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  • Extreme down-regulation of chromosome Y and cancer risk in men
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2020-01-16
    Cáceres A, Jene A, Esko T, et al.

    BackgroundUnderstanding the biological differences between sexes in cancer is essential for personalized treatment and prevention. We hypothesized that the extreme down-regulation of chromosome Y gene expression (EDY) is a signature of cancer risk in men and the functional mediator of the reported association between the mosaic loss of chromosome Y (LOY) and cancer. MethodsWe advanced a method to measure EDY from transcriptomic data. We studied EDY across 47 nondiseased tissues from the GTEx project (n = 371) and its association with cancer status across 12 cancer studies from the Cancer Genome Atlas (TCGA) (n = 1,774), and seven other studies (n = 7,562). Associations of EDY with cancer status and presence of loss-off function mutations in chromosome X were tested with logistic regression models, while a Fisher’s test was used to assess genome-wide association of EDY with the proportion of copy number gains. All statistical tests were two-sided. ResultsEDY was likely to occur in multiple nondiseased tissues (P<0.001) and statistically significantly associated with the EGFR tyrosine kinase inhibitor resistance pathway (FDR=0.028). EDY strongly associated with cancer risk in men (OR = 3.66, 95%CI = 1.58, 8.46, P = 0.002), adjusted by LOY and age, and its variability was largely explained by several genes of the non-recombinant region (NRY) whose chromosome X homologs showed loss-of-function mutations that co-occurred with EDY during cancer (OR = 2.82, 95%CI = 1.32, 6.01, P = 0.007). EDY associated with a high proportion of EGFR amplifications (OR = 5.64, 95%CI = 3.70, 8.59, FDR<0.001) and EGFR overexpression, along with SRY hypomethylation and NRY hypermethylation, indicating alternative causes of EDY in cancer other than LOY. EDY associations were independently validated for different cancers and exposure to smoking, and its status was accurately predicted from individual methylation patterns. ConclusionsEDY is a male-specific signature of cancer susceptibility that supports the escape from X-inactivation tumor suppressor hypothesis for genes that protect females with respect to males from cancer risk.

  • Cost-Effectiveness and Quality-Adjusted Survival of Watch-and-Wait after Complete Response to Chemoradiotherapy for Rectal Cancer
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2020-01-13
    Miller J, Wang H, Chang D, et al.

    BackgroundNeoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment for locally-advanced rectal cancer. There is interest in de-escalating local therapy after a clinical complete response (cCR) to CRT. We hypothesized that a watch-and-wait (WW) strategy offers comparable cancer-specific survival (CSS), superior quality-adjusted survival, and reduced cost compared to upfront TME. MethodsWe developed a decision-analytic model to compare WW, low anterior resection (LAR), and abdominoperineal resection (APR) for patients achieving a cCR to CRT. Rates of local regrowth, pelvic recurrence, and distant metastasis were derived from series comparing WW to TME after pathologic complete response. Lifetime incremental costs and quality-adjusted life-years (QALYs) were calculated between strategies, and sensitivity analyses were performed to study model uncertainty. ResultsThe base case 5-year CSS was 93.5% (95% confidence interval [CI] 91.5 to 94.9%) on a WW program, compared to 95.9% (95% CI 93.6 to 97.4%) after upfront TME. WW was dominant relative to LAR, with cost savings of $28,500 (95% CI $22,200 to $39,000) and incremental QALY of 0.527 (95% CI 0.138 to 1.125). WW was also dominant relative to APR, with cost savings of $32,100 (95% CI $21,800 to $49,200) and incremental QALY of 0.601 (95% CI 0.213 to 1.208). WW remained dominant in sensitivity analysis unless the rate of surgical salvage fell to 73.0%. ConclusionsUsing current multi-institutional recurrence estimates, we observed comparable CSS, superior quality-adjusted survival, and decreased costs with WW compared to upfront TME. Upfront TME was preferred when surgical salvage rates were low.

    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2020-01-10
    Flaherty K, Gray R, Chen A, et al.

    BackgroundThe proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and the National Cancer Institute (NCI), was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology. MethodsTrial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, enrollment rates, as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational Next Generation DNA targeted Sequencing assay (NGS) of alterations in 143 genes, and protein expression of PTEN, MLH1, MSH2 and Rb. Treatments were allocated with a validated computational platform (MATCHBOX). A pre-planned interim analysis evaluated assumptions and feasibility in this novel trial. ResultsAt interim analysis, accrual was robust, tumor biopsies were safe (< 1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments and improved assay throughput and efficiency (93.9% completion and 14-day turnaround). ConclusionsThe experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.

  • A Transcriptome-Wide Association Study (TWAS) Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2020-01-09
    Zhong J, Jermusyk A, Wu L, et al.

    BackgroundAlthough 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. MethodsTo discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 pancreatic cancer cases and 12,496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples). ResultsWe identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at 6 known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci, and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1 and BCAR1 at known loci) remained statistically significant after Bonferroni correction. ConclusionsBy integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

  • Interventions to enhance adherence to oral anti-neoplastic agents: A Scoping Review
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2020-01-03
    Rosenberg S, Petrie K, Stanton A, et al.

    BackgroundAs new targeted oral anti-neoplastic therapies have emerged in recent years, the development of effective strategies that promote optimal adherence to cancer medication regimens has become an important priority. MethodsWe conducted a scoping literature review to search for English language articles published through July 15, 2019 to identify studies that reported the testing and/or evaluation of interventions to improve adherence to oral anti-neoplastic agents. ResultsA total of 56 articles were selected for review. Of the studies evaluated, 14 were randomized trials. All interventions except two targeted adult patients. Thirty-three studies enrolled fewer than 100 patients. The majority of interventions were education and counseling-based and centered on provision of information about the drug and strategies to manage side effects. Only 8 studies used an mHealth tool and/or text messages to target non-adherence. Among studies with a comparison sample, fewer than half (44.7%) reported statistically significant improvements in adherence or persistence associated with the intervention; however, some pharmacist-directed programs, particularly those that integrated monitoring or routine follow-up with a provider, did demonstrate efficacy. ConclusionAlthough the development of adherence-promoting interventions for oral anti-neoplastic therapies has increased recently, few have been rigorously tested. The nascent literature suggests those that are pharmacist-directed and utilize regular monitoring show promise though additional prospective studies are needed. Study methodology, population selection, and potential challenges that may be encountered in the implementation and dissemination phases should be considered when developing new interventions to address non-adherence to oral anti-neoplastic treatment.

  • Genetic factors, adherence to healthy lifestyle behavior, and risk of invasive breast cancer among women in the UK Biobank
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2020-01-03
    Arthur R, Wang T, Xue X, et al.

    BackgroundBreast cancer is considered to result from a combination of genetic and lifestyle-related factors, but the degree to which an overall healthy lifestyle may attenuate the impact of multiple genetic variants on invasive breast cancer risk remains equivocal. MethodsUsing Cox proportional hazards regression models, we examined the association of a modified healthy lifestyle index (HLI) with risk of invasive breast cancer by genetic risk group among 146,326 women from the UK Biobank. We generated an HLI score based on a combination of diet, physical activity, smoking, alcohol consumption and anthropometry, and a polygenic risk score (PRS) using 304 breast cancer-associated genetic loci. ResultsAmong premenopausal and postmenopausal women, a favorable lifestyle (highest tertile) was associated with 22% and 31% reductions in invasive breast cancer risk, respectively (HRhigh vs low: 0.78, 95% CI = 0.64 to 0.94 and 0.69, 0.63 to 0.77), while a high PRS (highest tertile) was associated with more than a doubling in the risk in both groups. For premenopausal women, the greatest risk reduction in association with the HLI was seen among those with a high PRS (HRhigh vs low: 0.73, 95% CI = 0.75 to 0.95). In postmenopausal women, those with a favorable lifestyle had 30%, 29% and 32% reductions in risk of invasive breast cancer in the low, intermediate and high PRS groups, respectively (HRhigh vs low: 0.70, 95% CI = 0.56 to 0.88, 0.71, 0.59 to 0.84 and 0.68, 0.59 to 0.78, respectively). There was an additive but not multiplicative interaction between the HLI score and PRS for postmenopausal and, to a lesser extent, premenopausal women. ConclusionOur findings support the view that an overall healthy lifestyle may attenuate the impact of genetic factors on invasive breast cancer risk among women of European ancestry.

  • Oral Oncology Parity Laws, Medication Use, and Out-of-Pocket Spending for Patients with Blood Cancers
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-27
    Dusetzina S, Huskamp H, Jazowski S, et al.

    BackgroundIn this study we sought to estimate the association between oral oncology parity law adoption and anticancer medication use for patients with chronic myeloid leukemia (CML) or multiple myeloma. MethodsThis was an observational study of administrative claims from 2008-2017. Among individuals initiating tyrosine kinase inhibitors (TKI) for CML or immunomodulatory drugs for multiple myeloma, we compared out-of-pocket spending, adherence, and discontinuation before and after parity among individuals in fully-insured plans (subject to parity) versus self-funded plans (exempt from parity) using propensity-score weighted difference-in-differences regression models. ResultsAmong patients initiating TKIs (N = 2,082) or immunomodulatory drugs (N = 3,326) there were no statistically significant differences in adherence or discontinuation associated with parity. The proportion of patients with initial out-of-pocket payments of $0 increased in fully-insured plans after parity from 5.7% to 46.1% for TKIs and from 10.9% to 48.8% for immunomodulatory drugs. Relative to changes in self-funded plans, those in fully-insured plans were 4.27 (95%CI:2.20-8.27) times as likely to pay nothing for TKIs and 1.96 (95%CI:1.40-2.73) times as likely to pay nothing for immunomodulatory drugs after parity. Similarly, the proportion paying >$100 decreased from 30.3% to 24.7% for TKIs and 30.6% to 27.5% for immunomodulatory drugs in fully-insured plans after parity. Relative to changes in self-funded plans, those in fully-insured plans were 0.74 (95%CI:0.54-1.01) times as likely to pay >$100 for TKIs and 0.85 (95%CI:0.68-1.06) times as likely to pay >$100 for immunomodulatory drugs after parity. ConclusionsAmong patients initiating TKIs or immunomodulatory drugs, parity was not associated with better adherence or less discontinuation of therapy, but yielded decreased patient out-of-pocket payments for some patients.

  • Developing and sustaining an effective and resilient oncology careforce: Opportunities for action
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-23
    Takvorian S, Balogh E, Nass S, et al.

    Advances in cancer care have led to improved survival, which coupled with demographic trends have contributed to rapid growth in the number of patients needing cancer care services. However, with increasing caseload, care complexity, and administrative burden, the current workforce is ill-equipped to meet these burgeoning new demands. These trends have contributed to clinician burnout, compounding a widening workforce shortage. Moreover, family caregivers, who have unique knowledge of patient preferences, symptoms, and goals of care, are infrequently appreciated and supported as integral members of the oncology “careforce.” A crisis is looming, which will hinder access to timely, high-quality cancer care if left unchecked. Stemming from the proceedings of a 2019 workshop convened by the National Cancer Policy Forum of the National Academies of Sciences, Engineering, and Medicine, this article characterizes the factors contributing to an increasingly strained oncology careforce, and presents multilevel strategies to improve its efficiency, effectiveness, and resilience. Together, these will enable today’s oncology careforce to provide high-quality care to more patients while simultaneously improving the patient, caregiver, and clinician experience.

  • Moving Molecular Profiling to Routine Clinical Practice: A Way Forward?
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-23
    Freidlin B, Allegra C, Korn E.

    Molecular profiling of a patient’s tumor to guide targeted treatment selection offers the potential to advance patient care by improving outcomes and minimizing toxicity (by avoiding ineffective treatments). However, current development of molecular profile panels is often based on applying institution-specific or subjective algorithms to non-randomized patient cohorts. Consequently, obtaining reliable evidence that molecular profiling is offering clinical benefit and is ready for routine clinical practice is challenging. In particular, we discuss here the problems with interpreting for clinical utility nonrandomized studies that compare outcomes in patients treated based on their molecular profile versus those treated with standard of care, studies that compare the progression-free survival (PFS) seen on a molecular-profile-directed treatment to the PFS seen for the same patient on a previous standard treatment (PFS ratio), and multi-basket trials that evaluate the response rates of targeted therapies in specific molecularly defined subpopulations (regardless of histology). We also consider some limitations of randomized trial designs. A two-step strategy is proposed in which multiple mutation/agent pairs are tested for activity in one or more multi-basket trials in the first step. The results of the first step are then used to identify promising mutation/agent pairs that are combined in a molecular panel that is then tested in the step-two strategy-design randomized clinical trial (the molecular-panel guided treatment for the selected mutations versus standard of care). This two-step strategy should allow rigorous evidence-driven identification of mutation/agent pairs that can be moved into routine clinical practice.

  • Oral leukoplakia and risk of progression to oral cancer: A population-based cohort study
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-20
    Chaturvedi A, Udaltsova N, Engels E, et al.

    BackgroundThe optimal clinical management of oral precancer remains uncertain. We investigated the natural-history of oral leukoplakia, the most common oral precancerous lesion, to estimate the relative and absolute risks of progression to cancer, the predictive accuracy of a clinician’s decision to biopsy a leukoplakia vis-à-vis progression, and histopathologic predictors of progression. MethodsWe conducted a retrospective cohort study (1996-2012) of patients with oral leukoplakia (N = 4,886), identified using electronic medical records within Kaiser Permanente Northern California (KPNC). Among patients with leukoplakia who received a biopsy (n = 1,888), we conducted a case-cohort study to investigate histopathologic predictors of progression. Analyses included indirect standardization and unweighted/weighted Cox regression. ResultsCompared with the overall KPNC population, oral cancer incidence was substantially elevated in oral leukoplakia patients (standardized incidence ratio [SIR]=40.8; 95%CI=34.8-47.6; n = 161 cancers over 22,582 person-years). Biopsied leukoplakias had a higher oral cancer risk compared to those that were not biopsied (adjusted-hazard ratio [HR]=2.38; 95%CI=1.73-3.28). However, to identify a prevalent/incident oral cancer, the biopsy-decision had low sensitivity (59.6%), low specificity (62.1%), and moderate positive-predictive-value (PPV=5.1%). Risk of progression to oral cancer statistically significantly increased with the grade of dysplasia; 5-year competing-risk-adjusted absolute risks: leukoplakia overall=3.3% (95%CI=2.7%-3.9%); no-dysplasia=2.2% (95%CI=1.5%-3.1%); mild-dysplasia=11.9% (95%CI=7.1%-18.1%); moderate-dysplasia=8.7% (3.2%-17.9%); and severe-dysplasia=32.2% (8.1%-60.0%). Yet, 39.6% of cancers arose from biopsied-leukoplakias without dysplasia. ConclusionsThe modest accuracy of the decision to biopsy a leukoplakia vis-à-vis presence/eventual development of oral cancer highlights the need for routine biopsy of all leukoplakias, regardless of visual/clinical impression. Leukoplakia patients, particularly those with dysplasia, need to be closely-monitored for signs of early cancer.

  • Colorectal Cancer Care among Young Adult Patients after the Dependent Coverage Expansion under the Affordable Care Act
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-19
    Nogueira L, Chawla N, Han X, et al.

    The impact of the Dependent Coverage Expansion (DCE) under the Affordable Care Act (ACA) on receipt of colorectal cancer treatment has yet to be determined. We identified newly diagnosed DCE-eligible (aged 19-25 years, n = 1,924) and DCE-ineligible (aged 27-34 years, n = 8,313) colorectal cancer patients from the National Cancer Database during 2007-2013. All statistical tests were two-sided. Post-ACA, there was a statistically significant increase in early stage diagnosis among DCE-eligible (15 percentage points increase, p<.001), but not DCE-ineligible (p =.09) patients. DCE-eligible patients resected for IIB-IIIC colorectal cancer were more likely to receive timely adjuvant chemotherapy (HR = 1.34, CI = 1.05, 1.71; 7.0 days decrease in restricted mean time from surgery to chemotherapy, p=.01), with no differences in DCE-ineligible patients (HR = 1.10, CI = 0.98, 1.24; 2.1 days decrease, p=.41) post-ACA. Our findings highlight the role of the ACA in improving access to potentially life-saving cancer care, including a shift to early-stage diagnosis and more timely receipt of adjuvant chemotherapy.

  • Sustained weight loss and risk of breast cancer in women ≥50 years: a pooled analysis of prospective data
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-17
    Teras L, Patel A, Wang M, et al.

    BACKGROUNDExcess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk. METHODSAssociations between weight change and risk of breast cancer were examined among women aged ≥50 years in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (Interval 1 median= 5.2 years; Interval 2 median = 4.0 years). Sustained weight loss was defined as ≥ 2kg lost in Interval 1 that was not regained in Interval 2. Among 180,885 women, 6,930 invasive breast cancers were identified during follow-up. RESULTSCompared with women with stable weight (± 2kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2-4.5kg lost: Hazard Ratio (HR)= 0.82, 95% confidence interval (CI): 0.70-0.96; >4.5-<9kg lost: HR = 0.75, 95% CI: 0.63-0.90; ≥9kg lost: HR = 0.68, 95% CI: 0.50-0.93). Women who lost ≥9kg and gained some (but not all) of it back were also at a lower risk of breast cancer. Other patterns of weight loss and gain over the two intervals had a similar risk of breast cancer to women with stable weight. CONCLUSIONSThese results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged ≥50 years. Breast cancer prevention may be a strong weight loss motivator for the two-thirds of American women who are overweight or obese.

  • Breast cancer mortality after implementation of organized population-based breast cancer screening in Norway
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-17
    Sebuødegård S, Botteri E, Hofvind S.

    ABSTRACT BackgroundWe estimated breast cancer (BC) mortality reduction associated with invitations to a nation-wide population based screening program and changes in treatment, in Norway. Material and methodsBreastScreen Norway started in 1996 and became nationwide in 2005. It invites women aged 50–69 to biennial mammographic screening. We retrieved individual-level data for 1,340,333 women from national registries. During 1996–2014 (screening window), women contributed person-years (PY) in non-invited and invited periods. We created comparable periods for 1977–1995 (pre-screening window) by dividing the follow-up time for each woman into a pseudo-non-invited and pseudo-invited periods. We estimated BC mortality for the four periods, using the so-called evaluation model: counting BC deaths in each period for all women diagnosed within the period, counting BC deaths and person-years after screening-age only for women diagnosed within screening-age. We used a multivariable flexible parametric survival model to estimate hazard ratio (HR) for the effect of invitation and improved treatment. ResultsThere were 5818 BC deaths across 16,533,281 PY. Invitations to screening reduced BC mortality by 20% (HR: 0.80, 95%CI: 0.70-0.91) among women ≥50 years old and by 25% (HR: 0.75, 95%CI: 0.65-0.86) among screening-aged women. The treatment effect was 23% (HR: 0.77, 95%CI: 0.65-0.92) for women ≥50 years old, and 17% (HR: 0.83, 95%CI: 0.74-0.94) for screening-aged women. ConclusionWe observed a similar reduction in BC mortality associated with invitations to screening and improvements in treatment among women ≥50 years old, during 1977–2014.

  • HER2-HER3 heterodimer quantification by FRET-FLIM and patient subclass analysis of the COIN colorectal trial
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-18
    Barber P, Weitsman G, Lawler K, et al.

    BackgroundThe phase 3 MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response. MethodsHER2-HER3 dimerization was quantified by “FLIM Histology” in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy +/-cetuximab. Bayesian latent class analysis (LCA) and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation and cetuximab on progression-free survival (PFS) and overall survival (OS). All statistical tests were two-sided. ResultsLCA on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS: 1624 days [95%CI=1466-1816] vs 461 [95%CI=431-504]): Class 1 (15.6%) showed a benefit from cetuximab in OS (HR = 0.43 [95%CI=0.25-0.76]; p = 0.004). Class 2 showed an association of increased HER2-HER3 with better OS (HR = 0.64 [95%CI=0.44-0.94]; p = 0.02). A class prediction signature was formed and tested on an independent validation cohort (N = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (N = 1,630) based on 10 baseline clinicopathological and genetic covariates. ConclusionsOur work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment.

  • Emergency Department Visits for Opioid Overdoses Among Patients with Cancer
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-17
    Jairam V, Yang D, Yu J, et al.

    BackgroundPatients with cancer may be at risk of high opioid use due to physical and psychosocial factors, although little data exists to inform providers and policymakers. Our aim is to examine overdoses from opioids leading to emergency department (ED) visits among patients with cancer in the United States. MethodsThe Healthcare Cost and Utilization Project Nationwide Emergency Department Sample (HCUP-NEDS) was queried for all adult cancer-related patient visits with a primary diagnosis of opioid overdose between 2006 and 2015. Temporal trends and baseline differences between patients with and without opioid-related ED visits were evaluated. Multivariable logistic regression analysis was utilized to identify risk factors associated with opioid overdose. All statistical tests were two-sided. ResultsBetween 2006 and 2015, there were a weighted total of 35,339 opioid-related ED visits among patients with cancer. During this timeframe, the incidence of opioid-related ED visits for overdose increased 2.0-fold (P<0.001). On multivariable regression (P<0.001), comorbid diagnoses of chronic pain (odds ratio [OR] 4.51; 95% confidence interval [CI], 4.13-4.93), substance use disorder (OR 3.54; 95% CI, 3.28-3.82), and mood disorder (OR 3.40; 95% CI, 3.16-3.65) were strongly associated with an opioid-related visit. Patients with head and neck cancer (odds ratio [OR] 2.04; 95% CI, 1.82-2.28) and multiple myeloma (OR 1.73; 95% CI, 1.32-2.26) were also at risk for overdose. ConclusionsOver the study period, the incidence of opioid-related ED visits in patients with cancer increased approximately two-fold. Comorbid diagnoses and primary disease site may predict risk for opioid overdose.

  • Evolution of Cancer Care Delivery Research in the NCI Community Oncology Research Program
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-17
    Geiger A, O’Mara A, McCaskill-Stevens W, et al.

    Research seeking to improve patient engagement with decision-making, use of evidence-based guidelines, and coordination of multi-specialty care has made important contributions to the decades-long effort to improve cancer care. The National Cancer Institute (NCI) expanded support for these efforts by including cancer care delivery research in the 2014 formation of the NCI Community Oncology Research Program (NCORP). Cancer care delivery research is a multi-disciplinary effort to generate evidence-based practice change that improves clinical outcomes and patient well-being. NCORP scientists and community-based clinicians and organizations rapidly embraced the addition of this type of research into the network, resulting in a robust portfolio of observational studies and intervention studies within the first five years of funding. This commentary describes the initial steps in conducting this type of research in a network previously focused on cancer prevention, control, and treatment studies; characterizes the protocols developed to date; and outlines future directions for cancer care delivery research in the second round of NCORP funding.

  • CDH1 on multigene panel testing: Look before you leap
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-16
    Katona B, Clark D, Domchek S.

    Multigene panel testing (MGPT) has become a critical component of cancer risk assessment in clinical practice. As technology and access improves, and costs decrease, more individuals than ever are undergoing MGPT for genetic evaluation. One gene that deserves special consideration when included on MGPT is CDH1, which codes for the cell-cell adhesion protein E-cadherin. Pathogenic germline variants in CDH1 have been associated with hereditary diffuse gastric cancer syndrome, and in highly penetrant families, testing for these variants is critical for proper risk management. However, recent data demonstrated that gastric cancer penetrance in unselected CDH1 carriers may be lower than expected. Further complicating matters are the lack of effective screening strategies for gastric cancer and recommendation for risk-reducing total gastrectomy in CDH1 carriers. Therefore, the discovery of an unexpected pathogenic CDH1 variant on multigene panel testing, when testing for CDH1 would not normally be considered based on personal or family history alone, creates dilemmas for both patients and providers. In this commentary, we highlight the potential for unexpected CDH1 variants on MGPT, outline the uncertainties associated with these variants, and emphasize the importance of pre-test counseling regarding the potential for an unexpected CDH1 variant. While CDH1 testing is often important for clinical decision making, individuals and providers need to be aware of the potential for an unexpected CDH1 variant when CDH1 is included on MGPT for cancer risk assessment.

  • Lack of Availability and Efficacy of Phase I and Basket Trials for Patients with Gastrointestinal Cancers
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-13
    Agarwal R, Cangemi N, Epstein A, et al.

    In the modern era of targeted and immune-based therapies, investigator and patient expectations of availability and efficacy in phase I trials have increased. We assessed availability of, and benefit from, early drug development trials, specifically in patients with gastrointestinal cancers. We reviewed computerized referral records of the Early Drug Development Service at our institution to identify patients internally referred from our Gastrointestinal Oncology Service in calendar year 2018. End points were treatment on a trial, 3 and 6-month progression-free survival (PFS), and any tumor shrinkage. Of 394 gastrointestinal cancer patients referred in 2018, 54 enrolled on a trial and 53 (13.5%) were treated (1 withdrew before treatment): 34 on immune-based and 19 on targeted (3 to phase II basket) studies. None of the 52 patients who had exhausted standard therapy achieved 6-month PFS; two (3.8%) met 3-month PFS with tumor growth below RECIST progression at 3 months; both came off study for progression at 4 months. One patient who was to receive an irinotecan-based regimen as standard therapy instead received irinotecan plus an investigational targeted agent and remained stable for 8 months. No patients achieved any degree of tumor shrinkage. The most common reasons for non-accrual were lack of available protocol treatment openings and failure to meet eligibility criteria for specific trials. Thus, availability, and benefit, from investigational treatment in this treatment-refractory gastrointestinal cancer patient population was extremely modest. Expectations regarding both availability and efficacy of phase I investigational therapy in gastrointestinal cancer patients likely exceed what our experience suggests.

  • Estimating the Natural History of Cervical Carcinogenesis Using Simulation Models: A CISNET Comparative Analysis
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-12-10
    Burger E, de Kok I, Groene E, et al.

    BackgroundThe natural history of human papillomavirus (HPV)-induced cervical cancer (CC) is not directly observable, yet the age of HPV acquisition and duration of preclinical disease (dwell time) impacts the effectiveness of alternative preventive policies. We performed a Cancer Intervention and Surveillance Modeling Network (CISNET) comparative modeling analysis to characterize the age of acquisition of cancer-causing HPV infections and implied dwell times for distinct phases of cervical carcinogenesis. MethodsUsing four CISNET-cervical models with varying underlying structures but fit to common U.S. epidemiological data, we estimated the age of acquisition of causal HPV infections and dwell times associated with three phases of cancer development: HPV, high-grade precancer, and cancer sojourn time. We stratified these estimates by HPV genotype under both natural history and CC screening scenarios, as screening prevents cancer development that impacts the mix of detected cancers. ResultsMedian time from HPV acquisition to cancer detection ranged from 17.5-26.0 years across the four models. Three models projected that 50% of unscreened women acquired their causal HPV infection between ages 19-23 years, while one model projected these infections occurred later (age 34 years). In the context of imperfect compliance with U.S. screening guidelines, the median age of causal infection was 4.4-15.9 years later compared with model projections in the absence of screening. ConclusionsThese validated CISNET-cervical cancer models, which reflect some uncertainty in the development of CC, elucidate important drivers of HPV vaccination and CC screening policies and emphasize the value of comparative modeling when evaluating public health policies.

  • Predicting Persistent Opioid Use, Abuse and Toxicity Among Cancer Survivors
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-22
    Vitzthum L, Riviere P, Sheridan P, et al.

    BackgroundWhile opioids play a critical role in the management of cancer pain, the ongoing opioid epidemic has raised concerns regarding their persistent use and abuse. We lack data-driven tools in oncology to understand the risk of adverse opioid-related outcomes. This project seeks to identify clinical risk factors and create a risk score to help identify patients at risk of persistent opioid use and abuse. MethodsWithin a cohort of 106,732 Veteran cancer survivors diagnosed between 2000 and 2015, we determined rates of persistent post-treatment opioid use, diagnoses of opioid abuse or dependence, and admissions for opioid toxicity. A multivariable logistic regression model was used to identify patient, cancer, and treatment risk factors associated with adverse opioid-related outcomes. Predictive risk models were developed and validated using a least absolute shrinkage and selection operator (LASSO) regression technique. ResultsThe rate of persistent opioid use in cancer survivors was 8.3% (95% CI = 8.1 - 8.4%), the rate of opioid abuse or dependence was 2.9% (95%CI=2.8-3.0%), and the rate of opioid-related admissions was 2.1% (95%CI=2.0-2.2%). On multivariable analysis, several patient, demographic, cancer and treatment factors were associated with risk of persistent opioid use. Predictive models showed a high level of discrimination when identifying individuals at risk of adverse opioid-related outcomes including persistent opioid use (area under curve [AUC]= 0.85), future diagnoses of opioid abuse or dependence (AUC=0.87) and admission for opioid abuse or toxicity (AUC=0.78). ConclusionThis study demonstrates the potential to predict adverse opioid-related outcomes among cancer survivors. With further validation, personalized risk stratification approaches could guide management when prescribing opioids in cancer patients.

  • Recent trends in squamous cell carcinoma of the anus incidence and mortality in the United States, 2001-2015
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-19
    Deshmukh A, Suk R, Shiels M, et al.

    BackgroundSquamous cell carcinoma of the anus (SCCA) incidence is rising in the United States (US). Study of incidence trends by stage at diagnosis, age-specific and birth cohort patterns, and trends in mortality could provide evidence for a true increase and etiological clues for this rise. MethodsUsing the US Cancer Statistics dataset, we examined trends in SCCA incidence (2001-2015) and mortality (2001-2016) rates. Joinpoint regression was used to compute annual and average annual percentage change (AAPC). Incidence patterns by five-year age group and birth cohort were evaluated using incidence rate ratios (IRRs) and age-period-cohort modeling. ResultsSCCA incidence increased 2.7% per year (95% confidence interval [CI] = 2.1%-3.3%) with pronounced increases in age groups 50 years and older. Distant stage SCCA incidence tripled (AAPC, 8.6% [95% CI = 5.4%-12.0%]) among men and 7.5% [95% CI = 4.8%-10.2%] among women) and regional stage SCCA incidence nearly doubled (AAPC, 4.7% for men and women) in both sexes; the AAPC for localized stage was 1.3% [95% CI = 0.6%-2.0%] in men and 2.3% [95% CI = 1.8%-2.8%] in women. Compared to adults born circa 1946, recent born Black men (born circa 1986) had nearly fivefold higher (IRR, 4.7; 95% CI = 2.1-10.2) risk of SCCA and the risk doubled among White men (IRR= 2.0; 95% CI = 1.7-2.2) and White women (IRR, 2.1; 95% CI = 1.9-2.3) born after circa 1960. Anal cancer mortality rates increased 3.1% per year (95% CI = 2.6%-3.5%) with statistically significant increases in age groups 50 years and older. Incidence-based mortality increased 1.9% annually (95% CI = 0.5%-3.4%) with a notable (4.9% [95% CI = 2.4%-7.3%] per year) rise in 60-69-year-old adults. ConclusionThe rise in SCCA incidence, particularly advanced stage disease, and a similar rise in mortality, suggests a true increase in the occurance of SCCA. Future research and improved prevention is urgently needed to mitigate the rising disease burden.

  • PIK3CA mutation in HPV-associated OPSCC patients receiving deintensified chemoradiation
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-20
    Beaty B, Moon D, Shen C, et al.

    PIK3CA is the most frequently mutated gene in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Prognostic implications of such mutations remain unknown. We sought to elucidate the clinical significance of PIK3CA mutations in HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Seventy-seven patients with HPV-associated OPSCC were enrolled on two phase II clinical trials of de-intensified CRT (60 Gy intensity-modulated radiotherapy with concurrent weekly cisplatin). Targeted next-generation sequencing was performed. Nine of 77 patients had disease recurrence (2 regional, 4 distant, 3 regional and distant). Thirty-four patients had mutation(s) identified; 16 had PIK3CA mutations. Patients with wild-type-PIK3CA had statistically significantly higher 3-year disease-free survival than PIK3CA-mutant patients (93.4% [95% CI 85.0-99.9%] vs. 68.8% [95% CI 26.7-89.8%]; p = 0.004. On multivariate analysis, PIK3CA mutation was the only variable statistically significantly associated with disease recurrence (HR 5.71 [95% CI 1.53, 21.3], p = 0.01). PIK3CA mutation is associated with worse disease-free survival in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with de-intensified CRT.

  • Borderline estrogen receptor-positive breast cancers in black and white women
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-19
    Benefield H, Allott E, Reeder-Hayes K, et al.

    BackgroundSome breast tumors expressing ≥1% and <10% estrogen receptor (ER) positivity (“ER-borderline”) are clinically aggressive; others exhibit luminal biology. Prior ER-borderline studies included few black participants. MethodsUsing the Carolina Breast Cancer Study (Phase 1: 1993 – 1996, 2: 1996 – 2001, 3: 2008-2013), a population-based study that oversampled black women, we compared ER-borderline (n = 217) to ER-positive (n = 1,885) and ER-negative (n = 757) tumors. PAM50 subtype and risk of recurrence score (ROR-PT, incorporates subtype, proliferation, tumor size) were measured. Relative frequency differences (RFD) were estimated using multivariable linear regression. Disease-free interval (DFI) was evaluated by ER category and endocrine therapy receipt, overall and by race using Kaplan Meier and Cox models. Statistical tests were two-sided. ResultsER-borderlines were more frequently Basal-like (RFD = +37.7%, 95% CI = 27.1, 48.4) and high ROR-PT (RFD = +52.4%, 95% CI = 36.8, 68.0) relative to ER-positives. Having a high ROR-PT ER-borderline tumor was statistically significantly associated with black race (RFD = +26.2%, 95% CI = 9.0, 43.3). Compared to ER-positives, DFI of ER-borderlines treated with endocrine therapy was poorer but not statistically significantly different (hazard ratio [HR]=2.03, 95% CI = 0.89, 4.65), whereas DFI was statistically significantly worse for ER-borderlines without endocrine therapy (HR = 3.33, 95% CI = 1.84, 6.02). However, black women with ER-borderline had worse DFI compared to ER-positives, even when treated with endocrine therapy (HR = 2.77, 95% CI = 1.09, 7.04). ConclusionsER-borderline tumors were genomically heterogeneous with survival outcomes that differed by endocrine therapy receipt and race. Black race predicted high-risk ER-borderlines and may be associated with poorer endocrine therapy response.

  • Prostate Cancer Outcomes Following Solid-Organ Transplantation: A SEER-Medicare Analysis
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-15
    Liauw S, Ham S, Das L, et al.

    BackgroundImmunosuppressive regimens associated with organ transplantation increase the risk of developing cancer. Transplant candidates and recipients with prostate cancer are often treated, even if low risk features would ordinarily justify active surveillance. MethodsUsing SEER-Medicare, we identified 163,676 men aged ≥66, diagnosed with non-metastatic prostate cancer. History of solid organ transplant was identified using diagnosis or procedure codes. A propensity score-matched cohort was identified by matching transplanted men to non-transplanted controls by age, race, region, year, T-stage, grade, comorbidity and cancer therapy. Fine-Gray competing risk models assessed associations between transplant status and prostate cancer-specific (PCSM) and overall mortality (OM). ResultsWe identified 620 men (0.4%) with transplant up to 10 years before (n = 320) or 5 years after (n = 300) prostate cancer diagnosis and matched them to 3,100 men. At 10-years, OM was 55.7% and PCSM was 6.0% in the transplant cohort, compared to 42.4% (p < 0.001) and 7.6% (p = 0.70) in the non-transplant cohort, respectively. Adjusted models showed no difference in PCSM for transplanted men (HR = 0.88, 95% CI = 0.61-1.27, p = 0.70) or differences by prostate cancer therapy. Among 334 transplanted men with T1-2N0, well/moderately differentiated ‘low-risk’ prostate cancer, PCSM was similar for treated and untreated men (HR = 0.92, 95% CI = 0.47 to 1.81). ConclusionsAmong men age ≥66 y with prostate cancer, an organ transplant is associated with higher OM but no observable difference in PCSM. These findings suggest men with prostate cancer and previous or future organ transplantation should be managed per usual standards of care, including consideration of active surveillance for low-risk cancer characteristics.

  • Tegavivint and the β-Catenin/ALDH Axis in Chemotherapy-Resistant and Metastatic Osteosarcoma
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-02-21
    Nomura M, Rainusso N, Lee Y, et al.

    BackgroundThe Wnt/β-catenin pathway is closely associated with osteosarcoma (OS) development and metastatic progression. We investigated the antitumor activity of Tegavivint, a novel β-catenin/transducin β-like protein 1 (TBL1) inhibitor, against OS employing in vitro, ex vivo, and in vivo cell line and patient-derived xenograft (PDX) models that recapitulate high risk disease. MethodsThe antitumor efficacy of Tegavivint was evaluated in vitro using established OS and PDX-derived cell lines. Use of an ex vivo three-dimensional pulmonary metastasis assay assessed targeting of β-catenin activity during micro- and macrometastatic development. The in vivo activity of Tegavivint was evaluated using chemoresistant and metastatic OS PDX models. Gene and protein expression were quantified by quantitative Reverse transcription polymerase chain reaction or immunoblot analysis. Bone integrity was determined via microCT. All statistical tests were two-sided. ResultsTegavivint exhibited antiproliferative activity against OS cells in vitro and actively reduced micro- and macrometastatic development ex vivo. Multiple OS PDX tumors (n = 3), including paired patient primary and lung metastatic tumors with inherent chemoresistance, were suppressed by Tegavivint in vivo. We identified that metastatic lung OS cell lines (n = 2) exhibited increased stem cell signatures, including enhanced concomitant aldehyde dehydrogenase (ALDH1) and β-catenin expression and downstream activity, which were suppressed by Tegavivint (ALDH1: control group, mean relative mRNA expression = 1.00, 95% confidence interval [CI] = 0.68 to 1.22 vs Tegavivint group, mean = 0.011, 95% CI = 0.0012 to 0.056, P < .001; β-catenin: control group, mean relative mRNA expression = 1.00, 95% CI = 0.71 to 1.36 vs Tegavivint group, mean = 0.45, 95% CI = 0.36 to 0.52, P < .001). ALDH1high PDX-derived lung OS cells, which demonstrated enhanced metastatic potential compared with ALDHlow cells in vivo, were sensitive to Tegavivint. Toxicity studies revealed decreased bone density in male Tegavivint-treated mice (n = 4 mice per group). ConclusionsTegavivint is a promising therapeutic agent for advanced stages of OS via its targeting of the β-catenin/ALDH1 axis.

  • Differences in Genomic Profiles and Outcomes Between Thoracic and Adrenal Neuroblastoma
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-02-21
    Oldridge D, Truong B, Russ D, et al.

    BackgroundNeuroblastoma is a biologically and clinically heterogeneous disease. Based on recent studies demonstrating an association between the primary tumor site, prognosis, and commonly measured tumor biological features, we hypothesized that neuroblastomas arising in different sites would show distinct genomic features reflective of the developmental biology of the sympathicoadrenal nervous system. MethodsWe first compared genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) compared to thoracic sympathetic ganglia (n = 118). We also evaluated association of common germline variation with these primary sites in 1027 European-American neuroblastoma patients. ResultsWe observed higher rates of MYCN amplification, chromosome 1q gain, and chromosome 11q deletion among adrenal tumors, which were highly predictive of functional RNA signatures. Surprisingly, thoracic neuroblastomas were more likely to harbor ALK driver mutations than adrenal cases among all cases (odds ratio = 1.89, 95% confidence interval = 1.04 to 3.43), and among cases without MYCN amplification (odds ratio = 2.86, 95% confidence interval = 1.48 to 5.49). Common germline single nucleotide polymorphisms (SNPs) in BARD1 (previously associated with high-risk neuroblastoma) were found to be strongly associated with predisposition for origin at adrenal, rather than thoracic, sites. ConclusionsNeuroblastomas arising in the adrenal gland are more likely to harbor structural DNA aberrations including MYCN amplification, whereas thoracic tumors show defects in mitotic checkpoints resulting in hyperdiploidy. Despite the general association of ALK mutations with high-risk disease, thoracic tumors are more likely to harbor gain-of-function ALK aberrations. Site of origin is likely reflective of stage of sympathetic nervous system development when malignant transformation occurs and is a surrogate for underlying tumor biology.

  • Corrigendum
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-01-25

    Corrigendum: CN Landen, Jr, C Lu, LY Han, KT Coffman, E Bruckheimer, et al. Efficacy and Antivascular Effects of EphA2 Reduction With an Agonistic Antibody in Ovarian Cancer JNCI J Natl Cancer Inst (2006) 98(21):1558-70.doi.org/10.1093/jnci/djj414.

  • Corrigendum
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-01-17

    Correction to: Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma. Tang QL#, Xie XB#, Wang J#, Chen Q, Han AJ, Zou CY, Yin JQ, Liu DW, Liang Y, Zhao ZQ, Yong BC, Zhang RH, Feng QS, Deng WG, Zhu XF, Zhou BP, Zeng YX, Shen* JN, Kang T*. J Natl Cancer Inst. 2012 May 16;104(10):749-63. doi:10.1093/jnci/djs210.

  • Corrigendum
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2018-10-17

    Corrigendum to: M Lambertini, C Campbell, J Bines, et al. Adjuvant Anti-HER2 Therapy, Treatment-Related Amenorrhea, and Survival in Premenopausal HER2-Positive Early Breast Cancer Patients, JNCI J Natl Cancer Inst (2019) 111(1): djy094; published online on June 5th, 2018. Co-author Jose Baselga has updated his disclosures in the Notes section of the manuscript.

  • Corrigendum
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2018-10-05

    Corrigendum to “Prognostic Power of a Tumor Differentiation Gene Signature for Bladder Urothelial Carcinomas” by Qianxing Mo. JNCI. J Natl Cancer Inst. 110(5),2018;doi: 10.1093/jnci/djx243.

  • Colorectal Cancer Screening in Childhood Cancer Survivors
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-04-09
    Teepen J, Ronckers C, Kremer L.

    Survivors of childhood, adolescent, and young adult cancer are at increased risk of developing subsequent colorectal cancers (CRCs) (1–4). Those who received abdominal radiotherapy or certain chemotherapeutic agents such as procarbazine (1,4) or platinum agents (1) for their first cancer are particularly at risk.

  • Reporting Standards for Patient-Reported Outcomes in Clinical Trial Protocols and Publications
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-04-11
    Basch E, Leahy A.

    Over the past 20 years, interest has grown to include patient-reported outcomes (PRO) in cancer clinical trials, evidenced by guidance documents from international regulatory authorities (1) and a steady increase of PRO-based endpoints in protocols (eg, pain improvement) (2). But is inclusion of PRO endpoints rigorous and systematic? Concerns have been raised previously about incomplete reporting of PRO results in clinical trial publications, which may reflect underlying design weaknesses (3). These concerns have prompted recent international collaborative efforts to standardize expectations for describing PRO endpoints in protocols and publications.

  • Cost-Effectiveness of Colonoscopy-Based Colorectal Cancer Screening in Childhood Cancer Survivors
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-04-13
    Gini A, Meester R, Keshavarz H, et al.

    BackgroundChildhood cancer survivors (CCS) are at increased risk of developing colorectal cancer (CRC) compared to the general population, especially those previously exposed to abdominal or pelvic radiation therapy (APRT). However, the benefits and costs of CRC screening in CCS are unclear. In this study, we evaluated the cost-effectiveness of early-initiated colonoscopy screening in CCS. MethodsWe adjusted a previously validated model of CRC screening in the US population (MISCAN-Colon) to reflect CRC and other-cause mortality risk in CCS. We evaluated 91 colonoscopy screening strategies varying in screening interval, age to start, and age to stop screening for all CCS combined and for those treated with or without APRT. Primary outcomes were CRC deaths averted (compared to no screening) and incremental cost-effectiveness ratios (ICERs). A willingness-to-pay threshold of $100 000 per life-years gained (LYG) was used to determine the optimal screening strategy. ResultsCompared to no screening, the US Preventive Services Task Force’s average risk screening schedule prevented up to 73.2% of CRC deaths in CCS. The optimal strategy of screening every 10 years from age 40 to 60 years averted 79.2% of deaths, with ICER of $67 000/LYG. Among CCS treated with APRT, colonoscopy every 10 years from age 35 to 65 years was optimal (CRC deaths averted: 82.3%; ICER: $92 000/LYG), whereas among those not previously treated with APRT, screening from age 45 to 55 years every 10 years was optimal (CRC deaths averted: 72.7%; ICER: $57 000/LYG). ConclusionsEarly initiation of colonoscopy screening for CCS is cost-effective, especially among those treated with APRT.

  • Systematic Evaluation of Patient-Reported Outcome Protocol Content and Reporting in Cancer Trials
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-04-11
    Kyte D, Retzer A, Ahmed K, et al.

    BackgroundPatient-reported outcomes (PROs) are captured within cancer trials to help future patients and their clinicians make more informed treatment decisions. However, variability in standards of PRO trial design and reporting threaten the validity of these endpoints for application in clinical practice. MethodsWe systematically investigated a cohort of randomized controlled cancer trials that included a primary or secondary PRO. For each trial, an evaluation of protocol and reporting quality was undertaken using standard checklists. General patterns of reporting where also explored. ResultsProtocols (101 sourced, 44.3%) included a mean (SD) of 10 (4) of 33 (range = 2–19) PRO protocol checklist items. Recommended items frequently omitted included the rationale and objectives underpinning PRO collection and approaches to minimize/address missing PRO data. Of 160 trials with published results, 61 (38.1%, 95% confidence interval = 30.6% to 45.7%) failed to include their PRO findings in any publication (mean 6.43-year follow-up); these trials included 49 568 participants. Although two-thirds of included trials published PRO findings, reporting standards were often inadequate according to international guidelines (mean [SD] inclusion of 3 [3] of 14 [range = 0–11]) CONSORT PRO Extension checklist items). More than one-half of trials publishing PRO results in a secondary publication (12 of 22, 54.5%) took 4 or more years to do so following trial closure, with eight (36.4%) taking 5–8 years and one trial publishing after 14 years. ConclusionsPRO protocol content is frequently inadequate, and nonreporting of PRO findings is widespread, meaning patient-important information may not be available to benefit patients, clinicians, and regulators. Even where PRO data are published, there is often considerable delay and reporting quality is suboptimal. This study presents key recommendations to enhance the likelihood of successful delivery of PROs in the future.

  • Medicaid Insurance Coverage Disruptions and Stage of Disease at Diagnosis Among Adolescent and Young Adult Cancer Patients
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-04-01
    Yabroff K, Han X, Nogueira L, et al.

    In the United States, disparities in access to cancer screening, treatment, survivorship care, and survival have been well documented by patient race and/or ethnicity, socioeconomic status, and geographic region (1,2). Having health insurance coverage is one of the strongest predictors of patient access to high-quality care across the cancer control continuum, earlier stage diagnosis, and better survival (1,2). Because insurance coverage and benefit design are modifiable, they have been a major focus of health policy efforts to reduce disparities and improve population health. To date, most research evaluating the health effects of insurance coverage has measured coverage at only a single point in time. Little is known about health effects of insurance coverage disruptions, which are especially common in the poor and those with Medicaid coverage (3), the state-based health insurance programs for some low-income populations. Disruptions in insurance coverage may interfere with access to high-quality cancer care and adversely affect patient outcomes.

  • Impact of Health Insurance on Stage at Cancer Diagnosis Among Adolescents and Young Adults
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-04-01
    Keegan T, Parsons H, Chen Y, et al.

    BackgroundUninsured adolescents and young adults (AYAs) and those with publicly funded health insurance are more likely to be diagnosed with cancer at later stages. However, prior population-based studies have not distinguished between AYAs who were continuously uninsured from those who gained Medicaid coverage at the time of cancer diagnosis. MethodsAYA patients (ages 15–39 years) with nine common cancers diagnosed from 2005 to 2014 were identified using California Cancer Registry data. This cohort was linked to California Medicaid enrollment files to determine continuous enrollment, discontinuous enrollment, or enrollment at diagnosis, with other types of insurance determined from registry data. Multivariable logistic regression was used to evaluate factors associated with later stages at diagnosis. ResultsThe majority of 52 774 AYA cancer patients had private or military insurance (67.6%), followed by continuous Medicaid (12.4%), Medicaid at diagnosis (8.5%), discontinuous Medicaid (3.9%), other public insurance (1.6%), no insurance (2.9%), or unknown insurance (3.1%). Of the 13 069 with Medicaid insurance, 50.1% were continuously enrolled. Compared to those who were privately insured, AYAs who enrolled in Medicaid at diagnosis were 2.2–2.5 times more likely to be diagnosed with later stage disease, whereas AYAs discontinuously enrolled were 1.7–1.9 times and AYAs continuously enrolled were 1.4–1.5 times more likely to be diagnosed with later stage disease. Males, those residing in lower socioeconomic neighborhoods, and AYAs of Hispanic or black race and ethnicity (vs non-Hispanic white) were more likely to be diagnosed at a later stage, independent of insurance. ConclusionsOur findings suggest that access to continuous medical insurance is important for decreasing the likelihood of late stage cancer diagnosis.

  • Association of Indoor Tanning Exposure With Age at Melanoma Diagnosis and BRAF V600E Mutations
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-03-28
    Burbidge T, Bastian B, Guo D, et al.

    There is limited information on how indoor tanning promotes melanoma development. We investigated indoor tanning use in patients with melanomas in sun-exposed skin and studied the clinicopathological and molecular characteristics in relation to indoor tanning exposure. Patients from a multidisciplinary clinic for cutaneous cancers completed standardized questionnaires on risk factors for melanoma as a component of medical history at their initial consultations. For this study, we included patients from December 2013 to May 2015. The 114 patients who reported indoor tanning exposure were younger at diagnosis than the 222 patients who did not (51.5 vs 64.0 years, two-sided P < .001). BRAF V600E genotype was more prevalent in ever-users than in nonusers (42.9% vs 28.3%, two-sided P = .04) and higher in ever-users who initiated indoor tanning prior to age 25 years compared with age 25 years or older (62.2% vs 31.1%, two-sided P = .003). There were more melanomas in intermittently sun-exposed skin in ever-users than nonusers (65.7% vs 51.9%, respectively, two-sided P = .02). Our data suggest indoor tanning may promote melanomas that arise in skin with low-chronic sun-induced damage through BRAF V600E-mediated melanomagenesis.

  • Assessing Long-Term Survival Benefits of Immune Checkpoint Inhibitors Using the Net Survival Benefit
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-03-05
    Péron J, Lambert A, Munier S, et al.

    BackgroundThe treatment effect in survival analysis is commonly quantified as the hazard ratio, and tested statistically using the standard log-rank test. Modern anticancer immunotherapies are successful in a proportion of patients who remain alive even after a long-term follow-up. This new phenomenon induces a nonproportionality of the underlying hazards of death. MethodsThe properties of the net survival benefit were illustrated using the dataset from a trial evaluating ipilimumab in metastatic melanoma. The net survival benefit was then investigated through simulated datasets under typical scenarios of proportional hazards, delayed treatment effect, and cure rate. The net survival benefit test was computed according to the value of the minimal survival difference considered clinically relevant. As comparators, the standard and the weighted log-rank tests were also performed. ResultsIn the illustrative dataset, the net survival benefit favored ipilimumab [Δ(0) = 15.8%, 95% confidence interval = 4.6% to 27.3%, P=.006]. This favorable effect was maintained when the analysis was focused on long-term survival differences (eg, >12 months, Δ(12) = 12.5% (95% confidence interval = 4.4% to 20.6%, P=.002). Under the scenarios of a delayed treatment effect and cure rate, the power of the net survival benefit test compared favorably to the standard log-rank test power and was comparable to the power of the weighted log-rank test for large values of the threshold of clinical relevance. ConclusionThe net long-term survival benefit is a measure of treatment effect that is meaningful whether or not hazards are proportional. The associated statistical test is more powerful than the standard log-rank test when a delayed treatment effect is anticipated.

  • Cumulative Toxicity in Targeted Therapies: What to Expect at the Recommended Phase II Dose
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-03-05
    Altzerinakou M, Collette L, Paoletti X.

    BackgroundIn the era of molecularly targeted agents (MTAs), it is recommended to account for toxicity over several cycles to identify the recommended phase II dose (RP2D). We investigated the relationship between the risk of toxicity at cycle 1 and the cumulative incidence of toxicity over subsequent cycles in trials of single MTAs. MethodsOn individual patient data from 26 phase I clinical trials of single MTAs provided by the National Cancer Institute, we estimated the probability of first-severe toxicity per treatment cycle as well as the cumulative incidence at, below, and above the maximum tolerated dose (MTD). Toxicity was further subclassified into nonhematologic and hematologic. A prediction table was developed to estimate the cumulative incidence up to six cycles based on the toxicity rate observed in the first cycle. ResultsOverall, 942 patients were included. For patients treated at the MTD, the probability of first-severe toxicity decreased from 24.8% (95% prediction interval [PI] = 20.3% to 32.9%) to 2.2% (95% PI = 0.1% to 7.7%) from cycle 1 to 6, whereas the cumulative incidence of toxicity reached 51.7% (95% PI = 40.5% to 66.3%) after six cycles. Toxicity rates ranging from 20.0% to 30.0% in the first cycle were associated with 46.8% (95% PI = 39.5% to 54.2%) and 65.8% (95% PI = 57.7% to 73.1%) cumulative incidence after six cycles. ConclusionThis study examined the risk of severe toxicity over time of single MTAs. The cumulative incidence of toxicity at the MTD was higher than the usually accepted toxicity targets, challenging the definition of the RP2D of MTAs. The prediction table may help calibrate the target rate at the RP2D.

  • TP53 Status and Estrogen Receptor-Beta in Triple-Negative Breast Cancer: Company Matters
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-04-16
    Badve S, Gökmen-Polar Y.

    Estrogen receptor β (ESR2) shares a structural homology at the DNA and ligand binding domains (96% and 58%, respectively) with estrogen receptor α (ESR1), the major type of estrogen receptor in breast cancer (1,2). Similarities notwithstanding, ESR2 has functions and expression patterns distinct from ESR1 and is widely expressed in both basal and luminal epithelial cells (3–6). The exact role of ESR2 in breast cancer is not clear, with both antiproliferative and proliferative roles being described (7, 8). The mechanisms for these opposing actions of ESR2 in breast tumorigenesis have not been fully elucidated; this, in part, is due to different isoforms and binding partners.

  • RE: Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer During Follow-Up and Prognosis
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-06-11
    Di Cosimo S, Torri V, Porcu L.

    In their study on the prognostic relevance of circulating tumor cells (CTCs) in breast cancer follow-up in the phase III SUCCESS A trial, Trapp et al. (1) report that patients with CTCs 2 years after chemotherapy have an increased risk of relapse and death as compared with patients without CTCs. However, as we summarize in Table 1 following a partial re-analysis of the data by Trapp et. al., some issues need consideration. The predictive value of CTC classification at 40 months after 2 years from the end of chemotherapy was estimated by Kaplan-Meier plots and reported in Table 1. The standard error of survival distribution was calculated using the formula reported by Altman et al. (2). Restricted mean survival time at 40 months (ie, the mean disease-free survival time up to 40 months) was estimated assuming uniform risk of relapse in the time interval 0–40 months, RMST40. According to Figures 2B and 3B of the article, we considered the time interval 0–40 months because we aimed to analyze the longest amount of patient time, the numbers of patients at risk were reported, and survival curves were still stable.

  • Response to Di Cosimo, Torri, and Porcu
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-06-11
    Trapp E, Janni W, Schindlbeck C, et al.

    We are grateful to Di Cosimo, Torri, and Porcu for their valuable comment on our article. We showed that the presence of circulating tumor cells (CTCs) as assessed 2 years after chemotherapy was prognostic for poor disease-free survival (DFS) and overall survival (OS). Di Cosimo et al. raise the question of clinical relevance of this finding by recalculating positive and negative predictive values for a 0- to 40-month interval.

  • Corrigendum
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-10-17

    Corrigendum to “Augmentation of response to chemotherapy by microRNA-506 through regulation of RAD51 in serous ovarian cancers” by G Liu et al. J Natl Cancer Inst 2015; 107(7):doi:10.1093/jnci/djv108

  • Physical Activity and the Risk of Liver Cancer: A Systematic Review and Meta-Analysis of Prospective Studies and a Bias Analysis
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-06-05
    Baumeister S, Leitzmann M, Linseisen J, et al.

    BackgroundPhysical inactivity is an established risk factor for several cancers of the digestive system and female reproductive organs, but the evidence for liver cancers is less conclusive. MethodsThe aim of this study was to synthesize prospective observational studies on the association of physical activity and liver cancer risk by means of a systematic review and meta-analysis. We searched Medline, Embase, and Scopus from inception to January 2019 for prospective studies investigating the association of physical activity and liver cancer risk. We calculated mean hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model. We quantified the extent to which an unmeasured confounder or an unaccounted selection variable could shift the mean hazard ratio to the null. ResultsFourteen prospective studies, including 6,440 liver cancers, were included in the systematic review and meta-analysis. The mean hazard ratio for high compared with low physical activity was 0.75 (95% CI = 0.63 to 0.89; 95% prediction interval = 0.52 to 1.07; I² = 64.2%). We estimated that 67.6% (95% CI = 56.6% to 78.5%) of all true effect estimates would have a hazard ratio less than 0.8. Bias analysis suggested than an unobserved confounder would have to be associated with a 1.99-fold increase in the risk of physical activity or liver cancer to explain away the observed mean hazard ratio. An unaccounted for selection variable would have to be related to exposure and endpoint with a relative risk of 1.58 to explain away the mean hazard ratio. ConclusionsPhysical activity is inversely related to the risk of liver cancer. Further studies with objectively measured physical activity and quasi-experimental designs addressing confounding are needed.

  • Immunotherapy for Colorectal Cancer: A Review of Current and Novel Therapeutic Approaches
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-05-20
    Franke A, Skelton W, IV, Starr J, et al.

    Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the United States. Although immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, the benefit in CRC has thus far been limited to patients with microsatellite instability high (MSI-H):DNA mismatch repair–deficient (dMMR) tumors. Recent studies in the refractory CRC setting have led to US Food and Drug Administration approvals for pembrolizumab as well as nivolumab (with or without ipilimumab) for tumors harboring an MSI-H:dMMR molecular profile. Several randomized controlled trials are underway to move immunotherapy into the frontline for metastatic cancer (with or without chemotherapy) and the adjuvant setting. Awareness of these studies is critical given the relatively low incidence (approximately 3%–5%) of MSI-H:dMMR in advanced or metastatic CRC to support study completion, because the results could be potentially practice changing. The real challenge in this disease is related to demonstrating the benefit of immunotherapy for the vast majority of patients with CRC not harboring MSI-H:dMMR. Given the rapid pace of scientific changes, this article provides a narrative review regarding the current landscape of immunotherapy for CRC. Particular attention is paid to the currently available data that inform today’s clinical practice along with upcoming randomized controlled trials that may soon dramatically change the treatment landscape for CRC.

  • Developing a Quality of Cancer Survivorship Care Framework: Implications for Clinical Care, Research, and Policy
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-05-16
    Nekhlyudov L, Mollica M, Jacobsen P, et al.

    There are now close to 17 million cancer survivors in the United States, and this number is expected to continue to grow. One decade ago the Institute of Medicine report, From Cancer Patient to Cancer Survivor: Lost in Transition, outlined 10 recommendations aiming to provide coordinated, comprehensive care for cancer survivors. Although there has been noteworthy progress made since the release of the report, gaps remain in research, clinical practice, and policy. Specifically, the recommendation calling for the development of quality measures in cancer survivorship care has yet to be fulfilled. In this commentary, we describe the development of a comprehensive, evidence-based cancer survivorship care quality framework and propose the next steps to systematically apply it in clinical settings, research, and policy.

  • TP53 Status as a Determinant of Pro- vs Anti-Tumorigenic Effects of Estrogen Receptor-Beta in Breast Cancer
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-04-16
    Mukhopadhyay U, Oturkar C, Adams C, et al.

    BackgroundAnti-tumorigenic vs pro-tumorigenic roles of estrogen receptor-beta (ESR2) in breast cancer remain unsettled. We investigated the potential of TP53 status to be a determinant of the bi-faceted role of ESR2 and associated therapeutic implications for triple negative breast cancer (TNBC). MethodsESR2-TP53 interaction was analyzed with multiple assays including the in situ proximity ligation assay. Transcriptional effects on TP53-target genes and cell proliferation in response to knocking down or overexpressing ESR2 were determined. Patient survival according to ESR2 expression levels and TP53 mutation status was analyzed in the basal-like TNBC subgroup in the Molecular Taxonomy of Breast Cancer International Consortium (n = 308) and Roswell Park Comprehensive Cancer Center (n = 46) patient cohorts by univariate Cox regression and log-rank test. All statistical tests are two-sided. ResultsESR2 interaction with wild-type and mutant TP53 caused pro-proliferative and anti-proliferative effects, respectively. Depleting ESR2 in cells expressing wild-type TP53 resulted in increased expression of TP53-target genes CDKN1A (control group mean [SD] = 1 [0.13] vs ESR2 depletion group mean [SD] = 2.08 [0.24], P = .003) and BBC3 (control group mean [SD] = 1 [0.06] vs ESR2 depleted group mean [SD] = 1.92 [0.25], P = .003); however, expression of CDKN1A (control group mean [SD] = 1 [0.21] vs ESR2 depleted group mean [SD] = 0.56 [0.12], P = .02) and BBC3 (control group mean [SD] = 1 [0.03] vs ESR2 depleted group mean [SD] = 0.55 [0.09], P = .008) was decreased in cells expressing mutant TP53. Overexpressing ESR2 had opposite effects. Tamoxifen increased ESR2-mutant TP53 interaction, leading to reactivation of TP73 and apoptosis. High levels of ESR2 expression in mutant TP53-expressing basal-like tumors is associated with better prognosis (Molecular Taxonomy of Breast Cancer International Consortium cohort: log-rank P = .001; hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.84, univariate Cox P = .02). ConclusionsTP53 status is a determinant of the functional duality of ESR2. Our study suggests that ESR2-mutant TP53 combination prognosticates survival in TNBC revealing a novel strategy to stratify TNBC for therapeutic intervention potentially by repurposing tamoxifen.

  • Impact of Precision Medicine on Efficiencies of Novel Drug Development in Cancer
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-13
    Sarvas H, Carlisle B, Dolter S, et al.

    Precision medicine offers opportunities for reducing the costs, burdens, and time associated with drug development. We examined time, number of trials, indications tested and patient burden needed to achieve first FDA license for all 5 novel anti-cancer precision-medicine drugs and all 10 novel non-precision medicine drugs receiving FDA approval 2010-2014. The 15 drug portfolios encompassed 242 trials: 87 for precision medicine drugs and 155 for non-precision medicine drugs. Embase and MEDLINE databases were searched for all pre-licensure clinical trials, and data on time, patient numbers, indications tested and total treatment-emergent grade 3-5 adverse events were measured from the first trial of each drug. We did not find patterns suggesting greater efficiencies in precision medicine compared to non-precision medicine. Gains in efficiency for precision-medicine drug development may be offset by challenges with recruitment.

  • Factors associated with utilization of high cost agents for the treatment of metastatic non-small cell lung cancer
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-09
    Bradley C, Eguchi M, Perraillon M.

    BackgroundAntineoplastic agents approved in recent decades are a marked advancement in cancer treatment but come at considerable cost. These drugs may widen survival disparities between patients who receive these agents and those who do not. We examine factors associated with the utilization of high cost antineoplastic agents for the treatment of metastatic non-small cell lung cancer (mNSCLC). MethodsWe conducted a retrospective observational study using 2007-2015 SEER-Medicare data supplemented with the Area Health Resource File. Patients were aged 66 years or older enrolled in fee-for-service Medicare Part D, were diagnosed with a first primary diagnosis of mNSCLC, and received an antineoplastic agent. High cost agents were defined as agents costing $5000 or more per month. Independent variables include race/ethnicity, urban or rural residency, census tract poverty, and treatment facility type (e.g., National Cancer Institute (NCI) designation). ResultsPatients who lived in areas of high poverty were 4 percentage points less likely to receive high cost agents (two-sided p < 0.001). Patients who were not treated at a NCI designated center were 10 percentage points less likely to receive these agents (two-sided p < 0.001). A 27 percentage point increase in the likelihood of receiving a high cost agent was observed in 2015 compared to 2007, highlighting the rapid change in practice patterns (two-sided p < 0.001). ConclusionPotential policy and care delivery solutions involve outreach and support to community physicians who treat patients in remote areas. We estimate that widespread use of these agents conservatively cost approximately $3 billion per year for metastatic non-small cell lung cancer alone.

  • Corrigendum
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-08

    Correction to “Physical activity and the risk of liver cancer: a systematic review and meta-analysis of prospective studies and a bias analysis” by Sebastian E. Baumeister et al. JNCI J Natl Cancer Inst (2019) 111(11): djz111

  • Efficacy of the AS04-adjuvanted HPV-16/18 vaccine: Pooled analysis of the Costa Rica Vaccine and PATRICIA randomized controlled trials
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-07
    Tota J, Struyf F, Sampson J, et al.

    BackgroundThe AS04-adjuvanted HPV-16/18 (AS04-HPV-16/18) vaccine provides excellent protection against targeted HPV types and a variable degree of cross-protection against others, including types 6/11/31/33/45. High efficacy against any cervical intraepithelial neoplasia grade 3 or greater (CIN3+; >90%) suggests lower levels of protection may exist for a wide-range of oncogenic HPV types, which is difficult to quantify in individual trials. Pooling individual-level data from two randomized controlled trials (RCTs), we aimed to evaluate AS04-HPV-16/18 vaccine efficacy against incident HPV infections and cervical abnormalities. MethodsData were available from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT00122681) – two large-scale, double-blind RCTs of the AS04-HPV-16/18 vaccine. Primary analyses focused on disease-free women with no detectable cervicovaginal HPV at baseline. Results12,550 women were included in our primary analyses (HPV arm=6,271; control arm=6,279). Incidence of six month persistent oncogenic/non-oncogenic infections, excluding known/accepted protected types 6/11/16/18/31/33/45 (focusing on 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74), was statistically significantly lower in the HPV arm than in the control arm (efficacy=9.9%, 95% Confidence Interval [CI] 1.7%-17.4%). Statistically significant efficacy (p < 0.05) was observed for individual oncogenic types 16/18/31/33/45/52 and non-oncogenic types 6/11/53/74. Efficacy against cervical abnormalities (all types) increased with severity, ranging from 27.7% (95% CI 21.7%-33.3%) to 58.7% (95% CI 34.1%-74.7%) for cytologic outcomes (low-grade squamous intraepithelial neoplasia lesion or greater, and high-grade squamous intraepithelial neoplasia lesion or greater, respectively) and 66.0% (95% CI 54.4%-74.9%) to 87.8% (95% CI 71.1%-95.7%) for histologic outcomes (CIN2+ and CIN3+, respectively). Comparing CVT and PATRICIA results, there was no evidence of heterogeneity, except for type 51 (efficacy=-28.6% and 20.7%, respectively; two-sided p = 0.03). ConclusionsThe AS04-HPV-16/18 vaccine provides some additional cross-protection beyond established protected types, which partially explains the high efficacy against CIN3+.

  • Antihistamines and ovarian cancer survival: nationwide cohort study and in vitro cell viability assay
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-05
    Verdoodt F, Dehlendorff C, Jäättelä M, et al.

    Antihistamines with cationic amphiphilic drug (CAD) characteristics induce cancer-specific cell death in experimental studies. Epidemiologic evidence is, however, limited. In a Danish nationwide cohort of ovarian cancer patients diagnosed during 2000-2015 (n = 5075), we evaluated the association between antihistamine prescriptions and cancer mortality. We used Cox regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for ovarian cancer mortality. In an in vitro cell viability assay, we evaluated cell-death in three ovarian cancer cell lines after treatment with clinically relevant doses of eight antihistamines. In our cohort study, CAD antihistamine use (≥1 prescription; n = 133) was associated with a HR of 0.63 (95% CI: 0.40 to 0.99) compared to use of non-CAD antihistamines (n = 304), and we found a tendencytowards a dose-response association. In our cell viability assay, we found consistent and dose-dependent cytotoxicity for all CAD but not non-CAD antihistamines. In this nationwide cohort study, use of antihistamines with CAD characteristics is associated with a prognostic benefit in ovarian cancer patients.

  • Changes in noninsurance and care unaffordability among cancer survivors following the Affordable Care Act
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-05
    Han X, Jemal A, Zheng Z, et al.

    BackgroundLittle is known about changes in socioeconomic disparities in noninsurance and care unaffordability among non-elderly cancer survivors following the Affordable Care Act (ACA). MethodsCancer survivors aged 18-64 years nationwide were identified from Behavioral Risk Factor Surveillance System. Trend and difference-in-differences (DD) analyses were conducted to examine changes in percent uninsured and percent reporting care unaffordability pre-(2011-2013) and post-(2014-2017) ACA Medicaid expansion, by sociodemographic factors. ResultsA total of 118,631 cancer survivors were identified from Medicaid expansion (N = 72,124) and nonexpansion (N = 46,507) states. Following the ACA, percent uninsured and percent reporting care unaffordability decreased nationwide. Medicaid expansion was associated with a 1.8 (95% CI: 0.1, 3.5) percentage points (ppt) net decrease in noninsurance and a 2.9 (95% CI: 0.7, 5.1) ppt net decrease in care unaffordability. In stratified analyses by sociodemographic factors, substantial decreases were observed in female survivors, those with low/medium household incomes, unemployed and survivors with multiple comorbidities. However, we observed slightly increased percentages in reporting noninsurance (1.7 [95% CI: -1.2, 4.5] ppt) and care unaffordability (3.1 [95% CI: -0.4, 6.5] ppt) in nonexpansion states between 2016-2017, translating to 67,163 and 124,160 survivors, respectively. ConclusionWe observed reductions in disparities by sociodemographic factors in noninsurance and care unaffordability among nonelderly cancer survivors following the ACA, with largest decreases in females, those with low/medium income, multiple comorbid conditions, the unemployed, and those residing in Medicaid expansion states. However, the uptick of 82,750 uninsured survivors in 2017, mainly from nonexpansion states, is concerning. Ongoing monitoring of the effects of the ACA is warranted, especially in evaluating health outcomes.

  • HIV RNA, CD4+ Percentage, and Risk of Hepatocellular Carcinoma by Cirrhosis Status
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-05
    Torgersen J, Kallan M, Carbonari D, et al.

    BackgroundDespite increasing incidence of hepatocellular carcinoma (HCC) among HIV-infected patients, it remains unclear if HIV-related factors contribute to development of HCC. We examined if higher or prolonged HIV viremia and lower CD4+ cell percentage were associated with HCC. MethodsWe conducted a cohort study of HIV-infected individuals who had HIV RNA, CD4+, and CD8+ cell counts and percentages assessed in the Veterans Aging Cohort Study (1999-2015). HCC was ascertained using Veterans Health Administration cancer registries and electronic records. Cox regression was used to determine hazard ratios (HR, 95% confidence interval [CI]) of HCC associated with higher current HIV RNA, longer duration of detectable HIV viremia (≥500 copies/mL), and current CD4+ cell percentage <14%, adjusting for traditional HCC risk factors. Analyses were stratified by previously validated diagnoses of cirrhosis prior to start of follow-up. ResultsAmong 35,659 HIV-infected patients, 302 (0.8%) developed HCC over 281,441 person-years (incidence rate, 107.3/100,000 person-years). Among patients without baseline cirrhosis, higher HIV RNA (HR = 1.25 [95%CI=1.12-1.40] per 1.0 log10 copies/mL) and ≥12 months of detectable HIV (HR = 1.47 [95%CI=1.02-2.11]) were independently associated with higher risk of HCC. CD4+ percentage <14% was not associated with HCC in any model. Hepatitis C coinfection was a statistically significant predictor of HCC regardless of baseline cirrhosis status. ConclusionAmong HIV-infected patients without baseline cirrhosis, higher HIV RNA and longer duration of HIV viremia increased risk of HCC, independent of traditional HCC risk factors. This is the strongest evidence to date that HIV viremia contributes to risk of HCC in this group.

  • Factors associated with oncologist discussions of the costs of genomic testing and related treatments
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2019-11-01
    Yabroff K, Zhao J, de Moor J, et al.

    BackgroundUse of genomic testing is increasing in the United States. Testing can be expensive, and not all tests and related treatments are covered by health insurance. Little is known about how often oncologists discuss costs of testing and treatment, or about the factors associated with those discussions. MethodsWe identified 1220 oncologists who reported discussing genomic testing with their cancer patients from the 2017 National Survey of Precision Medicine in Cancer Treatment. Multivariable polytomous logistic regression analyses were used to assess associations between oncologist and practice characteristics and the frequency of cost discussions. All statistical tests were two-sided. ResultsAmong oncologists who discussed genomic testing with patients, 50.0% reported often discussing the likely costs of testing and related treatments; 26.3% reported sometimes discussing costs; and 23.7% reported never or rarely discussing costs. In adjusted analyses, oncologists with training in genomic testing or working in practices with electronic medical record (EMR) alerts for genomic tests were more likely to have cost discussions sometimes or often [(OR = 2.09; 95% Confidence Interval (CI): 1.19, 3.69) and (OR = 2.22; 95%CI: 1.30, 3.79), respectively] compared to rarely/never. Other factors statistically significantly associated with more frequent cost discussions included treating solid tumors (rather than only hematological cancers), using next-generation sequencing gene panel tests, having higher patient volume, and working in practices with higher percentages of patients insured by Medicaid, or self-paid or uninsured. ConclusionsInterventions targeting modifiable oncologist and practice factors, such as training in genomic testing and use of EMR alerts, may help improve cost discussions about genomic testing and related treatments.

  • Risk of Advanced Neoplasia Using the National Cancer Institute's Colorectal Cancer Risk Assessment Tool.
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2016-09-02
    Thomas F Imperiale,Menggang Yu,Patrick O Monahan,Timothy E Stump,Rebeka Tabbey,Elizabeth Glowinski,David F Ransohoff

    Background There is no validated, discriminating, and easy-to-apply tool for estimating risk of colorectal neoplasia. We studied whether the National Cancer Institute's (NCI's) Colorectal Cancer (CRC) Risk Assessment Tool, which estimates future CRC risk, could estimate current risk for advanced colorectal neoplasia among average-risk persons. Methods This cross-sectional study involved individuals age 50 to 80 years undergoing first-time screening colonoscopy. We measured medical and family history, lifestyle information, and physical measures and calculated each person's future CRC risk using the NCI tool's logistic regression equation. We related quintiles of future CRC risk to the current risk of advanced neoplasia (sessile serrated polyp or tubular adenoma ≥ 1 cm, a polyp with villous histology or high-grade dysplasia, or CRC). All statistical tests were two-sided. Results For 4457 (98.5%) with complete data (mean age = 57.2 years, SD = 6.6 years, 51.7% women), advanced neoplasia prevalence was 8.26%. Based on quintiles of five-year estimated absolute CRC risk, current risks of advanced neoplasia were 2.1% (95% confidence interval [CI] = 1.3% to 3.3%), 4.8% (95% CI = 3.5% to 6.4%), 6.4% (95% CI = 4.9% to 8.2%), 10.0% (95% CI = 8.1% to 12.1%), and 17.6% (95% CI = 15.5% to 20.6%; P < .001). For quintiles of estimated 10-year CRC risk, corresponding current risks for advanced neoplasia were 2.2% (95% CI = 1.4% to 3.5%), 4.8% (95% CI = 3.5% to 6.4%), 6.5% (95% CI = 5.0% to 8.3%), 9.3% (95% CI = 7.5% to 11.4%), and 18.4% (95% CI = 15.9% to 21.1%; P < .001). Among persons with an estimated five-year CRC risk above the median, current risk for advanced neoplasia was 12.8%, compared with 3.7% among those below the median (relative risk = 3.4, 95 CI = 2.7 to 4.4). Conclusions The NCI's Risk Assessment Tool, which estimates future CRC risk, may be used to estimate current risk for advanced neoplasia, making it potentially useful for tailoring and improving CRC screening efficiency among average-risk persons.

  • Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2017-04-05
    Karoline B Kuchenbaecker,Lesley McGuffog,Daniel Barrowdale,Andrew Lee,Penny Soucy,Joe Dennis,Susan M Domchek,Mark Robson,Amanda B Spurdle,Susan J Ramus,Nasim Mavaddat,Mary Beth Terry,Susan L Neuhausen,Rita Katharina Schmutzler,Jacques Simard,Paul D P Pharoah,Kenneth Offit,Fergus J Couch,Georgia Chenevix-Trench,Douglas F Easton,Antonis C Antoniou

    Background Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P =  8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P =  7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

  • Stress and immune responses after surgical treatment for regional breast cancer.
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 1998-01-15
    B L Andersen,W B Farrar,D Golden-Kreutz,L A Kutz,R MacCallum,M E Courtney,R Glaser

    BACKGROUND Adults who undergo chronic stress, such as the diagnosis and surgical treatment of breast cancer, often experience adjustment difficulties and important biologic effects. This stress can affect the immune system, possibly reducing the ability of individuals with cancer to resist disease progression and metastatic spread. We examined whether stress influences cellular immune responses in patients following breast cancer diagnosis and surgery. METHODS We studied 116 patients recently treated surgically for invasive breast cancer. Before beginning their adjuvant therapy, all subjects completed a validated questionnaire assessing the stress of being cancer patients. A 60-mL blood sample taken from each patient was subjected to a panel of natural killer (NK) cell and T-lymphocyte assays. We then developed multiple regression models to test the contribution of psychologic stress in predicting immune function. All regression equations controlled for variables that might exert short- or long-term effects on these responses, and we also ruled out other potentially confounding variables. RESULTS We found, reproducibly between and within assays, the following: 1) Stress level significantly predicted lower NK cell lysis, 2) stress level significantly predicted diminished response of NK cells to recombinant interferon gamma, and 3) stress level significantly predicted decreased proliferative response of peripheral blood lymphocytes to plant lectins and to a monoclonal antibody directed against the T-cell receptor. CONCLUSIONS The data show that the physiologic effects of stress inhibit cellular immune responses that are relevant to cancer prognosis, including NK cell toxicity and T-cell responses. Additional, longitudinal studies are needed to determine the duration of these effects, their health consequences, and their biologic and/or behavioral mechanisms.

  • Molecular characterization of defective antigen processing in human prostate cancer.
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 1995-02-15
    M G Sanda,N P Restifo,J C Walsh,Y Kawakami,W G Nelson,D M Pardoll,J W Simons

    BACKGROUND Gene-modified tumor cell vaccines have shown efficacy in animal models of malignancy, including prostate cancer. Class I major histocompatibility complex (MHC) assembly and function in the cellular targets of such therapies is pivotal in determining the efficacy of specific cytokine-secreting tumor vaccines. PURPOSE To help guide development of genetically engineered vaccine therapy for human prostate cancer, potential immune resistance pathways were evaluated by analysis of class I MHC assembly in prostate cancer cells. METHOD Class I MHC assembly in metastasis-derived human prostate cancer cell lines (LNCaP, PPC-1, DU-145, PC-3, and TSU) and a normal prostate-derived cell line (TP-2) were characterized by phenotypic, molecular, and functional assays. Assembled class I MHC and antigen was measured by flow cytometry; mRNA levels of assembly components (class I MHC heavy chain, beta 2-microglobulin, and the antigen transporter gene product TAP-2) were determined; and antigen processing was measured with a chimeric reconstituted system using vaccinia vectors. Restoration of antigen processing was attempted by interferon gamma stimulation and by transfection with mouse class I MHC heavy-chain cDNA. RESULTS Assembled class I MHC was underexpressed in two (LNCaP and PPC-1) of five prostate cancer cell lines compared with normal prostate-derived controls. PPC-1 cells underexpressed TAP-2 mRNA despite abundant class I MHC and beta 2-microglobulin message. Induction of TAP-2 by interferon gamma indicated that coding sequences for TAP-2 message were present in PPC-1. Resistance to cytotoxic T lymphocytes (CTL) lysis showed a functional defect in antigen transport by PPC-1 cells; reversal of the molecular defect with interferon gamma led to restoration of functional antigen processing. In contrast, LNCaP cells had competent antigen transport but deficient class I MHC heavy-chain function despite abundant class I MHC RNA; though refractory to stimulation by interferon gamma, this defect responded to transfection of class I MHC heavy-chain cDNA. CONCLUSIONS Metastatic prostate cancer cells can escape T-cell recognition via divergent mechanisms of defective class I MHC assembly. The specific underexpression of TAP-2 gene product in PPC-1 cells contrasts with prior studies of TAP gene underexpression in lung cancer (which concurrently underexpressed class I MHC heavy chain) and provides evidence for a regulatory pathway controlling TAP-2 gene expression in human cancers that may not affect class I MHC heavy-chain expression. IMPLICATIONS In clinical application of gene therapy for prostate cancer, these findings provide a rationale for focusing on strategies that can circumvent sole reliance on class I MHC-mediated tumor cell recognition by CTL.

  • 更新日期:2019-11-01
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