus early recurrences.
A total of 541 estrogen receptor-positive, tamoxifen-treated (ER
/TAM
) and 300 ER-negative, tamoxifen-untreated (ER
/TAM
) breast cancer patients who experienced recurrence within 10 years of primary diagnosis and matched recurrence-free controls were selected from a cohort of 11,251 Danish breast cancer patients diagnosed with stage I, II, or III breast cancer during 1985 to 2001. The association between IHC expression of STC1 and STC2 in primary breast tumor tissue microarrays and breast cancer recurrence was evaluated within median time to recurrence quintiles.
The association between STC1 expression, dichotomized as positive or negative, and recurrence was strongly positive for the final time quintile (6-10 years postdiagnosis) in the ER
/TAM
group aOR = 2.70; 95% confidence interval (CI): 1.22-5.98. Regression of the log ORs relating dichotomous STC1 and STC2 expression to recurrence by median time to recurrence (year) resulted in a relatively large positive effect estimate for STC1 (β = 0.16; 95% CI, -0.03-0.36) and a near-null positive effect estimate for STC2 (β = 0.04; 95% CI, -0.14-0.21).
Our results suggest a stronger association between primary tumor STC1 expression and late recurrence, as opposed to early recurrence, although no clear trend was apparent.
STC1 expression in the primary tumor may potentiate late recurrences, suggesting dormancy pathways that merit further investigation.
.
There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of ...this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer.
We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity.
Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 95% CI, 0.89 to 0.99) and a 10% (HR, 0.90 95% CI, 0.85 to 0.95) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship (
= .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 95% CI, 0.39 to 0.84;
= .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity.
This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.
Adolescent diet is thought to play an important role in future chronic disease risk. However, few studies have examined the reproducibility of adult-reported adolescent diet, and evidence for ...possible differences in reproducibility by demographic characteristics is limited.
We assessed the ability of adults to consistently report past high school diet over a 1-y period and examined differences in reproducibility by selected demographic characteristics.
By using age-adjusted partial Spearman (ρ) or Pearson (r) correlations, we assessed 1-y reproducibility for 33 line items, 20 food groups, and 2 dietary patterns of high school diet reported in adulthood via a questionnaire completed by 742 participants in the Cancer Prevention Study 3 (CPS-3) Diet Substudy.
Participants’ median age was 53 y (range: 31–70 y), 65.2% were women, 59.8% were non-Hispanic white, 24.8% were non-Hispanic black, and 15.4% were Hispanic. The mean Spearman correlation assessing reproducibility across the 33 line items was 0.60 and ranged from 0.44 to 0.72, with no differences in mean correlations by age, sex, race/ethnicity, education, or body mass index (BMI). Reproducibility was similar across food groups (ρ = 0.62; range: 0.44–0.68), with differences by sex, ethnicity, age, or BMI observed for some food groups (e.g., sugar-sweetened beverages). Pearson correlations for the reproducibility of 2 major eating patterns, “fast food” and “whole food,” were 0.73 and 0.72, respectively.
These results show good 1-y reproducibility of assessed high school diet, as reported from memory in adulthood, by line item, food group, and dietary pattern, with noted differences by demographic characteristics.
Physical activity is generally associated with better outcomes following diagnosis; however, few studies have evaluated change in pre- to postdiagnosis activity and repeated measures of activity by ...intensity and type.
We evaluated physical activity and survival following a breast cancer diagnosis in the Nurses' Health Study and Nurses' Health Study II (n = 9308 women, n = 1973 deaths). Physical activity was evaluated as updated cumulative average of metabolic equivalent of task (MET)-h/wk (assigned per activity based on duration and intensity) and change in pre- to postdiagnosis activity. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
Higher postdiagnosis activity was inversely associated with breast cancer-specific mortality in categories from ≥9 MET-h/wk (vs <3 MET h/wk, HR≥9 to <18 = 0.74 95% CI = 0.55 to 0.99; HR≥27 = 0.69 95% CI = 0.50 to 0.95; Ptrend = .04) and all-cause mortality from ≥3 MET-h/wk (HR≥3 to <9 = 0.73 95% CI = 0.61 to 0.88; HR≥27 = 0.51 95% CI = 0.41 to 0.63; Ptrend < .001). Associations were predominantly observed for estrogen receptor-positive tumors and in postmenopausal women. Walking was associated with lower risk of all-cause mortality (≥9 vs <3 MET-h/wk, HR= 0.69 95% CI = 0.57 to 0.84) as was strength training. Relative to stable activity pre- to postdiagnosis (±3 MET-h/wk), increases from ≥3 to 9 MET-h/wk were associated with lower all-cause mortality risk (Ptrend < .001). Results were robust to adjustment for prediagnosis physical activity.
Physical activity was associated with lower risk of death following diagnosis. Increased pre- to postdiagnosis activity corresponding to at least 1-3 h/wk of walking was associated with lower risk of death. These results provide further impetus for women to increase their activity after a breast cancer diagnosis, though reverse causation cannot be fully excluded.
Background: Insurance status impacts access and survival for cancer patients within mixed healthcare systems, such as the US (Walker et al., 2014). Universal healthcare, as in Canada, provides broad ...coverage, though new drug funding is delayed for financial evaluations given escalating costs of oncologic therapies. Brentuximab Vedotin (BV) was the first FDA approved medication (2011) for Hodgkin lymphoma (HL) since 1977, with a 75% response rate and median overall survival (OS) 40.5 months in patients relapsing post transplant, compared to OS 10.5 to 27.6 months with prior therapies (Chen et al., 2016). Approximately 20% of HL patients develop refractory/relapsed disease, and most proceed to transplant; a further 50% relapse however, thus effective therapy is critical. Given the cost ($232 320 CAD per course; pCODR, 2018), an extensive cost-efficacy analysis was completed in Canada prior to funding, leading to a 3 year delay compared to FDA approval and US funding. We therefore compared OS for US and Canadian patients diagnosed with HL pre/post FDA approval of BV for post-transplant relapse, hypothesizing that 1) survival differences within the US according to insurance would be present and widen after approval and 2) a survival gap would emerge between privately insured US vs. Canadian patients.
Methods: A retrospective cohort study was performed of patients 16-64 years diagnosed with classical HL in 2007-2010 (period 1) or 2011-2014 (period 2) from the US SEER and Canadian Cancer Registry (CCR), with vital status updated to November 2016 and December 31, 2014 respectively. A surrogate date for access (FDA approval) was used as neither dataset captures chemotherapy. Exclusion criteria included missing histology, follow-up or insurance data, or post-mortem diagnosis. Log-rank test and Kaplan-Meier analysis compared OS (primary outcome) between groups: in period 2 vs. 1 by US insurance status (aim 1) and including a Canadian/universal category (aim 2). Analysis was performed within each dataset to allow for maximal adjustment utilizing Cox proportional hazards by covariates (age, gender, insurance status, stage, lymphoma subtype, race, ethnicity, marital status within SEER; age, gender, subtype within CCR), then merged using common variables. Secondary outcomes examined 36-month OS (longest calculable given censoring dates) to compare the direction and degree of change in survival between time periods.
Results: 12,003 US and 4,210 Canadian patients were included. Demographics were similar, though follow up was shorter for the latter due to censoring date. US patients demonstrated improved survival (crude HR=0.90 (95%CI 0.80-1.02), adjusted HR=0.80 (95%CI 0.71-0.91)), between periods. Canadian patients had a similar reduced risk of death between periods, though this became statistically insignificant after adjustment (crude HR=0.72 (95%CI 0.54-0.95), adjusted HR=0.77 (95%CI 0.59-1.02)). Comparing all patients by country (periods combined) demonstrated a non-significant increased crude risk of death in US vs. Canadian patients (HR 1.13, p=0.059, 95% CI 1.00-1.27). Stratifying US patients by insurance demonstrated stable OS for privately insured, significantly improved OS for Medicaid and non-significantly worse survival for uninsured patients, demonstrating divergence by time likely not solely due to BV access. No difference in OS improvement occurred between periods for privately insured vs. universal patients. In an adjusted model including time period, compared with universal there was increased risk for both uninsured (HR 1.80, p<0.0001, 95% CI 1.46-2.20) and Medicaid patients (HR 2.36, p<0.0001, 95% CI 2.02-2.76), and reduced risk in privately insured patients (HR 0.87, p=0.044, 95% CI 0.77-1.00). Unadjusted 36-month OS quantified divergence according to insurance, with a large (+7.4%) and small (+2.4%) improvement in Medicaid and universal patients respectively, no change in privately insured and worse survival (-4.1%) for uninsured patients.
Conclusions: HL survival was worse for Medicaid/uninsured compared to privately/universally insured patients, however all had stable or improved survival in period 2 except uninsured patients. No difference in change between periods for privately or universally insured patients occurred due to delayed access, however robust datasets capturing chemotherapy and comorbidities are needed.
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Davies:Novartis: Honoraria; TEVA: Honoraria.
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