Timothy L. Lash

Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis

BackgroundGene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified.ResultsTo investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes.ConclusionsThese findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.

Superficial and deep venous thrombosis, pulmonary embolism and subsequent risk of cancer

BACKGROUNDnIn contrast to deep venous thrombosis and pulmonary embolism, superficial venous thrombosis has not been considered to be a marker of occult cancer. However, actual data regarding the association are very limited.nnnMETHODSnWe identified all patients in Denmark from 1994 to 2009 with a diagnosis of superficial venous thrombosis, deep venous thrombosis in the legs or pulmonary embolism using population-based health registries. The occurrence of cancer in the three venous thromboembolism cohorts was compared with the expected numbers of cases estimated using national incidence rates to compute standardised incidence ratios (SIRs).nnnFINDINGSnWe identified a total of 7663 patients with superficial venous thrombosis, 45,252 with deep venous thrombosis and 24,332 with pulmonary embolism. In the first year of follow-up, very similar proportions of patients in the three cohorts were diagnosed with cancer. The SIR was 2.46 (95% CI, 2.10-2.86) for superficial venous thrombosis, 2.75 (95% CI, 2.60-2.90) for deep venous thrombosis, and 3.27 (95% CI, 3.03-3.52) for pulmonary embolism. After one year, the SIRs declined to 1.05 (95% CI, 0.96-1.16), 1.11 (95% CI 1.07-1.16) and 1.15 (95% CI, 1.09-1.22), respectively. For all three patient cohorts, particularly strong associations were found for cancers of the liver, lung, ovaries and pancreas as well as for non-Hodgkins lymphoma.nnnINTERPRETATIONnVenous thrombosis, whenever it is seen in the lower limbs, is a preclinical marker of prevalent cancer, particularly during the first year after diagnosis.

Heart Disease May Be a Risk Factor for Pulmonary Embolism Without Peripheral Deep Venous Thrombosis

Background— Heart diseases increase the risk of arterial embolism; whether they increase the risk of pulmonary embolism without peripheral venous thrombosis is less certain. Methods and Results— We conducted a nationwide, population-based case-control study in Denmark using patients diagnosed with pulmonary embolism and/or deep venous thrombosis between 1980 and 2007. We computed odds ratios to estimate relative risks associating preceding heart disease with pulmonary embolism, pulmonary embolism and deep venous thrombosis, or deep venous thrombosis alone. In this study, 45 282 patients had pulmonary embolism alone, 4680 had pulmonary embolism and deep venous thrombosis, and 59 790 had deep venous thrombosis alone; 541 561 were population controls. Myocardial infarction and heart failure in the preceding 3 months conferred high risks of apparently isolated pulmonary embolism (odds ratio, 43.5 [95% confidence interval (CI), 39.6–47.8] and 32.4 [95% CI, 29.8–35.2], respectively), whereas the risks of combined pulmonary embolism and deep venous thrombosis (19.7 [95% CI, 16.0–24.2] and 22.1 [95% CI, 18.7–26.0], respectively) and deep venous thrombosis alone (9.6 [95% CI, 8.6–10.7] and 12.7 [95% CI, 11.6–13.9], respectively) were lower. Left-sided valvular disease was associated with an odds ratio of 13.5 (95% CI, 11.3–16.1), whereas the odds ratio was 74.6 (95% CI, 28.4–195.8) for right-sided valvular disease. Restricting the analysis to cases diagnosed after 2000 led to lower risk estimates but the same overall pattern. Conclusion— Heart diseases increase the near-term risk for pulmonary embolism not associated with diagnosed peripheral vein thrombosis.

Longitudinal Assessment of Concurrent Changes in Left Ventricular Ejection Fraction and Left Ventricular Myocardial Tissue Characteristics After Administration of Cardiotoxic Chemotherapies Using T1-Weighted and T2-Weighted Cardiovascular Magnetic Resonance

Background—In a murine anthracycline-related cardiotoxicity model, increases in cardiovascular magnetic resonance myocardial contrast-enhanced T1-weighted signal intensity are associated with myocellular injury and decreases with left ventricular ejection fraction. We sought to determine whether T1- and T2-weighted measures of signal intensity associate with decreases in left ventricular ejection fraction in human subjects receiving potentially cardiotoxic chemotherapy. Methods and Results—In 65 individuals with breast cancer (n=51) or a hematologic malignancy (n=14), we measured left ventricular volumes, ejection fraction, and contrast-enhanced T1-weighted and T2-weighted signal intensity before and 3 months after initiating potentially cardiotoxic chemotherapy using blinded, unpaired analysis of cardiovascular magnetic resonance images. Participants were aged 51±12 years, of whom 55% received an anthracycline, 38% received a monoclonal antibody, and 6% received an antimicrotubule agent. Overall, left ventricular ejection fraction decreased from 57±6% to 54±7% (P<0.001) because of an increase in end-systolic volume (P<0.05). T1-weighted signal intensities also increased from 14.1±5.1 to 15.9±6.8 (P<0.05), with baseline values trending higher among individuals who received chemotherapy before study enrollment (P=0.06). Changes in T1-weighted signal intensity did not differ within the 17 LV myocardial segments (P=0.97). Myocardial edema quantified from T2-weighted images did not change significantly after 3 months (P=0.70). Conclusions—Concordant with previous animal studies, cardiovascular magnetic resonance measures of contrast-enhanced T1-weighted signal intensity occur commensurate with small but significant left ventricular ejection fraction declines 3 months after the receipt of potentially cardiotoxic chemotherapy. These data indicate that changes in T1-weighted signal intensity may serve as an early marker of subclinical injury related to the administration of potentially cardiotoxic chemotherapy in human subjects.

Leveraging Epidemiology and Clinical Studies of Cancer Outcomes: Recommendations and Opportunities for Translational Research

As the number of cancer survivors continues to grow, research investigating the factors that affect cancer outcomes, such as disease recurrence, risk of second malignant neoplasms, and the late effects of cancer treatments, becomes ever more important. Numerous epidemiologic studies have investigated factors that affect cancer risk, but far fewer have addressed the extent to which demographic, lifestyle, genomic, clinical, and psychosocial factors influence cancer outcomes. To identify research priorities as well as resources and infrastructure needed to advance the field of cancer outcomes and survivorship research, the National Cancer Institute sponsored a workshop titled Utilizing Data from Cancer Survivor Cohorts: Understanding the Current State of Knowledge and Developing Future Research Priorities on November 3, 2011, in Washington, DC. This commentary highlights recent findings presented at the workshop, opportunities to leverage existing data, and recommendations for future research, data, and infrastructure needed to address high priority clinical and research questions. Multidisciplinary teams that include epidemiologists, clinicians, biostatisticians, and bioinformaticists will be essential to facilitate future cancer outcome studies focused on improving clinical care of cancer patients, identifying those at high risk of poor outcomes, and implementing effective interventions to ultimately improve the quality and duration of survival.

Acute stress reaction and completed suicide.

BACKGROUNDnAcute stress reaction is a diagnosis given immediately following the experience of an exceptional mental or physical stressor. To the best of our knowledge, no study has examined the association between acute stress reaction diagnosis and suicide. The current study examined this association in a population-based sample. In addition, we examined comorbid psychiatric diagnoses as modifiers of this association.nnnMETHODSnData for the current study were obtained from the nationwide Danish health and administrative registries, which include data for all 5.4 million residents of Denmark. All suicides between 1 January 1994 and 31 December 2006 were included and controls were selected from a sample of all Danish residents. Using this nested case-control design, we examined 9612 suicide cases and 199 306 controls matched to cases with respect to gender, date of birth and time.nnnRESULTSnIn total, 95 cases (0.99%) and 165 controls (0.08%) had a diagnosis of acute stress reaction. Those diagnosed with acute stress reaction had 10 times the rate of completed suicide compared with those without this diagnosis, adjusting for the control to case matching, depression and marital status (95% confidence interval 7.7-14). Additionally, persons with acute stress reaction and depression, or acute stress reaction and substance abuse, had a greater rate of suicide than expected based on their independent effects.nnnCONCLUSIONSnAcute stress reaction is a risk factor for completed suicide.

Use of glucocorticoids and risk of breast cancer: a Danish population-based case-control study

IntroductionGlucocorticoids are widely prescribed drugs. In the human body, glucocorticoid is the main stress hormone and controls a variety of physiological and cellular processes, including metabolism and immune response. It belongs to the same steroid superfamily as estrogens, which are known to play a role in breast cancer. However, the effect of glucocorticoid use on the risk of breast cancer is not clear.MethodsWe conducted a case-control study using population-based medical databases from Northern Denmark (1.8 million inhabitants) to investigate the association between glucocorticoid prescriptions and breast cancer risk. The study included 9,488 incident breast cancer cases diagnosed between 1994 and 2008 and 94,876 population controls. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) associating glucocorticoid use with breast cancer occurrence, controlling for prescriptions of postmenopausal hormone replacement therapy, anti-diabetics, immunosuppressive drugs, and hospital diagnosis of obesity, diabetes, chronic pulmonary diseases and autoimmune diseases.ResultsWe found no effect on breast cancer risk in ever users (> 2 prescriptions) of any glucocorticoids (adjusted odds ratio (aOR) = 1.0; 95% CI: 0.96, 1.1), systemic glucocorticoids (aOR = 1.0; 95% CI: 0.96, 1.1), or inhaled glucocorticoids (aOR = 1.0; 95% CI: 0.95, 1.1), each compared to never users of any glucocorticoids. Associations for recent use (preceding two years) and former use (more than two years earlier) were near null in all dose categories (low, medium and high number of prescriptions). Intensity of systemic glucocorticoid use (cumulative prednisolone equivalent doses), regardless of duration (< 1, 1 to 5, 5+ years), was also not associated with breast cancer risk.ConclusionsOverall, our study provides no evidence that glucocorticoid use affects the risk of breast cancer.

Advanced age and adjuvant tamoxifen prescription in early-stage breast carcinoma patients.

Adjuvant tamoxifen is recommended for all women with estrogen receptor‐positive breast carcinoma without regard for age. We investigated age‐dependent variations in adjuvant tamoxifen prescription patterns in a cohort of women 80 years of age and older.

Clinical epidemiology and pharmacology of CYP2D6 inhibition related to breast cancer outcomes.

Adjuvant tamoxifen therapy of breast cancer patients with estrogen receptor-positive tumors reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized by several polymorphic enzymes, including cytochrome P450 2D6 (CYP2D6), to more active metabolites. We have reviewed the clinical pharmacology of tamoxifen and evaluated the evidence from clinical epidemiology studies regarding the association between CYP2D6 inhibition and tamoxifen effectiveness. We conclude that the impact of CYP2D6 inhibition on tamoxifen effectiveness is likely to be null or small, at least in the populations studied so far. Understanding the effect of variations in tamoxifen metabolism on breast cancer outcomes, if any, will likely require a broader perspective, including examination of the complete metabolic pathway and subgroups of patients with other markers of potentially poor tamoxifen response.

Determinants and patterns of utilization of primary percutaneous coronary intervention across 12 European countries: 2003–2008

BACKGROUNDnImportant differences exist between European countries in the degree of implementation of primary percutaneous coronary intervention (PPCI) for patients with ST-elevation myocardial infarction (STEMI). To investigate whether health care-associated economic and demographic country-level characteristics were associated with differences in utilization of PPCI, we aimed to examine 5-year trends in the implementation of PPCI for STEMI across 12 EU countries.nnnMETHODSnAn ecological study of aggregated data from national and international registries. Main outcome was the number of PPCI per 1,000,000 population, collected annually for the years 2003 to 2008. Impact of year on PPCI implementation was modeled using linear regression and mixed effects models used to quantify associations between PPCI use and country-level parameters.nnnRESULTSnThe annual growth in utilization of PPCI was 1.11 (1.03,1.20) per million. Country-level utilization rates varied from 0.82 (95% CI 0.52, 1.30) to 1.38 (95% CI 1.15, 1.64) per million per year. Number of physicians per 100,000 population, number of nurses and midwifes per 100,000 population, number of acute care beds per 100,000 population, population density per km(2), and proportion of population under 50 years old were associated with PPCI utilization.nnnCONCLUSIONSnAll 12 EU countries demonstrated evidence of PPCI implementation from 2003 to 2008. However, there was substantial variation in the use and rate of uptake of PPCI between countries. Differences in utilization rates of PPCI are associated with supply factors, such as numbers of beds and physicians, rather than healthcare economic characteristics. Further studies are needed to explore the influence of patient-level factors.