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Journal of the National Cancer Institute

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

Controversy exists regarding the impact of CYP2D6 genotype on tamoxifen responsiveness. We examined loss of heterozygosity (LOH) at the CYP2D6 locus and determined its impact on genotyping error when tumor tissue is used as a DNA source.

Methods:

Genomic tumor data from the adjuvant and metastatic settings (The Cancer Genome Atlas [TCGA] and Foundation Medicine [FM]) were analyzed to characterize the impact of CYP2D6 copy number alterations (CNAs) and LOH on Hardy Weinberg equilibrium (HWE). Additionally, we analyzed CYP2D6 *4 genotype from formalin-fixed paraffin-embedded (FFPE) tumor blocks containing nonmalignant tissue and buccal (germline) samples from patients on the North Central Cancer Treatment Group (NCCTG) 89-30-52 tamoxifen trial. All statistical tests were two-sided.

Results:

In TCGA samples (n =627), the CYP2D6 LOH rate was similar in estrogen receptor (ER)–positive (41.2%) and ER-negative (35.2%) but lower in HER2-positive tumors (15.1%) (P < .001). In FM ER+ samples (n = 290), similar LOH rates were observed (40.8%). In 190 NCCTG samples, the agreement between CYP2D6 genotypes derived from FFPE tumors and FFPE tumors containing nonmalignant tissue was moderate (weighted Kappa = 0.74; 95% CI = 0.63 to 0.84). Comparing CYP2D6 genotypes derived from buccal cells to FFPE tumor DNA, CYP2D6*4 genotype was discordant in six of 31(19.4%). In contrast, there was no disagreement between CYP2D6 genotypes derived from buccal cells with FFPE tumors containing nonmalignant tissue.

Conclusions:

LOH at the CYP2D6 locus is common in breast cancer, resulting in potential misclassification of germline CYP2D6 genotypes. Tumor DNA should not be used to determine germline CYP2D6 genotype without sensitive techniques to detect low frequency alleles and quality control procedures appropriate for somatic DNA.


Background:

Tumor heterogeneity and evolutionary complexity may underlie treatment failure in spite of the development of many targeted agents. We suggest a novel strategy termed induced phenotype targeted therapy (IPTT) to simplify complicated targets because of tumor heterogeneity and overcome tumor evolutionary complexity.

Methods:

We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis locally in the tumor, we used a gamma knife, which can irradiate a very small, defined target area. The in vivo antitumor activity of the caspase-3–specific activatable prodrug combined with radiation was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student’s t test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP).

Results:

A single exposure of radiation was able to induce apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3. Caspase-3 cleaved DEVD and activated the prodrug. The released free DOX further activated DEVD-S-DOX by exerting cytotoxic effects on neighboring tumor or supporting cells, which repetitively induced the expression of caspase-3 and the activation of DEVD-S-DOX. This sequential and repetitive process propagated the induction of apoptosis. This novel therapeutic strategy showed not only high efficacy in inhibiting tumor growth (14-day tumor volume [mm3] vs radiation alone: 848.21±143.24 vs 2511.50±441.89, P < .01) but also low toxicity to normal cells and tissues.

Conclusion:

Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects.





Background:

PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence.

Methods:

A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5–11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with 2 test. Student’s t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided.

Results:

AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3±39% (P < .001), decreased cellular proliferation by 46±14% (P = .016), and increased apoptosis by 326±170% (P = .039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients.

Conclusions:

PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation.


Background:

The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.

Methods:

Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with 2 and Fisher’s exact tests. P values under .05 were considered statistically significant (one-tailed with Yates’ correction).

Results:

Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma.

Conclusions:

Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.


Background:

One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy.

Methods:

SV40 T antigen–specific T cells from T cell receptor (TCR)-I–transgenic mice were transduced with a truncated human epidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR–anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murine gastric cancer cell line GC8 (SV40+ and EpCAM+). Anti-EGFR x anti-c-Met BiAb was used for targeting of human tumor-specific T cells to c-Met+ human tumor cell lines. Differences between experimental conditions were analyzed using the Student’s t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided.

Results:

The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of human EGFR–transduced T cells to immobilized c-Met and recognition of tyrosinase+ melanoma cells by TCR-, as well as of CEA+ colon cancer cells by chimeric antigen receptor (CAR)–modified T cells.

Conclusions:

BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of ACT.


Modern breast cancer treatment offers many women greater prospects of cure or lengthier, good quality survival than was possible in the past. Advances include improved diagnostic and staging procedures, sophisticated onco-plastic surgery, enhanced radiotherapy techniques, and targeted systemic therapies. Much more attention has also been paid to cancer care delivery and access to specialist nurses, counsellors, support groups, and services provided by breast cancer charities. However, there are some concerns that these considerable improvements in treatment delivery and clinical outcomes have not led to similar benefits in the psychosocial, functional, and sexual well-being of women. The impact that non–life threatening, long-term iatrogenic harms of otherwise efficacious anticancer treatments has on patients is often overlooked; this is in part because of the emphasis given to physician-reported safety data in trials and the general exclusion of patient-reported outcomes (PROs). A failure to utilise reliable PRO measures has meant that some problems are underreported, which consequently has hampered much-needed research into ameliorative interventions. Systematic monitoring of quality of life-threatening side effects would permit early implementation of effective interventions and enhance long-term survivorship. Some examples of the pervasive difficulties that continue to affect survivors and evidence that certain interventions might help are provided in this commentary.


Background:

In the United States, patients who enroll in chemotherapy trials seldom reflect the attributes of the general population with cancer, as they are often younger, more functional, and have less comorbidity. We compared survival following three chemotherapy regimens according to the setting in which care was delivered (ie, clinical trial vs usual care) to determine the generalizability of clinical trial results to unselected elderly Medicare patients.

Methods:

Using SEER-Medicare data, we estimated survival for elderly patients (ie, age 65 years or older, n = 14097) with advanced pancreatic or lung cancer following receipt of one of three guideline-recommended first-line chemotherapy regimens. We compared their survival to that of similarly treated clinical trial enrollees, without age restrictions, with the same diagnosis and stage (n = 937). All statistical tests were two-sided.

Results:

Trial patients were 9.5 years younger than elderly Medicare patients. Medicare patients were more often white and tended to live in areas of greater educational attainment than trial enrollees. For each tumor type, Medicare patients who were 75 years or older had median survivals that were six to eight weeks shorter than those of trial patients (4.3 vs 5.8 months following treatment with single agent gemcitabine for advanced pancreatic cancer, P = .03; 7.3 vs 8.9 months following treatment with carboplatin and paclitaxel for stage IV non–small cell lung cancer, P = .91; 8.2 vs 10.2 months following treatment with CDDP/ VP16 for extensive stage small cell lung cancer, P ≤ .01), whereas younger Medicare patients had survival times that were similar to those of trial patients.

Conclusions:

Results of clinical trials for advanced pancreatic cancer and lung cancers tended to correctly estimate survival for Medicare patients aged 65 to 74 years, but to overestimate survival for older Medicare patients by six to eight weeks. These estimates of Medicare patients’ survival may aid subsequent patients and their oncologists in treatment decision-making.


We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients.




Background:

Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing.

Methods:

In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided.

Results:

One thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%.

Conclusion:

Compared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn’t adversely affect short-term psychological/quality-of-life outcomes and may detect 56% additional BRCA carriers.


Background:

Population-based testing for BRCA1/2 mutations detects the high proportion of carriers not identified by cancer family history (FH)–based testing. We compared the cost-effectiveness of population-based BRCA testing with the standard FH-based approach in Ashkenazi Jewish (AJ) women.

Methods:

A decision-analytic model was developed to compare lifetime costs and effects amongst AJ women in the UK of BRCA founder-mutation testing amongst: 1) all women in the population age 30 years or older and 2) just those with a strong FH (≥10% mutation risk). The model assumes that BRCA carriers are offered risk-reducing salpingo-oophorectomy and annual MRI/mammography screening or risk-reducing mastectomy. Model probabilities utilize the Genetic Cancer Prediction through Population Screening trial/published literature to estimate total costs, effects in terms of quality-adjusted life-years (QALYs), cancer incidence, incremental cost-effectiveness ratio (ICER), and population impact. Costs are reported at 2010 prices. Costs/outcomes were discounted at 3.5%. We used deterministic/probabilistic sensitivity analysis (PSA) to evaluate model uncertainty.

Results:

Compared with FH-based testing, population-screening saved 0.090 more life-years and 0.101 more QALYs resulting in 33 days’ gain in life expectancy. Population screening was found to be cost saving with a baseline-discounted ICER of -£2079/QALY. Population-based screening lowered ovarian and breast cancer incidence by 0.34% and 0.62%. Assuming 71% testing uptake, this leads to 276 fewer ovarian and 508 fewer breast cancer cases. Overall, reduction in treatment costs led to a discounted cost savings of £3.7 million. Deterministic sensitivity analysis and 94% of simulations on PSA (threshold £20000) indicated that population screening is cost-effective, compared with current NHS policy.

Conclusion:

Population-based screening for BRCA mutations is highly cost-effective compared with an FH-based approach in AJ women age 30 years and older.


Background:

Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins including PGE-2 linking inflammation with mitogenic signaling. COX-2 is also an anticancer target, however, treatment strategies have been limited by unreliable expression assays and by inconsistent tumor responses to COX-2 inhibition.

Methods:

We analyzed the TCGA and Director’s Challenge lung cancer datasets (n = 188) and also generated an LKB1-null lung cancer gene signature (n = 53) to search the Broad Institute/Connectivity-MAP (C-MAP) dataset. We performed ChIP analyses, real-time polymerase chain reaction, immunoblotting, and drug testing of tumor cell lines (n = 8) and primary lung adenocarcinoma surgical resections (n = 13).

Results:

We show that COX-2 is a target of the cAMP/CREB coactivator CRTC1 signaling pathway. In addition, we detected a correlation between LKB1 status, CRTC1 activation, and presence of glycosylated, but not inactive hypoglycosylated COX-2 in primary lung adenocarcinoma. A search of the C-MAP drug database discovered that all high-ranking drugs positively associated with the LKB1-null signature are known CRTC1 activators, including forskolin and six different PGE-2 analogues. Somatic LKB1 mutations are present in 20.0% of lung adenocarcinomas, and we observed growth inhibition with COX-2 inhibitors in LKB1-null lung cancer cells with activated CRTC1 as compared with LKB1-wildtype cells (NS-398, P = .002 and Niflumic acid, P = .006; two-tailed t test).

Conclusion:

CRTC1 activation is a key event that drives the LKB1-null mRNA signature in lung cancer. We also identified a positive feedback LKB1/CRTC1 signaling loop for COX-2/PGE2 regulation. These data suggest a role for LKB1 status and glycosylated COX-2 as specific biomarkers that provide a framework for selecting patients for COX-2 inhibition studies.




Background:

Tamoxifen has been US Food and Drug Administration–approved for primary prevention of breast cancer since 1998 but has not been widely adopted, in part because of increased risk of serious side effects. Little is known about the risk-benefit profiles of women who use chemoprevention outside of a clinical trial. We examined characteristics associated with initiation and discontinuation of tamoxifen for primary prevention of breast cancer within a large cohort of women with a first-degree family history of breast cancer.

Methods:

This research was conducted within The Sister Study, a cohort of 50884 US and Puerto Rican women age 35 to 74 years enrolled from 2003 to 2009. Eligible women were breast cancer–free at enrollment and had a sister who had been diagnosed with breast cancer. Participants reported tamoxifen use, ages started and stopped taking tamoxifen, and total duration of use at enrollment. We identified 788 tamoxifen users and 3131 nonusers matched on age and year of enrollment who had no history of contraindicating factors (stroke, transient ischemic attack, cataract, endometrial or uterine cancer). Characteristics associated with tamoxifen initiation were evaluated with multivariable conditional logistic regression. All statistical tests were two-sided.

Results:

Based on published risk-benefit indices, 20% of women who used tamoxifen had insufficient evidence that the benefits of tamoxifen outweigh the risk of serious side effects. After 4.5 years, 46% of women had discontinued tamoxifen.

Conclusions:

While the majority of women who used tamoxifen for primary prevention of breast cancer were likely to benefit, substantial discontinuation of tamoxifen before five years and use by women at risk of serious side effects may attenuate benefits for breast cancer prevention.




Background:

Massively parallel gene expression profiling has provided a more objective, molecular-level characterization of breast cancer subtypes. Several bioinformatics tools are available to infer patient subtype from a gene expression profile including the well-studied PAM50. The specific algorithmic methods used in these tools require access to a broad patient dataset. The choice of subtype for an individual is determined relative to all other patients across the panel, making subtypes heavily dependent on the composition of the dataset. Our aim was to develop a bioinformatics approach assigning absolute breast cancer subtypes, independent of dataset composition.

Methods:

Using a dataset of 4924 breast cancer patients, we defined a new bioinformatics approach: Absolute Intrinsic Molecular Subtyping (AIMS) that assigns subtype from a gene expression profile for an individual sample without the need for a large, diverse, and normalized dataset. We evaluated the agreement of AIMS with PAM50 and compared subtype assignment and prognostic value of the subtypes. We assessed AIMS’ robustness using a benchmark set of tests including subtype reproducibility between technologies, gene removal, and normal gene expression contamination, and compared it with PAM50. All statistical tests, except where noted, were two-sided.

Results:

AIMS vastly agreed with PAM50, with 76% and 77% agreement for cross validation and the test set, respectively, and the prognostic capacity of the intrinsic subtypes was preserved. AIMS is fully stable, and its absolute nature enables its use on a wide range of datasets and technologies, including RNA-seq.

Conclusions:

The instability of a breast cancer subtyping scheme like PAM50 could have important consequences in clinical management of patients. AIMS is a fully stable and robust subtyping scheme that recapitulates PAM50.



Background:

Self-collected human papillomavirus (HPV) testing could reduce barriers to cervical cancer screening, with performance comparable to clinician-collected specimens. The ability of self-collected specimens to cross-sectionally and prospectively detect precursor lesions was investigated in an HPV vaccine randomized trial in Costa Rica.

Methods:

In the trial, 7466 women age 18 to 25 years received an HPV16/18 or control vaccine and were followed at least annually for four years. In this secondary analysis, we included all women who provided a self-collected cervicovaginal specimen six months after enrollment (5109 women = full analytical cohort). A subset (615 women = restricted cohort) also had clinician-collected specimens at the six-month postenrollment visit. High-grade squamous intraepithelial lesion or repeat low-grade squamous intraepithelial lesion prompted colposcopic referral throughout the study. HPV testing was performed with SPF10PCR/DEIA/LiPA25. Cross-sectional and prospective sensitivity, specificity, and predictive values were estimated.

Results:

In the full cohort, one-time HPV testing on self-collected samples detected prevalent CIN2+ with a sensitivity of 88.7% (95% confidence interval [CI] =77.0% to 95.7%) and a specificity of 68.9% (95% CI = 67.6% to 70.1%). For predicting incident CIN2+ in the subsequent four years, sensitivity was 73.9% (95% CI = 65.8% to 81.0%) and specificity 69.4% (95% CI = 68.1% to 70.7%). In the restricted cohort, for incident CIN2+, self-collected HPV was much more sensitive than cytology (80.0% vs 10.0%); relative sensitivity was 0.1 (95% CI = 0.03% to 0.5%). Furthermore, three times more women with normal baseline cytology developed incident CIN2+ than those with negative self-collected HPV. Self-collected and clinician-collected HPV testing had comparable performance. Agreement between self- and clinician-collected samples was 89.7% (kappa = 0.78, McNemar 2 = 0.62) for carcinogenic HPV types.

Conclusions:

Self-collected specimens can be used for HPV-based screening, providing sensitivity and specificity comparable with clinician-collected specimens and detecting disease earlier than cytology.


Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.


Background:

Several reports indicated that volunteers enrolled in preventive trials tend to show a different profile, with respect to sociodemographic characteristics, health-related behaviors, or medical history, compared with the source population. We conducted an incidence and mortality follow-up within a cohort of subjects who had been mailed a recruitment questionnaire in the SCORE trial of sigmoidoscopy (FS) screening for colorectal cancer (CRC) to assess the impact of self-selection in the study of volunteers willing to be screened on the outcomes estimates and on the generalizability of the results.

Methods:

We compared baseline demographics, CRC risk, and overall mortality at 11-year follow-up of responders declaring their interest in screening, with those of nonresponders and of responders not interested in screening using logistic regression and Cox proportional hazards multivariable models.

Results:

Both subjects who volunteered in the trial and those who refused were better educated than nonresponders. Men and people younger than age 60 years were more likely to volunteer among responders. At 11-year follow-up, interested responders showed a similar CRC risk as nonresponders, while CRC mortality was substantially reduced (hazard ratio [HR] = 0.70, 95% confidence interval [CI] = 0.54 to 0.91). All-cause mortality was reduced both among interested (HR = 0.61, 95% CI = 0.57 to 0.65) and uninterested responders (HR = 0.81, 95% CI = 0.76 to 0.86).

Conclusion:

The implementation of an FS population–based screening program would result in a similar reduction in CRC incidence, as observed in the SCORE trial, and likely in a larger impact on CRC mortality.


Background:

Few studies have evaluated the relation between selenium supplementation after diagnosis and prostate cancer outcomes.

Methods:

We prospectively followed 4459 men initially diagnosed with nonmetastatic prostate cancer in the Health Professionals Follow-Up Study from 1988 through 2010 and examined whether selenium supplement use (from selenium-specific supplements and multivitamins) after diagnosis was associated with risk of biochemical recurrence, prostate cancer mortality, and, secondarily, cardiovascular disease mortality and overall mortality, using Cox proportional hazards models. All P values were from two-sided tests.

Results:

We documented 965 deaths, 226 (23.4%) because of prostate cancer and 267 (27.7%) because of cardiovascular disease, during a median follow-up of 8.9 years. In the biochemical recurrence analysis, we documented 762 recurrences during a median follow-up of 7.8 years. Crude rates per 1000 person-years for prostate cancer death were 5.6 among selenium nonusers and 10.5 among men who consumed 140 or more μg/day. Crude rates per 1000 person-years were 28.2 vs 23.5 for all-cause mortality and 28.4 vs 29.3 for biochemical recurrence, for nonuse vs highest-dose categories, respectively. In multivariable analyses, men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 or more μg/day of supplemental selenium had a 1.18 (95% confidence interval [CI] = 0.73 to 1.91), 1.33 (95% CI = 0.77 to 2.30), and 2.60-fold (95% CI = 1.44 to 4.70) greater risk of prostate cancer mortality compared with nonusers, respectively, P trend = .001. There was no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality.

Conclusion:

Selenium supplementation of 140 or more μg/day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. Caution is warranted regarding usage of such supplements among men with prostate cancer.


Background:

Regulatory T cells (Treg) and tumor-exosomes are thought to play a role in preventing the rejection of malignant cells in patients bearing nasopharyngeal carcinoma (NPC).

Methods:

Treg recruitment by exosomes derived from NPC cell lines (C15/C17-Exo), exosomes isolated from NPC patients’ plasma (Patient-Exo), and CCL20 were tested in vitro using Boyden chamber assays and in vivo using a xenograft SCID mouse model (n = 5), both in the presence and absence of anti-CCL20 monoclonal antibodies (mAb). Impact of these NPC exosomes (NPC-Exo) on Treg phenotype and function was determined using adapted assays (FACS, Q-PCR, ELISA, and MLR). Experiments were performed in comparison with exosomes derived from plasma of healthy donors (HD-Exo). The Student’s t test was used for group comparisons. All statistical tests were two-sided.

Results:

CCL20 allowed the intratumoral recruitment of human Treg. NPC-Exo also facilitated Treg recruitment (3.30±0.34 fold increase, P < .001), which was statistically significantly inhibited (P < .001) by an anti-CCL20 blocking mAb. NPC-Exo also recruited conventional CD4+CD25- T cells and mediated their conversion into inhibitory CD4+CD25high cells. Moreover, NPC-Exo enhanced (P = .0048) the expansion of human Treg, inducing the generation of Tim3Low Treg with increased expression of CD25 and FOXP3. Finally, NPC-Exo induced an overexpression of cell markers associated with Treg phenotype, properties and recruitment capacity. For example, GZMB mean fold change was 21.45±1.75 (P < .001). These results were consistent with a stronger suppression of responder cells’ proliferation and the secretion of immunosuppressive cytokines (IL10, TGFB1).

Conclusion:

Interactions between NPC-Exo and Treg represent a newly defined mechanism that may be involved in regulating peripheral tolerance by tumors and in supporting immune evasion in human NPC.


Background:

There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods:

A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided.

Results:

A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile [HRQ5-Q1] = 0.92, 95% CI = 0.83 to 1.01, P trend = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P trend = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P trend = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (>12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P interaction = .035).

Conclusions:

Higher dietary folate intake may be associated with a lower risk of sex hormone receptor–negative BC in premenopausal women.



Background:

The evidence for an association between migraine and breast cancer risk is inconclusive. While female sex hormones have been proposed as one underlying mechanism, data on sex hormone levels in migraineurs are sparse.

Methods:

We prospectively evaluated the association between migraine and breast cancer risk among 115378 Nurses’ Health Study II participants using Cox proportional hazards models. Differences in endogenous sex hormone levels according to migraine status were assessed among 2034 premenopausal women using linear regression. We performed a meta-analysis of studies investigating the association between migraine and invasive breast cancer risk published through October 2013. All statistical tests were two-sided.

Results:

Seventeen thousand six hundred ninety-six women (15.3%) reported a physician’s diagnosis of migraine at baseline. Over 20 years of follow-up, 833 in situ and 3091 invasive breast malignancies occurred. Migraine was not associated with total (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.88 to 1.04), in situ (HR = 0.97, 95% CI = 0.82 to 1.15), or invasive breast cancer risk (HR = 0.95, 95% CI = 0.87 to 1.04). Endogenous sex hormone levels did not differ according to migraine status. In the meta-analysis, migraine was associated with a lower risk of breast cancer overall (pooled risk ratio [RR] = 0.84, 95% CI = 0.73 to 0.98). However, this inverse association was apparent only among case-control studies (pooled RR = 0.72, 95% CI = 0.66 to 0.79), and not among cohort studies (pooled RR = 0.98, 95% CI = 0.87 to 1.10).

Conclusion:

In this large cohort study, migraine was not associated with breast cancer risk or differences in endogenous sex hormone levels. While case-control studies suggest an inverse association between migraine and breast cancer risk, prospective cohort studies do not support an association in pooled analyses.


Background:

Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis.

Methods:

We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided.

Results:

POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06).

Conclusion:

POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC.



Background:

The results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial showed a statistically significant 29% prostate cancer mortality reduction for the men screened in the intervention arm and a 23% negative impact on the life-years gained because of quality of life. However, alternative prostate-specific antigen (PSA) screening strategies for the population may exist, optimizing the effects on mortality reduction, quality of life, overdiagnosis, and costs.

Methods:

Based on data of the ERSPC trial, we predicted the numbers of prostate cancers diagnosed, prostate cancer deaths averted, life-years and quality-adjusted life-years (QALY) gained, and cost-effectiveness of 68 screening strategies starting at age 55 years, with a PSA threshold of 3, using microsimulation modeling. The screening strategies varied by age to stop screening and screening interval (one to 14 years or once in a lifetime screens), and therefore number of tests.

Results:

Screening at short intervals of three years or less was more cost-effective than using longer intervals. Screening at ages 55 to 59 years with two-year intervals had an incremental cost-effectiveness ratio of $73000 per QALY gained and was considered optimal. With this strategy, lifetime prostate cancer mortality reduction was predicted as 13%, and 33% of the screen-detected cancers were overdiagnosed. When better quality of life for the post-treatment period could be achieved, an older age of 65 to 72 years for ending screening was obtained.

Conclusion:

Prostate cancer screening can be cost-effective when it is limited to two or three screens between ages 55 to 59 years. Screening above age 63 years is less cost-effective because of loss of QALYs because of overdiagnosis.


Background:

We compared the estimated clinical outcomes, costs, and physician workload resulting from available strategies for deciding which women with an adnexal mass should be referred to a gynecologic oncologist.

Methods:

We used a microsimulation model to compare five referral strategies: 1) American Congress of Obstetricians and Gynecologists (ACOG) guidelines, 2) Multivariate Index Assay (MIA) algorithm, 3) Risk of Malignancy Algorithm (ROMA), 4) CA125 alone with lowered cutoff values to prioritize test sensitivity over specificity, 5) referral of all women (Refer All). Test characteristics and relative survival were obtained from the literature and data from a biomarker validation study. Medical costs were estimated using Medicare reimbursements. Travel costs were estimated using discharge data from Surveillance, Epidemiology and End Results–Medicare and State Inpatient Databases. Analyses were performed separately for pre- and postmenopausal women (60 000 "subjects" in each), repeated 10 000 times.

Results:

Refer All was cost-effective compared with less expensive strategies in both postmenopausal (incremental cost-effectiveness ratio [ICER] $9423/year of life saved (LYS) compared with CA125) and premenopausal women (ICER $10 644/YLS compared with CA125), but would result in an additional 73 cases/year/subspecialist. MIA was more expensive and less effective than Refer All in pre- and postmenopausal women. If Refer All is not a viable option, CA125 is an optimal strategy in postmenopausal women.

Conclusions:

Referral of all women to a subspecialist is an efficient strategy for managing women with adnexal masses requiring surgery, assuming sufficient capacity for additional surgical volume. If a test-based triage strategy is needed, CA125 with lowered cutoff values is a cost-effective strategy.


Cancer research is drawing on the human genome project to develop new molecular-targeted treatments. This is an exciting but insufficient response to the growing, global burden of cancer, particularly as the projected increase in new cases in the coming decades is increasingly falling on developing countries. The world is not able to treat its way out of the cancer problem. However, the mechanistic insights from basic science can be harnessed to better understand cancer causes and prevention, thus underpinning a complementary public health approach to cancer control. This manuscript focuses on how new knowledge about the molecular and cellular basis of cancer, and the associated high-throughput laboratory technologies for studying those pathways, can be applied to population-based epidemiological studies, particularly in the context of large prospective cohorts with associated biobanks to provide an evidence base for cancer prevention. This integrated approach should allow a more rapid and informed translation of the research into educational and policy interventions aimed at risk reduction across a population.



Since the millennium, personalized medicine has been at the forefront of therapeutic endeavors in medical oncology. The latest technology has given researchers the ability to define cancer at its molecular core. This has led to the development of "targeted therapies," designed to eliminate driver mutations while leaving healthy cells unscathed. Unfortunately, more than 10 years into the targeted molecular therapy era, successes have been infrequent, and toxicity remains largely unchanged compared with relatively indiscriminant, traditional chemotherapy. Emerging data suggests that the malignant clonal heterogeneity within solid tumors is so diverse that targeting one or even several mutations is likely to have minimal, transient impact. In recent years, new therapies have emerged that can effectively stimulate the immune system and improve survival in patients with metastatic disease. Through immune activation, there is the potential to target the cancer with a biologic diversity that can potentially rival the multiplicity of malignant mutations within tumors. Stimulating the immune system to become an evolving adversary against malignant cells may revolutionize cancer therapy in the years to come.











"Personalized medicine" has become a generic term referring to techniques that evaluate either the host or the disease to enhance the likelihood of beneficial patient outcomes from treatment interventions. There is, however, much more to personalization of care than just identifying the biotherapeutic strategy with the highest likelihood of benefit. In its new meaning, "personalized medicine" could overshadow the individually tailored, whole-person care that is at the bedrock of what people need and want when they are ill. Since names and definitional terms set the scope of the discourse, they have the power to define what personalized medicine includes or does not include, thus influencing the scope of the professional purview regarding the delivery of personalized care. Taxonomic accuracy is important in understanding the differences between therapeutic interventions that are distinguishable in their aims, indications, scope, benefits, and risks. In order to restore the due emphasis to the patient and his or her needs, we assert that it is necessary, albeit belated, to deconflate the contemporary term "personalized medicine" by taxonomizing this therapeutic strategy more accurately as "biologically personalized therapeutics" (BPT). The scope of truly personalized medicine and its relationship to biologically personalized therapeutics is described, emphasizing that the best of care must give due recognition and emphasis to both BPT and truly personalized medicine.


Background

Pancreatic ductal adenocarcinoma (PDA) is frequently driven by oncogenic KRAS(KRAS*) mutations. We developed a mouse model of KRAS*-induced PDA and, based on genetic results demonstrating that KRAS* tumorigenicity depends on Myc activity, we evaluated the therapeutic potential of an orally administered anti-Myc drug.

Methods

We tested the efficacy of Mycro3, a small-molecule inhibitor of Myc-Max dimerization, in the treatment of mouse PDA (n = 9) and also of xenografts of human pancreatic cancer cell lines (NOD/SCID mice, n = 3–12). Tumor responses to the drug were evaluated by PET/CT imaging, and histological, immunohistochemical, molecular and microarray analyses. The Student’s t test was used for differences between groups. All statistical tests were two-sided.

Results

Transgenic overexpression of KRAS* in the pancreas resulted in pancreatic intraepithelial neoplasia in two-week old mice, which developed invasive PDA a week later and became moribund at one month. However, this aggressive form of pancreatic tumorigenesis was effectively prevented by genetic ablation of Myc specifically in the pancreas. We then treated moribund, PDA-bearing mice daily with the Mycro3 Myc-inhibitor. The mice survived until killed at two months. PET/CT image analysis (n = 5) demonstrated marked shrinkage of PDA, while immunohistochemical analyses showed an increase in cancer cell apoptosis and reduction in cell proliferation (treated/untreated proliferation index ratio: 0.29, P < .001, n = 3, each group). Tumor growth was also drastically attenuated in Mycro3-treated NOD/SCID mice (n = 12) carrying orthotopic or heterotopic xenografts of human pancreatic cancer cells (eg, mean tumor weight ± SD of treated heterotopic xenografts vs vehicle-treated controls: 15.2±5.8mg vs 230.2±43.9mg, P < .001).

Conclusion

These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA.


Background

The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome.

Methods

We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296). In parallel, using next-generation sequencing data from breast cancer patients (n = 684), we assessed microRNA association with stem cell markers. All statistical tests were two-sided.

Results

In healthy tissues, the MIR302 (high)/MIR203 (low) asymmetry was exclusive for pluripotent stem cells. MIR302 was expressed in a small population of cancer cells within invasive ductal carcinoma, but not in normal breast (P < .001). Furthermore, MIR302 was expressed in the tumor cells together with stem cell markers, such as CD44 and BMI1. Conversely, MIR203 expression in 684 breast tumors negatively correlated with CD44 (Spearman correlation, Rho = -0.08, P = .04) and BMI1 (Rho = -0.11, P = .004), but positively correlated with differentiation marker CD24 (Rho = 0.15, P < .001). Primary tumors with lymph node metastasis had cancer cells showing scattered expression of MIR302 and widespread repression of MIR203. Finally, overall survival was statistically significantly shorter in patients with MIR302-positive cancer cells (P = .03).

Conclusions

In healthy tissues the MIR302(high)/MIR203(low) asymmetry was characteristic of embryonic and induced pluripotency. In invasive ductal carcinoma, the MIR302/MIR203 asymmetry was associated with stem cell markers, metastasis, and shorter survival.


Background

Diabetes is an emerging risk factor for hepatocellular carcinoma (HCC), but prospective data from different ethnic populations are scarce. We examined the association between diabetes and HCC in 168679 African Americans, Native Hawaiians, Japanese Americans, Latinos and whites in the Multiethnic Cohort.

Methods

During a 15.7-year follow up period, 470 incident HCC cases were identified. Risk factor data were obtained from the baseline questionnaire. Cox regressions were used to calculate hazard rate ratios (RRs) and 95% confidence intervals (CIs) for HCC associated with self-reported diabetes. The population attributable risk percent associated with diabetes was also calculated. All statistical tests were two-sided.

Results

The RRs for developing HCC (vs whites) were 2.73 (95% CI = 2.00 to 3.72) for Latinos, 2.48 (95% CI = 1.59 to 3.87) for Hawaiians, 2.16 (95% CI = 1.52 to 3.07) for African Americans, and 2.05 (95% CI = 1.50 to 2.81) for Japanese. Diabetes was associated with HCC across ethnic groups (RRLatinos = 3.36 [95% CI = 2.41 to 4.70], RRHawaiians = 2.50 [95% CI = 1.11 to 5.64], RRJapanese = 2.34 [95% CI = 1.60 to 3.41], RRwhites = 2.15 [95% CI = 0.95 to 4.90], and RRAfrican Americans = 2.02 [95% CI = 1.17 to 3.48]). We estimated that 27% of HCC cases in Latinos, 18% in Hawaiians, 13% in African Americans, 12% in Japanese, and 6% in whites were attributed to diabetes.

Conclusions

Latinos were at the highest risk of developing HCC, followed by Native Hawaiians, African Americans, Japanese and whites. Diabetes is a risk factor for HCC in all ethnic groups, and eliminating diabetes could potentially reduce HCC incidence in all ethnic groups, with the largest potential for reduction in Latinos.


Background

Tumor microenvironment, and particularly tumor-associated macrophages (TAMs), represent a key contributing factor in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. Here we report that heparanase (predominant enzyme degrading heparan sulfate, the main polysaccharide found at the cell surface and extracellular matrix) directs tumor-promoting behavior of TAM in PDAC.

Methods

A mouse model of heparanase-overexpressing pancreatic carcinoma (n = 5 mice/group), tumor-associated macrophages ex vivo, primary wild-type and heparanase-null macrophages, and histological specimens from PDAC patients (n = 16), were analyzed, applying immunostaining, enzyme-linked immunosorbent assay, real-time reverse transcription–polymerase chain reaction, cell proliferation, and heparanase activity assays. All statistical tests are two-sided.

Results

We found that overexpression of heparanase is associated with increased TAM infiltration in both experimental (P = .002) and human (P = .01) PDAC. Moreover, macrophages derived from heparanase-rich tumors (which grew faster in mouse hosts), display pronounced procancerous phenotype, evidenced by overexpression of MSR-2, IL-10, CCL2, VEGF, and increased production of IL-6, an important player in PDAC pathogenesis. Furthermore, in vitro heparanase enzyme–rendered macrophages (stimulated by necrotic cells which are often present in PDAC tissue) procancerous, as exemplified by their enhanced production of key cytokines implicated in PDAC (including IL-6), as well as by their ability to induce STAT3 signaling and to augment pancreatic carcinoma cell proliferation. In agreement, we observed activation of STAT3 in experimental and clinical specimens of heparanase-overexpressing PDAC.

Conclusions

Our findings underscore a novel function of heparanase in molecular decision-making that guides cancer-promoting action of TAM and imply that heparanase expression status may become highly relevant in defining a target patient subgroup that is likely to benefit the most from treatment modalities targeting TAM/IL-6/STAT3.


Background

"Waterfall plots" are used to describe changes in tumor size observed in clinical studies. Here we assess criteria for generation of waterfall plots and the impact of measurement error in generating them.

Methods

We reviewed published waterfall plots to investigate variability in criteria used to define them. We then compared waterfall plots generated by different observers for 24 patients enrolled in a completed phase I study of solid tumors with available computed tomography (CT) scans. Tumor measurements were made independently from CT scans according to Response Evaluation Criteria in Solid Tumors 1.1 by four board-certified radiologists and four medical oncologists. Interobserver variability was quantified and compared with reference measurements reported for the phase 1 study. All statistical tests were two-sided.

Results

There was substantial variability in criteria used to generate published waterfall plots. In the internal study, the results were statistically significantly different between all eight readers (P = .01, variance = 197.1, SD = 14.0) and between the oncologists (P = .01, variance = 319.0, SD = 17.9), but not between the radiologists (P = .68, variance = 70.8, SD = 8.4). Different observers classified one to five patients as having a partial response and 12–19 patients as having stable disease. Similar variability in categorization of response was observed when these error rates were applied to published waterfall plots.

Conclusion

Waterfall plots are subject to substantial variability in criteria used to define them and are influenced by measurement errors; they should be generated by trained radiologists. Caution should be exercised when interpreting results of waterfall plots in the context of clinical trials.


Background

Current prognostic tools in colon cancer use relatively few patient characteristics. We constructed and validated clinical calculators for overall survival (OS) and time to recurrence (TTR) for stage III colon cancer and compared their performance against an existing tool (Numeracy) and American Joint Committee on Cancer (AJCC) version 7 staging.

Methods

Data from 15936 stage III patients accrued to phase III clinical trials since 1989 were used to construct Cox models for TTR and OS. Variables included age, sex, race, body mass index, performance status, tumor grade, tumor stage, ratio of positive lymph nodes to nodes examined, number and location of primary tumors, and adjuvant treatment (fluoropyrimidine single agent or in combination). Missing data were imputed, and final models internally validated for optimism-corrected calibration and discrimination and compared with AJCC. External validation and comparisons against Numeracy were performed using stage III patients from NSABP trial C-08. All statistical tests were two-sided.

Results

All variables were statistically and clinically significant for OS prediction, while age and race did not predict TTR. No meaningful interactions existed. Models for OS and TTR were well calibrated and associated with C-indices of 0.66 and 0.65, respectively, compared with C-indices of 0.58 and 0.59 for AJCC. These tools, available online, better predicted patient outcomes than Numeracy, both overall and within patient subgroups, in external validation.

Conclusions

The proposed ACCENT calculators are internally and externally valid, better discriminate patient risk than AJCC version 7 staging, and better predict patient outcomes than Numeracy. These tools have replaced Numeracy for online clinical use and will aid prognostication and patient/physician communication.


The frequency of overdiagnosis associated with breast cancer screening is a topic of controversy. Published estimates vary widely, but identifying which estimates are reliable is challenging. In this article we present an approach that provides a check on these estimates. Our approach leverages the close link between overdiagnosis and lead time by identifying the average lead time most consistent with a given overdiagnosis frequency. We consider a high-profile study that suggested that 31% of breast cancers diagnosed in the United States in 2008 were overdiagnosed and show that this corresponds to an average lead time of about nine years among localized cases. Comparing this estimate with the average lead time for invasive, screen-detected breast cancers of 40 months, around which there is a relative consensus, suggests the published estimate of overdiagnosis is excessive. This approach provides a novel way to appraise estimates of overdiagnosis given knowledge of disease natural history.



Background

The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival.

Methods

The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided.

Results

EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4th and 1st quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P trend < .001. We found similar results after adjusting for potential confounders (adjusted P trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4th and 1st quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P trend < .001).

Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P trend = .02). No association was evident for the other measured biomarkers.

Conclusion

Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts.


Background

The growing demand for cancer genetic services underscores the need to consider approaches that enhance access and efficiency of genetic counseling. Telephone delivery of cancer genetic services may improve access to these services for individuals experiencing geographic (rural areas) and structural (travel time, transportation, childcare) barriers to access.

Methods

This cluster-randomized clinical trial used population-based sampling of women at risk for BRCA1/2 mutations to compare telephone and in-person counseling for: 1) equivalency of testing uptake and 2) noninferiority of changes in psychosocial measures. Women 25 to 74 years of age with personal or family histories of breast or ovarian cancer and who were able to travel to one of 14 outreach clinics were invited to participate.

Randomization was by family. Assessments were conducted at baseline one week after pretest and post-test counseling and at six months. Of the 988 women randomly assigned, 901 completed a follow-up assessment. Cluster bootstrap methods were used to estimate the 95% confidence interval (CI) for the difference between test uptake proportions, using a 10% equivalency margin. Differences in psychosocial outcomes for determining noninferiority were estimated using linear models together with one-sided 97.5% bootstrap CIs.

Results

Uptake of BRCA1/2 testing was lower following telephone (21.8%) than in-person counseling (31.8%, difference = 10.2%, 95% CI = 3.9% to 16.3%; after imputation of missing data: difference = 9.2%, 95% CI = -0.1% to 24.6%). Telephone counseling fulfilled the criteria for noninferiority to in-person counseling for all measures.

Conclusions

BRCA1/2 telephone counseling, although leading to lower testing uptake, appears to be safe and as effective as in-person counseling with regard to minimizing adverse psychological reactions, promoting informed decision making, and delivering patient-centered communication for both rural and urban women.


Background

Mammographic density is a strong heritable trait, but data on its genetic component are limited to area-based and qualitative measures. We studied the heritability of volumetric mammographic density ascertained by a fully-automated method and the association with breast cancer susceptibility loci.

Methods

Heritability of volumetric mammographic density was estimated with a variance component model in a sib-pair sample (N pairs = 955) of a Swedish screening based cohort. Associations with 82 established breast cancer loci were assessed in an independent sample of the same cohort (N = 4025 unrelated women) using linear models, adjusting for age, body mass index, and menopausal status. All tests were two-sided, except for heritability analyses where one-sided tests were used.

Results

After multivariable adjustment, heritability estimates (standard error) for percent dense volume, absolute dense volume, and absolute nondense volume were 0.63 (0.06) and 0.43 (0.06) and 0.61 (0.06), respectively (all P < .001). Percent and absolute dense volume were associated with rs10995190 (ZNF365; P = 9.0 x 10–6 and 8.9 x 10–7, respectively) and rs9485372 (TAB2; P = 1.8 x 10–5 and 1.8 x 10–3, respectively). We also observed associations of rs9383938 (ESR1) and rs2046210 (ESR1) with the absolute dense volume (P = 2.6 x 10–4 and 4.6 x 10–4, respectively), and rs6001930 (MLK1) and rs17356907 (NTN4) with the absolute nondense volume (P = 6.7 x 10–6 and 8.4 x 10–5, respectively).

Conclusions

Our results support the high heritability of mammographic density, though estimates are weaker for absolute than percent dense volume. We also demonstrate that the shared genetic component with breast cancer is not restricted to dense tissues only.


Background

In breast cancer studies, many different endpoints are used. Definitions are often not provided or vary between studies. For instance, "local recurrence" may include different components in similar studies. This limits transparency and comparability of results. This project aimed to reach consensus on the definitions of local event, second primary breast cancer, regional and distant event for breast cancer studies.

Methods

The RAND-UCLA Appropriateness method (modified Delphi method) was used. A Consensus Group of international breast cancer experts was formed, including representatives of all involved clinical disciplines. Consensus was reached in two rounds of online questionnaires and one meeting.

Results

Twenty-four international breast cancer experts participated. Consensus was reached on 134 items in four categories. Local event is defined as any epithelial breast cancer or ductal carcinoma in situ (DCIS) in the ipsilateral breast, or skin and subcutaneous tissue on the ipsilateral thoracic wall. Second primary breast cancer is defined as epithelial breast cancer in the contralateral breast. Regional events are breast cancer in ipsilateral lymph nodes. A distant event is breast cancer in any other location. Therefore, this includes metastasis in contralateral lymph nodes and breast cancer involving the sternal bone. If feasible, tissue sampling of a first, solitary, lesion suspected for metastasis is highly recommended.

Conclusion

This project resulted in consensus-based event definitions for classification of recurrence in breast cancer research. Future breast cancer research projects should adopt these definitions to increase transparency. This should facilitate comparison of results and conducting reviews as well as meta-analysis.


Background

Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data.

Methods

We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided.

Results

In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P < .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P < .001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P = .02), diarrhea (P = .003), leukopenia (P = .002), neutropenia (P < .001), and thrombocytopenia (P < .001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P = .48).

Conclusion

In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy.







Background

The study aimed to determine the effect of preference-based tailored navigation on colorectal cancer (CRC) screening adherence and related outcomes among African Americans (AAs).

Methods

We conducted a randomized controlled trial that included 764 AA patients who were age 50 to 75 years, were eligible for CRC screening, and had received care through primary care practices in Philadelphia. Consented patients completed a baseline telephone survey and were randomized to either a Standard Intervention (SI) group (n = 380) or a Tailored Navigation Intervention (TNI) group (n = 384). The SI group received a mailed stool blood test kit plus colonoscopy instructions, and a reminder. The TNI group received tailored navigation (a mailed stool blood test kit or colonoscopy instructions based on preference, plus telephone navigation) and a reminder. A six-month survey and a 12-month medical records review were completed to assess screening adherence, change in overall screening preference, and perceptions about screening. Multivariable analyses were performed to assess intervention impact on outcomes.

Results

At six months, adherence in the TNI group was statistically significantly higher than in the SI group (OR = 2.1, 95% CI = 1.5 to 2.9). Positive change in overall screening preference was also statistically significantly greater in the TNI group compared with the SI group (OR = 1.5, 95% CI = 1.0 to 2.3). There were no statistically significant differences in perceptions about screening between the study groups.

Conclusions

Tailored navigation in primary care is a promising approach for increasing CRC screening among AAs. Research is needed to determine how to maximize intervention effects and to test intervention impact on race-related disparities in mortality and survival.



Background

Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE). However, the relationships may be affected by bias and confounding.

Methods

We used data from the Barrett’s and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided.

Results

The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m2 increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses.

Conclusions

People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.


Background

Screening with mammography has been shown by randomized controlled trials to reduce breast cancer mortality in women aged 40 to 74 years. Estimates from observational studies following screening implementation in different countries have produced varyied findings. We report findings for seven Canadian breast screening programs.

Methods

Canadian breast screening programs were invited to participate in a study aimed at comparing breast cancer mortality in participants and nonparticipants. Seven of 12 programs, representing 85% of the Canadian population, participated in the study. Data were obtained from the screening programs and corresponding cancer registries on screening mammograms and breast cancer diagnoses and deaths for the period between 1990 and 2009. Standardized mortality ratios were calculated comparing observed mortality in participants to that expected based upon nonparticipant rates. A substudy using data from British Columbia women aged 35 to 44 years was conducted to assess the potential effect of self-selection participation bias. All statistical tests were two-sided.

Results

Data were obtained on 2796472 screening participants. The average breast cancer mortality among participants was 40% (95% confidence interval [CI] = 33% to 48%), lower than expected with a range across provinces of 27% to 59%. Age at entry into screening did not greatly affect the magnitude of the average reduction in mortality, which varied between 35% and 44% overall. The substudy found no evidence that self-selection biased the reported mortality results, although the confidence intervals of this assessment were wide.

Conclusion

Participation in mammography screening programs in Canada was associated with substantially reduced breast cancer mortality.



Background

Treatment with bisphosphonates in women with breast cancer and established bone metastasis delays further skeletal-related events. Evidence is emerging that bisphosphonates are beneficial for secondary prevention of bone metastasis. The study aimed to estimate the effect of oral bisphosphonates for treatment or prevention of osteoporosis on development of bone metastasis in a population of women with breast cancer.

Methods

A historical cohort of 21664 women diagnosed with breast cancer was created from health administrative data in Quebec, Canada. The primary outcome was time to develop bone metastasis; exposure was bisphosphonate use prediagnosis, postdiagnosis, both, or neither and a cumulative index of drug exposure. The sample was stratified according to stage (0-II or III) at time of diagnosis. Cox proportional hazards tested the effect of bisphosphonate use on time to develop bone metastases.

Results

Taking bisphosphonates postdiagnosis of breast cancer only or continuing bisphosphonates started prior to diagnosis after diagnosis was associated with a reduction in risk of bone metastasis from 45% to 28% in women with local disease at diagnosis.

In women with regional disease, postdiagnosis bisphosphonate use, with or without prediagnosis use, reduced risk by almost 50%. A statistically significant dose-response trend was observed relating increased use to lower risk (slope = 0.94, 95% confidence interval = 0.90 to 0.99). Bisphosphonates were also associated with a decreased risk of all-cause mortality similar to that of the development of bone metastasis.

Conclusion

Low-dose oral bisphosphonates administered for prevention or treatment of postmenopausal osteoporosis were associated with lower risk of skeletal metastasis in patients with early- or more advanced-stage breast cancer.


Background

Sipuleucel-T is a US Food and Drug Administration–approved immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its mechanism of action is not fully understood. This prospective trial evaluated the direct immune effects of systemically administered sipuleucel-T on prostatic cancer tissue in the preoperative setting.

Methods

Patients with untreated localized prostate cancer were treated on an open-label Phase II study of sipuleucel-T prior to planned radical prostatectomy (RP). Immune infiltrates in RP specimens (posttreatment) and in paired pretreatment biopsies were evaluated by immunohistochemistry (IHC). Correlations between circulating immune response and IHC were assessed using Spearman rank order.

Results

Of the 42 enrolled patients, 37 were evaluable. Adverse events were primarily transient, mild-to-moderate and infusion related. Patients developed T cell proliferation and interferon- responses detectable in the blood following treatment. Furthermore, a greater-than-three-fold increase in infiltrating CD3+, CD4+ FOXP3-, and CD8+ T cells was observed in the RP tissues compared with the pretreatment biopsy (binomial proportions: all P < .001). This level of T cell infiltration was observed at the tumor interface, and was not seen in a control group consisting of 12 concurrent patients who did not receive any neoadjuvant treatment prior to RP. The majority of infiltrating T cells were PD-1+ and Ki-67+, consistent with activated T cells. Importantly, the magnitude of the circulating immune response did not directly correlate with T cell infiltration within the prostate based upon Spearman’s rank order correlation.

Conclusions

This study is the first to demonstrate a local immune effect from the administration of sipuleucel-T. Neoadjuvant sipuleucel-T elicits both a systemic antigen-specific T cell response and the recruitment of activated effector T cells into the prostate tumor microenvironment.


Background

The 12-gene Recurrence Score assay is a validated predictor of recurrence risk in stage II and III colon cancer patients. We conducted a prospectively designed study to validate this assay for prediction of recurrence risk in stage II and III rectal cancer patients from the Dutch Total Mesorectal Excision (TME) trial.

Methods

RNA was extracted from fixed paraffin-embedded primary rectal tumor tissue from stage II and III patients randomized to TME surgery alone, without (neo)adjuvant treatment. Recurrence Score was assessed by quantitative real time–polymerase chain reaction using previously validated colon cancer genes and algorithm. Data were analysed by Cox proportional hazards regression, adjusting for stage and resection margin status. All statistical tests were two-sided.

Results

Recurrence Score predicted risk of recurrence (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.11 to 2.21, P = .01), risk of distant recurrence (HR = 1.50, 95% CI = 1.04 to 2.17, P = .03), and rectal cancer-specific survival (HR = 1.64, 95% CI = 1.15 to 2.34, P = .007). The effect of Recurrence Score was most prominent in stage II patients and attenuated with more advanced stage (P interaction ≤ .007 for each endpoint). In stage II, five-year cumulative incidence of recurrence ranged from 11.1% in the predefined low Recurrence Score group (48.5% of patients) to 43.3% in the high Recurrence Score group (23.1% of patients).

Conclusion

The 12-gene Recurrence Score is a predictor of recurrence risk and cancer-specific survival in rectal cancer patients treated with surgery alone, suggesting a similar underlying biology in colon and rectal cancers.


Background

Computed tomography (CT) screening for lung cancer has been associated with a high frequency of false positive results because of the high prevalence of indeterminate but usually benign small pulmonary nodules. The acceptability of reducing false-positive rates and diagnostic evaluations by increasing the nodule size threshold for a positive screen depends on the projected balance between benefits and risks.

Methods

We examined data from the National Lung Screening Trial (NLST) to estimate screening CT performance and outcomes for scans with nodules above the 4mm NLST threshold used to classify a CT screen as positive. Outcomes assessed included screening results, subsequent diagnostic tests performed, lung cancer histology and stage distribution, and lung cancer mortality. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the different nodule size thresholds. All statistical tests were two-sided.

Results

In 64% of positive screens (11598/18141), the largest nodule was 7mm or less in greatest transverse diameter. By increasing the threshold, the percentages of lung cancer diagnoses that would have been missed or delayed and false positives that would have been avoided progressively increased, for example from 1.0% and 15.8% at a 5 mm threshold to 10.5% and 65.8% at an 8 mm threshold, respectively. The projected reductions in postscreening follow-up CT scans and invasive procedures also increased as the threshold was raised. Differences across nodules sizes for lung cancer histology and stage distribution were small but statistically significant. There were no differences across nodule sizes in survival or mortality.

Conclusion

Raising the nodule size threshold for a positive screen would substantially reduce false-positive CT screenings and medical resource utilization with a variable impact on screening outcomes.


To meet the complex needs of a growing number of cancer survivors, it is essential to accelerate the translation of survivorship research into evidence-based interventions and, as appropriate, recommendations for care that may be implemented in a wide variety of settings. Current progress in translating research into care is stymied, with results of many studies un- or underutilized. To better understand this problem and identify strategies to encourage the translation of survivorship research findings into practice, four agencies (American Cancer Society, Centers for Disease Control and Prevention, LIVE STRONG Foundation, National Cancer Institute) hosted a meeting in June, 2012, titled: "Biennial Cancer Survivorship Research Conference: Translating Science to Care." Meeting participants concluded that accelerating science into care will require a coordinated, collaborative effort by individuals from diverse settings, including researchers and clinicians, survivors and families, public health professionals, and policy makers. This commentary describes an approach stemming from that meeting to facilitate translating research into care by changing the process of conducting research—improving communication, collaboration, evaluation, and feedback through true and ongoing partnerships. We apply the T0-T4 translational process model to survivorship research and provide illustrations of its use. The resultant framework is intended to orient stakeholders to the role of their work in the translational process and facilitate the transdisciplinary collaboration needed to translate basic discoveries into best practices regarding clinical care, self-care/management, and community programs for cancer survivors. Finally, we discuss barriers to implementing translational survivorship science identified at the meeting, along with future directions to accelerate this process.


Background

Molecular characterization of breast cancer allows subtype-directed interventions. Estrogen receptor (ER) is the longest-established molecular marker.

Methods

We used six established population models with ER-specific input parameters on age-specific incidence, disease natural history, mammography characteristics, and treatment effects to quantify the impact of screening and adjuvant therapy on age-adjusted US breast cancer mortality by ER status from 1975 to 2000. Outcomes included stage-shifts and absolute and relative reductions in mortality; sensitivity analyses evaluated the impact of varying screening frequency or accuracy.

Results

In the year 2000, actual screening and adjuvant treatment reduced breast cancer mortality by a median of 17 per 100000 women (model range = 13–21) and 5 per 100000 women (model range = 3–6) for ER-positive and ER-negative cases, respectively, relative to no screening and no adjuvant treatment. For ER-positive cases, adjuvant treatment made a higher relative contribution to breast cancer mortality reduction than screening, whereas for ER-negative cases the relative contributions were similar for screening and adjuvant treatment. ER-negative cases were less likely to be screen-detected than ER-positive cases (35.1% vs 51.2%), but when screen-detected yielded a greater survival gain (five-year breast cancer survival = 35.6% vs 30.7%). Screening biennially would have captured a lower proportion of mortality reduction than annual screening for ER-negative vs ER-positive cases (model range = 80.2%–87.8% vs 85.7%–96.5%).

Conclusion

As advances in risk assessment facilitate identification of women with increased risk of ER-negative breast cancer, additional mortality reductions could be realized through more frequent targeted screening, provided these benefits are balanced against screening harms.


Background

Nearly half of muscle-invasive bladder cancer patients succumb to their disease following cystectomy. Selecting candidates for adjuvant therapy is currently based on clinical parameters with limited predictive power. This study aimed to develop and validate genomic-based signatures that can better identify patients at risk for recurrence than clinical models alone.

Methods

Transcriptome-wide expression profiles were generated using 1.4 million feature-arrays on archival tumors from 225 patients who underwent radical cystectomy and had muscle-invasive and/or node-positive bladder cancer. Genomic (GC) and clinical (CC) classifiers for predicting recurrence were developed on a discovery set (n = 133). Performances of GC, CC, an independent clinical nomogram (IBCNC), and genomic-clinicopathologic classifiers (G-CC, G-IBCNC) were assessed in the discovery and independent validation (n = 66) sets. GC was further validated on four external datasets (n = 341). Discrimination and prognostic abilities of classifiers were compared using area under receiver-operating characteristic curves (AUCs). All statistical tests were two-sided.

Results

A 15-feature GC was developed on the discovery set with area under curve (AUC) of 0.77 in the validation set. This was higher than individual clinical variables, IBCNC (AUC = 0.73), and comparable to CC (AUC = 0.78). Performance was improved upon combining GC with clinical nomograms (G-IBCNC, AUC = 0.82; G-CC, AUC = 0.86). G-CC high-risk patients had elevated recurrence probabilities (P < .001), with GC being the best predictor by multivariable analysis (P = .005). Genomic-clinicopathologic classifiers outperformed clinical nomograms by decision curve and reclassification analyses. GC performed the best in validation compared with seven prior signatures. GC markers remained prognostic across four independent datasets.

Conclusions

The validated genomic-based classifiers outperform clinical models for predicting postcystectomy bladder cancer recurrence. This may be used to better identify patients who need more aggressive management.


Human epidermal growth factor receptor 2 (HER2)–positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906mm3, 95% confidence interval = 1274 to 538 mm3; trastuzumab+doxorubicin: 259mm3, 95% confidence interval = 387 to 131 mm3; P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells.


Background

A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease.

Methods

Levels of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models.

Results

Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin [IL]-15, IL-1RA, IL-1β, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval [CI] = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1β, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking.

Conclusions

Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time.



The impressive first results of the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) and the adjuvant Tamoxifen To offer more (aTTom) trials both demonstrate that 10 years of tamoxifen is superior to five years of treatment. Tamoxifen is a nonsteroidal antiestrogen that blocks estrogen-stimulated tumor growth. Paradoxically, mortality decreases dramatically only in the decade after long-term tamoxifen is stopped. It is proposed that the evolution and clonal selection of micrometastases that acquire tamoxifen resistance now become increasingly vulnerable to endogenous estrogen-induced apoptosis. Laboratory and clinical studies confirm the concept, and supporting clinical evidence from the estrogen-alone trial in the Women’s Health Initiative (WHI), demonstrate that long-term estrogen-deprived women given exogenous physiologic estrogen have a decreased incidence of breast cancer and decreased mortality. It is proposed that a natural process of apoptosis is recruited to execute the long-term survival benefit of stopping ten years of adjuvant tamoxifen, but only after clonal selection of vulnerable breast cancer cells in an estrogen-deprived environment.



Background

There has been little improvement in the survival of adolescent and young adult (AYA) cancer patients aged 15 to 39 years relative to other age groups, raising the question of whether such patients receive appropriate initial treatment.

Methods

We examined receipt of initial cancer treatment for a population-based sample of 504 AYAs diagnosed in 2007–2008 with acute lymphoblastic leukemia (ALL), Hodgkin’s or non-Hodgkin’s lymphoma, germ cell cancer, or sarcoma. Registry data, patient surveys, and detailed medical record reviews were used to evaluate the association of patient demographic, socioeconomic, and health care setting characteristics with receipt of appropriate initial treatment, which was defined by clinical specialists in AYA oncology based on adult guidelines and published literature available before 2009 and analyzed with multivariable logistic regression. All statistical tests were two-sided.

Results

Approximately 75% of AYA cancer patients in our sample received appropriate treatment, 68% after excluding stage I male germ cell patients who all received appropriate treatment. After this exclusion, appropriate treatment ranged from 79% of sarcoma patients to 56% of ALL patients. Cancer type (P < .01) and clinical trial participation (P = .04) were statistically significantly associated with appropriate treatment in multivariable analyses. Patients enrolled in clinical trials were more likely to receive appropriate therapy relative to those not enrolled (78% vs 67%, adjusted odds ratio = 2.6, 95% confidence interval = 1.1 to 6.4).

Conclusions

Except for those with early stage male germ cell tumors, approximately 30% (or 3 in 10) AYA cancer patients did not receive appropriate therapy. Further investigation is required to understand the reasons for this potential shortfall in care delivery.



Background

In oncology clinical trials, the assumption that a prior cancer diagnosis could interfere with study conduct or outcomes results in frequent exclusion of such patients. We determined the prevalence and characteristics of this practice in lung cancer clinical trials and estimated impact on trial accrual.

Methods

We reviewed lung cancer clinical trials sponsored or endorsed by the Eastern Oncology Cooperative Group for exclusion criteria related to a prior cancer diagnosis. We estimated prevalence of prior primary cancer diagnoses among lung cancer patients using Surveillance Epidemiology and End Results (SEER)-Medicare linked data. We assessed the association between trial characteristics and prior cancer exclusion using chi-square analysis. All statistical tests were two-sided.

Results

Fifty-one clinical trials (target enrollment 13072 patients) were included. Forty-one (80%) excluded patients with a prior cancer diagnosis as follows: any prior (14%), within five years (43%), within two or three years (7%), or active cancer (16%). In SEER-Medicare data (n = 210509), 56% of prior cancers were diagnosed within five years before the lung cancer diagnosis. Across trials, the estimated number and proportion of patients excluded because of prior cancer ranged from 0–207 and 0%-18%. Prior cancer was excluded in 94% of trials with survival primary endpoints and 73% of trials with nonsurvival primary endpoints (P = .06).

Conclusions

A substantial proportion of patients are reflexively excluded from lung cancer clinical trials because of prior cancer. This inclusion criterion is applied widely across studies, including more than two-thirds of trials with nonsurvival endpoints. More research is needed to understand the basis and ramifications of this exclusion policy.




Genome-wide association studies (GWAS) have identified hundreds of genetic susceptibility loci for cancers and other complex diseases. However, the public health and clinical relevance of these discoveries is unclear. Evaluating the combined associations of genetic and environmental risk factors, particularly those that can be modified, will be critical in assessing the utility of genetic information for risk stratified prevention. In this commentary, using breast cancer as a model, we show that genetic information in combination with other risk factors can provide levels of risk stratification that could be useful for individual decision-making or population-based prevention programs. Our projections are theoretical and rely on a number of assumptions, including multiplicative models for the combined associations of the different risk factors, which need confirmation. Thus, analyses of epidemiological studies with high-quality risk factor information, as well as prevention trials, are needed to empirically assess the impact of genetics in risk stratified prevention.


Background

The majority of newly diagnosed prostate cancers will remain indolent, but distinguishing between aggressive and indolent disease is imprecise. This has led to the important clinical problem of overtreatment. THOC1 encodes a nuclear ribonucleoprotein whose expression is higher in some cancers than in normal tissue. The hypothesis that THOC1 may be a functionally relevant biomarker that can improve the identification of aggressive prostate cancer has not been tested.

Methods

THOC1 protein immunostaining was evaluated in a retrospective collection of more than 700 human prostate cancer specimens and the results associated with clinical variables and outcome. Thoc1 was conditionally deleted in an autochthonous mouse model (n = 22 or 23 per genotype) to test whether it is required for prostate cancer progression. All statistical tests were two-sided.

Results

THOC1 protein immunostaining increases with higher Gleason score and more advanced Tumor/Node/Metastasis stage. Time to biochemical recurrence is statistically significantly shorter for cancers with high THOC1 protein (log-rank P = .002, and it remains statistically significantly associated with biochemical recurrence after adjusting for Gleason score, clinical stage, and prostate-specific antigen levels (hazard ratio = 1.61, 95% confidence interval = 1.03 to 2.51, P = .04). Thoc1 deletion prevents prostate cancer progression in mice, but has little effect on normal tissue. Prostate cancer cells deprived of Thoc1 show gene expression defects that compromise cell growth.

Conclusions

Thoc1 is required to support the unique gene expression requirements of aggressive prostate cancer in mice. In humans, high THOC1 protein immunostaining associates with prostate cancer aggressiveness and recurrence. Thus, THOC1 protein is a functionally relevant molecular marker that may improve the identification of aggressive prostate cancers, potentially reducing overtreatment.


Background

Survival after an ovarian cancer diagnosis is poor. Given the high mortality in these patients, efforts to identify modifiable lifestyle behaviors that could influence survival are needed. Earlier evidence suggests a protective role for vegetables, but no prior studies have evaluated overall dietary quality and ovarian cancer survival. The purpose of this analysis was to evaluate the role of prediagnosis diet quality in ovarian cancer survival.

Methods

We identified 636 centrally adjudicated cases of ovarian cancer within the Women’s Health Initiative Observational Study or Clinical Trials of 161808 postmenopausal women followed from 1995 to 2012. Dietary quality was assessed for the Healthy Eating Index (2005) using a food frequency questionnaire, covariables were obtained from standardized questionnaires, and adiposity was measured by clinic-based measurements of height, weight, and waist circumference. The association between diet quality and mortality was analyzed using Cox proportional hazards regression, adjusted for potential confounders, and stratified by waist circumference, physical activity level, and diabetes status. Tests of statistical significance were two-sided.

Results

Overall, higher diet quality was associated with lower all-cause mortality after ovarian cancer (hazard ratio [HR] for highest vs lowest tertile = 0.73; 95% confidence interval [CI] = 0.55 to 0.97, P trend = .03). The effect was strongest among women with waist circumference of 88cm or less and with no history of diabetes (HR = 0.73, 95% CI = 0.54 to 0.98). Physical activity level did not modify the association between diet quality and survival.

Conclusion

Our results suggest that overall higher prediagnosis diet quality may protect against mortality after ovarian cancer.


Background

Early data on breast cancer screening utilizing digital breast tomosynthesis (DBT) combined with digital mammography (DM) have shown improvements in false-positive and false-negative screening rates compared with DM alone. However, these trials were performed at sites where conventional mammographic screening was concurrently performed, possibly leading to selection biases or with complex, multireader algorithms not reflecting general clinical practice. Our study reports the impact on screening outcomes for DBT screening implemented in an entire clinic population.

Methods

Recall rates, cancer detection, and positive predictive values of screening were compared for 15571 women screened with DBT and 10728 screened with DM alone prior to DBT implementation at a single breast imaging center. Generalized linear mixed-effects models were used to estimate the odds ratio (OR) for recall rate adjusted for age, race, presence of prior mammograms, breast density and reader. All statistical tests were two-sided.

Results

DBT screening showed a statistically significant reduction in recalls compared to DM alone. For the entire population, there were 16 fewer recalls (8.8% vs 10.4%, P <.001, adjusted OR = 0.80, 95% confidence interval [CI] = 0.74 to 0.88, P < .001) and 0.9 additional cancers detected per 1000 screened with DBT compared to DM alone. There was a statistically significant increase in PPV1 (6.2% vs 4.4%, P = .047). In women younger than age 50 years screened with DBT, there were 17 fewer recalls (12.3% vs 14.0%, P = .02) and 3.6 additional cancer detected per 1000 screened (5.7 vs 2.2 per 1000, P = .02).

Conclusions

Our data support the clinical implementation of DBT in breast cancer screening; however, larger prospective trials are needed to validate our findings in specific patient subgroups.



Background

The Sonic Hedgehog (SHH) signaling pathway plays an important role in neural crest cell fate during embryonic development and has been implicated in the progression of multiple cancers that include neuroblastoma, a neural crest cell-derived disease. While most of the SHH signaling is mediated by the well-described canonical pathway leading to the activation of Smoothened and Gli, it has recently been shown that cell-adhesion molecule-related/downregulated by oncogenes (CDON) serves as a receptor for SHH and contributes to SHH-induced signaling. CDON has also been recently described as a dependence receptor, triggering apoptosis in the absence of SHH. This CDON proapoptotic activity has been suggested to constrain tumor progression.

Methods

CDON expression was analyzed by quantitative–reverse transcription–polymerase chain reaction in a panel of 226 neuroblastoma patients and associated with stages, overall survival, and expression of miR181 family members using Kaplan Meier and Pearson correlation methods. Cell death assays were performed in neuroblastoma cell lines and tumor growth was investigated in the chick chorioallantoic model. All statistical tests were two-sided.

Results

CDON expression was inversely associated with neuroblastoma aggressiveness (P < .001). Moreover, re-expression of CDON in neuroblastoma cell lines was associated with apoptosis in vitro and tumor growth inhibition in vivo. We show that CDON expression is regulated by the miR181 miRNA family, whose expression is directly associated with neuroblastoma aggressiveness (survival: high miR181-b 73.2% vs low miR181-b 54.6%; P = .03).

Conclusions

Together, these data support the view that CDON acts as a tumor suppressor in neuroblastomas, and that CDON is tightly regulated by miRNAs.


Background

Nonadherence to hormonal therapy is common and is associated with increased copayment amount. We investigated the change in adherence after the introduction of generic aromatase inhibitors (AIs) in 2010.

Methods

Using deidentified pharmacy and claims data from OptumInsight, we identified women older than 50 years on brand-name AIs (BAIs) and/or generic AIs (GAIs) for early breast cancer between January 1, 2007 and December 31, 2012. Clinical, demographic, and financial variables were evaluated. Adherence was defined as a medication possession ratio (MPR) 80% or greater.

Results

We identified 5511 women, 2815 (51.1%) on BAI, 1411 (25.6%) on GAI, and 1285 (23.3%) who switched from BAI to GAI. The median 30-day copayment was higher for BAI ($33.3) than for GAI ($9.04). In a multivariable Cox-proportional hazard analysis, women who took GAI were less likely to discontinue therapy (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.57 to 0.84) compared with BAI. Discontinuation was positively associated with a higher monthly copayment of $15 to $30 (HR = 1.21, 95% CI = 1.01 to 1.44) and more than $30 (HR = 1.49, 95% CI = 1.23 to 1.80) compared with less than $15. In a multivariable logistic regression analysis, adherence (medication possession ratio ≥ 80%) was positively associated with GAI use (odds ratio = 1.53, 95% CI = 1.22 to 1.91) compared with BAI and inversely associated with increased monthly copayment. In addition, adherence was associated with a high annual income of more than $100k/year (odds ratio = 1.58, 95% CI = 1.17 to 2.11).

Conclusions

Higher prescription copayment amount was associated with nonadherence and discontinuation of AIs. After controlling for copayment, discontinuation was higher and adherence was lower with Brand AIs. Because nonadherence is associated with worse survival, efforts should be directed towards reducing out-of-pocket costs for these life-saving medications.



Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes.