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Preview: JNCI Journal of the National Cancer Institute - current issue

JNCI Journal of the National Cancer Institute - current issue

JNCI Journal of the National Cancer Institute - RSS feed of current issue


Prediagnostic Body Mass Index Trajectories in Relation to Prostate Cancer Incidence and Mortality in the PLCO Cancer Screening Trial


Background: Evidence suggests that obesity in adulthood is associated with increased risk of "clinically significant" prostate cancer. However, studies of body mass index (BMI) across the adult life course and prostate cancer risks remain limited.

Methods: In a prospective cohort of 69 873 men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we examined associations of prediagnostic BMI across the adult life course with risk of incident prostate cancer and fatal prostate cancer (prostate cancer–specific mortality). At 13 years of follow-up, we identified 7822 incident prostate cancer cases, of which 3078 were aggressive and 255 fatal. BMI trajectories were determined using latent-class trajectory modeling. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: BMI at age 20 years, 50 years, and baseline questionnaire (mean age = 63 years) were associated with increased risks of fatal prostate cancer (HRs = 1.27–1.32 per five-unit increase). In five BMI trajectories identified, fatal prostate cancer risk was increased in men who had a normal BMI (HR = 1.95, 95% CI = 1.21 to 3.12) or who were overweight (HR = 2.65, 95% CI = 1.35 to 5.18) at age 20 years and developed obesity by baseline compared with men who maintained a normal BMI. Aggressive and nonaggressive prostate cancer were not associated with BMI, and modest inverse associations were seen for total prostate cancer.

Conclusions: Our results suggest that BMI trajectories during adulthood that result in obesity lead to an elevated risk of fatal prostate cancer.

The Association of Dyslipidemia With Chronic Lymphocytic Leukemia: A Population-Based Study


Background: Metabolic syndrome (MetS) is a risk factor for development of cancer. Because aberrant lipid metabolism is a pathogenic feature of chronic lymphocytic leukemia (CLL), our objective was to determine if CLL patients have a higher prevalence of MetS preceding diagnosis and to determine the impact of lipid-lowering medications on survival.

Methods: We conducted a population-based case-control study in Ontario, Canada, using administrative databases of adults age 66 years and older to compare the prevalence of MetS preceding CLL with age- and sex-matched control subjects. Logistic regression was used to study the association between MetS and its components to CLL. The Kaplan-Meier method and Cox Regression were used to investigate survival. All statistical tests were two-sided.

Results: We identified 2124 persons with CLL and 7935 control subjects from January 1, 2000, to December 31, 2005, with follow-up until March 31, 2014, three years from the date of last contact with the health care system, or death. The mean age was 75.6 years, 20.2% had diabetes, 35.8% had hypertension, and 17.6% had dyslipidemia. In multivariable analysis, dyslipidemia (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.11 to 1.44, P < .001) and hypertension (OR = 1.12, 95% CI = 1.01 to 1.25, P = .03) were associated with the development of CLL, whereas MetS and diabetes were not. Lipid-lowering medication was associated with a statistically significant improved survival in patients with CLL (HR = 0.53, 95% CI = 0.47 to 0.61, P < .001).

Conclusions: We demonstrate a higher prevalence of dyslipidemia preceding a diagnosis of CLL compared with control subjects, supporting preclinical data. Lipid-lowering medications appear to confer a survival advantage in CLL. Prospective studies are needed to confirm these results and test their potential as therapeutic applications.

Association of Uba6-Specific-E2 (USE1) With Lung Tumorigenesis


Background: The UBA6-specific E2 conjugating enzyme 1 (USE1) ubiquitin enzyme cascade is a poorly characterized arm of the ubiquitin-proteasome system. We investigated whether the UBA6-USE1 enzyme cascade plays a role in lung cancer tumorigenesis.

Methods: USE1 expression was assessed in tumor-normal paired samples from 106 lung cancer patients by immunoblot. USE1 was stably overexpressed and knocked down in lung cancer cell lines to evaluate cell proliferation, colony formation, and invasion. Xenograft models were used to determine the effects of USE1 on tumor growth (n = 7). Proteomics analysis was used to identify proteins interacting with USE1. The USE1 gene was sequenced in lung cancer patients, and missense mutations of USE1 were generated to evaluate its function. All statistical tests were two-sided.

Results: USE1 proteins were frequently overexpressed in lung cancer patients (92.5%) Stable overexpression of USE1 increased cell proliferation (P = .002), migration (P < .001), and invasion (P < .001), whereas knockdown of USE1 reduced cell proliferation (P < .001), migration (P = .003), and invasion in lung cancer cells and xenograft models (P < .001). USE1 was found to have a conserved D-box domain, and the level of the protein was regulated by the anaphase-promoting complex. Several missense mutations in USE1 identified in patients prolong the stability of the protein.

Conclusions: USE1 proteins are frequently overexpressed in lung cancer, and missense mutations in USE1 prolong the half-life of the protein, promoting tumor formation. Our findings reveal novel roles for USE1 in lung cancer and the possible use of USE1 as a novel biomarker and therapeutic target for lung cancer treatment.

Biospecimen Sharing Among Hispanic Women in a Safety-Net Clinic: Implications for the Precision Medicine Initiative


Biospecimen donation is key to the Precision Medicine Initiative, which pioneers a model for accelerating biomedical research through individualized care. Personalized medicine should be made available to medically underserved populations, including the large and growing US Hispanic population. We present results of a study of 140 Hispanic women who underwent a breast biopsy at a safety-net hospital and were randomly assigned to receive information and request for consent for biospecimen and data sharing by the patient’s physician or a research assistant. Consent rates were high (97.1% and 92.9% in the physician and research assistant arms, respectively) and not different between groups (relative risk [RR] = 1.05, 95% confidence interval [CI] = 0.96 to 1.10). Consistent with a small but growing literature, we show that perceptions of Hispanics’ unwillingness to participate in biospecimen sharing for research are not supported by data. Safety-net clinics and hospitals offer untapped possibilities for enhancing participation of underserved populations in the exciting Precision Medicine Initiative.

Adjuvant Therapy for Resected Gallbladder Cancer: Analysis of the National Cancer Data Base


Background: Management of resected gallbladder cancer relies on single-arm trials and retrospective observations. Our objective was to evaluate adjuvant therapy in a nationwide data set using causal inference methods to address sources of bias.

Methods: We studied patients with T2–3 or node-positive, nonmetastatic gallbladder cancer, resected with grossly negative margins and reported to the National Cancer Data Base between 2004 and 2011. We defined adjuvant therapy as any chemotherapy within 90 days of surgery, and upfront concurrent chemoradiation as radiation within 14 days of first chemotherapy. After adjusting for missing data and guarantee-time bias, and using propensity score analysis to minimize indication bias, we compared overall survival of patients receiving adjuvant therapies with untreated case subjects.

Results: Adjuvant chemotherapy was administered to 28.8% of 4775 patients, and upfront chemoradiation to 13.5%. Treatment was less frequent among patients who were older, patients with comorbidities, and among white Hispanic women. T3 or node-positive disease, microscopically positive margins, or extended resection increased the likelihood of adjuvant therapy. Overall survival at three years was 39.9% (95% confidence interval [CI] = 38.4% to 41.4%) and was unaffected by adjuvant therapy after adjusting for multiple confounders (hazard ratio = 1.01, 95% CI = 0.92 to 1.10). Patients with T3 or node-positive tumors treated with upfront adjuvant chemoradiation had a modest early survival advantage (absolute difference at two years = 6.8%, 95% CI = 1.1% to 12.6%), but survival curves converged after five years of follow-up.

Conclusions: The curative potential of current adjuvant therapy in gallbladder cancer is questionable, justifying placebo-controlled investigation of novel chemotherapy combinations or alternative approaches. Chemoradiation may provide a short-term benefit in locally advanced tumors.

Optimal Cervical Cancer Screening in Women Vaccinated Against Human Papillomavirus


Background: Current US cervical cancer screening guidelines do not differentiate recommendations based on a woman’s human papillomavirus (HPV) vaccination status. Changes to cervical cancer screening policies in HPV-vaccinated women should be evaluated.

Methods: We utilized an individual-based mathematical model of HPV and cervical cancer in US women to project the health benefits, costs, and harms associated with screening strategies in women vaccinated with the bivalent, quadrivalent, or nonavalent vaccine. Strategies varied by the primary screening test, including cytology, HPV, and combined cytology and HPV "cotesting"; age of screening initiation and/or switching to a new test; and interval between routine screens. Cost-effectiveness analysis was conducted from the societal perspective to identify screening strategies that would be considered good value for money according to thresholds of $50 000 to $200 000 per quality-adjusted life-year (QALY) gained.

Results: Among women fully vaccinated with the bivalent or quadrivalent vaccine, optimal screening strategies involved either cytology or HPV testing alone every five years starting at age 25 or 30 years, with cost-effectiveness ratios ranging from $34 680 to $138 560 per QALY gained. Screening earlier or more frequently was either not cost-effective or associated with exceedingly high cost-effectiveness ratios. In women vaccinated with the nonavalent vaccine, only primary HPV testing was efficient, involving decreased frequency (ie, every 10 years) starting at either age 35 years ($40 210 per QALY) or age 30 years ($127 010 per QALY); with lower nonavalent vaccine efficacy, 10-year HPV testing starting at earlier ages of 25 or 30 years was optimal. Importantly, current US guidelines for screening were inefficient in HPV-vaccinated women.

Conclusions: This model-based analysis suggests screening can be modified to start at later ages, occur at decreased frequency, and involve primary HPV testing in HPV-vaccinated women, providing more health benefit at lower harms and costs than current screening guidelines.

When Less is More


Urinary Cadmium and Breast Cancer: A Prospective Danish Cohort Study


Background: Cadmium is a human lung carcinogen, and recent evidence suggests it may play a role in hormone-related cancers because of its estrogenic activity. Case-control studies consistently show higher cadmium concentrations in urine from women diagnosed with breast cancer compared with control women. Our aim was to investigate the association between urinary cadmium and breast cancer in a prospective design.

Methods: We conducted a case-cohort study using the population-based Danish Diet Cancer and Health Cohort. Women age 50 to 64 years were recruited in 1993–1997 and provided urine for analysis. We identified 900 incident case patients in the Danish Cancer Registry and compared with 898 individuals in a subcohort. Urine samples collected at enrollment into the cohort were analyzed for cadmium and creatinine. We estimated incidence rate ratios (IRRs) for breast cancer in Cox proportional hazards models with age as time axis and calculated 95% confidence intervals (CIs).

Results: The linear analysis showed no association between urinary cadmium and risk for breast cancer (IRR = 1.00, 95% CI = 0.81 to 1.24 per ng Cd/mL urine). The categorical analyses showed a slightly higher risk for breast cancer for the second (IRR = 1.10, 95% CI = 0.86 to 1.42) and third (IRR = 1.14, 95% CI = 0.83 to 1.55) exposure tertiles compared with the lowest tertile. Results were similar in analyses of breast cancer subtypes defined by estrogen and progesterone receptor status and by histology, and analyses stratified by years from baseline to diagnosis.

Conclusions: This large prospective study showed no association between urinary concentration of cadmium and subsequent risk for development of postmenopausal breast cancer.

Financial Hardships Experienced by Cancer Survivors: A Systematic Review


Background: With rising cancer care costs, including high-priced cancer drugs, financial hardship is increasingly documented among cancer survivors in the United States; research findings have not been synthesized.

Methods: We conducted a systematic review of articles published between 1990 and 2015 describing the financial hardship experienced by cancer survivors using PubMed, Embase, Scopus, and CINAHL databases. We categorized measures of financial hardship into: material conditions (eg, out-of-pocket costs, productivity loss, medical debt, or bankruptcy), psychological responses (eg, distress or worry), and coping behaviors (eg, skipped medications). We abstracted findings and conducted a qualitative synthesis.

Results: Among 676 studies identified, 45 met the inclusion criteria and were incorporated in the review. The majority of the studies (82%, n = 37) reported financial hardship as a material condition measure; others reported psychological (7%, n = 3) and behavioral measures (16%, n = 7). Financial hardship measures were heterogeneous within each broad category, and the prevalence of financial hardship varied by the measure used and population studied. Mean annual productivity loss ranged from $380 to $8236, 12% to 62% of survivors reported being in debt because of their treatment, 47% to 49% of survivors reported experiencing some form of financial distress, and 4% to 45% of survivors did not adhere to recommended prescription medication because of cost.

Conclusions: Financial hardship is common among cancer survivors, although we found substantial heterogeneity in its prevalence. Our findings highlight the need for consistent use of definitions, terms, and measures to determine the best intervention targets and inform intervention development in order to prevent and minimize the impact of financial hardship experienced by cancer survivors.

Efficacy of NEDD8 Pathway Inhibition in Preclinical Models of Poorly Differentiated, Clinically Aggressive Colorectal Cancer


Background: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing.

Methods: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry. Associations between pevonedistat sensitivity and CRC molecular features were assessed by Student’s t test. A 184-gene transcriptional predictor was generated in cell lines and applied to 87 metastatic CRC samples for which patient-derived xenografts (PDXs) were available. In vivo reponse to pevonedistat was assessed in PDX models (≥5 mice per group). All statistical tests were two-sided.

Results: Sixteen (13.1%) cell lines displayed a marked response to pevonedistat, featuring DNA re-replication, proliferative block, and increased apoptosis. Pevonedistat sensitivity did not statistically significantly correlate with microsatellite instability or mutations in KRAS or BRAF and was functionally associated with low EGFR pathway activity. While ineffective on predicted resistant PDXs, in vivo administration of pevonedistat statistically significantly impaired growth of five out of six predicted sensitive models (P < .01). In samples from CRC patients, transcriptional prediction of pevonedistat sensitivity was associated with poor prognosis after surgery (hazard ratio [HR] = 2.49, 95% confidence interval [CI] = 1.34 to 4.62, P = .003) and early progression under cetuximab treatment (HR = 3.59, 95% CI = 1.60 to 8.04, P < .001). Histological and immunohistochemical analyses revealed that the pevonedistat sensitivity signature captures transcriptional traits of poor differentiation and high-grade mucinous adenocarcinoma.

Conclusions: These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective treatment for poorly differentiated, clinically aggressive CRC.

Inactivation of Cancer Mutations Utilizing CRISPR/Cas9


Although whole-genome sequencing has uncovered a large number of mutations that drive tumorigenesis, functional ratification for most mutations remains sparse. Here, we present an approach to test functional relevance of tumor mutations employing CRISPR/Cas9. Combining comprehensive sgRNA design and an efficient reporter assay to nominate efficient and selective sgRNAs, we establish a pipeline to dissect roles of cancer mutations with potential applicability to personalized medicine and future therapeutic use.

Risk of Advanced Neoplasia Using the National Cancer Institutes Colorectal Cancer Risk Assessment Tool


Background: There is no validated, discriminating, and easy-to-apply tool for estimating risk of colorectal neoplasia. We studied whether the National Cancer Institute’s (NCI’s) Colorectal Cancer (CRC) Risk Assessment Tool, which estimates future CRC risk, could estimate current risk for advanced colorectal neoplasia among average-risk persons.

Methods: This cross-sectional study involved individuals age 50 to 80 years undergoing first-time screening colonoscopy. We measured medical and family history, lifestyle information, and physical measures and calculated each person’s future CRC risk using the NCI tool’s logistic regression equation. We related quintiles of future CRC risk to the current risk of advanced neoplasia (sessile serrated polyp or tubular adenoma ≥ 1 cm, a polyp with villous histology or high-grade dysplasia, or CRC). All statistical tests were two-sided.

Results: For 4457 (98.5%) with complete data (mean age = 57.2 years, SD = 6.6 years, 51.7% women), advanced neoplasia prevalence was 8.26%. Based on quintiles of five-year estimated absolute CRC risk, current risks of advanced neoplasia were 2.1% (95% confidence interval [CI] = 1.3% to 3.3%), 4.8% (95% CI = 3.5% to 6.4%), 6.4% (95% CI = 4.9% to 8.2%), 10.0% (95% CI = 8.1% to 12.1%), and 17.6% (95% CI = 15.5% to 20.6%; P < .001). For quintiles of estimated 10-year CRC risk, corresponding current risks for advanced neoplasia were 2.2% (95% CI = 1.4% to 3.5%), 4.8% (95% CI = 3.5% to 6.4%), 6.5% (95% CI = 5.0% to 8.3%), 9.3% (95% CI = 7.5% to 11.4%), and 18.4% (95% CI = 15.9% to 21.1%; P < .001). Among persons with an estimated five-year CRC risk above the median, current risk for advanced neoplasia was 12.8%, compared with 3.7% among those below the median (relative risk = 3.4, 95 CI = 2.7 to 4.4).

Conclusions: The NCI’s Risk Assessment Tool, which estimates future CRC risk, may be used to estimate current risk for advanced neoplasia, making it potentially useful for tailoring and improving CRC screening efficiency among average-risk persons.



Bilateral Oophorectomy and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers


Background: Whether oophorectomy reduces breast cancer risk among BRCA mutation carriers is a matter of debate. We undertook a prospective analysis of bilateral oophorectomy and breast cancer risk in BRCA mutation carriers.

Methods: Subjects had no history of cancer, had both breasts intact, and had information on oophorectomy status (n = 3722). Women were followed until breast cancer diagnosis, prophylactic bilateral mastectomy, or death. A Cox regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with oophorectomy (coded as a time-dependent variable). All statistical tests were two-sided.

Results: Over a mean follow-up of 5.6 years, 350 new breast cancers were diagnosed. Among women with a BRCA1 or BRCA2 mutation, oophorectomy was not associated with breast cancer risk compared with women who did not undergo an oophorectomy. The age-adjusted hazard ratio associated with oophorectomy was 0.96 (95% CI = 0.73 to 1.26, P = .76) for BRCA1 and was 0.65 (95% CI = 0.37 to 1.16, P = .14) for BRCA2 mutation carriers. In stratified analyses, the effect of oophorectomy was statistically significant for breast cancer in BRCA2 mutation carriers diagnosed prior to age 50 years (age-adjusted HR = 0.18, 95% CI = 0.05 to 0.63, P = .007). Oophorectomy was not associated with risk of breast cancer prior to age 50 years among BRCA1 mutation carriers (age-adjusted HR = 0.79, 95% CI = 0.55 to 1.13, P = .51).

Conclusions: Findings from this large prospective study support a role of oophorectomy for the prevention of premenopausal breast cancer in BRCA2, but not BRCA1 mutation carriers. These findings warrant further evaluation.

Effects of In Utero Exposure to Ethinyl Estradiol on Tamoxifen Resistance and Breast Cancer Recurrence in a Preclinical Model


Background: Responses to endocrine therapies vary among patients with estrogen receptor (ER+) breast cancer. We studied whether in utero exposure to endocrine-disrupting compounds might explain these variations.

Methods: We describe a novel ER+ breast cancer model to study de novo and acquired tamoxifen (TAM) resistance. Pregnant Sprague Dawley rats were exposed to 0 or 0.1 ppm ethinyl estradiol (EE2), and the response of 9,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors to 15 mg/kg TAM, with (n = 17 tumors in the controls and n = 20 tumors in EE2 offspring) or without 1.2 g/kg valproic acid and 5 mg/kg hydralazine (n = 24 tumors in the controls and n = 32 tumors in EE2 offspring) in the female offspring, was assessed. One-sided Chi2 tests were used to calculate P values. Comparisons of differentially expressed genes between mammary tumors in in utero EE2-exposed and control rats, and between anti-estrogen-resistant LCC9 and -sensitive LCC1 human breast cancer cells, were also performed.

Results: In our preclinical model, 54.2% of mammary tumors in the control rats exhibited a complete response to TAM, of which 23.1% acquired resistance with continued anti-estrogen treatment and recurred. Mammary tumors in the EE2 offspring were statistically significantly less likely to respond to TAM (P = .047) and recur (P = .007). In the EE2 offspring, but not in controls, adding valproic acid and hydralazine to TAM prevented recurrence (P < .001). Three downregulated and hypermethylated genes (KLF4, LGALS3, MICB) and one upregulated gene (ETV4) were identified in EE2 tumors and LCC9 breast cancer cells, and valproic acid and hydralazine normalized the altered expression of all four genes.

Conclusions: Resistance to TAM may be preprogrammed by in utero exposure to high estrogen levels and mediated through reversible epigenetic alterations in genes associated with epithelial-mesenchymal transition and tumor immune responses.

Selective Activation of Anticancer Chemotherapy by Cancer-Associated Fibroblasts in the Tumor Microenvironment


Background: The tumor microenvironment has recently emerged as a new target of anticancer chemotherapy. Selective activation of anticancer chemotherapy in the tumor microenvironment would further reduce the toxicity of anticancer drugs toward normal tissues. Fibroblast activation protein (FAP) is known to be selectively overexpressed on cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Here, we designed an anticancer chemotherapeutic system based on promelittin, a peptide toxin that is selectively converted from an inactive form to the pore-forming melittin upon cleavage by FAP in the tumor microenvironment.

Methods: We conjugated promelittin-containing FAP-cleavable sequences to pegylated phospholipids and anchored them to reduced graphene oxide (rGO) nanosheets. The resulting nanosheets, PL-rGO, were tested for hemolysis and used for doxorubicin delivery. In vitro cocultures and in vivo tumor growth (n = 5 mice per group) with tissue immunostaining were used to test the selective activation of anticancer chemotherapy by FAP expressed on CAFs.

Results: FAP-specific hemolytic activity of PL-rGO was observed in cocultures of CAFs and HT29 cells but not in HT29 cells alone. Doxorubicin-loaded PL-rGO (Dox/PL-rGO) showed 3.4-fold greater cell-killing efficacy (compared with free Dox in the CAF/HT29 coculture system, effects that were not observed in HT29 cells alone). Intravenously administered Dox/PL-rGO reduced the growth of HT29 tumors more effectively than other treatments (Dox/PL-rGO: mean = 200.6 mm3, 95% confidence interval [CI] = 148.7 to 252.5 mm3; free Dox: mean = 697.0 mm3, 95% CI = 646.9 to 747.1 mm3, PL: mean = 565.0 mm3, 95% CI = 550.5 to 579.6 mm3; Dox/rGO: mean = 637.6 mm3, 95% CI = 619.5 to 655.7 mm3; PL-rGO: mean = 464.4 mm3, 95% CI = 433.0 to 495.8 mm3). Immunostaining of tumor tissues revealed that survival of CAFs and HT29 cells was lowest in the group treated with Dox/PL-rGO.

Conclusions: The demonstration of selective activation of PL-rGO by FAP on CAFs suggests that PL-rGO may serve as a tumor microenvironment–responsive anticancer chemotherapy system.

Regulation of Head and Neck Squamous Cancer Stem Cells by PI3K and SOX2


Background: We have an incomplete understanding of the differences between cancer stem cells (CSCs) in human papillomavirus–positive (HPV-positive) and –negative (HPV-negative) head and neck squamous cell cancer (HNSCC). The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but the differential signaling between CSCs and non-CSCs is also unknown.

Methods: We addressed these unresolved questions using CSCs identified from 10 HNSCC patient-derived xenografts (PDXs). Sorted populations were serially passaged in nude mice to evaluate tumorigenicity and tumor recapitulation. The transcription profile of HNSCC CSCs was characterized by mRNA sequencing, and the susceptibility of CSCs to therapy was investigated using an in vivo model. SOX2 transcriptional activity was used to follow the asymmetric division of PDX-derived CSCs. All statistical tests were two-sided.

Results: CSCs were enriched by high aldehyde dehydrogenase (ALDH) activity and CD44 expression and were similar between HPV-positive and HPV-negative cases (percent tumor formation injecting ≤ 1x103 cells: ALDH+CD44high = 65.8%, ALDH-CD44high = 33.1%, ALDH+CD44high = 20.0%; and injecting 1x105 cells: ALDH-CD44low = 4.4%). CSCs were resistant to conventional therapy and had PI3K/mTOR pathway overexpression (GSEA pathway enrichment, P < .001), and PI3K inhibition in vivo decreased their tumorigenicity (40.0%–100.0% across cases). PI3K/mTOR directly regulated SOX2 protein levels, and SOX2 in turn activated ALDH1A1 (P < .001 013C and 067C) expression and ALDH activity (ALDH+ [%] empty-control vs SOX2, 0.4% ± 0.4% vs 14.5% ± 9.8%, P = .03 for 013C and 1.7% ± 1.3% vs 3.6% ± 3.4%, P = .04 for 067C) in 013C and 067 cells. SOX2 enhanced sphere and tumor growth (spheres/well, 013C P < .001 and 067C P = .04) and therapy resistance. SOX2 expression prompted mesenchymal-to-epithelial transition (MET) by inducing CDH1 (013C P = .002, 067C P = .01), followed by asymmetric division and proliferation, which contributed to tumor formation.

Conclusions: The molecular link between PI3K activation and CSC properties found in this study provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies.



Cost and Complications of Local Therapies for Early-Stage Breast Cancer


Background: Guideline-concordant local therapy options for early breast cancer include lumpectomy plus whole breast irradiation (Lump+WBI), lumpectomy plus brachytherapy, mastectomy alone, mastectomy plus reconstruction, and, in older women, lumpectomy alone. We performed a comparative examination of each treatment’s complications and cost to assess their relative values.

Methods: Using the MarketScan database of younger women with private insurance and the SEER-Medicare database of older women with public insurance, we identified 105 211 women with early breast cancer diagnosed between 2000 and 2011. We used diagnosis and procedural codes to identify treatment complications within 24 months of diagnosis and compared complications by treatment using two-sided logistic regression. Mean total and complication-related cost, relative to Lump+WBI, were calculated from a payer’s perspective and adjusted for differences in covariables using linear regression. All statistical tests were two-sided.

Results: Lump+WBI was the most commonly used treatment. Mastectomy plus reconstruction was associated with nearly twice the complication risk of Lump+WBI (Marketscan: 54.3% vs 29.6%, relative risk [RR] = 1.87, 95% confidence interval [CI] = 1.82 to 1.91, P < .001; SEER-Medicare: 66.1% vs 37.6%, RR = 1.75, 95% CI = 1.69 to 1.82, P < .001) and was also associated with higher adjusted total cost (Marketscan: $22 481 greater than Lump+WBI; SEER-Medicare: $1748 greater) and complication-related cost (Marketscan: $9017 greater; SEER-Medicare: $2092 greater). Brachytherapy had modestly higher total cost and complications than WBI. Lumpectomy alone entailed lower cost and complications in the SEER-Medicare cohort only.

Conclusions: Mastectomy plus reconstruction results in substantially higher complications and cost than other guideline-concordant treatment options for early breast cancer. These findings are relevant to patients evaluating their local therapy options and to value-based population health management.

Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer


Background: Previously we identified a DNA damage response–deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance.

Methods: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided.

Results: We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher’s exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response–proficient cells (P < .01). Conditioned medium from DDRD cells statistically significantly attracted PBMCs when compared with medium from DNA damage response–proficient cells (P < .05), and this was dependent on CXCL10 and CCL5. DDRD cells demonstrated increased cytosolic DNA and constitutive activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle–specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner.

Conclusions: We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification of patients for immune checkpoint–based therapies.

Development of a RNA-Seq Based Prognostic Signature in Lung Adenocarcinoma


Background: Precision therapy for lung cancer will require comprehensive genomic testing to identify actionable targets as well as ascertain disease prognosis. RNA-seq is a robust platform that meets these requirements, but microarray-derived prognostic signatures are not optimal for RNA-seq data. Thus, we undertook the first prognostic analysis of lung adenocarcinoma RNA-seq data and generated a prognostic signature.

Methods: Lung adenocarcinoma RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) were divided chronologically into training (n = 255) and validation (n = 157) cohorts. In the training cohort, prognostic association was assessed by univariate Cox analysis. A prognostic signature was built with stepwise multivariable Cox analysis. Outcomes by risk group, stage, and mutation status were analyzed with Kaplan-Meier and multivariable Cox analyses. All the statistical tests were two-sided.

Results: In the training cohort, 96 genes had prognostic association with P values of less than or equal to 1.00x10-4, including five long noncoding RNAs (lncRNAs). Stepwise regression generated a four-gene signature, including one lncRNA. Signature high-risk cases had worse overall survival (OS) in the TCGA validation cohort (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 2.00 to 14.62) and a University of Michigan institutional cohort (n = 67; HR = 2.05, 95% CI = 1.18 to 4.55), and worse metastasis-free survival in the TCGA validation cohort (HR = 3.05, 95% CI = 2.31 to 13.37). The four-gene prognostic signature also statistically significantly stratified overall survival in important clinical subsets, including stage I (HR = 2.78, 95% CI = 1.91 to 11.13), EGFR wild-type (HR = 3.01, 95% CI = 1.73 to 14.98), and EGFR mutant (HR = 8.99, 95% CI = 62.23 to 141.44). The four-gene prognostic signature also stood out on top when compared with other prognostic signatures.

Conclusions: Here, we present the first RNA-seq prognostic signature for lung adenocarcinoma that can provide a powerful prognostic tool for precision oncology as part of an integrated RNA-seq clinical sequencing program.

Relevance of Tumor-Infiltrating Immune Cell Composition and Functionality for Disease Outcome in Breast Cancer


Background: Not all breast cancer patients benefit from neoadjuvant or adjuvant therapy, resulting in considerable undertreatment or overtreatment. New insights into the role of tumor-infiltrating immune cells suggest that their composition, as well as their functionality, might serve as a biomarker to enable optimal patient selection for current systemic therapies and upcoming treatment options such as immunotherapy.

Methods: We performed several complementary unbiased in silico analyses on gene expression profiles of 7270 unrelated tumor samples of nonmetastatic breast cancer patients with known clinical follow-up. CIBERSORT was used to estimate the fraction of 22 immune cell types to study their relations with pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). In addition, we used four previously reported immune gene signatures and a CD8+ T-cell exhaustion signature to assess their relationships with breast cancer outcome. Multivariable binary logistic regression and multivariable Cox regression were used to assess the association of immune cell–type fractions and immune signatures with pCR and DFS/OS, respectively.

Results: Increased fraction of regulatory T-cells in human epidermal growth factor receptor 2 (HER2)–positive tumors was associated with a lower pCR rate (odds ratio [OR] = 0.15, 95% confidence interval [CI] = 0.03 to 0.69), as well as shorter DFS (hazard ratio [HR] = 3.13, 95% CI = 1.23 to 7.98) and OS (HR = 7.69, 95% CI = 3.43 to 17.23). A higher fraction of M0 macrophages in estrogen receptor (ER)–positive tumors was associated with worse DFS (HR = 1.66, 95% CI = 1.18 to 2.33) and, in ER-positive/HER2-negative tumors, with worse OS (HR = 1.71, 95% CI = 1.12 to 2.61). Increased fractions of T-cells in all breast cancer patients related to a higher pCR rate (OR = 1.55, 95% CI = 1.01 to 2.38), prolonged DFS (HR = 0.68, 95% CI = 0.48 to 0.98), and, in HER2-positive tumors, with prolonged OS (HR = 0.27, 95% CI = 0.10 to 0.73). A higher fraction of activated mast cells was associated with worse DFS (HR = 5.85, 95% CI = 2.20 to 15.54) and OS (HR = 5.33, 95% CI = 2.04 to 13.91) in HER2-positive tumors. The composition of relevant immune cell types frequently differed per breast cancer subtype. Furthermore, a high CD8+ T-cell exhaustion signature score was associated with shortened DFS in patients with ER-positive tumors regardless of HER2 status (HR = 1.80, 95% CI = 1.07 to 3.04).

Conclusions: The main hypothesis generated in our unbiased in silico approach is that a multitude of immune cells are related to treatment response and outcome in breast cancer.

Beyond Composite Endpoints Analysis: Semicompeting Risks as an Underutilized Framework for Cancer Research


Background: Composite endpoints (CEP), such as progression-free survival, are commonly used in cancer research. Notwithstanding their popularity, however, CEP analyses suffer from a number of drawbacks, especially when death is combined with a nonterminal event (ie, progression or recurrence), exemplifying the semicompeting risks setting. We investigated the semicompeting risks framework as a complementary analysis strategy that avoids certain drawbacks of CEPs.

Methods: The illness-death model under the semicompeting risks framework was compared with standard analysis approaches: CEP analyses and (separate) univariate analyses for each component endpoint. Data from a previously published phase III randomized clinical trial in metastatic colon cancer including 1419 participants in the N9741 trial (conducted between 1997 and 2003) were used to determine the impact of the loss of information associated with combining multiple endpoints, as well as of ignoring the potentially informative role of death. A simulation study was conducted to further explore these issues.

Results: Failure to account for critical features of semicompeting risks data can lead to potentially severely misleading conclusions. Advantages of semicompeting risks analyses include a clear delineation of treatment effects on both events, the ability to draw conclusions about a patient’s joint risk of the two events, and an assessment of the dependence between the two event types.

Conclusions: Embedding and analyzing component outcomes in the semicompeting risks framework, either as a supplement or alternative to CEP analyses, represents an important, underutilized, and feasible opportunity for cancer research.

Distribution and Patterns of Industry-Related Payments to Oncologists in 2014


Background: Industry-physician collaboration is critical for anticancer therapeutic development, but financial relationships introduce conflicts of interest. We examined the specialty variation and context of physician payments and ownership interest among oncologists.

Methods: We performed a population-based multivariable analysis of 2014 Open Payments reports of industry payments to US physicians matched to physician and practice data, including sex, specialty, practice location, and sole proprietor status. Payment data were aggregated per physician and compared by specialty (medical, radiation, surgical, and nononcology), and practice location linked with spending level (low, average, and high). Primary outcomes included likelihood, mean annual amount, and number of general payments. Secondary outcomes included likelihood of holding ownership interests and receipt of royalty/license payments. Estimates for each outcome were determined using multivariable models, including logistic regression for likelihood and linear regression with gamma distribution and log-link for value, adjusted for physician specialty, sex, sole proprietor status, and practice spending. All statistical tests were two-sided.

Results: In 2014, there were 883 438 physicians, including 22 712 oncologists, licensed to practice in the United States. Among oncology specialties, 52.4% to 63.0% of physicians received a general payment in 2014, totaling $76 million, $4 million, and $5 million to medical, radiation, and surgical oncology, respectively. The median annual per-physician payment to medical oncologists was $632 (IQR = 136–2500), compared with $124 (IQR = 39–323) in radiation oncology and $250 (IQR = 84–1369) in surgical oncology. After controlling for physician and practice characteristics, oncologists were 1.09 to 1.75 times as likely to receive a general payment compared with nononcologists (overall P < .001). There was a 67.6% difference (95% confidence interval [CI] = 63.6 to 71.5, P < .001) in the mean annual value of payments between medical oncology and nononcology specialties (vs –92.7%, 95%CI = –100.2 to –85.0, P < .001] for radiation oncology). Medical and radiation oncologists were more likely to hold ownership interest (adjusted OR = 3.72, 95% CI = 3.22 to 4.27, and 2.27, 95% CI = 1.65 to 3.03, respectively, P < .001 both comparisons).

Conclusions: In 2014, industry-oncologist financial relationships were common, and their impact on oncology practice should be further explored.

Repeat Prostate-Specific Antigen Tests Before Prostate Biopsy Decisions


Despite limited scientific support, a repeat prostate-specific antigen (PSA) test before prostate biopsy decisions is common. We analyzed biopsy outcomes in 1686 men from the STHLM3 study with PSA 3-10 ng/mL and two PSA tests taken within eight weeks and before prostate biopsy using percentages and multinomial logistic regression. We found that omitting prostate biopsy for men with PSA values decreasing to PSAs of 3 ng/mL or less would save 16.8% of biopsy procedures, while missing 5.4% of the cancers with Gleason scores (GSs) of 7 or higher. The proportion of cancers with GSs of 6 or lower was independent of the first PSA value, as well as of PSA change. Also, the risk of tumors with GSs of 7 or higher decreased with both decreasing and increasing PSA levels: It was 18.6% (95% confidence interval [CI] = 16.3% to 20.9%) for men with PSA changes of less than 20%, 12.1% (95% CI = 8.0% to 16.2%) for men with PSA levels increasing at least 20%, and 6.6% (95% CI = 3.8% to 9.3%) for men with PSA levels decreasing at least 20%.

Long-term Outcome of an Organ Preservation Program After Neoadjuvant Treatment for Rectal Cancer


Background: The aim of this study was to establish the oncological and functional results of organ preservation with a watch-and-wait approach (W&W) and selective transanal endoscopic microsurgery (TEM) in patients with a clinical complete or near-complete response (cCR) after neoadjuvant chemoradiation for rectal cancer.

Methods: Between 2004 and 2014, organ preservation was offered if response assessment with digital rectal examination, endoscopy, and MRI showed (near) cCR. Watch-and-wait was offered for cCR, and two options were offered for near cCR: TEM or reassessment after three months. Follow-up included endoscopy and MRIs every three months during the first year, and every six months thereafter. Long-term outcome was assessed with Kaplan-Meier curves. Functional outcome was assessed with colostomy-free survival and Vaizey incontinence score (0 = perfect continence, 24 = totally incontinent).

Results: One hundred patients were included, with median follow-up of 41.1 months. Sixty-one had cCR at initial response assessment. Thirty-nine had near cCR, of whom 24 developed cCR at the second assessment and 15 patients underwent TEM (9 ypT0, 1 ypT1, 5 ypT2). Fifteen patients developed a local regrowth (12 luminal, 3 nodal), all salvageable and within 25 months. Five patients developed metastases, and five patients died. Three-year overall survival was 96.6% (95% confidence interval [CI] = 89.9% to 98.9%), distant metastasis–free survival was 96.8% (95% CI = 90.4% to 99.0%), local regrowth–free survival was 84.6% (95% CI = 75.8% to 90.5%), and disease-free survival was 80.6% (95% CI = 70.9% to 87.4%). Colostomy-free survival was 94.8% (95% CI = 88.0% to 97.8%), with a good continence after watch-and-wait (Vaizey = 3.4, SD = 3.9) and moderate after TEM (Vaizey = 9.7, SD = 5.1).

Conclusions: Organ preservation appears oncologically safe for selected rectal cancer patients with a cCR or near cCR after neoadjuvant chemoradiation when applying strict selection criteria and frequent follow-up, including endoscopy and MRI. The low colostomy rate and the good long-term functional outcome warrant discussing this option with the patient as an alternative to major surgery.

Celecoxib for the Prevention of Colorectal Adenomas: Results of a Suspended Randomized Controlled Trial


Background: Cyclooxygenase (COX)-2 inhibitors such as celecoxib were designed to preserve anti-inflammatory activity without inhibiting COX-1. Downregulation of COX-2 inhibits colorectal carcinogenesis.

Methods: The Selenium and Celecoxib Trial was a randomized, placebo-controlled trial of once-daily selenium 200 µg and celecoxib 400 mg, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of adenomas. The primary outcome was development of new adenomas. Celecoxib was suspended early because of cardiovascular toxicity in other trials. Accrual to selenium or placebo continued. Before suspension, 824 participants were randomly assigned to celecoxib or placebo, of whom 712 (86.4%) were available for analysis. All statistical tests were two-sided.

Results: In the placebo and celecoxib arms of 356 participants each, adenoma detection was 47.5% and 49.7% (relative risk [RR] = 1.04, 95% confidence interval [CI] = 0.90 to 1.21, P = .58), respectively, after median periods of 13.6 and 14.2 months on intervention. Among participants colonoscoped within 12 months of discontinuing intervention (n = 244), overall adenoma recurrence (RR = 0.69, 95% CI = 0.48 to 0.98, P = .04) and recurrence with advanced adenomas (RR = 0.23, 95% CI = 0.07 to 0.80, P = .02) were reduced with celecoxib. Reduction of adenoma recurrence was greatest in participants with previous advanced adenomas. Celecoxib increased risk of hypertension in participants with pre-existing cardiovascular risk factors compared with placebo (hazard ratio = 2.19, 95% CI = 1.07 to 4.50, P = .03).

Conclusions: Limited-duration celecoxib prevents adenoma recurrence in patients with prior high-risk adenomas, in whom strategies to minimize cardiovascular toxicity might be feasible.

Selenium Supplementation for Prevention of Colorectal Adenomas and Risk of Associated Type 2 Diabetes


Background: Selenium supplementation may help to prevent colorectal cancer; as precursors of colorectal cancer, colorectal adenomas are a surrogate for colorectal cancer. Selenium supplementation may increase risk of type 2 diabetes (T2D).

Methods: The Selenium and Celecoxib (Sel/Cel) Trial was a randomized, placebo controlled trial of selenium 200 µg daily as selenized yeast and celecoxib 400 mg once daily, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of colorectal adenomas. The primary outcome was adenoma development. Celecoxib was suspended because of cardiovascular toxicity in other trials, but accrual continued to selenium and placebo. A total of 1621 participants were randomly assigned to selenium or placebo, of whom 1374 (84.8%) were available for analysis. All statistical tests were two-sided.

Results: In the respective placebo and selenium arms of 689 and 685 participants, adenoma detection after medians of 33.6 (range = 0.0–85.1 months) and 33.0 months (range = 0.0–82.6 months) were 42.8% and 44.1% (relative risk [RR] = 1.03, 95% confidence interval [CI] = 0.91 to 1.16, P = .68). In participants with baseline advanced adenomas, adenoma recurrence was reduced by 18% with selenium (RR = 0.82, 95% CI = 0.71 to 0.96, P = .01). In participants receiving selenium, the hazard ratio for new-onset T2D was 1.25 (95% CI = 0.74 to 2.11, P = .41), with a statistically significantly increased risk of selenium-associated T2D among older participants (RR = 2.21; 95% CI = 1.04 to 4.67, P = .03).

Conclusions: Overall, selenium did not prevent colorectal adenomas and showed only modest benefit in patients with baseline advanced adenomas. With limited benefit and similar increases in T2D to other trials, selenium is not recommended for preventing colorectal adenomas in selenium-replete individuals.

Pleiotropic Analysis of Lung Cancer and Blood Triglycerides


Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10-6) and blood triglycerides (P = 1.39x10-5). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 x 10-4) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21, Pcombined = 5.20x10-9). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer.

Long-term Consequences of Finasteride vs Placebo in the Prostate Cancer Prevention Trial


Background: Finasteride has been found to reduce the risk of low-grade prostate cancer but to have no impact on overall survival. The long-term adverse and beneficial consequences of finasteride have not been examined.

Methods: We used a linkage between data from the Prostate Cancer Prevention Trial (PCPT) and Medicare claims. Patients were examined by randomized study arm (finasteride vs placebo for 7 years) for long-term consequences of the intervention, including cardiac, endocrine, and sexual dysfunction, depression, diabetes, and benign prostatic hyperplasia (BPH)–related events. To examine time to events, we used cumulative incidence and Cox regression, adjusting for covariates. All statistical tests were two-sided.

Results: A total of 13 935 of 18 880 participants (73.8%) in the PCPT were linked to Medicare claims, with median Medicare follow-up assessment time of 16 years from trial registration. There were no differences between finasteride and placebo participants with respect to important baseline factors or amount of Medicare follow-up assessment time. Finasteride patients had a 10% higher risk of new claims for depression (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.01 to 1.19, P = .04) and a 6% lower risk of procedures for BPH-related events (primarily lower urinary tract symptoms; HR = 0.94, 95% CI = 0.89 to 1.00, P = .03). No other differences were found in rates of long-term consequences of intervention in the two study arms.

Conclusions: Finasteride use is associated with reduced need for procedures for relief of BPH-related events and a modest increase in depression. Overall, there is little need to worry about long-term noncancer consequences of finasteride use in those who use it for treatment of symptomatic BPH, hair growth, or prevention of cancer.

IGF-1R and mTOR Blockade: Novel Resistance Mechanisms and Synergistic Drug Combinations for Ewing Sarcoma


Background: Therapies cotargeting insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) have demonstrated remarkable, albeit short-lived, clinical responses in a subset of Ewing sarcoma (ES) patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to the IGF-1R/mTOR blockade are still undefined.

Methods: To elucidate predominant mechanism(s) of acquired drug resistance while identifying synergistic drug combinations that improve clinical efficacy, we generated more than 18 ES cell lines resistant to IGF-1R- or mTOR-targeted therapy. Two small-molecule inhibitors of IGF-1R were chosen, NVP-ADW-742 (IGF-1R-selective) and OSI-906 (a dual IGF-1R/insulin receptor alpha [IR-α] inhibitor). Reverse-phase protein lysate arrays (RPPAs) revealed proteomic changes linked to IGF-1R/mTOR resistance, and selected proteins were validated in cell-based assays, xenografts, and within human clinical samples. All statistical tests were two-sided.

Results: Novel mechanisms of resistance (MOR) emerged after dalotuzumab-, NVP-ADW-742-, and OSI-906-based targeting of IGF-1R. MOR to dalotuzumab included upregulation of IRS1, PI3K, and STAT3, as well as p38 MAPK, which was also induced by OSI-906. pEIF4E(Ser209), a key regulator of Cap-dependent translation, was induced in ridaforolimus-resistant ES cell lines. Unique drug combinations targeting IGF-1R and PI3K-alpha or Mnk and mTOR were synergistic in vivo and vitro (P < .001) as assessed respectively by Mantel-Cox and isobologram testing.

Conclusions: We discovered new druggable targets expressed by chemoresistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets, in concert with IGF-1R or mTOR blockade, should improve clinical outcomes.

Adverse Clinical Outcome Associated With Mutations That Typify African American Colorectal Cancers


African Americans have the highest incidence and mortality from colorectal cancer (CRC) of any US racial group. We recently described a panel of 15 genes that are statistically significantly more likely to be mutated in CRCs from African Americans than in Caucasians (AA-CRC genes). The current study investigated the outcomes associated with these mutations in African American CRCs (AA-CRCs). In a cohort of 66 patients with stage I-III CRCs, eight of 27 CRCs with AA-CRC gene mutations (Mut+) developed metastatic disease vs only four of 39 mutation-negative (Mut-) cases (P = .03, Cox regression model with two-sided Wald test). Moreover, among stage III cases (n = 33), Mut+ cancers were nearly three times more likely to relapse as Mut- cases (7 of 15 Mut+ vs 3 of 18 Mut-; P = .03, Cox regression model with two-sided Wald test). AA-CRC mutations may thus define a high-risk subset of CRCs that contributes to the overall disparity in CRC outcomes observed in African Americans.



Night Shift Work and Breast Cancer Incidence: Three Prospective Studies and Meta-analysis of Published Studies


Background: It has been proposed that night shift work could increase breast cancer incidence. A 2007 World Health Organization review concluded, mainly from animal evidence, that shift work involving circadian disruption is probably carcinogenic to humans. We therefore aimed to generate prospective epidemiological evidence on night shift work and breast cancer incidence.

Methods: Overall, 522 246 Million Women Study, 22 559 EPIC-Oxford, and 251 045 UK Biobank participants answered questions on shift work and were followed for incident cancer. Cox regression yielded multivariable-adjusted breast cancer incidence rate ratios (RRs) and 95% confidence intervals (CIs) for night shift work vs no night shift work, and likelihood ratio tests for interaction were used to assess heterogeneity. Our meta-analyses combined these and relative risks from the seven previously published prospective studies (1.4 million women in total), using inverse-variance weighted averages of the study-specific log RRs.

Results: In the Million Women Study, EPIC-Oxford, and UK Biobank, respectively, 673, 28, and 67 women who reported night shift work developed breast cancer, and the RRs for any vs no night shift work were 1.00 (95% CI = 0.92 to 1.08), 1.07 (95% CI = 0.71 to 1.62), and 0.78 (95% CI = 0.61 to 1.00). In the Million Women Study, the RR for 20 or more years of night shift work was 1.00 (95% CI = 0.81 to 1.23), with no statistically significant heterogeneity by sleep patterns or breast cancer risk factors. Our meta-analysis of all 10 prospective studies included 4660 breast cancers in women reporting night shift work; compared with other women, the combined relative risks were 0.99 (95% CI = 0.95 to 1.03) for any night shift work, 1.01 (95% CI = 0.93 to 1.10) for 20 or more years of night shift work, and 1.00 (95% CI = 0.87 to 1.14) for 30 or more years.

Conclusions: The totality of the prospective evidence shows that night shift work, including long-term shift work, has little or no effect on breast cancer incidence.

Night Shift Work and Breast Cancer Risk


Comparison of Eligibility Criteria Between Protocols, Registries, and Publications of Cancer Clinical Trials


Trial registration and public accessibility of appended or published protocols of phase III randomized clinical trials (RCTs) allow comparison of reported research with essential aspects of trial design. We determined how eligibility criteria of participants specified in protocols were described in trial registries and articles of 255 cancer RCTs published in leading journals. The mean proportion of matching eligibility criteria between protocols and publications per trial (the primary endpoint) was 44.0% (95% confidence interval [CI] = 40.8% to 47.3%). Almost all discrepancies in eligibility criteria (96.7%, 95% CI = 96.1% to 97.3%) suggested to readers of articles that a broader study population was included. The mean proportion of matching eligibility criteria between protocols and registries was 72.9% (95% CI = 68.2% to 77.7%, the secondary endpoint). We conclude that there are substantial differences in eligibility criteria between trial protocols, registries and articles. Inaccurate reporting of eligibility criteria may prevent appropriate assessment of the applicability of trial results.

Germline CDKN2A Mutation Status and Survival in Familial Melanoma Cases


Background: Germline mutations in CDKN2A have been associated with increased risk of melanoma and tobacco-related cancers in respiratory and upper digestive tissues. In CDKN2A wild-type (wt) melanoma families, other known high-risk, melanoma-predisposing mutations are rare, and no increased risk has been observed for nonskin cancers in this group. This study is the first to compare survival in germline CDKN2A mutated (mut) and nonmutated melanoma cases.

Methods: Melanoma-prone families participating in this study were identified through a nationwide predictive program starting in 1987. Information on cancer diagnoses (types, stages, and dates) and deaths (causes and dates) were obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan Meier and Cox proportional hazards regression models were used to assess survival in CDKN2Amut (n = 96) and CDKN2Awt (n = 377) familial melanoma cases and in matched sporadic melanoma cases (n = 1042). All statistical tests were two-sided.

Results: When comparing CDKN2Amut and CDKN2Awt melanoma cases, after adjusting for age, sex, and T classification, CDKN2Amut had worse survival than melanoma (hazard ratio [HR] = 2.50, 95% confidence interval [CI] = 1.49 to 4.21) and than nonmelanoma cancers (HR = 7.77, 95% CI = 3.65 to 16.51). Compared with matched sporadic cases, CDKN2Amut cases had statistically significantly worse survival from both melanoma and nonmelanoma cancers while no differences in survival were seen in CDKN2Awt compared with sporadic cases.

Conclusions: CDKN2Amut cases had statistically significantly worse survival than nonmelanoma cancers and, intriguingly, also from melanoma, compared with melanoma cases with no CDKN2A mutations. Further studies are required to elucidate possible mechanisms behind increased carcinogen susceptibility and the more aggressive melanoma phenotype in CDKN2A mutation carriers.

Molecularly Defined Adult Granulosa Cell Tumor of the Ovary: The Clinical Phenotype


The histopathologic features of adult granulosa cell tumors (AGCTs) are relatively nonspecific, resulting in misdiagnosis of other cancers as AGCT, a problem that has not been well characterized. FOXL2 mutation testing was used to stratify 336 AGCTs from three European centers into three categories: 1) FOXL2 mutant molecularly defined AGCT (MD-AGCT) (n = 256 of 336), 2) FOXL2 wild-type AGCT (n = 17 of 336), 3) misdiagnosed other tumor types (n = 63 of 336). All statistical tests were two-sided. The overall and disease-specific survival of the misdiagnosed cases was lower than in the MD-AGCTs (P < .001). The misdiagnosed cases accounted for 71.9% of disease-specific deaths within five years. In the population-based cohort, overall survival of MD-AGCT patients was not different from age-matched, population-based controls. Even though 35.2% of all the MD-AGCT patients in our study experienced a relapse, AGCT is usually an indolent disease. The historical, premolecular data underpinning our clinical understanding of AGCT was likely skewed by inclusion of misdiagnosed cases, and future management strategies should reflect the potential for surgical cure and long survival even after relapse.

Effect Modification by Time Since Blood Draw on the Association Between Circulating Fatty Acids and Prostate Cancer Risk


A recent meta-analysis suggested that circulating fatty acids do not play an important role in prostate carcinogenesis. We hypothesized that the relation between circulating fatty acids and prostate cancer (PCa) risk is modified by time between blood draw and diagnosis. We tested this hypothesis in a prospective case-control study of 476 PCa cases and matched control subjects nested in the Physicians’ Health Study. The previously reported associations between fatty acids and PCa in this cohort were dramatically stronger among men diagnosed 10 or more years after blood collection. Statistically significant effect modification by time since blood collection was identified for mono-unsaturated and poly-unsaturated fatty acids and was more pronounced for aggressive tumors. Among men diagnosed fewer than 10 years since blood collection, the relative risks per interquartile range were 1.03 (95% confidence interval [CI] = 0.86 to 1.25) for total mono-unsaturated fatty acids (MUFA) and 0.95 (95% CI = 0.78 to 1.15) for total poly-unsaturated fatty acids (PUFA) whereas among men diagnosed 10 or more years after blood draw the relative risks per interquartile range were 1.69 (95% CI = 1.21 to 2.34) for MUFA (Pheterogeneity = .01) and 0.59 (95% CI = 0.42 to 0.83) for PUFA (Pheterogeneity = .02). These data suggest that the results of the meta-analysis may be partly explained by insufficient follow-up time. Furthermore, they suggest that some environmental and metabolic factors may play a role in prostate carcinogenesis decades before clinical identification of this disease.

Genomic Analysis of Immune Cell Infiltrates Across 11 Tumor Types


Background: Immune infiltration of the tumor microenvironment has been associated with improved survival for some patients with solid tumors. The precise makeup and prognostic relevance of immune infiltrates across a broad spectrum of tumors remain unclear.

Methods: Using mRNA sequencing data from The Cancer Genome Atlas (TCGA) from 11 tumor types representing 3485 tumors, we evaluated lymphocyte and macrophage gene expression by tissue type and by genomic subtypes defined within and across tumor tissue of origin (Cox proportional hazards, Pearson correlation). We investigated clonal diversity of B-cell infiltrates through calculating B-cell receptor (BCR) repertoire sequence diversity. All statistical tests were two-sided.

Results: High expression of T-cell and B-cell signatures predicted improved overall survival across many tumor types including breast, lung, and melanoma (breast CD8_T_Cells hazard ratio [HR] = 0.36, 95% confidence interval [CI] = 0.16 to 0.81, P = .01; lung adenocarcinoma B_Cell_60gene HR = 0.71, 95% CI = 0.58 to 0.87, P = 7.80E-04; melanoma LCK HR = 0.86, 95% CI = 0.79 to 0.94, P = 6.75E-04). Macrophage signatures predicted worse survival in GBM, as did B-cell signatures in renal tumors (Glioblastoma Multiforme [GBM]: macrophages HR = 1.62, 95% CI = 1.17 to 2.26, P = .004; renal: B_Cell_60gene HR = 1.17, 95% CI = 1.04 to 1.32, P = .009). BCR diversity was associated with survival beyond gene segment expression in melanoma (HR = 2.67, 95% CI = 1.32 to 5.40, P = .02) and renal cell carcinoma (HR = 0.36, 95% CI = 0.15 to 0.87, P = .006).

Conclusions: These data support existing studies suggesting that in diverse tissue types, heterogeneous immune infiltrates are present and typically portend an improved prognosis. In some tumor types, BCR diversity was also associated with survival. Quantitative genomic signatures of immune cells warrant further testing as prognostic markers and potential biomarkers of response to cancer immunotherapy.

Role of Myeloma-Derived MIF in Myeloma Cell Adhesion to Bone Marrow and Chemotherapy Response


Background: Multiple myeloma (MM) remains an incurable cancer characterized by accumulation of malignant plasma cells in the bone marrow (BM). The mechanism underlying MM homing to BM is poorly elucidated.

Methods: The clinical significance of migration inhibitory factor (MIF) expression was examined by analyzing six independent gene expression profile databases of primary MM cells using the Student’s t test and Kaplan-Meier test. Enzyme-linked immunosorbent assay was used to examine MIF expression. In vivo bioluminescent imaging was used to determine MM cell localization and treatment efficacy in human MM xenograft mouse models, with three to four mice per group. MM cell attachment to BM stromal cells (BMSCs) was monitored by cell adhesion assay. MIF regulation of the expression of adhesion molecules was determined by chromatin immunoprecipitation (ChIP) assay. Statistical tests were two-sided.

Results: High levels of MIF were detected in MM BM (MIF level in BM plasma: healthy = 10.72 ± 5.788 ng/mL, n = 5; MM = 1811 ± 248.7 ng/mL, n = 10; P < .001) and associated with poor survival of patients (Kaplan-Meier test for MM OS: 87 MIFhigh patients, 86 MIFlow patients, P = .02). Knocking down MIF impaired MM cell adhesion to BMSCs in vitro and led to formation of extramedullary tumors in SCID mice. MIF acted through surface receptor CXCR4 and adaptor COPS5 to regulate the expression of adhesion molecules ALCAM, ITGAV, and ITGB5 on MM cells. More importantly, MIF-deficient MM cells were sensitive to chemotherapy in vitro when cocultured with BMSCs and in vivo. MIF inhibitor 4-IPP sensitized MM cells to chemotherapy.

Conclusions: MIF is an important player and a novel therapeutic target in MM. Inhibiting MIF activity will sensitize MM cells to chemotherapy.

Longitudinal Body Composition Changes in Diffuse Large B-cell Lymphoma Survivors: A Retrospective Cohort Study of United States Veterans


Background: Body composition parameters are associated with long-term health outcomes. We assessed longitudinal body composition changes in diffuse large B-cell lymphoma (DLBCL) survivors and identified clinical variables associated with the long-term development of sarcopenia and visceral obesity.

Methods: A retrospective cohort of United States veterans with DLBCL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab, was assembled. Muscle, subcutaneous fat, and visceral fat areas were measured with computed tomography analysis. Data were analyzed with repeated-measures analysis of variance and logistic regression. All statistical tests were two-sided.

Results: Three hundred forty-two patients were included. Muscle area initially decreased during treatment, then returned to baseline by 24 months after treatment. Subcutaneous fat area increased from baseline by 6.5% (95% confidence interval [CI] = 2.6% to 10.5%) during treatment and by 21.4% (95% CI = 15.7% to 27.2%) by 24 months after treatment. Visceral fat area increased from baseline by 4.5% (95% CI = -0.9% to 9.9%) during treatment and by 21.6% (95% CI = 14.8% to 28.4%) by 24 months after treatment. Variables associated with long-term development of sarcopenia included: baseline sarcopenia (adjusted odds ratio [aOR] = 17.21, 95% CI = 8.48 to 34.94), older than age 60 years (aOR = 2.93, 95% CI = 1.46 to 5.88), and weight loss greater than 5% during treatment (aOR = 2.40, 95% CI = 1.12 to 5.14). Variables associated with long-term visceral fat gain included: weight gain greater than 5% during treatment (aOR = 4.60, 95% CI = 2.42 to 8.74).

Conclusions: DLBCL survivors undergo unfavorable long-term body composition changes. Patients at risk for the long-term development of sarcopenia or visceral obesity can be identified based on clinical risk factors and targeted for lifestyle interventions.

The Doppelgänger Effect: Hidden Duplicates in Databases of Transcriptome Profiles


Whole-genome analysis of cancer specimens is commonplace, and investigators frequently share or re-use specimens in later studies. Duplicate expression profiles in public databases will impact re-analysis if left undetected, a so-called "doppelgänger" effect. We propose a method that should be routine practice to accurately match duplicate cancer transcriptomes when nucleotide-level sequence data are unavailable, even for samples profiled by different microarray technologies or by both microarray and RNA sequencing. We demonstrate the effectiveness of the method in databases containing dozens of datasets and thousands of ovarian, breast, bladder, and colorectal cancer microarray profiles and of matching microarray and RNA sequencing expression profiles from The Cancer Genome Atlas (TCGA). We identified probable duplicates among more than 50% of studies, originating in different continents, using different technologies, published years apart, and even within the TCGA itself. Finally, we provide the doppelgangR Bioconductor package for screening transcriptome databases for duplicates. Given the potential for unrecognized duplication to falsely inflate prediction accuracy and confidence in differential expression, doppelgänger-checking should be a part of standard procedure for combining multiple genomic datasets.

Mechanisms of Therapy Resistance in Patient-Derived Xenograft Models of BRCA1-Deficient Breast Cancer


Background: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer.

Methods: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time polymerase chain reaction and immunoblotting. Next-generation sequencing, methylation-specific multiplex ligation-dependent probe amplification (MLPA) and Target Locus Amplification (TLA)–based sequencing were used to determine mechanisms of BRCA1 re-expression in therapy-resistant tumors.

Results: BRCA1 protein was not detected in therapy-sensitive tumors but was found in 31 out of 42 resistant cases. Apart from previously described mechanisms involving BRCA1-intragenic deletions and loss of BRCA1 promoter hypermethylation, a novel resistance mechanism was identified in four out of seven BRCA1-methylated PDX tumors that re-expressed BRCA1 but retained BRCA1 promoter hypermethylation. In these tumors, we found de novo gene fusions that placed BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and acquisition of therapy resistance.

Conclusions: In addition to previously described clinically relevant resistance mechanisms in BRCA1-deficient tumors, we describe a novel resistance mechanism in BRCA1-methylated PDX tumors involving de novo rearrangements at the BRCA1 locus, demonstrating that BRCA1-methylated breast cancers may acquire therapy resistance via both epigenetic and genetic mechanisms.

Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies


Background: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade.

Methods: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided.

Results: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, Pheterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, Ptrend < .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, Pheterogeneity = .08).

Conclusions: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.

Comparison of EndoPredict and EPclin With Oncotype DX Recurrence Score for Prediction of Risk of Distant Recurrence After Endocrine Therapy


Background: Estimating distant recurrence (DR) risk among women with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2 (HER2)–negative early breast cancer helps decisions on using adjuvant chemotherapy. The 21-gene Oncotype DX recurrence score (RS) is widely used for this. EndoPredict (EPclin) is an alternative test combining prognostic information from an eight-gene signature (EP score) with tumor size and nodal status. We compared the prognostic information provided by RS and EPclin for 10-year DR risk.

Methods: We used likelihood ratio ² and Kaplan-Meier survival analyses to compare prognostic information provided by EP, EPclin, RS, and the clinical treatment score (CTS) of clinicopathologic parameters in 928 patients with ER+ disease treated with five years’ anastrozole or tamoxifen. Comparisons were made for early (0-5 years) and late (5-10 years) DR according to nodal status. All statistical tests were two-sided.

Results: In the overall population, EP and EPclin provided substantially more prognostic information than RS (LR2: EP = 49.3; LR2: EPclin = 139.3; LR2: RS = 29.1), with greater differences in late DR and in node-positive patients. EP and EPclin remained statistically significantly prognostic when adjusted for RS (LR2: EP+RS vs RS = 20.2; LR2: EPclin+RS vs RS = 113.8). Using predefined cut-offs, EPclin and RS identified 58.8% and 61.7% patients as low risk, with hazard ratios for non-low vs low risk of 5.99 (95% confidence interval [CI] = 3.94 to 9.11) and 2.73 (95% CI = 1.91 to 3.89), respectively.

Conclusions: EP and EPclin were highly prognostic for DR in endocrine-treated patients with ER+, HER2-negative disease. EPclin provided more prognostic information than RS. This was partly but not entirely because of EPclin integrating molecular data with nodal status and tumor size.



Editorial Board




Table of Contents


Endogenous Estrogens, Estrogen Metabolites, and Breast Cancer Risk in Postmenopausal Chinese Women


Background: The role of estrogen metabolism in determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood.

Methods: We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women’s Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided.

Results: Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (ORQ4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, Ptrend = .01). Of the pathway ratios, the 2-pathway:total estrogens/estrogen metabolites and 2-pathway:parent estrogens were inversely associated with risk (ORQ4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, Ptrend = .03, and ORQ4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, Ptrend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (ORQ4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, Ptrend = .12 and ORQ4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, Ptrend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women.

Conclusions: Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States.

Racial Differences in Quantitative Measures of Area and Volumetric Breast Density


Background: Increased breast density is a strong risk factor for breast cancer and also decreases the sensitivity of mammographic screening. The purpose of our study was to compare breast density for black and white women using quantitative measures.

Methods: Breast density was assessed among 5282 black and 4216 white women screened using digital mammography. Breast Imaging-Reporting and Data System (BI-RADS) density was obtained from radiologists’ reports. Quantitative measures for dense area, area percent density (PD), dense volume, and volume percent density were estimated using validated, automated software. Breast density was categorized as dense or nondense based on BI-RADS categories or based on values above and below the median for quantitative measures. Logistic regression was used to estimate the odds of having dense breasts by race, adjusted for age, body mass index (BMI), age at menarche, menopause status, family history of breast or ovarian cancer, parity and age at first birth, and current hormone replacement therapy (HRT) use. All statistical tests were two-sided.

Results: There was a statistically significant interaction of race and BMI on breast density. After accounting for age, BMI, and breast cancer risk factors, black women had statistically significantly greater odds of high breast density across all quantitative measures (eg, PD nonobese odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.02 to 1.37, P = .03, PD obese OR = 1.26, 95% CI = 1.04 to 1.53, P = .02). There was no statistically significant difference in BI-RADS density by race.

Conclusions: After accounting for age, BMI, and other risk factors, black women had higher breast density than white women across all quantitative measures previously associated with breast cancer risk. These results may have implications for risk assessment and screening.

Statins and Reduced Risk of Liver Cancer: Evidence for Confounding


A negative association of statin use with liver cancer risk has been reported frequently. We added laboratory measurements, to our knowledge not included in previous investigations, to a case-control analysis of 2877 case patients and 142 850 matched control subjects enrolled in Kaiser Permanente Northern California. Addressing confounding by indication by restricting subjects to those with elevated cholesterol greatly attenuated the negative association; eg, the multivariable-adjusted odds ratio (OR) rose from 0.41 (95% confidence interval [CI] = 0.35 to 0.49) to 0.87 (95% CI = 0.55 to 1.39) for receipt of 18 or more prescriptions. Confounding by contraindication was addressed by controlling for degree of abnormality of liver function tests, alanine or aspartate transaminase, measured within one year of the elevated cholesterol and strongly related to risk. The negative association of statins disappeared for all numbers of prescriptions received, with an odds ratio of 1.21 (95% CI = 0.53 to 2.75) for 18 or more prescriptions. Findings cast doubt on the causality of the frequently observed preventive association.

Family History and Probability of Prostate Cancer, Differentiated by Risk Category: A Nationwide Population-Based Study


Background: Familial prostate cancer risk estimates are inflated by clinically insignificant low-risk cancer, diagnosed after prostate-specific antigen testing. We provide age-specific probabilities of non-low- and high-risk prostate cancer.

Methods: Fifty-one thousand, eight hundred ninety-seven brothers of 32 807 men with prostate cancer were identified in Prostate Cancer data Base Sweden (PCBaSe). Nelson-Aalen estimates with 95% confidence intervals (CIs) were calculated for cumulative, family history–stratified probabilities of any, non-low- (any of Gleason score ≥ 7, prostate-specific antigen [PSA] ≥ 10 ng/mL, T3-4, N1, and/or M1) and high-risk prostate cancer (Gleason score ≥ 8 and/or T3-4 and/or PSA ≥ 20 ng/mL and/or N1 and/or M1).

Results: The population probability of any prostate cancer was 4.8% (95% CI = 4.8% to 4.9%) at age 65 years and 12.9% (95% CI = 12.8% to 12.9%) at age 75 years, of non-low-risk prostate cancer 2.8% (95% CI = 2.7% to 2.8%) at age 65 years and 8.9% (95% CI = 8.8% to 8.9%) at age 75 years, and of high-risk prostate cancer 1.4% (95% CI = 1.3% to 1.4%) at age 65 years and 5.2% (95% CI = 5.1% to 5.2%) at age 75 years. For men with one affected brother, probabilities of any prostate cancer were 14.9% (95% CI = 14.1% to 15.8%) at age 65 years and 30.3% (95% CI = 29.3% to 31.3%) at age 75 years, of non-low-risk prostate cancer 7.3% (95% CI = 6.7% to 7.9%) at age 65 years and 18.8% (95% CI = 17.9% to 19.6%) at age 75 years, and of high-risk prostate cancer 3.0% (95% CI = 2.6% to 3.4%) at age 65 years and 8.9% (95% CI = 8.2% to 9.5%) at age 75 years. Probabilities were higher for men with a stronger family history. For example, men with two affected brothers had a 13.6% (95% CI = 9.9% to 17.6 %) probability of high-risk cancer at age 75 years.

Conclusions: The age-specific probabilities of non-low- and high-risk cancer presented here are more informative than relative risks of any prostate cancer and more suitable to use for counseling men with a family history of prostate cancer.

Multiple Myeloma Mortality in Relation to Obesity Among African Americans


Multiple myeloma (MM) incidence and mortality are higher among African Americans (AAs) than among other population groups. The prevalence of obesity is also elevated among AAs, but few studies have examined risk of this cancer in relation to body size among AAs. We combined data from seven prospective cohorts tracking mortality among 239 597 AA adults and used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for death because of MM according to body mass index (BMI) at cohort entry, adjusted for age (as time-scale) and sex. Relative to those with normal BMIs (18.5-25 kg/m2), mortality increased monotonically as BMI increased, with hazard ratios reaching 1.43 (95% CI = 1.03 to 1.97) for BMIs of 35 kg/m2 or greater. The findings suggest that obesity is a risk factor for MM and a contributor to the elevated rates and rising incidence trends of MM among AAs in the United States.

De Novo vs Nevus-Associated Melanomas: Differences in Associations With Prognostic Indicators and Survival


Background: Although 20% to 30% of melanomas are histopathologically ‘nevus associated,’ the majority of melanomas arise de novo, ie, in clinically normal skin with no associated nevus. We examined whether these forms of melanoma differed in their associations with clinical and histopathologic features and patient survival. Methods: We analyzed two prospective cohorts from our institution with protocol-driven follow-up information (NYU1, n = 1024; NYU2, n = 1125). We used univariate and multivariable analyses to examine associations between de novo vs nevus-associated melanoma classification and age, anatomic site, tumor thickness, tumor ulceration, mitotic index, histological subtype, clinical stage, and survival. We tested the associations identified in NYU1 using NYU2 as a replication cohort. All tests of statistical significance were two-sided. Results: In NYU1, de novo melanomas were associated with tumor thickness greater than 1.0 mm (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.43 to 2.70, P < .001), ulceration (OR = 1.65, 95% CI = 1.10 to 2.54, P = .02), nodular subtype (OR = 3.26, 95% CI = 1.70 to 7.11, P = .001), greater than stage I (OR = 2.35, 95% CI = 1.65 to 3.40, P < .001), older age (OR = 1.64, 95% CI = 1.18 to 2.30, P = .004), and shorter overall survival (HR = 1.63, 95% CI = 1.22 to 2.18, P < .001). In NYU2, de novo melanoma was again statistically significantly associated with thickness greater than 1.0 mm (OR = 2.24, 95% CI = 1.72 to 2.93, P < .001), ulceration (OR = 2.88, 95% CI = 1.95 to 4.37, P < .001), nodular subtype (OR = 2.41, 95% CI = 1.75 to 3.37, P < .001), greater than stage I (OR = 2.42, 95% CI = 1.80 to 3.29, P < .001), older age (OR = 1.68, 95% CI = 1.31 to 2.17, P < .001), and shorter overall survival (HR = 2.52, 95% CI = 1.78 to 3.56, P < .001). In multivariable analysis, de novo classification was an independent, poor prognostic indicator in NYU2 (HR = 1.70, 95% CI = 1.19 to 2.44, P = .004). Male patients had a statistically significantly worse survival than female patients if their melanoma was de novo (NYU1, P < .001; NYU2, P < .001); unexpectedly, there was no sex difference in survival among patients with nevus-associated tumors. Conclusions: These data suggest that de novo melanomas are more aggressive than nevus-associated melanomas. This classification scheme [...]

Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression


Background: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat.

Methods: Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103 US Food and Drug Administration–approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. The compounds were screened in triplicate at nine concentrations with a 96-hour exposure time using an ATP Lite endpoint. Gene expression was assessed by exon array, and microRNA expression was derived by direct digital detection. Activity across the SCLC lines was associated with molecular characteristics using pair-wise Pearson correlations.

Results: Results are presented for inhibitors of targets: BCL2, PARP1, mTOR, IGF1R, KSP/Eg5, PLK-1, AURK, and FGFR1. A relational map identified compounds with similar patterns of response. Unsupervised microRNA clustering resulted in three distinct SCLC subgroups. Associating drug response with micro-RNA expression indicated that lines most sensitive to etoposide and topotecan expressed high miR-200c-3p and low miR-140-5p and miR-9-5p. The BCL-2/BCL-XL inhibitors produced similar response patterns. Sensitivity to ABT-737 correlated with higher ASCL1 and BCL2. Several classes of compounds targeting nuclear proteins regulating mitosis produced a response pattern distinct from the etoposide response pattern.

Conclusions: Agents targeting nuclear kinases appear to be effective in SCLC lines. Confirmation of SCLC line findings in xenografts is needed. The drug and compound response, gene expression, and microRNA expression data are publicly available at

Sweetened Beverage Consumption and Risk of Biliary Tract and Gallbladder Cancer in a Prospective Study


Background: Sugar-sweetened beverage consumption raises blood glucose concentration and has been positively associated with weight gain and type 2 diabetes, all of which have been implicated in the development of biliary tract cancer (BTC). This study examined the hypothesis that sweetened beverage consumption is positively associated with risk of BTC in a prospective study.

Methods: The study population comprised 70 832 Swedish adults (55.9% men, age 45-83 years) from the Swedish Mammography Cohort and Cohort of Swedish Men who were free of cancer and diabetes and completed a food frequency questionnaire at baseline. Incident BTC case patients were ascertained through linkage with the Swedish Cancer Register. Cox proportional hazards regression model was used to analyze the data. All statistical tests were two-sided.

Results: During a mean follow-up of 13.4 years, 127 extrahepatic BTC case patients (including 71 gallbladder cancers) and 21 intrahepatic BTC case patients were ascertained. After adjustment for other risk factors, women and men in the highest category of combined sugar-sweetened and artificially sweetened beverage consumption had a statistically significantly increased risk of extrahepatic BTC and gallbladder cancer. The multivariable hazard ratios for two or more servings per day (200 mL/serving) of sweetened beverages compared with no consumption were 1.79 (95% confidence interval [CI] = 1.02 to 3.13) for extrahepatic BTC and 2.24 (95% CI = 1.02 to 4.89) for gallbladder cancer. The corresponding hazard ratio for intrahepatic BTC was 1.69 (95% CI = 0.41 to 7.03).

Conclusions: These findings support the hypothesis that high consumption of sweetened beverages may increase the risk of BTC, particularly gallbladder cancer.

Burden of Cancer in a Large Consortium of Prospective Cohorts in Europe


Background: Disability-adjusted life-years (DALYs) are an indicator of mortality, morbidity, and disability. We calculated DALYs for cancer in middle-aged and older adults participating in the Consortium on Health and Ageing Network of Cohorts in Europe and the United States (CHANCES) consortium.

Methods: A total of 90 199 participants from five European cohorts with 10 455 incident cancers and 4399 deaths were included in this study. DALYs were calculated as the sum of the years of life lost because of premature mortality (YLLs) and the years lost because of disability (YLDs). Population-attributable fractions (PAFs) were also estimated for five cancer risk factors, ie, smoking, adiposity, physical inactivity, alcohol intake, and type II diabetes.

Results: After a median follow-up of 12 years, the total number of DALYs lost from cancer was 34 474 (382 per 1000 individuals) with a similar distribution by sex. Lung cancer was responsible for the largest number of lost DALYs (22.9%), followed by colorectal (15.3%), prostate (10.2%), and breast cancer (8.7%). Mortality (81.6% of DALYs) predominated over disability. Ever cigarette smoking was the risk factor responsible for the greatest total cancer burden (24.0%, 95% confidence interval [CI] = 22.2% to 26.0%), followed by physical inactivity (4.9%, 95% CI = 0.8% to 8.1%) and adiposity (1.8%, 95% CI = 0.2% to 2.8%).

Conclusions: DALYs lost from cancer were substantial in this large European sample of middle-aged and older adults. Even if the burden of disease because of cancer is predominantly caused by mortality, some cancers have sizeable consequences for disability. Smoking remained the predominant risk factor for total cancer burden.

Breast Density: More Than Meets the Eye


The Efficacy and Safety of First-line Chemotherapy in Advanced Esophagogastric Cancer: A Network Meta-analysis


Background: A globally accepted standard first-line chemotherapy regimen in advanced esophagogastric cancer (AEGC) is not clearly established. We conducted a systematic review to investigate the efficacy and safety of first-line chemotherapy using Network meta-analysis (NMA).

Methods: Medline, EMBASE, CENTRAL, and conferences were searched until June 2015 for randomized controlled trials that compared regimens containing: fluoropyrimidine (F), platinum (cisplatin [C] and oxaliplatin [Ox]), taxane (T), anthracycline (A), irinotecan (I), or methotrexate (M). Direct and indirect evidence for overall survival (OS) and progression-free-survival (PFS) were combined using random-effects NMA on the hazard ratio (HR) scale and calculated as combined hazard ratios and 95% credible intervals (CrIs).

Results: The NMA incorporated 17 chemotherapy regimens with 37 direct comparisons between regimens for OS (50 studies, n = 10 249) and 29 direct comparisons for PFS (34 studies, n = 7795). Combining direct and indirect effects showed increased efficacy for fluoropyrimidine noncisplatin doublets (F-doublets) over cisplatin doublets (C-doublets): FI vs CF (combined HR = 0.85, 95% CrI = 0.71 to 0.99), FOx vs CF (combined HR = 0.83, 95% CrI = 0.71 to 0.98) in OS and FOx vs CF (combined HR = 0.82, 95% CrI = 0.66 to 0.99) in PFS. Anthracycline-containing triplets (A-triplets: ACF, AFOx, AFM) and TCF triplet showed no benefit over F-doublets in OS and PFS. The triplet FOxT showed increased PFS vs F-doublets FT (combined HR = 0.61, 95% CrI = 0.38 to 0.99), FI (combined HR = 0.62, 95% CrI = 0.38 to 0.99), and FOx (combined HR = 0.67, 95% CrI = 0.44 to 0.99). Increased grade 3 to 4 toxicity was found for CF vs F-doublets, for ACF vs FI for TCF vs CF, and for FOxT vs FOx.

Conclusions: Based on efficacy and toxicity, F-doublets FOx, FI, and FT are preferred as first-line treatment for AEGC compared with C-doublets, A-triplets, and TCF. FOxT is the most promising triplet.

New Guidelines for Treating Ovarian Cancer


PDQ (Physician Data Query)


Autophagy Inhibitors: The Hunt Is On


Obesity Trends in the United States


Does Skin Cancer Screening Work?