Purpose:
Several viruses have been casually linked to human cancers, including cervical, nasopharyngeal, liver, sarcoma, and Merkel cell carcinomas. However, the etiologic contribution of viral ...infections to breast cancer, the number one incident cancer among women worldwide, is not well established. Among studies exploring associations of viruses with breast cancer, potential linkages have been identified between breast cancer and five viruses: beta retrovirus, (i.e., mouse mammary tumor virus), human papillomavirus, Epstein Barr virus. bovine leukemia virus, and human cytomegalovirus.
Methods:
In this review, we provide a comprehensive evaluation of epidemiological ecologic, case–control, case-only, and cohort studies investigating these associations. We discuss results from several existing reviews and meta-analyses, evaluate epidemiological studies published in the past five years, and assess the relationship between these viruses and breast tumor clinicopathological factors.
Results:
The strongest epidemiological evidence for a viral role in breast cancer exists for MMTV and HPV, though limitations include lack of prospective studies for MMTV and potential detection bias in HPV studies. Viral detection challenges have limited studies of EBV and HCMV. Fewer studies have evaluated BLV, and though it has been associated with higher risk of breast cancer, sample sizes are quite small.
Conclusion:
While epidemiologic evidence exists for an association between these five viruses and breast cancer, various methodological issues and lack of prospective studies preclude robust conclusions. Future research should prioritize establishing a temporal relationship between infection and disease, minimizing misclassification of detection assays, and further exploring the influence of co-infections.
Cost-effectiveness analyses are required for therapies within Canada’s universal healthcare system, leading to delays relative to U.S. healthcare. Patients with Hodgkin lymphoma (HL) generally have ...an excellent prognosis, but those who relapse after or are ineligible for transplant benefit from novel therapies, including brentuximab vedotin (BV). BV was FDA-approved in 2011 but not Canadian-funded until 2014. To assess the impact of access delays, we compared changes in survival for U.S. (by insurer) and Canadian patients in periods pre/post-U.S. approval. Patients were 16–64 years, diagnosed with HL in 2007–2010 (Period 1) and 2011–2014 (Period 2) from the U.S. SEER and Canadian Cancer Registries. Approval date (surrogate) was utilized as therapy was unavailable in registries. Kaplan-Meier survival curves and adjusted Cox regression models compared survival between periods by insurance category. Among 12,003 U.S. and 4210 Canadian patients, survival was better in U.S. patients (adjusted hazard ratio (aHR) 0.87 (95%CI 0.77–0.98)) between periods; improvement in Canadian patients (aHR 0.84 (95%CI 0.69–1.03) was similar but non-significant. Comparisons between insurers showed survival was significantly worse for U.S. uninsured and Medicaid vs. U.S. privately insured and Canadian patients. Given the increasingly complex nature of oncologic funding, this merits further investigation to ensure equity in access to therapy developments.
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.
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.
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.
.
•Serum lipid levels may serve as a prognostic marker for colorectal cancer recurrence.•High HDL-C may be associated with increased RFS time for CRC patients.•The association between HDL-C levels and ...RFS for CRC patients was more pronounced in statin users.
Biologic and epidemiologic evidence suggests that tumor cells depend on reprogrammed lipid metabolic function for survival and growth. Lipids may promote tumor recurrence by providing energy needed for proliferation. Studies have found associations of serum lipids with cancer incidence, mortality, and disease-free mortality, though they have yet to evaluate the prognostic potential of serum lipids for colorectal cancer (CRC) recurrence.
341 Danish CRC patients who underwent surgical resection were actively followed between 2003–2011 from date of surgery until December 31, 2012, or death. Serum lipids including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), were collected at regular intervals. Lipids were assigned as time-varying exposures evaluated with a one-year lag. Cox proportional hazards models were used to assess recurrence rate, adjusting for clinically relevant covariates. A restricted analysis was performed in a group of non-statin users (n = 236).
Among 341 CRC patients, increased HDL-C appeared to have a beneficial impact on recurrence-free survival (RFS) for CRC patients, especially among statin users (hazard ratio HR for 0.1 mmol/L increase = 0.58; 95 % confidence interval CI: 0.43, 0.78). Increased LDL-C and TG were not associated with RFS. Increased lipids showed a near-null effect on CRC recurrence e.g. HR (95 % CI) for 0.1 mmol/L increase LDL = 1.01 (0.97, 1.19) among non-statin users.
Serum lipid levels of LDL-C and TG do not appear to be associated with CRC recurrence. Further investigation of the role of HDL-C in CRC recurrence may be of interest based on the suggestive inverse association observed here.
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.
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