• Home
  • News
  • Calendar
  • About DF/HCC
  • Membership
  • Visitor Center
 

Member Resources

Publications

Journal of the National Cancer Institute

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

Genetic interactions play a critical role in cancer development. Existing knowledge about cancer genetic interactions is incomplete, especially lacking evidences derived from large-scale cancer genomics data. The Cancer Genome Atlas (TCGA) produces multimodal measurements across genomics and features of thousands of tumors, which provide an unprecedented opportunity to investigate the interplays of genes in cancer.

Methods:

We introduce Zodiac, a computational tool and resource to integrate existing knowledge about cancer genetic interactions with new information contained in TCGA data. It is an evolution of existing knowledge by treating it as a prior graph, integrating it with a likelihood model derived by Bayesian graphical model based on TCGA data, and producing a posterior graph as updated and data-enhanced knowledge. In short, Zodiac realizes "Prior interaction map + TCGA data -> Posterior interaction map."

Results:

Zodiac provides molecular interactions for about 200 million pairs of genes. All the results are generated from a big-data analysis and organized into a comprehensive database allowing customized search. In addition, Zodiac provides data processing and analysis tools that allow users to customize the prior networks and update the genetic pathways of their interest. Zodiac is publicly available at www.compgenome.org/ZODIAC.

Conclusions:

Zodiac recapitulates and extends existing knowledge of molecular interactions in cancer. It can be used to explore novel gene-gene interactions, transcriptional regulation, and other types of molecular interplays in cancer.


Broglio and Berry (2009) examined the impact of survival postprogression (SPP) on overall survival (OS) when progression-free survival (PFS) was used to assess treatment effect in metastatic cancer. Their simulation studies found no statistical difference in OS because of dilution effect from SPP, although there was a statistical difference in PFS between treatment arms. Recently, two phase III clinical trials showed efficacy of experimental treatments in OS, but not PFS. These results seem counterintuitive, because it may be reasonable to consider that the effect of treatment in prolonging PFS can influence OS prolongation. We conducted simulations to examine the role of SPP in OS under the assumption that only SPP, and not PFS, differed between treatment arms. We also explored the impact of patient heterogeneity on the OS analysis. Our study offers a reasonable explanation for the two phase III trials and recommends further discussion of PFS as an adequate endpoint and what role SPP might play in OS to evaluate current treatment regimens.


Background:

Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling.

Methods:

We characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested the FAK inhibitor PF-04554878 in human PanNET cells in vitro and in vivo (at least three mice per group). In addition, we evaluated the effect of combined FAK and mTOR inhibition on PanNET viability and apoptosis. All statistical tests were two-sided.

Results:

We found that FAK is overexpressed and hyperphosphorylated in human PanNETs and that PF-04554878 strongly inhibited FAK (Tyr397) autophosphorylation in a dose-dependent manner. We found that PF-04554878 inhibited cell proliferation and clonogenicity and induced apoptosis in PanNET cells. Moreover, oral administration of PF-04554878 statistically significantly reduced tumor growth in a patient-derived xenograft model of PanNET (P = .02) and in a human PanNET xenograft model of peritoneal carcinomatosis (P = .03). Importantly, PF-04554878 synergized with the mTOR inhibitor everolimus by preventing feedback AKT activation.

Conclusions:

We demonstrate for the first time that FAK is overexpressed in PanNETs and that inhibition of FAK activity induces apoptosis and inhibits PanNET proliferation. We found that the novel FAK inhibitor PF-04554878 synergizes with everolimus, a US Food and Drug Administration–approved agent for PanNETs. Our findings warrant the clinical investigation of combined FAK and mTOR inhibition in PanNETs.


Background:

Aromatase inhibitors (AIs) substantially reduce breast cancer mortality in clinical trials, but high rates of nonadherence to these long-term oral therapies have reduced their impact outside of trials. We examined the association of generic AI availability with AI adherence among a large national breast cancer cohort.

Methods:

Using a quasi-experimental prepost design, we examined the effect of generic AI introductions (7/2010 and 4/2011) on adherence among a national cohort of women with incident breast cancer in 2006 and 2007 who were enrolled in the Medicare D pharmaceutical coverage program. Medicare D claims were used to calculate AI adherence, defined as a medication possession ratio of 80% or more of eligible days, over 36 months. Multivariable logistic regression models estimated with generalized estimating equations were applied to longitudinal adherence data to control for possible confounders, including receipt of a Medicare D low-income subsidy, and to account for repeated measures. All statistical tests were two-sided.

Results:

Sixteen thousand four hundred sixty-two Medicare D enrollees were eligible. Adherence declined throughout the study. However, among women without a subsidy, the median quarterly out-of-pocket cost of anastrozole fell from $183 in the fourth quarter of 2009 to $15 in 2011, and declines in adherence were attenuated with generic AI introductions. Regression-adjusted adherence probabilities were estimated to be 5.4% higher after generic anastrozole was introduced in 2010 and 11% higher after generic letrozole/exemestane was introduced in 2011. Subsidy recipients had higher adherence rates throughout the study.

Conclusions:

The introduction of generic medications attenuated the decline in adherence to AIs over three years of treatment among breast cancer survivors not receiving low-income subsidies for Medicare D coverage.


Cancer recurrence and disease-free survival are key outcomes for measuring the burden of illness, assessing the quality of cancer care, and informing decisions about increasingly costly cancer therapies. Yet information about recurrence is not collected in cancer registries or other population-based data sources. To address the lack of population-based recurrence information, researchers are increasingly using algorithms applied to health claims to infer recurrence. However, the validity of these approaches has not been comprehensively evaluated. In this commentary, we review existing studies and discuss options for improving the availability of recurrence data. We found that the validity of claims-based approaches appears promising in small, single institution studies, but larger population-based studies have identified substantial limitations with using claims to identify recurrence. With the increasing availability of health data, there are potential options that can be implemented to enhance information about recurrence. These options include design of software for the electronic medical record that enables rapid and standardized reporting of recurrence, use of electronic pathology reports to facilitate streamlined collection of recurrence by cancer registries, and mandates by insurers to require reporting of recurrence on health claims submitted by physicians. All of these options will require that governmental agencies, health insurers, professional societies, and other groups recognize the importance of population-based recurrence data and determine that this information is a priority for assessing cancer outcomes and costs.


Background:

Fibrinogen-like protein 2 (FGL2) may promote glioblastoma multiforme (GBM) cancer development by inducing multiple immune-suppression mechanisms.

Methods:

The biological significance of FGL2 expression was assessed using the The Cancer Genome Atlast (TCGA) glioma database and tumor lysates analysis. The therapeutic effects of an anti-Fgl2 antibody and the role of immune suppression regulation by Fgl2 were determined in immune-competent, NOD-scid IL2Rgammanull (NSG), and FcRIIB-/- mice (n = 3–18 per group). Data were analyzed with two-way analysis of variance, log-rank survival analysis, and Pearson correlation. All statistical tests were two-sided.

Results:

In low-grade gliomas, 72.5% of patients maintained two copies of the FGL2 gene, whereas 83.8% of GBM patients had gene amplification or copy gain. Patients with high levels of FGL2 mRNA in glioma tissues had a lower overall survival (P = .009). Protein levels of FGL2 in GBM lysates were higher relative to low-grade glioma lysates (11.48±5.75ng/mg vs 3.96±1.01ng/mg, P = .003). In GL261 mice treated with an anti-FGL2 antibody, median survival was 27 days compared with only 17 days for mice treated with an isotype control antibody (P = .01). The anti-FGL2 antibody treatment reduced CD39+ Tregs, M2 macrophages, programmed cell death protein 1 (PD-1), and myeloid-derived suppressor cells (MDSCs). FGL2-induced increases in M2, CD39, and PD-1 were ablated in FcRIIB-/- mice.

Conclusions:

FGL2 augments glioma immunosuppression by increasing the expression levels of PD-1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcRIIB pathway, and enhancing the number of MDSCs and CD39+ regulatory T cells. Collectively, these results show that FGL2 functions as a key immune-suppressive modulator and has potential as an immunotherapeutic target for treating GBM.


Background:

Studies have shown that antibodies targeting the intracellular (ICD) or extracellular domains (ECD) of human epidermal growth factor receptor 2 (HER2) are equivalent when traditional methods are used. We describe a new method to quantify ICD and ECD expression separately and assess the prognostic value of domain-specific HER2 results in patients who received adjuvant trastuzumab therapy.

Methods:

We measured HER2 protein expression with quantitative immunofluorescence (QIF) in tissue microarrays (TMA) using two different antibodies targeting the ICD (CB11 and A0485) and ECD (SP3 and D8F12). We assessed the prognostic value of ICD and ECD expression in 180 patients from a clinical trial of adjuvant chemotherapy followed by trastuzumab (HeCOG 10/05). We performed an exploratory univariate domain-specific, disease-free survival (DFS) analysis and compared DFS functions with Kaplan-Meier estimates. All statistical tests were two-sided.

Results:

HER2 ICD expression by QIF showed slightly higher sensitivity to predict ERBB2 (HER2) gene amplification than ECD expression, which was more specific and had higher positive predictive value. In the HeCOG 10/05 trial specimens, 15% of cases showed discordant results for ICD and ECD expression. High ECD was statistically associated with longer DFS (log-rank P = .049, HR = 0.31, 95% CI = 0.144 to 0.997), while ICD status was not. Among patients with low ECD, there was no difference in DFS by ICD status. However, when ICD was high, high ECD was statistically associated with longer DFS (log-rank P = .027, HR = 0.23, 95% CI = 0.037 to 0.82) compared with low ECD.

Conclusion:

Quantitative measurements of HER2 ICD and ECD expression in breast cancer suggest a subclassification of HER2-positive tumors. Trastuzumab-treated patients with high ECD showed better DFS than patients with low ECD. This suggests differential benefit from trastuzumab therapy based on HER2 ECD expression.


It is 45 years since a pleural effusion from a patient with metastatic breast cancer led to the generation of the MCF-7 breast cancer cell line. MCF-7 is the most studied human breast cancer cell line in the world, and results from this cell line have had a fundamental impact upon breast cancer research and patient outcomes. But of the authors for the nearly 25000 scientific publications that used this cell line, how many know the unique story of its isolation and development? In this commentary we will review the past, present, and future of research using MCF-7 breast cancer cells.


Background:

Many men with elevated prostate-specific antigen (PSA) levels in serum do not have aggressive prostate cancer and undergo unnecessary biopsy. Retrospective studies using cryopreserved serum suggest that four kallikrein markers can predict biopsy outcome.

Methods:

Free, intact and total PSA, and kallikrein-related peptidase 2 were measured in cryopreserved blood from 6129 men with elevated PSA (≥3.0ng/mL) participating in the prospective, randomized trial Prostate Testing for Cancer and Treatment. Marker levels from 4765 men providing anticoagulated plasma were incorporated into statistical models to predict any-grade and high-grade (Gleason score ≥7) prostate cancer at 10-core biopsy. The models were corrected for optimism by 10-fold cross validation and independently validated using markers measured in serum from 1364 men. All statistical tests were two-sided.

Results:

The four kallikreins enhanced prostate cancer detection compared with PSA and age alone. Area under the curve (AUC) for the four kallikreins was 0.719 (95% confidence interval [CI] = 0.704 to 0.734) vs 0.634 (95% CI = 0.617 to 0.651, P < .001) for PSA and age alone for any-grade cancer, and 0.820 (95% CI = 0.802 to 0.838) vs 0.738 (95% CI = 0.716 to 0.761) for high-grade cancer. Using a 6% risk of high-grade cancer as an illustrative cutoff, for 1000 biopsied men with PSA levels of 3.0ng/mL or higher, the model would reduce the need for biopsy in 428 men, detect 119 high-grade cancers, and delay diagnosis of 14 of 133 high-grade cancers. Models exhibited excellent discrimination on independent validation among men with only serum samples available for analysis.

Conclusions:

A statistical model based on kallikrein markers was validated in a large prospective study and reduces unnecessary biopsies while delaying diagnosis of high-grade cancers in few men.


Rapidly improving understanding of molecular oncology, emerging novel therapeutics, and increasingly available and affordable next-generation sequencing have created an opportunity for delivering genomically informed personalized cancer therapy. However, to implement genomically informed therapy requires that a clinician interpret the patient’s molecular profile, including molecular characterization of the tumor and the patient’s germline DNA. In this Commentary, we review existing data and tools for precision oncology and present a framework for reviewing the available biomedical literature on therapeutic implications of genomic alterations. Genomic alterations, including mutations, insertions/deletions, fusions, and copy number changes, need to be curated in terms of the likelihood that they alter the function of a "cancer gene" at the level of a specific variant in order to discriminate so-called "drivers" from "passengers." Alterations that are targetable either directly or indirectly with approved or investigational therapies are potentially "actionable." At this time, evidence linking predictive biomarkers to therapies is strong for only a few genomic markers in the context of specific cancer types. For these genomic alterations in other diseases and for other genomic alterations, the clinical data are either absent or insufficient to support routine clinical implementation of biomarker-based therapy. However, there is great interest in optimally matching patients to early-phase clinical trials. Thus, we need accessible, comprehensive, and frequently updated knowledge bases that describe genomic changes and their clinical implications, as well as continued education of clinicians and patients.


Background:

Prevention and treatment of advanced prostate cancer (PCa) by a nontoxic agent can improve outcome, while maintaining quality of life. 4-methylumbelliferone (4-MU) is a dietary supplement that inhibits hyaluronic acid (HA) synthesis. We evaluated the chemopreventive and therapeutic efficacy and mechanism of action of 4-MU.

Methods:

TRAMP mice (7–28 per group) were gavaged with 4-MU (450mg/kg/day) in a stage-specific treatment design (8–28, 12–28, 22–28 weeks). Efficacy of 4-MU (200–450mg/kg/day) was also evaluated in the PC3-ML/Luc+ intracardiac injection and DU145 subcutaneous models. PCa cells and tissues were analyzed for HA and Phosphoinositide 3-kinase (PI-3K)/Akt signaling and apoptosis effectors. HA add-back and myristoylated Akt (mAkt) overexpression studies evaluated the mechanism of action of 4-MU. Data were analyzed with one-way analysis of variance and unpaired t test or Tukey’s multiple comparison test. All statistical tests were two-sided.

Results:

While vehicle-treated transgenic adenocarcinoma of the prostate (TRAMP) mice developed prostate tumors and metastases at 28 weeks, both were abrogated in treatment groups, without serum/organ toxicity or weight loss; no tumors developed at one year, even after stopping the treatment at 28 weeks. 4-MU did not alter the transgene or neuroendocrine marker expression but downregulated HA levels. However, 4-MU decreased microvessel density and proliferative index (P < .0001,). 4-MU completely prevented/inhibited skeletal metastasis in the PC3-ML/Luc+ model and DU145-tumor growth (85–90% inhibition, P = .002). 4-MU also statistically significantly downregulated HA receptors, PI-3K/CD44 complex and activity, Akt signaling, and β-catenin levels/activation, but upregulated GSK-3 function, E-cadherin, and apoptosis effectors (P < .001); HA addition or mAkt overexpression rescued these effects.

Conclusion:

4-MU is an effective nontoxic, oral chemopreventive, and therapeutic agent that targets PCa development, growth, and metastasis by abrogating HA signaling.


Background:

The NCIC CTG LY.12 study showed that gemcitabine, dexamethasone, and cisplatin (GDP) were noninferior to dexamethasone, cytarabine, and cisplatin (DHAP) in patients with relapsed or refractory aggressive histology lymphoma prior to autologous stem cell transplantation. We conducted an economic evaluation from the perspective of the Canadian public healthcare system based on trial data.

Methods:

The primary outcome was an incremental cost utility analysis comparing costs and benefits associated with GDP vs DHAP. Resource utilization data were collected from 519 Canadian patients in the trial. Costs were presented in 2012 Canadian dollars and disaggregated to highlight the major cost drivers of care. Benefit was measured as quality-adjusted life-years (QALYs) based on utilities translated from prospectively collected quality-of-life data. All statistical tests were two-sided.

Results:

The mean overall costs of treatment per patient in the GDP and DHAP arms were $19 961 (95% confidence interval (CI) = $17 286 to $24 565) and $34 425 (95% CI = $31 901 to $39 520), respectively, with an incremental difference in direct medical costs of $14 464 per patient in favor of GDP (P < .001). The predominant cost driver for both treatment arms was related to hospitalizations. The mean discounted quality-adjusted overall survival with GDP was 0.161 QALYs and 0.152 QALYs for DHAP (difference = 0.01 QALYs, P = .146). In probabilistic sensitivity analysis, GDP was associated with both cost savings and improved quality-adjusted outcomes compared with DHAP in 92.6% of cost-pair simulations.

Conclusions:

GDP was associated with both lower costs and similar quality-adjusted outcomes compared with DHAP in patients with relapsed or refractory lymphoma. Considering both costs and outcomes, GDP was the dominant therapy.


Background:

Previous reports suggested that female breast cancer is associated with earlier ages at onset among Asian than Western populations. However, most studies utilized cross-sectional analyses that may be confounded by calendar-period and/or birth cohort effects. We, therefore, considered a longitudinal (forward-looking) approach adjusted for calendar-period changes and conditioned upon birth cohort.

Methods:

Invasive female breast cancer data (1988–2009) were obtained from cancer registries in China, Hong Kong, South Korea, Taiwan, Singapore, and the United States. Age-period-cohort models were used to extrapolate longitudinal age-specific incidence rates for the 1920, 1944, and 1970 birth cohorts.

Results:

Cross-sectional age-specific incidence rates rose continuously until age 80 years among US white women, but plateaued or decreased after age 50 years among Asian women. In contrast, longitudinal age-specific rates were proportional (similar) among all Asian countries and the United States with incidence rates rising continuously until age 80 years. The extrapolated estimates for the most recent cohorts in some Asian countries actually showed later ages at onset than in the United States. Additionally, over successive birth cohorts, the incidence rate ratios (IRRs) for the longitudinal curves converged (narrowed) between Asian and US white women.

Conclusions:

Similar longitudinal age-specific incidence rates along with converging IRRs indicate that the age effects for invasive breast cancer are more similar among Asian and Western populations than might be expected from a solely cross-sectional analysis. Indeed, the Asian breast cancer rates in recent generations are even surpassing the historically high rates in the United States, highlighting an urgent need for efficient prevention and treatment strategies among Asian populations.


Background:

Pretreatment cognitive impairment in cancer patients is well established but unexplained. Similar cognitive compromise has been observed in post-traumatic stress disorder (PTSD) patients, and PTSD symptoms are a frequent concomitant of cancer diagnosis. We tested the hypothesis that pretreatment cognitive impairment is attributable to cancer-related post-traumatic stress.

Methods:

Women aged 65 years or younger who were diagnosed with breast cancer (case patients) or had undergone negative routine breast imaging (control patients) at one of six participating breast centers underwent traditional and computerized neuropsychological testing, clinician-administered diagnostic assessment of stress disorders, and self-report assessments of cognitive function and depression. To minimize confounding, case patients were evaluated prior to any local or systemic treatment. Cognitive indices of case patients, control patients, and normative samples were compared. The patients’ risk of overall cognitive impairment was determined. Linear regression and a mediation model were used to test the study hypothesis. All statistical tests were two-sided.

Results:

The 166 case patients and 60 well-matched control patients showed near-identical deviations from population norms. Case patients scored worse than control patients on two of 20 cognitive indices (Go/Nogo commission errors, Go/Nogo omission errors). Self-reported cognitive problems were associated with Go/Nogo omission errors and more pronounced in case patients. Only PTSD symptoms (Beta = 0.27, P = .004) and age (Beta = 0.22, P = .04) statistically significantly predicted Go/Nogo errors. The effect of having cancer on Go/Nogo errors was mediated by PTSD symptoms. Case patients did not have an increased risk of overall cognitive impairment.

Conclusion:

Prior to any treatment, breast cancer patients may show limited cognitive impairment that is apparently largely caused by cancer-related post-traumatic stress.


The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with 2 tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants.


Background:

Earlier detection of second breast cancers after primary breast cancer (PBC) treatment improves survival, yet mammography is less accurate in women with prior breast cancer. The purpose of this study was to examine women presenting clinically with second breast cancers after negative surveillance mammography (interval cancers), and to estimate the five-year risk of interval-invasive second cancers for women with varying risk profiles.

Methods:

We evaluated a prospective cohort of 15 114 women with 47 717 surveillance mammograms diagnosed with stage 0-II unilateral PBC from 1996 through 2008 at facilities in the Breast Cancer Surveillance Consortium. We used discrete time survival models to estimate the association between odds of an interval-invasive second breast cancer and candidate predictors, including demographic, PBC, and imaging characteristics. All statistical tests were two-sided.

Results:

The cumulative incidence of second breast cancers after five years was 54.4 per 1000 women, with 325 surveillance-detected and 138 interval-invasive second breast cancers. The five-year risk of interval-invasive second cancer for women with referent category characteristics was 0.60%. For women with the most and least favorable profiles, the five-year risk ranged from 0.07% to 6.11%. Multivariable modeling identified grade II PBC (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.15 to 3.31), treatment with lumpectomy without radiation (OR = 3.27, 95% CI = 1.91 to 5.62), interval PBC presentation (OR = 2.01, 95% CI 1.28 to 3.16), and heterogeneously dense breasts on mammography (OR = 1.54, 95% CI = 1.01 to 2.36) as independent predictors of interval-invasive second breast cancers.

Conclusions:

PBC diagnosis and treatment characteristics contribute to variation in subsequent-interval second breast cancer risk. Consideration of these factors may be useful in developing tailored post-treatment imaging surveillance plans.


Background:

Breastfeeding is associated with decreased breast cancer risk, yet associations with prognosis and survival by tumor subtype are largely unknown.

Methods:

We conducted a cohort study of 1636 women from two prospective breast cancer cohorts. Intrinsic tumor subtype (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]–enriched, basal-like) was determined by the PAM50 gene expression assay. Breastfeeding history was obtained from participant questionnaires. Questionnaires and medical record reviews documented 383 recurrences and 290 breast cancer deaths during a median follow-up of nine years. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between breastfeeding and tumor subtype. Cox regression was used to estimate hazard ratios (HRs) for breast cancer recurrence or death. Statistical significance tests were two-sided.

Results:

Breast cancer patients with basal-like tumors were less likely to have previously breastfed than those with luminal A tumors (OR = 0.56, 95% CI = 0.39 to 0.80). Among all patients, ever breastfeeding was associated with decreased risk of recurrence (HR = 0.70, 95% CI = 0.53 to 0.93), especially breastfeeding for six months or more (HR = 0.63, 95% CI = 0.46 to 0.87, P trend = .01). Similar associations were observed for breast cancer death. Among women with luminal A subtype, ever breastfeeding was associated with decreased risks of recurrence (HR = 0.52, 95% CI = 0.31 to 0.89) and breast cancer death (HR = 0.52, 95% CI = 0.29 to 0.93), yet no statistically significant associations were observed among the other subtypes. Effects appeared to be limited to tumors with lower expression of proliferation genes.

Conclusions:

History of breastfeeding might affect prognosis and survival by establishing a luminal tumor environment with lower proliferative activity.


Background:

The aim of this study was to quantify the benefits and harms of mammography screening after age 74 years, focusing on the amount of overdiagnosis of invasive breast cancer and ductal carcinoma in situ (DCIS).

Methods:

Three well-established microsimulation models were used to simulate a cohort of American women born in 1960. All women received biennial screening starting at age 50 years with cessation ages varying from 74 up to 96 years. We estimated the number of life-years gained (LYG), quality-adjusted life-years, breast cancer deaths averted, false-positives, and overdiagnosed women per 1000 screens.

Results:

The models predicted that there were 7.8 to 11.4 LYG per 1000 screens at age 74 years (range across models), decreasing to 4.8 to 7.8 LYG per 1000 screens at age 80 years, and 1.4 to 2.4 LYG per 1000 screens at age 90 years. When adjusted for quality-of-life decrements, the LYG decreased by 5% to 13% at age 74 years and 11% to 22% at age 80 years. At age 90 to 92 years, all LYG were counterbalanced by a loss in quality-of-life, mainly because of the increasing number of overdiagnosed breast cancers per 1000 screens: 1.2 to 5.0 at age 74 years, 1.8 to 6.0 at age 80 years, and 3.7 to 7.5 at age 90 years. The age at which harms began to outweigh benefits shifted to a younger age when larger or longer utility losses because of a breast cancer diagnosis were assumed.

Conclusion:

The balance between screening benefits and harms becomes less favorable after age 74 years. At age 90 years, harms outweigh benefits, largely as a consequence of overdiagnosis. This age was the same across the three models, despite important model differences in assumptions on DCIS.


Background:

Clinical guidelines for breast cancer chemoprevention and MRI screening involve estimates of remaining lifetime risk (RLR); in the United States, women with an RLR of 20% or higher meet "high-risk" criteria for MRI screening.

Methods:

We prospectively followed 1764 women without breast cancer to compare the RLRs and 10-year risks assigned by the risk models International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and to compare both sets of model-assigned 10-year risks to subsequent incidence of breast cancer in the cohort. We used chi-square statistics to assess calibration and the area under the receiver operating characteristic curve (AUC) to assess discrimination. All statistical tests are two-sided.

Results:

The models classified different proportions of women as high-risk (IBIS = 59.3% vs BOADICEA = 20.1%) using the RLR threshold of 20%. The difference was smaller (IBIS = 52.9% vs BOADICEA = 43.2%) using a 10-year risk threshold of 3.34%. IBIS risks (mean = 4.9%) were better calibrated to observed breast cancer incidence (5.2%, 95% confidence interval (CI) = 4.2% to 6.4%) than were those of BOADICEA (mean = 3.7%) overall and within quartiles of model risk (P = .20 by IBIS and P = .07 by BOADICEA). Both models gave similar discrimination, with AUCs of 0.67 (95% CI = 0.61 to 0.73) using IBIS and 0.68 (95% CI = 0.62 to 0.74) using BOADICEA. Model sensitivities at thresholds for a 20% false-positive rate were also similar, with 41.8% using IBIS and 38.0% using BOADICEA.

Conclusion:

RLR-based guidelines for high-risk women are limited by discordance between commonly used risk models. Guidelines based on short-term risks would be more useful, as models are generally developed and validated under a short fixed time horizon (≤10 years).


A recent study reports that the log lifetime incidence rate across a selection of 31 cancer types is highly correlated with the log of the estimated tissue-specific lifetime number of stem cell divisions. This observation, which underscores the importance of errors in DNA replication, has been viewed as implying that most cancers arise through unavoidable bad luck, leading to the suggestion that research efforts should focus on early detection, rather than etiology or prevention. We argue that three statistical issues can, if ignored, lead analysts to incorrect conclusions. Statistics for traffic fatalities across the United States provide an example to demonstrate those inferential pitfalls. While the contribution of random cellular events to disease is often underappreciated, the role of chance is necessarily difficult to quantify. The conclusion that most cases of cancer are fundamentally unpreventable because they are the result of chance is unwarranted.


Background:

Clinically lymph node–positive (cN+) prostate cancer (PCa) is an often-fatal disease. Its optimal management remains largely undefined given a lack of prospective, randomized data to inform practice. We sought to describe modern practice patterns in the management of cN+ PCa and assess the effect of adding radiation therapy (RT) to androgen deprivation therapy (ADT) on survival using the National Cancer Data Base.

Methods:

Patients with cN+ PCa and without distant metastases diagnosed between 2004 and 2011 were included. Five-year overall survival for patients diagnosed between 2004 and 2006 and treated with ADT alone or ADT+RT were compared. Propensity score (PS) matching was used to balance baseline characteristics, and Cox multivariate regression analysis was used to estimate hazard ratios (HRs) for all-cause mortality.

Results:

Of 3540 total patients, 32.2% were treated with ADT alone and 51.4% received ADT+RT. Compared with ADT alone, patients treated with ADT+RT were younger and more likely to have private insurance, lower comorbidity scores, higher Gleason scores, and lower PSA values. After PS matching, 318 patients remained in each group. Compared with ADT alone, ADT+RT was associated with a 50% decreased risk of five-year all-cause mortality (HR = 0.50, 95% CI = 0.37 to 0.67, two-sided P < .001; crude OS rate: 71.5% vs 53.2%).

Conclusions:

Using a large national database, we have identified a statistically significant survival benefit for patients with cN+ PCa treated with ADT+RT. These data, if appropriately validated by randomized trials, suggest that a substantial proportion of such patients at high risk for prostate cancer death may be undertreated, warranting a reevaluation of current practice guidelines.


Background:

How exosomic microRNAs (miRNAs) contribute to the development of drug resistance in the context of the tumor microenvironment has not been previously described in neuroblastoma (NBL).

Methods:

Coculture experiments were performed to assess exosomic transfer of miR-21 from NBL cells to human monocytes and miR-155 from human monocytes to NBL cells. Luciferase reporter assays were performed to assess miR-155 targeting of TERF1 in NBL cells. Tumor growth was measured in NBL xenografts treated with Cisplatin and peritumoral exosomic miR-155 (n = 6 mice per group) CD163, miR-155, and TERF1 levels were assessed in 20 NBL primary tissues by Human Exon Arrays and quantitative real-time polymerase chain reaction. Student’s t test was used to evaluate the differences between treatment groups. All statistical tests were two-sided.

Results:

miR-21 mean fold change (f.c.) was 12.08±0.30 (P < .001) in human monocytes treated with NBL derived exosomes for 48 hours, and miR-155 mean f.c. was 4.51±0.25 (P < .001) in NBL cells cocultured with human monocytes for 48 hours. TERF1 mean luciferase activity in miR-155 transfected NBL cells normalized to scrambled was 0.36 ± 0.05 (P <.001). Mean tumor volumes in Dotap-miR-155 compared with Dotap-scrambled were 322.80±120mm3 and 76.00±39.3mm3, P = .002 at day 24, respectively. Patients with high CD163 infiltrating NBLs had statistically significantly higher intratumoral levels of miR-155 (P = .04) and lower levels of TERF1 mRNA (P = .02).

Conclusions:

These data indicate a unique role of exosomic miR-21 and miR-155 in the cross-talk between NBL cells and human monocytes in the resistance to chemotherapy, through a novel exosomic miR-21/TLR8-NF-B/exosomic miR-155/TERF1 signaling pathway.


Background:

Chemoresistance is a major challenge in cancer treatment. miR-506 is a potent inhibitor of the epithelial-to-mesenchymal transition (EMT), which is also associated with chemoresistance. We characterized the role of miR-506 in chemotherapy response in high-grade serous ovarian cancers.

Methods:

We used Kaplan-Meier and log-rank methods to analyze the relationship between miR-506 and progression-free and overall survival in The Cancer Genome Atlas (TCGA) (n = 468) and Bagnoli (n = 130) datasets, in vitro experiments to study whether miR-506 is associated with homologous recombination, and response to chemotherapy agents. We used an orthotopic ovarian cancer mouse model (n = 10 per group) to test the effect of miR-506 on cisplatin and PARP inhibitor sensitivity. All statistical tests were two-sided.

Results:

MiR-506 was associated with better response to therapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (PFS: high vs low miR-506 expression; Bagnoli: hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.90 to 4.70, P < .0001; TCGA: HR = 1.49, 95% CI = 1.00 to 2.25, P = 0.04). MiR-506 sensitized cells to DNA damage through directly targeting the double-strand DNA damage repair gene RAD51. Systemic delivery of miR-506 in 8–12 week old female athymic nude mice statistically significantly augmented the cisplatin and olaparib response (mean tumor weight ± SD, control miRNA plus cisplatin vs miR-506 plus cisplatin: 0.36±0.05g vs 0.07±0.02g, P < .001; control miRNA plus olaparib vs miR-506 plus olaparib: 0.32±0.13g vs 0.05±0.02g, P = .045, respectively), thus recapitulating the clinical observation.

Conclusions:

MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy.





Background:

Statins have been associated with moderate reductions in mortality among colorectal cancer (CRC) patients, but these studies lacked adjustment for some potentially relevant factors associated with statin use. We aimed to provide more detailed results on this association from a population-based patient cohort study.

Methods:

Use of statins and other risk or protective factors were assessed in standardized interviews with 2697 patients from southern Germany with a diagnosis of incident CRC between 2003 and 2009 (Darmkrebs: Chancen der Verhütung durch Screening [DACHS] study). Follow-up included assessment of therapy details, recurrence, vital status, and cause of death. Information about molecular pathological subtypes of CRC was available for 1209 patients. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). All statistical tests were two-sided.

Results:

Patients were age 68 years on average, 412 used statins (15%), and 769 died during follow-up (29%). After a median follow-up time of 3.4 years, use of statins was not associated with overall (HR = 1.10, 95% CI = 0.85 to 1.41), CRC-specific (HR = 1.11, 95% CI = 0.82 to 1.50), or recurrence-free survival (HR = 0.90, 95% CI = 0.63 to 1.27). Analyses in relevant subgroups also showed no association of statin use with overall and CRC-specific survival, and no associations were observed after stratifying for major pathological subtypes. Among stage I and II patients, statin use was associated with better recurrence-free but not with better CRC-specific survival.

Conclusions:

Statin use was not associated with reduced mortality among CRC patients. Effects reported in previous studies might reflect incomplete control for stage at diagnosis and other factors associated with the use of statins.


Supplemental security income (SSI) and social security disability insurance (DI) are federal programs that provide disability benefits. We report on SSI/DI enrollment in a random sample of adult, long-term survivors of childhood cancer (n = 698) vs a comparison group without cancer (n = 210) from the Childhood Cancer Survivor Study who completed a health insurance survey. A total of 13.5% and 10.0% of survivors had ever been enrolled on SSI or DI, respectively, compared with 2.6% and 5.4% of the comparison group. Cranial radiation doses of 25 Gy or more were associated with a higher risk of current SSI (relative risk [RR] = 3.93, 95% confidence interval [CI] = 2.05 to 7.56) and DI (RR = 3.65, 95% CI = 1.65 to 8.06) enrollment. Survivors with severe/life-threatening conditions were more often enrolled on SSI (RR = 3.77, 95% CI = 2.04 to 6.96) and DI (RR = 2.73, 95% CI = 1.45 to 5.14) compared with those with mild/moderate or no health conditions. Further research is needed on disability-related financial challenges after childhood cancer.


Lung cancer is the leading cause of cancer death worldwide. Low-dose computed tomography screening (LDCT) was recently shown to anticipate the time of diagnosis, thus reducing lung cancer mortality. However, concerns persist about the feasibility and costs of large-scale LDCT programs. Such concerns may be addressed by clearly defining the target "high-risk" population that needs to be screened by LDCT. We recently identified a serum microRNA signature (the miR-Test) that could identify the optimal target population. Here, we performed a large-scale validation study of the miR-Test in high-risk individuals (n = 1115) enrolled in the Continuous Observation of Smoking Subjects (COSMOS) lung cancer screening program. The overall accuracy, sensitivity, and specificity of the miR-Test are 74.9% (95% confidence interval [CI] = 72.2% to 77.6%), 77.8% (95% CI = 64.2% to 91.4%), and 74.8% (95% CI = 72.1% to 77.5%), respectively; the area under the curve is 0.85 (95% CI = 0.78 to 0.92). These results argue that the miR-Test might represent a useful tool for lung cancer screening in high-risk individuals.


Background:

For women with hormone receptor–positive, operable breast cancer, surgical oophorectomy plus tamoxifen is an effective adjuvant therapy. We conducted a phase III randomized clinical trial to test the hypothesis that oophorectomy surgery performed during the luteal phase of the menstrual cycle was associated with better outcomes.

Methods:

Seven hundred forty premenopausal women entered a clinical trial in which those women estimated not to be in the luteal phase of their menstrual cycle for the next one to six days (n = 509) were randomly assigned to receive treatment with surgical oophorectomy either delayed to be during a five-day window in the history-estimated midluteal phase of the menstrual cycles, or in the next one to six days. Women who were estimated to be in the luteal phase of the menstrual cycle for the next one to six days (n = 231) were excluded from random assignment and received immediate surgical treatments. All patients began tamoxifen within 6 days of surgery and continued this for 5 years. Kaplan-Meier methods, the log-rank test, and multivariable Cox regression models were used to assess differences in five-year disease-free survival (DFS) between the groups. All statistical tests were two-sided.

Results:

The randomized midluteal phase surgery group had a five-year DFS of 64%, compared with 71% for the immediate surgery random assignment group (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 0.91 to 1.68, P = .18). Multivariable Cox regression models, which included important prognostic variables, gave similar results (aHR = 1.28, 95% CI = 0.94 to 1.76, P = .12). For overall survival, the univariate hazard ratio was 1.33 (95% CI = 0.94 to 1.89, P = .11) and the multivariable aHR was 1.43 (95% CI = 1.00 to 2.06, P = .05). Better DFS for follicular phase surgery, which was unanticipated, proved consistent across multiple exploratory analyses.

Conclusions:

The hypothesized benefit of adjuvant luteal phase oophorectomy was not shown in this large trial.


Background:

Racial disparities in cancer survival outcomes have been primarily attributed to underlying biologic mechanisms and the quality of cancer care received. Because prior literature shows little difference exists in the socioeconomic status of non-Hispanic whites and Asian Americans, any difference in cancer survival is less likely to be attributable to inequalities of care. We sought to examine differences in cancer-specific survival between whites and Asian Americans.

Methods:

The Surveillance, Epidemiology, and End Results Program was used to identify patients with lung (n = 130 852 [16.9%]), breast (n = 313 977 [40.4%]), prostate (n = 166 529 [21.4%]), or colorectal (n = 165 140 [21.3%]) cancer (the three leading causes of cancer-related mortality within each sex) diagnosed between 1991 and 2007. Fine and Gray’s competing risks regression compared the cancer-specific mortality (CSM) of eight Asian American groups (Chinese, Filipino, Hawaiian/Pacific Islander, Japanese, Korean, other Asian, South Asian [Indian/Pakistani], and Vietnamese) to non-Hispanic white patients. All P values were two-sided.

Results:

In competing risks regression, the receipt of definitive treatment was an independent predictor of CSM (hazard ratio [HR] = 0.37, 95% confidence interval [CI] = 0.35 to 0.40; HR = 0.55, 95% CI = 0.53 to 0.58; HR = 0.61, 95% CI = 0.60 to 0.62; and HR = 0.27, 95% CI = 0.25 to 0.29) for prostate, breast, lung, and colorectal cancers respectively, all P < .001). In adjusted analyses, most Asian subgroups (except Hawaiians and Koreans) had lower CSM relative to white patients, with hazard ratios ranging from 0.54 (95% CI = 0.38 to 0.78) to 0.88 (95% CI = 0.84 to 0.93) for Japanese patients with prostate and Chinese patients with lung cancer, respectively.

Conclusions:

Despite adjustment for potential confounders, including the receipt of definitive treatment and tumor characteristics, most Asian subgroups had better CSM than non-Hispanic white patients. These findings suggest that underlying genetic/biological differences, along with potential cultural variations, may impact survival in Asian American cancer patients.


Background:

Population-based estimates of absolute risk of lung cancer recurrence, and of mortality rates after recurrence, can inform clinical management.

Methods:

We evaluated prognostic factors for recurrences and survival in 2098 lung cancer case patients from the general population of Lombardy, Italy, from 2002 to 2005. We conducted survival analyses and estimated absolute risks separately for stage IA to IIIA surgically treated and stage IIIB to IV non–surgically treated patients.

Results:

Absolute risk of metastases exceeded that of local recurrence in every stage and cell type, highlighting the systemic threat of lung cancer. In stage I, the probability of dying within the first year after diagnosis was 2.7%, but it was 48.3% within first year after recurrence; in stage IV, the probabilities were 57.3% and 80.6%, respectively. Over half the patients died within one year of first metastasis. Although in stages IA to IB about one-third of patients had a recurrence, stage IIA patients had a recurrence risk (61.2%) similar to stage IIB (57.9%) and IIIA (62.8%) patients. Risk of brain metastases in stage IA to IIIA surgically treated non–small cell lung cancer patients increased with increasing tumor grade. Absolute risk of recurrence was virtually identical in adenocarcinoma and squamous cell carcinoma patients.

Conclusions:

This population-based study provides clinically useful estimates of risks of lung cancer recurrence and mortality that are applicable to the general population. These data highlight the need for more effective adjuvant treatments overall and within specific subgroups. The estimated risks of various endpoints are useful for designing clinical trials, whose power depends on absolute numbers of events.


The consistent reports of mutations at Asp538 and Tyr537 in helix 12 of the ligand-binding domain (LBD) of estrogen receptors (ERs) from antihormone-resistant breast cancer metastases constitute an important advance. The mutant amino acids interact with an anchor amino acid, Asp351, to close the LBD, thereby creating a ligand-free constitutively activated ER. Amino acids Asp 538, Tyr 537, and Asp 351 are known to play a role in either the turnover of ER, the antiestrogenic activity of the ER complex, or the estrogen-like actions of selective ER modulators. A unifying mechanism of action for these amino acids to enhance ER gene activation and growth response is presented. There is a range of mutations described in metastases vs low to zero in primary disease, so the new knowledge is of clinical relevance, thereby confirming an additional mechanism of acquired resistance to antihormone therapy through cell population selection pressure and enrichment during treatment. Circulating tumor cells containing ER mutations can be cultured ex vivo, and tumor tissues can be grown as patient-derived xenografts to add a new dimension for testing drug susceptibility for future drug discovery.


Background:

Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown.

Methods:

We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) rat ortholog (neu) and lacks CB2 and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided.

Results:

We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P = .009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P = .003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P = .009). We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade and that an increased CB2 expression activates the HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells.

Conclusions:

Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with prognostic value in these tumors.


Background:

Current screening guidelines for colorectal cancer (CRC) do not consider thyroid dysfunction as a risk factor for disease development. We sought to determine the risk of developing CRC in patients with thyroid dysfunction, with and without thyroid hormone replacement (THR).

Methods:

We conducted a nested case-control study using a large population-based medical records database from the United Kingdom. Study case patients were defined as those with any medical code of CRC. Subjects with familial colorectal cancer syndromes or inflammatory bowel disease (IBD) were excluded. For every case patient, four eligible control patients matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence density sampling. Exposure was THR therapy before index date. We further divided the THR unexposed group into patients with hypothyroidism (TSH > 4mg/dl), patients with hyperthyroidism (TSH < 0.4mg/dl), and subjects without documented thyroid abnormality. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for CRC were estimated using conditional logistic regression. All statistical tests were two-sided.

Results:

We identified 20990 CRC patients and 82054 control patients. The adjusted odds ratio for CRC associated with THR was 0.88 (95% CI = 0.79 to 0.99, P = .03) and 0.68 (95% CI = 0.55 to 0.83, P < .001) for treatment initiated five to 10 years and more than 10 years before index date, respectively. This protective association increased with cumulative duration of therapy. In contrast, hyperthyroidism (adjusted OR = 1.21, 95% CI = 1.08 to 1.36, P = .001) or untreated hypothyroidism (adjusted OR = 1.16, 95% CI = 1.08 to 1.24, P < .001) were associated with increased risk of CRC.

Conclusion:

Long-term THR is associated with a decreased risk of CRC. Hyperthyroidism and untreated hypothyroidism are associated with modestly elevated risk of CRC.


Background:

Short telomeres in peripheral blood leukocytes are associated with older age and age-related diseases. We tested the hypotheses that short telomeres are associated with both increased cancer mortality and all-cause mortality.

Methods:

Individuals (n = 64637) were recruited from 1991 onwards from two Danish prospective cohort studies: the Copenhagen City Heart Study and the Copenhagen General Population Study. All had telomere length measured by quantitative polymerase chain reaction and the genotypes rs1317082 (TERC), rs7726159 (TERT), and rs2487999 (OBFC1) determined. The sum of telomere-shortening alleles from these three genotypes was calculated. We conducted Cox regression analyses and instrumental variable analyses using the allele sum as an instrument. All statistical tests were two-sided.

Results:

Among 7607 individuals who died during follow-up (0–22 years, median = 7 years), 2420 had cancer and 2633 had cardiovascular disease as causes of death. Decreasing telomere length deciles were associated with increasing all-cause mortality (P trend = 2*10–15). The multivariable-adjusted hazard ratio of all-cause mortality was 1.40 (95% confidence interval [CI] = 1.25 to 1.57) for individuals in the shortest vs the longest decile. Results were similar for cancer mortality and cardiovascular mortality. Telomere length decreased 69 base pairs (95% CI = 61 to 76) per allele for the allele sum, and the per-allele hazard ratio for cancer mortality was 0.95 (95% CI = 0.91 to 0.99). Allele sum was not associated with cardiovascular, other, or all-cause mortality.

Conclusion:

Short telomeres in peripheral blood leukocytes were associated with high mortality in association analyses. In contrast, genetically determined short telomeres were associated with low cancer mortality but not with all-cause mortality.



Background:

Several treatment strategies target the human epidermal growth factor receptor 2 (HER2) in breast carcinomas, including monoclonal antibodies directed against HER2’s extracellular domain (ECD) and small molecule inhibitors of its tyrosine kinase activity. Yet, novel therapies are needed that prevent HER2 dimerization with other HER family members, because current treatments are only partially effective.

Methods:

To test the hypothesis that HER2 activation requires a protein sequence in the HER2-ECD that mediates HER2 homo- and heterodimerization, we introduced a series of deletion mutations in the third subdomain of HER2-ECD. These deletion mutants were retrovirally expressed in breast cancer (BC) cells that naturally overexpress HER2 and in noncancerous, HER2-negative breast epithelial cells. One-factor analysis of variance or Student’s t test were used to analyze differences. All statistical tests were two-sided.

Results:

The smallest deletion in the ECD domain of HER2, which removed only 16 amino acids (HER2-ECD451–466), completely disrupted the oncogenic potential of HER2. In contrast to wild-type HER2, the mutant-inhibited anchorage-independent growth (mean number of colonies: mutant, 70, 95% confidence interval [CI] = 55 to 85; wild-type, 400, 95% CI = 320 to 480, P < .001) increased sensitivity to paclitaxel treatment in both transformed and nontransformed cells. Overexpression of HER2451–466 efficiently inhibited activation of HER1, HER2, and HER3 in all cell lines tested.

Conclusions:

These findings reveal that an essential "activating" sequence exists in the extracellular domain of HER2. Disruption of this sequence disables the HER2 dimerization loop, blocks subsequent activation of HER2-driven oncogenic signaling, and generates a dominant-negative form of HER2. Reagents specifically against this molecular activation switch may represent a novel targeted approach for the management of HER2-overexpressing carcinomas.




Background:

Epigenetic alterations, such as histone methylation, modulate Myc signaling, a pathway central to oncogenesis. We investigated the role of the histone demethylase KDM4B in N-Myc–mediated neuroblastoma pathogenesis.

Methods:

Spearman correlation was performed to correlate MYCN and KDM4B expression. RNA interference, microarray analysis, gene set enrichment analysis, and real-time polymerase chain reaction were used to define the functions of KDM4B. Immunoprecipitation and immunofluorescence were used to assess protein-protein interactions between N-Myc and KDM4B. Chromatin immunoprecipitation was used to assess the binding of Myc targets. Constitutive and inducible lentiviral-mediated KDM4B knockdown with shRNA was used to assess the effects on tumor growth. Kaplan-Meier survival analysis was used to assess the prognostic value of KDM4B expression. All statistical tests were two-sided.

Results:

KDM4B and MYCN expression were found to be statistically significantly correlated in a variety of cancers, including neuroblastoma (R = 0.396, P < .001). Functional studies demonstrated that KDM4B regulates the Myc pathway. N-Myc was found to physically interact with and recruit KDM4B. KDM4B was found to regulate neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo (5 mice/group, two-tailed t test, P ≤ 0.001). Finally, together with MYCN amplification, KDM4B was found to stratify a subgroup of poor-prognosis patients (122 case patients, P < .001).

Conclusions:

Our findings provide insight into the epigenetic regulation of Myc via histone demethylation and proof-of-concept for inhibition of histone demethylases to target Myc signaling in cancers such as neuroblastoma.


Background:

This study sought to determine the prevaccine type-specific prevalence of human papillomavirus (HPV)–associated cancers in the United States to evaluate the potential impact of the HPV types in the current and newly approved 9-valent HPV vaccines.

Methods:

The Centers for Disease Control and Prevention partnered with seven US population-based cancer registries to obtain archival tissue for cancers diagnosed from 1993 to 2005. HPV testing was performed on 2670 case patients that were fairly representative of all participating cancer registry cases by age and sex. Demographic and clinical data were evaluated by anatomic site and HPV status. Current US cancer registry data and the detection of HPV types were used to estimate the number of cancers potentially preventable through vaccination.

Results:

HPV DNA was detected in 90.6% of cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oropharyngeal, 68.8% of vulvar, 63.3% of penile, 32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical cancer in situ (CCIS). A vaccine targeting HPV 16/18 potentially prevents the majority of invasive cervical (66.2%), anal (79.4%), oropharyngeal (60.2%), and vaginal (55.1%) cancers, as well as many penile (47.9%), vulvar (48.6%) cancers: 24 858 cases annually. The 9-valent vaccine also targeting HPV 31/33/45/52/58 may prevent an additional 4.2% to 18.3% of cancers: 3944 cases annually. For most cancers, younger age at diagnosis was associated with higher HPV 16/18 prevalence. With the exception of oropharyngeal cancers and CCIS, HPV 16/18 prevalence was similar across racial/ethnic groups.

Conclusions:

In the United States, current vaccines will reduce most HPV-associated cancers; a smaller additional reduction would be contributed by the new 9-valent vaccine.






Background:

The American Cancer Society (ACS), Centers for Disease Control and Prevention (CDC), National Cancer Institute (NCI), and North American Association of Central Cancer Registries (NAACCR) collaborate annually to produce updated, national cancer statistics. This Annual Report includes a focus on breast cancer incidence by subtype using new, national-level data.

Methods:

Population-based cancer trends and breast cancer incidence by molecular subtype were calculated. Breast cancer subtypes were classified using tumor biomarkers for hormone receptor (HR) and human growth factor-neu receptor (HER2) expression.

Results:

Overall cancer incidence decreased for men by 1.8% annually from 2007 to 2011. Rates for women were stable from 1998 to 2011. Within these trends there was racial/ethnic variation, and some sites have increasing rates. Among children, incidence rates continued to increase by 0.8% per year over the past decade while, like adults, mortality declined. Overall mortality has been declining for both men and women since the early 1990’s and for children since the 1970’s. HR+/HER2- breast cancers, the subtype with the best prognosis, were the most common for all races/ethnicities with highest rates among non-Hispanic white women, local stage cases, and low poverty areas (92.7, 63.51, and 98.69 per 100000 non-Hispanic white women, respectively). HR+/HER2- breast cancer incidence rates were strongly, positively correlated with mammography use, particularly for non-Hispanic white women (Pearson 0.57, two-sided P < .001). Triple-negative breast cancers, the subtype with the worst prognosis, were highest among non-Hispanic black women (27.2 per 100000 non-Hispanic black women), which is reflected in high rates in southeastern states.

Conclusions:

Progress continues in reducing the burden of cancer in the United States. There are unique racial/ethnic-specific incidence patterns for breast cancer subtypes; likely because of both biologic and social risk factors, including variation in mammography use. Breast cancer subtype analysis confirms the capacity of cancer registries to adjust national collection standards to produce clinically relevant data based on evolving medical knowledge.


General frameworks of the cancer screening process are available, but none directly compare the process in detail across different organ sites. This limits the ability of medical and public health professionals to develop and evaluate coordinated screening programs that apply resources and population management strategies available for one cancer site to other sites. We present a trans-organ conceptual model that incorporates a single screening episode for breast, cervical, and colorectal cancers into a unified framework based on clinical guidelines and protocols; the model concepts could be expanded to other organ sites. The model covers four types of care in the screening process: risk assessment, detection, diagnosis, and treatment. Interfaces between different provider teams (eg, primary care and specialty care), including communication and transfer of responsibility, may occur when transitioning between types of care. Our model highlights across each organ site similarities and differences in steps, interfaces, and transitions in the screening process and documents the conclusion of a screening episode. This model was developed within the National Cancer Institute–funded consortium Population-based Research Optimizing Screening through Personalized Regimens (PROSPR). PROSPR aims to optimize the screening process for breast, cervical, and colorectal cancer and includes seven research centers and a statistical coordinating center. Given current health care reform initiatives in the United States, this conceptual model can facilitate the development of comprehensive quality metrics for cancer screening and promote trans-organ comparative cancer screening research. PROSPR findings will support the design of interventions that improve screening outcomes across multiple cancer sites.


Rapid advancements in massively parallel sequencing methods have enabled the analysis of breast cancer genomes at an unprecedented resolution, which have revealed the remarkable heterogeneity of the disease. As a result, we now accept that despite originating in the breast, estrogen receptor (ER)–positive and ER-negative breast cancers are completely different diseases at the molecular level. It has become apparent that there are very few highly recurrently mutated genes such as TP53, PIK3CA, and GATA3, that no two breast cancers display an identical repertoire of somatic genetic alterations at base-pair resolution and that there might not be a single highly recurrently mutated gene that defines each of the "intrinsic" subtypes of breast cancer (ie, basal-like, HER2-enriched, luminal A, and luminal B). Breast cancer heterogeneity, however, extends beyond the diversity between tumors. There is burgeoning evidence to demonstrate that at least some primary breast cancers are composed of multiple, genetically diverse clones at diagnosis and that metastatic lesions may differ in their repertoire of somatic genetic alterations when compared with their respective primary tumors. Several biological phenomena may shape the reported intratumor genetic heterogeneity observed in breast cancers, including the different mutational processes and multiple types of genomic instability. Harnessing the emerging concepts of the diversity of breast cancer genomes and the phenomenon of intratumor genetic heterogeneity will be essential for the development of optimal methods for diagnosis, disease monitoring, and the matching of patients to the drugs that would benefit them the most.


Background:

Oncogene-induced senescence (OIS) is a tumor suppressor mechanism. However, senescent cells remain viable and display a distinct secretome (also known as senescence-associated secretory phenotype [SASP] or senescence messaging secretome, [SMS]) that, paradoxically, includes protumorigenic factors. OIS can be triggered by ectopic overexpression of HER2, a receptor tyrosine kinase and the driving oncogene in a subtype of human breast cancer. However, cellular senescence has not been characterized in HER2-positive tumors.

Methods:

Using an approach based on their inability to proliferate, we isolated naturally occurring senescent cells from a variety of tumor models including HER2-positive cells, transgenic mice (n = 3), and patient-derived xenografts (PDXs) (n = 6 mice per group from one PDX derived from one patient). Using different biochemical and cell biological techniques, we characterized the secretome of these senescent cells. All statistical tests were two-sided.

Results:

We found that senescent cells arise constantly in different models of advanced breast cancers overexpressing HER2 and constitute approximately 5% of tumor cells. In these models, IL-6 and other cytokines were expressed mainly, if not exclusively, by the naturally occurring senescent cells (95.1% and 45.0% of HCC1954 cells and cells from a HER2-positive PDX expressing a senescent marker expressed IL-6, respectively). Furthermore, inhibition of IL-6 impaired the growth of the HER2-positive PDX (mean tumor volume at day 101, control vs anti–huIL-6 treated, 332.2mm3 [95% confidence interval {CI} = 216.6 to 449.8] vs 114.4mm3 [95% CI = 12.79 to 216.0], P = .005).

Conclusions:

Senescent cells can contribute to the growth of tumors by providing cytokines not expressed by proliferating cells, but required by these to thrive.


Internet marketing may accelerate the use of care based on genomic or tumor-derived data. However, online marketing may be detrimental if it endorses products of unproven benefit. We conducted an analysis of Internet websites to identify personalized cancer medicine (PCM) products and claims. A Delphi Panel categorized PCM as standard or nonstandard based on evidence of clinical utility. Fifty-five websites, sponsored by commercial entities, academic institutions, physicians, research institutes, and organizations, that marketed PCM included somatic (58%) and germline (20%) analysis, interpretive services (15%), and physicians/institutions offering personalized care (44%). Of 32 sites offering somatic analysis, 56% included specific test information (range 1–152 tests). All statistical tests were two-sided, and comparisons of website content were conducted using McNemar’s test. More websites contained information about the benefits than limitations of PCM (85% vs 27%, P < .001). Websites specifying somatic analysis were statistically significantly more likely to market one or more nonstandard tests as compared with standard tests (88% vs 44%, P = .04).


Background:

There is strong evidence that breast cancer risk is influenced by environmental factors. Blood lipid and lipoprotein levels are also influenced by environmental factors and are associated with some breast cancer risk factors. We examined whether serial measures of serum lipids and lipoproteins were associated with breast cancer risk.

Methods:

We carried out a nested case-control study within a randomized long-term dietary intervention trial with 4690 women with extensive mammographic density followed for an average of 10 years for breast cancer incidence. We measured lipids in an average of 4.2 blood samples for 279 invasive breast cancer case subjects and 558 matched control subjects. We calculated subaverages of lipids for each subject based on menopausal status and use of hormone replacement therapy (HRT) at blood collection and analyzed their association with breast cancer using generalized estimating equations. All statistical tests were two-sided.

Results:

High-density lipoprotein-cholesterol (HDL-C) (P = .05) and apoA1 (P = .02) levels were positively associated with breast cancer risk (75th vs 25th percentile: HDL-C, 23% higher; apoA1, 28% higher) and non-HDL-C (P = .03) and apoB (P = .01) levels were negatively associated (75th vs 25th percentile: non-HDL-C, 19% lower; apoB, 22% lower). These associations were observed only when lipids were measured when HRT was not used. Total cholesterol and triglyceride levels were not statistically significantly associated with breast cancer risk.

Conclusions:

These results demonstrate that serum lipids are associated with breast cancer risk in women with extensive mammographic density. The possibility that interventions for heart disease prevention, which aim to reduce non-HDL-C or raise HDL-C, may have effects on breast cancer risk merits examination.


Background:

Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO.

Methods:

We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO.

Results:

Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval [CI] = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77).

Conclusion:

In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.


Background:

Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma.

Methods:

The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF in melanoma progression was investigated using assays of colony formation, invasion, cell cycle, sensitivity to selective BRAF inhibitors, and in xenograft models of melanoma progression (n = 12 mice per group). The biomarker role of BPTF in melanoma progression was assessed using fluorescence in situ hybridization and immunohistochemical analyses. All statistical tests were two-sided.

Results:

shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF copy number (mean ≥ 3) was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival P = .03, and disease-specific survival P = .008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell subclones, indicating the continued presence of drug-responsive subclones within tumors demonstrating overall resistance to anti-BRAF agents.

Conclusions:

These studies demonstrate multiple protumorigenic functions for BPTF and identify it as a novel target for anticancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF.


Background:

Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis.

Methods:

A genome-wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided.

Results:

Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3x10–8). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5x10–9). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin.

Conclusions:

A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing.


Background:

Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.

Methods:

We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.

Results:

There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.

Conclusions:

The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.


Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10-10) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors.


Exercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor–negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11–12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm2, 95% CI = 1223 to 1865 vs 2168 cells/mm2, 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer.


Background:

Lack of robust predictive biomarkers, other than MGMT promoter methylation, makes temozolomide responsiveness in newly diagnosed glioblastoma (GBM) patients difficult to predict. However, we identified patients with long-term survival (≥35 months) within a group of newly diagnosed GBM patients treated with standard or metronomic adjuvant temozolomide schedules. We thus investigated possible molecular profiles associated with longer survival following temozolomide treatment.

Methods:

We investigated the association of molecular features with progression-free (PFS) and overall survival (OS). Human-derived GBM cancer stem cells (CSCs) were used to investigate in vitro molecular mechanisms associated with temozolomide responsiveness. Surgically removed recurrences allowed investigation of molecular changes occurring during therapy in vivo. Statistical analyses included one- and two-way analysis of variance, Student’s t test, Cox proportional hazards, and the Kaplan-Meier method. All statistical tests were two-sided.

Results:

No association was found between survival and gene classifiers associated with different molecular GBM subtypes in the standard-treated group, while in metronomic-treated patients robust association was found between EGFR amplification/overexpression and PFS and OS (OS, EGFR-high vs low: hazard ratiodeath = 0.22, 95% confidence interval = 0.09 to 0.55, P = .001). The result for OS remained statistically significant after Bonferroni correction (P interaction < .0005). Long-term survival following metronomic temozolomide was independent from MGMT and EGFRvIII status and was more pronounced in EGFR-overexpressing GBM patients with PTEN loss. In vitro findings confirmed a selective dose- and time-dependent decrease in survival of temozolomide-treated EGFR+ human-derived glioblastoma CSCs, which occurred through inhibition of NF-B transcriptional activity. In addition, reduction in EGFR-amplified cells, along with a statistically significant decrease in NF-B/p65 expression, were observed in specimens from recurrent metronomic-treated EGFR-overexpressing GBM patients.

Conclusions:

EGFR-amplified/overexpressing glioblastomas strongly benefit from metronomic temozolomide–based therapies.



Background:

It is unclear how the extent of surgical lymph node clearance influences prognosis after surgery for esophageal cancer.

Methods:

This nationwide, population-based cohort study included 1044 esophageal cancer patients who had undergone esophagectomy between 1987 and 2010 in Sweden, with follow-up until 2012. The independent role of lymph node removal in relation to survival was analyzed using Cox proportional hazards regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for age, sex, comorbidity, tumor (T) stage, neo-adjuvant treatment, surgeon volume, and calendar period. Statistical tests were two-sided, except tests for trend.

Results:

Analyzed as a linear variable, a higher number of lymph nodes removed did not influence the overall five-year mortality (adjusted HR = 1.00, 95% CI = 0.99 to 1.01). Patients in the third (7–15 nodes) and fourth (16–114 nodes) quartiles of removed nodes did not demonstrate any decreased overall five-year mortality compared with those in the lowest two quartiles (<7 nodes) (HR = 1.13, 95% CI = 0.95 to 1.35 and HR = 1.17, 95% CI = 0.94 to 1.46, respectively). In early T stages (Tis-T1) the hazard ratios indicated a worse survival with more lymphadenectomy using the median as cutoff (HR = 1.53, 95% CI = 1.13 to 2.06). Increased lymph node removal did not decrease mortality in any specific T stage. A greater number of metastatic nodes and a higher positive-to-negative node ratio were associated with strongly increased mortality. All results were similar when disease-specific mortality was analyzed.

Conclusion:

This population-based study indicates that more extensive lymph node clearance during surgery for esophageal cancer may not improve survival. These results challenge current clinical guidelines, and further research is needed to change clinical practice.


Background:

Chemotherapy triggers endoplasmic reticulum (ER) stress, which in turn regulates levels of the active (LAP) and the natural dominant-negative (LIP) forms of the transcription factor C/EBP-β. LAP upregulates and LIP downregulates the multidrug resistance (MDR) protein P-glycoprotein (Pgp), but it is not known how critical is their role in establishing MDR.

Methods:

Cell viability was quantitated by crystal violet staining and measuring absorbance at 540nm. Expression of various proteins was determined by immunoblotting. mRNA levels were determined by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). LIP and LAP were overexpressed using expression plasmids followed by selection with blasticidin. Tumor cells expressing doxycycline-inducible LIP were orthotopically implanted in mice (n = 15 mice per group), and tumor size was measured daily by caliper. Tumor sections were stained with hematoxylin and eosin and immunostained for Pgp, proliferation, and ER stress markers.

Results:

MDR cells do not express basal, chemotherapy-triggered, or ER stress–triggered LIP and fail to activate the CHOP-caspase-3 death-triggering axis upon ER stress or chemotherapy challenge. Overexpression of LIP reversed the MDR phenotype in vitro and in tumors implanted in mice. LIP was undetectable in MDR cells, probably due to its ubiquitination, which was 3.56-fold higher, resulting in lysosomal and proteasomal degradation of LIP.

Conclusions:

Spontaneous and drug-selected MDR cells lack LIP, which is eliminated by ubiquitin-mediated degradation. Loss of LIP drives MDR not only by increasing Pgp expression but also by a two-fold attenuation of ER stress–triggered cell death.


Despite recent increased attention to healthcare performance and the burden of disease from cancer, measures of quality of cancer care are not readily available. In 2013, the California HealthCare Foundation convened an expert workgroup to explore the potential for leveraging data in the California Cancer Registry (CCR), one of the world’s largest population-based cancer registries, for measuring and improving the quality of cancer care. The workgroup assessed current registry operations, the value to be gained by linking CCR data with health insurance claims or encounter data and clinical data contained in health system electronic health records, and potential barriers to these linkages. The workgroup concluded that: 1) The CCR mandate should be expanded to include use of its data for quality of cancer care measurement and public reporting; and 2) a system should be developed to support linkage of registry data with both claims data and provider electronic health record data.


Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student’s t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six- and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P = .043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P = .033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene.











Background:

Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer–specific survival.

Methods:

We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)–negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided.

Results:

We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10–8). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust.

Conclusions:

This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.





Background:

Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis.

Methods:

Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided.

Results:

The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10–5).

Conclusion:

These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.










We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2nd quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population.