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Journal of the National Cancer Institute

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Background

National legislation is under consideration that would require women with mammographically dense breasts to be informed of their breast density and encouraged to discuss supplemental breast cancer screening with their health care providers. The number of US women potentially affected by this legislation is unknown.

Methods

We determined the mammographic breast density distribution by age and body mass index (BMI) using data from 1518 599 mammograms conducted from 2007 through 2010 at mammography facilities in the Breast Cancer Surveillance Consortium (BCSC). We applied these breast density distributions to age- and BMI-specific counts of the US female population derived from the 2010 US Census and the National Health and Nutrition Examination Survey (NHANES) to estimate the number of US women with dense breasts.

Results

Overall, 43.3% (95% confidence interval [CI] = 43.1% to 43.4%) of women 40 to 74 years of age had heterogeneously or extremely dense breasts, and this proportion was inversely associated with age and BMI. Based on the age and BMI distribution of US women, we estimated that 27.6 million women (95% CI = 27.5 to 27.7 million) aged 40 to 74 years in the United States have heterogeneously or extremely dense breasts. Women aged 40 to 49 years (N = 12.3 million) accounted for 44.3% of this group.

Conclusion

The prevalence of dense breasts among US women of common breast cancer screening ages exceeds 25 million. Policymakers and healthcare providers should consider this large prevalence when debating breast density notification legislation and designing strategies to ensure that women who are notified have opportunities to evaluate breast cancer risk and discuss and pursue supplemental screening options if deemed appropriate.


Background

Molecular biomarkers, a cornerstone of precision oncology, are critical in breast, gastroesophageal, and non–small cell lung cancer management (BC, GEC, NSCLC). Testing practices are intensely debated, impacting diagnostic quality and affecting pathologists, oncologists and patients. However, little is known about testing approaches used in practice. Our study described biomarker practices in BC, GEC, and NSCLC at the leading US cancer centers.

Methods

We conducted a survey of the National Cancer Institute (NCI) designated centers on BC, GEC, and NSCLC biomarker testing. We used simple frequencies to describe practices, two-sided Fisher’s exact test and two-sided McNemar’s test for cross-cancer comparison. All statistical tests were two-sided.

Results

For BC human epidermal growth factor receptor 2 (HER2), 39% of centers combine guidelines by using in situ hybridization (ISH) and immunohistochemistry (IHC) concurrently, and 21% reflex-test beyond guideline-recommended IHC2+. For GEC HER2, 44% use ISH and IHC concurrently, and 28% reflex-test beyond IHC2+. In NSCLC, the use of IHC is limited to 4% for epidermal growth factor receptor (EGFR) and 7% for anaplastic lymphoma kinase (ALK). 43.5% test NSCLC biomarkers on oncologist order; 34.5% run all biomarkers upfront, and 22% use a sequential protocol. NSCLC external testing is statistically significantly higher than BC (P < .0001) and GEC (P < .0001). NSCLC internally developed tests are statistically significantly more common than BC (P < .0001) and GEC (P < .0001).

Conclusions

At the NCI cancer centers, biomarker testing practices vary, but exceeding guidelines is a common practice for established biomarkers and emerging practice for newer biomarkers. Use of internally developed tests declines as biomarkers mature. Implementation of multibiomarker protocols is lagging. Our study represents a step toward developing a biomarker testing practice landscape.


Ligands for receptors of natural killer (NK) cells and CD8+ cytotoxic T lymphocytes (CTL), such as the inhibitory nonclassical HLA-G, the activating stress-induced major histocompatibility complex class I-related antigens MICA and MICB, and/or the UL16-binding proteins (ULBPs), are often aberrantly expressed upon viral infection and neoplastic transformation, thereby preventing virus-infected or malignant-transformed cells from elimination by immune effector cells. Recently, it has been shown that ligands of both NK and CD8+ T cells are regulated by a number of cellular and/or viral microRNAs (miRs). These miRs are involved in shaping the antiviral and/or antitumoral immune responses as well as neoplastic growth properties. This review summarizes the expression pattern and function of miRs directed against selected NK and T cell receptor ligands, their putative role in shaping immune surveillance and tumorigenicity, and their clinical relevance. In addition, the potential role of RNA-binding proteins in the post-transcriptional gene regulation of these ligands will be discussed.


Patient and physician awareness and acceptance of trials and patient ineligibility are major cancer clinical trial accrual barriers. Yet, trials are typically conceived and designed by small teams of researchers with limited patient input. We hypothesized that through crowdsourcing, the intellectual and creative capacity of a large number of researchers, clinicians, and patients could be harnessed to improve the clinical trial design process. In this study, we evaluated the feasibility and utility of using an internet-based crowdsourcing platform to inform the design of a clinical trial exploring an antidiabetic drug, metformin, in prostate cancer. Over a six-week period, crowdsourced input was collected from 60 physicians/researchers and 42 patients/advocates leading to several major (eg, eligibility) and minor modifications to the clinical trial protocol as originally designed. Crowdsourcing clinical trial design is feasible, adds value to the protocol development process, and may ultimately improve the efficiency of trial conduct.


Background

Clinical trials are essential to establish the effectiveness of new cancer therapies, but less than 5% of adults with cancer enroll in trials. In addition to ineligibility or lack of available trials, barriers to enrollment may include limited patient awareness about the option of participation.

Methods

We surveyed a multiregional cohort of patients with lung or colorectal cancer (or their surrogates) three to six months after diagnosis. We assessed whether respondents reported learning that clinical trial participation might be an option, and, if so, with whom they discussed trials. We used logistic regression to assess the association of patient characteristics with discussing trial participation and enrolling in trials. All statistical tests were two-sided.

Results

Of 7887 respondents, 1114 (14.1%) reported discussing the possibility of clinical trial participation; most learned about trials from their physicians, and 287 patients (3.6% of all patients, 25.8% of trial discussants) enrolled. Among 2173 patients who received chemotherapy for advanced (stage III/IV lung or stage IV colorectal) cancer, 25.7% discussed trials, and 7.6% (29.5% of trial discussants) enrolled. Discussions were less frequent among older patients, African American or Asian vs white patients, and those with lower incomes and more comorbidity. Enrollment was higher among patients reporting shared vs physician-driven decisions (all P < .05).

Conclusions

In this population-based cohort, only 14% of patients discussed participation in clinical trials. Discussions were more frequent among advanced cancer patients but were still reported by a minority of patients. Strategies to expand access to trials and facilitate patient-provider communication about participation may accelerate development of better cancer therapeutics.


Background

Substantial shortcomings in the quality of breast cancer (BC) care have been identified. While breast cancer is responsible for the largest share of cancer care spending, little is known about the value of care provided to US women with BC.

Methods

For women aged 65 to 70 years diagnosed July 1997 through December 2005 with stage 0-III BC who were continuously enrolled in fee-for-service Medicare, we evaluated performance relative to 20 measures recommending for proven therapies and seven measures recommending against unnecessary therapies. Using health care service area as the unit of analysis, we characterized quality for recommended and unnecessary therapies, median per-patient cost in the year after diagnosis for Medicare parts A and B, and five-year overall survival. We analyzed the relationships between quality, cost, and survival. All statistical tests were two-sided.

Results

We assessed the care provided to 15357 women and compiled quality, cost, and outcomes data for 99 regions. The median number of patients/region was 85 (interquartile range = 47–158); the five-year overall survival was 87.5%. Part B expenditure correlated positively with measures of recommended therapy (P = .027) and negatively with measures of unnecessary therapy (P = .004). Survival did not correlate with quality or cost. Regions demonstrating lower quality for both recommended and unnecessary therapy measures exhibited higher part A expenditure.

Conclusions

BC patients experience wide variation in quality, cost, and survival. Process measures that assess recommended and unnecessary therapies did not correlate with survival, but did shed light on spending for related and unrelated services. Additional efforts to identify factors that impact the relationships between quality, cost, and outcomes are needed.


Background

Accumulating evidence suggests that many ovarian cancers represent metastases from occult fallopian tube carcinomas or tumors arising within ovarian endometriosis. We hypothesized that small ovarian volumes, as reflected in nonvisualization by transvaginal ultrasound (TVU), would be a marker of lower ovarian cancer risk, whereas enlargement on serial examinations would indicate higher risk.

Methods

To address these hypotheses, we analyzed serial ovarian volume measurements determined by TVU for 29321 women (102787 scans) performed in the ovarian cancer screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial. Cox models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of association between TVU results and ovarian cancer. We assessed whether increasing ovarian volume preceded diagnosis of ovarian cancer in a nested case-control analysis comparing case patients and control patients matched on age, center, and screening year (1:4 ratio). All statistical tests were two-sided.

Results

Visualization of normal-appearing ovaries at the last TVU scan was associated with marginally higher ovarian cancer risk compared with nonvisualization of the ovaries (HR = 1.42, 95% CI = 1.00 to 2.01). Ovarian volume increased statistically significantly in ovarian cancer case patients one to two years before diagnosis (P < .001), but not in matched control patients.

Conclusion

Our analysis of TVU data suggests that increasing ovarian volume is associated with greater ovarian cancer risk, but it is only detectable one to two years before diagnosis.




Background

Data on clinical outcomes of infection with variants of oncogenic human papillomavirus (HPV) types other than HPV16 and HPV18 are rare. We investigated intratypic variations in non-HPV16/18 oncogenic types and their corresponding relationships with cervical intraepithelial neoplasia grades 2–3 (CIN2/3).

Methods

Study subjects were women who were positive for one or more of 11 non-HPV16/18 oncogenic types. Subjects were followed every six months for two years for detection of HPV and cervical lesions. Variant lineages were defined by sequencing the 3’ part of the long control region and the entire E6/E7 region of HPV genome. Lineage-associated risk of CIN2/3 was assessed using logistic regression with generalized estimating equations.

Results

A total of 4591 type-specific HPV infections among 2667 women were included in the analysis. The increase in risk of CIN2/3 was statistically significant for women with HPV31 A or B compared with C variants, HPV33 A1 compared with B variants, HPV45 A3 or B2 compared with B1 variants, HPV56 B compared with A2 variants, and HPV58 A1 or A3 compared with C variants. For these five types, the adjusted odds ratio associated with CIN2/3 was 2.0 (95% confidence interval [CI] = 1.5 to 2.6) for infections with single-type high-risk (HR) variants, 1.7 (95% CI = 1.0 to 2.7) for infections with two or more types but only one HR variant, and 5.3 (95% CI = 3.1 to 8.4) for infections with HR variants of two or more types as compared with those with single-type non-HR variants. The likelihood of CIN2/3 was similar for women with HPV16 infection and for those with HPV58 A1 variant infection.

Conclusions

These findings suggest that for a given HPV type, intratypic nucleotide changes may alter phenotypic traits that affect the probability of neoplasia.


Background

Cetuximab, a monoclonal blocking antibody against the epidermal growth factor receptor EGFR, has been approved for the treatment of squamous cell carcinomas of the head and neck (HNSCC). However, only few patients display long-term responses, prompting the search for cetuximab resistance mechanisms and new therapeutic options enhancing cetuximab effectiveness.

Methods

Cetuximab-sensitive HNSCC cells were retro-engineered to express PIK3CA and RAS oncogenes. These cells and HNSCC cells harboring endogenous PIK3CA and RAS oncogenes were xenografted into mice (n = 10 per group) and studied for their biochemical, antitumor, antiangiogenic, and antilymphangiogenic responses to cetuximab and mTOR targeting agents. All P values are two-sided.

Results

Cetuximab treatment of PIK3CA- and RAS-expressing HNSCC xenografts promoted an initial antitumor response, but all tumors relapsed within few weeks. In these tumors, cetuximab did not decrease the activity of mTOR, a downstream signaling target of EGFR, PIK3CA, and RAS. The combined administration of cetuximab and mTOR inhibitors exerted a remarkably increased antitumor activity, particularly in HNSCC cells that are resistant to cetuximab as a single agent. Indeed, cotargeting mTOR together with cetuximab caused a rapid tumor collapse of both PIK3CA- and RAS-expressing HNSCC xenografts (P < .001), concomitant with reduced proliferation (P < .001) and lymphangiogenesis (P < .001).

Conclusion

The presence of PIK3CA and RAS mutations and other alterations affecting the mTOR pathway activity in HNSCC could be exploited to predict the potential resistance to cetuximab, and to select the patients that may benefit the most from the concomitant administration of cetuximab and PI3K and/or mTOR inhibitors as a precision molecular therapeutic option for HNSCC patients.


Background

The use of neoadjuvant therapy before surgery for gastrointestinal cancer is increasing; however, patients may not complete both treatment components. Understanding completion rates of each treatment stage is necessary for treatment evaluation and to inform decision-making. This study evaluates reporting for recent neoadjuvant surgical trials, focusing on treatment progression and other key outcomes.

Methods

Systematic literature searches identified randomized and nonrandomized phase II and III studies evaluating neoadjuvant treatment and surgery for esophageal, stomach, and colorectal cancer, and colorectal liver metastases. Rates of reporting of failure to complete neoadjuvant treatment, nonprogression to surgery after neoadjuvant treatment, and nonresection at planned surgery were assessed. For each measure, reporting was categorized as "full," "partial," and "absent" according to predefined criteria, and reasons for nonprogression at each stage of treatment were examined to inform proposed standards.

Results

Of 9854 abstracts, 123 papers were reviewed and 62 articles were included, reporting outcomes for 9126 patients. Details of noncompletion of neoadjuvant treatment and nonprogression to surgery were completely absent in 21 (33.9%) and 19 (30.6%) studies, respectively. Reporting of nonresection at planned surgery was also deficient, with 21 (33.9%) studies providing no information about this outcome. Reasons for noncompletion and nonprogression were similar and included disease progression, treatment toxicity, and patient choice. Common reasons for nonresection were locally advanced disease and the discovery of unsuspected metastases.

Conclusions

Reports of recent neoadjuvant surgical trials often fail to include treatment progression and other key outcomes. These findings support the need for minimum reporting standards.


Background

Modern treatment of Hodgkin’s lymphoma (HL) has transformed its prognosis but causes late effects, including premature menopause. Cohort studies of premature menopause risks after treatment have been relatively small, and knowledge about these risks is limited.

Methods

Nonsurgical menopause risk was analyzed in 2127 women treated for HL in England and Wales at ages younger than 36 years from 1960 through 2004 and followed to 2003 through 2012. Risks were estimated using Cox regression, modified Poisson regression, and competing risks. All statistical tests were two-sided.

Results

During follow-up, 605 patients underwent nonsurgical menopause before age 40 years. Risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea [BCNU], etoposide, cytarabine, melphalan) chemotherapy for stem cell transplantation, but was not statistically significantly raised after adriamycin, bleomycin, vinblastine, dacarbazine (ABVD). Menopause generally occurred sooner after ovarian radiotherapy (62.5% within five years of ≥5 Gy treatment) and BEAM (50.9% within five years) than after alkylating chemotherapy (24.2% within five years of ≥6 cycles), and after treatment at older than at younger ages. Cumulative risk of menopause by age 40 years was 81.3% after greater than or equal to 5Gy ovarian radiotherapy, 75.3% after BEAM, 49.1% after greater than or equal to 6 cycles alkylating chemotherapy, 1.4% after ABVD, and 3.0% after solely supradiaphragmatic radiotherapy. Tables of individualized risk information for patients by future period, treatment type, dose and age are provided.

Conclusions

Patients treated with HL need to plan intended pregnancies using personalized information on their risk of menopause by different future time points.











Background

There are conflicting reports on the impact of soy on breast carcinogenesis. This study examines the effects of soy supplementation on breast cancer-related genes and pathways.

Methods

Women (n = 140) with early-stage breast cancer were randomly assigned to soy protein supplementation (n = 70) or placebo (n = 70) for 7 to 30 days, from diagnosis until surgery. Adherence was determined by plasma isoflavones: genistein and daidzein. Gene expression changes were evaluated by NanoString in pre- and posttreatment tumor tissue. Genome-wide expression analysis was performed on posttreatment tissue. Proliferation (Ki67) and apoptosis (Cas3) were assessed by immunohistochemistry.

Results

Plasma isoflavones rose in the soy group (two-sided Wilcoxon rank-sum test, P < .001) and did not change in the placebo group. In paired analysis of pre- and posttreatment samples, 21 genes (out of 202) showed altered expression (two-sided Student’s t-test, P < .05). Several genes including FANCC and UGT2A1 revealed different magnitude and direction of expression changes between the two groups (two-sided Student’s t-test, P < .05). A high-genistein signature consisting of 126 differentially expressed genes was identified from microarray analysis of tumors. This signature was characterized by overexpression (>2-fold) of cell cycle transcripts, including those that promote cell proliferation, such as FGFR2, E2F5, BUB1, CCNB2, MYBL2, CDK1, and CDC20 (P < .01). Soy intake did not result in statistically significant changes in Ki67 or Cas3.

Conclusions

Gene expression associated with soy intake and high plasma genistein defines a signature characterized by overexpression of FGFR2 and genes that drive cell cycle and proliferation pathways. These findings raise the concerns that in a subset of women soy could adversely affect gene expression in breast cancer.


Background

Hypomethylation in long interspersed nucleotide element-1 (LINE-1) and high-degree microsatellite instability (MSI-high) in colorectal cancer (CRC) have been associated with inferior and superior survival, respectively; however, it remains uncertain whether the prognostic association of LINE-1 hypomethylation differs by MSI status. We hypothesized that the adverse prognostic association of LINE-1 hypomethylation might be stronger in MSI-high CRCs than in microsatellite stable (MSS) CRCs.

Methods

Utilizing 1211 CRCs in the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined patient survival according to LINE-1 hypomethylation status in strata of MSI status. A Cox proportional hazards model was used to compute multivariable CRC-specific mortality hazard ratios (HRs) for a 10% decrease in LINE-1 methylation level (range = 23.1–93.1%), adjusting for potential confounders, including CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations. Statistical tests (log-rank test, chi-square test, and likelihood ratio test) were two-sided.

Results

In MSI-high cancers, the association of LINE-1 hypomethylation with higher mortality (HR = 2.45, 95% confidence interval [CI] = 1.64 to 3.66, P < .001) was stronger than that in MSS cancers (HR = 1.10, 95% CI = 0.98 to 1.24, P = .11) (P interaction < .001, between LINE-1 and MSI statuses). In MSI-high cases with CRC family history, the association of LINE-1 hypomethylation with higher mortality (HR = 5.13, 95% CI = 1.99 to 13.2; P < .001) was stronger than that in MSI-high cases without CRC family history (HR = 1.62, 95% CI = 0.89 to 2.94, P = .11) (P interaction = .02, between LINE-1 and CRC family history statuses).

Conclusions

The association of LINE-1 hypomethylation with inferior survival is stronger in MSI-high CRCs than in MSS CRCs. Tumor LINE-1 methylation level may be a useful prognostic biomarker to identify aggressive carcinomas among MSI-high CRCs.


The number and diversity of cancer therapeutics in the pipeline has increased over the past decade due to an enhanced understanding of cancer biology and the identification of novel therapeutic targets. At the same time, the cost of bringing new drugs to market and the regulatory burdens associated with clinical drug development have progressively increased. The finite number of eligible patients and limited financial resources available to evaluate promising new therapeutics represent rate-limiting factors in the effort to translate preclinical discoveries into the next generation of standard therapeutic approaches. Optimal use of resources requires understanding and ultimately addressing inefficiencies in the cancer clinical trials system. Prior analyses have demonstrated that a large proportion of trials initiated by the National Cancer Institute (NCI) Cooperative Group system are never completed. While NCI Cooperative Group trials are important, they represent only a small proportion of all cancer clinical trials performed. Herein, we explore the problem of cancer clinical trials that fail to complete within the broader cancer clinical trials enterprise. Among 7776 phase II–III adult cancer clinical trials initiated between 2005–2011, we found a seven-year cumulative incidence of failure to complete of approximately 20% (95% confidence interval = 18% to 22%). Nearly 48000 patients were enrolled in trials that failed to complete. These trials likely contribute little to the scientific knowledge base, divert resources and patients from answering other critical questions, and represent a barrier to progress.



Background

Papanicolaou (Pap) triage, with high specificity, has been recommended for primary Human papillomavirus (HPV) testing but is flawed by poor sensitivity and cytologist dependence. We evaluated the potential role of microRNA (miRNA) detection in cervical exfoliated cells in HPV-positive women from a clinic-based population.

Methods

Primary HPV testing as well as Pap test were performed on all eligible women. Six miRNAs (miR-424/miR-375/miR-34a/miR-218/miR-92a/miR-93) were detected by RT-qPCR in cervical exfoliated cells. All HPV-positive women underwent colposcopy and further biopsy if indicated. Mann–Whitney U test, the receiver operating characteristic curve, logistic regression, and Pearson’s Chi-square were used to assess data. All tests of statistical significance were two-sided.

Results

A total of 1021 eligible HPV-positive women were enrolled. The expression of miR-424/miR-375/miR-34a/miR-218 in high-grade cervical intraepithelial neoplasia (CIN) and abnormal cytology was statistically significantly lower than that in low-grade CIN and normal cytology, respectively (all P < .05). Compared with the Pap test, both miR-424 and miR-375 detection achieved higher sensitivity (76.0% and 74.9% vs 63.8%, P < .05), higher negative predictive value (NPV) (85.7% and 85.4% vs 79.3%, P < .05), and comparable specificity while identifying CIN2 or worse (CIN2+). Similar results were achieved while identifying CIN3+. Multi-marker panels based on miR-424, miR-375, and miR-218 further improved the performance over any single miRNA test or Pap test.

Conclusion

Single miR-424 or miR-375 detection and miR-424/miR-375/miR-218–based multimarker panels in cervical exfoliated cells show superior performance over Pap triage for high-grade CIN identification in a clinic-based population. Detection of miRNA may provide a new triage option for HPV-positive women.


Ibrutinib, which irreversibly inhibits Bruton tyrosine kinase, was evaluated for antitumor activity in a panel of non–small cell lung cancer (NSCLC) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells. Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, suggesting ibrutinib functions as an EGFR inhibitor. Survival was analyzed by Kaplan–Meier estimation and log-rank test. All statistical tests were two-sided. In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice (n = 5 per group). The mean survival times for solvent- and erlotinib-treated mice were both 17.8 days (95% confidence interval [CI] = 14.3 to 21.3 days), while the mean survival time for ibrutinib-treated mice was 29.8 days (95% CI = 26.0 to 33.6 days, P = .008). Our results indicate that ibrutinib could be a candidate drug for treatment of EGFR-mutant NSCLC, including erlotinib-resistant tumors.


Background

Case-control studies have reported an increased risk of ovarian cancer among talc users; however, the only cohort study to date found no association except for an increase in serous invasive ovarian cancers. The purpose of this analysis was to assess perineal powder use and risk of ovarian cancer prospectively in the Women’s Health Initiative Observational Study cohort.

Methods

Perineal powder use was assessed at baseline by self-report regarding application to genitals, sanitary napkins, or diaphragms and duration of use. The primary outcome was self-reported ovarian cancer centrally adjudicated by physicians. Cox proportional hazard regression was used to estimate risk, adjusting for covariates, including person-time until diagnosis of ovarian cancer (n = 429), death, loss to follow-up, or September 17, 2012. All statistical tests were two-sided.

Results

Among 61576 postmenopausal women, followed for a mean of 12.4 years without a history of cancer or bilateral oophorectomy, 52.6% reported ever using perineal powder. Ever use of perineal powder (hazard ratio [HR]adj = 1.06, 95% confidence interval [CI] = 0.87 to 1.28) was not associated with risk of ovarian cancer compared with never use. Individually, ever use of powder on the genitals (HRadj = 1.12, 95% CI = 0.92 to 1.36), sanitary napkins (HRadj = 0.95, 95% CI = 0.76 to 1.20), or diaphragms (HRadj = 0.92, 95% CI = 0.68 to 1.23) was not associated with risk of ovarian cancer compared with never use, nor were there associations with increasing durations of use. Estimates did not differ when stratified by age or tubal ligation status.

Conclusion

Based on our results, perineal powder use does not appear to influence ovarian cancer risk.


Cardiotoxicity resulting from direct myocyte damage has been a known complication of cancer treatment for decades. More recently, the emergence of hypertension as a clinically significant side effect of several new agents has been recognized as adversely affecting cancer treatment outcomes. With cancer patients living longer, in part because of treatment advances, these adverse events have become increasingly important to address. However, little is known about the cardiovascular pathogenic mechanisms associated with cancer treatment and even less about how to optimally prevent and manage short- and long-term cardiovascular complications, leading to improved patient safety and clinical outcomes. To identify research priorities, allocate resources, and establish infrastructure required to address cardiotoxicity associated with cancer treatment, the National Cancer Institute (NCI) and National Heart, Lung and Blood Institute (NHLBI) sponsored a two-day workshop, "Cancer treatment–related cardiotoxicity: Understanding the current state of knowledge and future research priorities," in March 2013 in Bethesda, MD. Participants included leading oncology and cardiology researchers and health professionals, patient advocates and industry representatives, with expertise ranging from basic to clinical science. Attendees were charged with identifying research opportunities to advance the understanding of cancer treatment–related cardiotoxicity across basic and clinical science. This commentary highlights the key discussion points and overarching recommendations from that workshop.


It is well established that increased nut consumption is associated with a reduced risk of major chronic diseases, such as cardiovascular disease and type 2 diabetes mellitus. On the other hand, the association between nut consumption and cancer mortality is less clear. Recent studies have suggested that nut consumption is associated with reduced cancer mortality. This evidence reinforces the interest to investigate the chemopreventive properties of nuts, and it raises questions about the specific cancer type(s) and setting that can be more affected by nut consumption, as well as the cellular mechanisms involved in this protective effect. Here we discuss recent studies on the association of nut consumption and cancer, and we propose specific cellular mechanisms by which nut components can affect cancer progression.


To assess the efficacy of combining radioimmunoconjugate [131I] metuximab with radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC) treatment compared with RFA alone, a single-center randomized controlled trial was conducted on 127 patients with Barcelona Clinic Liver Cancer staging system (BCLC) classifications of 0–B stage. Patients received either RFA followed by [131I] metuximab (n = 62) or RFA alone (n = 65). The primary outcome was overall tumor recurrence. Statistical tests were two-sided. The one- and two-year recurrence rates in the combination group were 31.8% and 58.5%, whereas those in the RFA group were 56.3% and 70.9%, respectively. The median time to overall tumor recurrence was 17 months in the combination group and 10 months in the RFA group (P = .03). The RFA-[131I] metuximab treatment showed a greater antirecurrence benefit than RFA in the metuximab target (ie, CD147)–positive subpopulation (P = .007). [131I] metuximab may yield prevention of tumor recurrence after RFA.


Background

Individual studies have suggested that some circulating fatty acids are associated with prostate cancer risk, but have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease.

Methods

Principal investigators of prospective studies on circulating fatty acids and prostate cancer were invited to collaborate. Investigators provided individual participant data on circulating fatty acids (weight percent) and other characteristics of prostate cancer cases and controls. Prostate cancer risk by study-specific fifths of 14 fatty acids was estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided.

Results

Five thousand and ninety-eight case patients and 6649 control patients from seven studies with an average follow-up of 5.1 (SD = 3.3) years were included. Stearic acid (18:0) was inversely associated with total prostate cancer (odds ratio [OR] Q5 vs Q1 = 0.88, 95% confidence interval [CI] = 0.78 to 1.00, P trend = .043). Prostate cancer risk was, respectively, 14% and 16% greater in the highest fifth of eicosapentaenoic acid (20:5n-3) (OR = 1.14, 95% CI = 1.01 to 1.29, Ptrend = .001) and docosapentaenoic acid (22:5n-3) (OR = 1.16, 95% CI = 1.02 to 1.33, P trend = .003), but in each case there was heterogeneity between studies (P = .022 and P < .001, respectively). There was heterogeneity in the association between docosapentaenoic acid and prostate cancer by grade of disease (P = .006); the association was statistically significant for low-grade disease but not high-grade disease. The remaining 11 fatty acids were not statistically associated with total prostate cancer risk.

Conclusion

There was no strong evidence that circulating fatty acids are important predictors of prostate cancer risk. It is not clear whether the modest associations of stearic, eicosapentaenoic, and docosapentaenoic acid are causal.


Background

Endometrioid endometrial carcinoma (EEC) is the most common form of endometrial carcinoma. The heterogeneous clinical course of EEC is an obstacle to individualized patient care.

Methods

We performed an integrated analysis on the multiple-dimensional data types including whole-exome and RNA sequencing, RPPA profiling, and clinical data from 271 EEC cases in The Cancer Genome Atlas (TCGA) to identify molecular fingerprints that may account for this clinical heterogeneity. Significance analysis of microarray was used to identify marker genes of each subtype that were subject to pathway analysis. Association of molecular subtypes with clinical features and mutation data was analyzed with the Mann Whitney, Chi-square, Fisher’s exact, and Kruskal-Wallis tests. Survival analysis was evaluated with log-rank test. All statistical tests were two-sided.

Results

Four transcriptome subtypes with distinct clinicopathologic characteristics and mutation spectra were identified from the TCGA dataset and validated in an independent sample cohort of 184 EEC cases. Cluster II consisted of younger, obese patients with low-grade EEC but diminished survival. CTNNB1 exon 3 mutations were present in 87.0% (47/54) of Cluster II (P < .001) that exhibited a low overall mutation rate; this was statistically significantly associated with Wnt/β-catenin signaling activation (P < .001). High expression levels of CTNNB1 (P = .001), MYC (P = .01), and CCND1 (P = .01) were associated with poorer overall survival in low-grade EEC tumors.

Conclusions

CTNNB1 exon 3 mutations are likely a driver that characterize an aggressive subset of low-grade and low-stage EEC occurring in younger women.









Background

Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics.

Methods

410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed.

Results

TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006).

Conclusions

UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis.


Background

Tumor microenvironment of metastasis (TMEM), consisting of direct contact between a macrophage, an endothelial cell, and a tumor cell, has been associated with metastasis in both rodent mammary tumors and human breast cancer. We prospectively examined the association between TMEM score and risk of distant metastasis and compared risk associated with TMEM score with that associated with IHC4.

Methods

We conducted a case–control study nested within a cohort of 3760 patients with invasive ductal breast carcinoma diagnosed between 1980 and 2000 and followed through 2010. Case patients were women who developed a subsequent distant metastasis; control subjects were matched (1:1) on age at and calendar year of primary diagnosis. TMEM was assessed by triple immunostain and IHC4 by standard methods; slides were read by pathologists blinded to outcome. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusted for clinical variables. A Receiver Operating Characteristic analysis was performed, and the area under the curve was estimated. All statistical tests were two-sided.

Results

TMEM score was associated with increased risk of distant metastasis in estrogen receptor (ER)+/human epidermal growth factor receptor (HER2) tumors (multivariable OR high vs low tertile = 2.70; 95% CI = 1.39 to 5.26; P trend = .004), whereas IHC4 score had a borderline positive association (OR10 unit increase = 1.06; 95% CI = 1.00 to 1.13); the association for TMEM score persisted after adjustment for IHC4 score. The area under the curve for TMEM, adjusted for clinical variables, was 0.78. Neither TMEM score nor IHC4 score was independently associated with metastatic risk overall or in the triple negative or HER2+ subgroups.

Conclusions

TMEM score predicted risk of distant metastasis in ER+/HER2 breast cancer independently of IHC4 score and classical clinicopathologic features.


Background

The clinical impact of the biological heterogeneity within HER2-positive (HER2+) breast cancer is not fully understood. Here, we evaluated the molecular features and survival outcomes of the intrinsic subtypes within HER2+ breast cancer.

Methods

We interrogated The Cancer Genome Atlas (n = 495) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets (n = 1730) of primary breast cancers for molecular data derived from DNA, RNA and protein, and determined intrinsic subtype. Clinical HER2 status was defined according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines or DNA copy-number aberration by single nucleotide polymorphism arrays. Cox models tested the prognostic significance of each variable in patients not treated with trastuzumab (n = 1711).

Results

Compared with clinically HER2 (cHER2)-negative breast cancer, cHER2+ breast cancer had a higher frequency of the HER2-enriched (HER2E) subtype (47.0% vs 7.1%) and a lower frequency of Luminal A (10.7% vs 39.0%) and Basal-like (14.1% vs 23.4%) subtypes. The likelihood of cHER2-positivity in HER2E, Luminal B, Basal-like and Luminal A subtypes was 64.6%, 20.0%, 14.4% and 7.3%, respectively. Within each subtype, only 0.3% to 3.9% of genes were found differentially expressed between cHER2+ and cHER2-negative tumors. Within cHER2+ tumors, HER2 gene and protein expression was statistically significantly higher in the HER2E and Basal-like subtypes than either luminal subtype. Neither cHER2 status nor the new 10-subtype copy number-based classification system (IntClust) added independent prognostic value to intrinsic subtype.

Conclusions

When the intrinsic subtypes are taken into account, cHER2-positivity does not translate into large changes in the expression of downstream signaling pathways, nor does it affect patient survival in the absence of HER2 targeting.


Primary human papillomavirus (HPV) testing (without concurrent Pap tests) every 3 years is under consideration in the United States as an alternative to the two recommended cervical cancer screening strategies: primary Pap testing every 3 years, or concurrent Pap and HPV testing ("cotesting") every 5 years. Using logistic regression and Weibull survival models, we estimated and compared risks of cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) for the three strategies among 1011092 women aged 30 to 64 years testing HPV-negative and/or Pap-negative in routine screening at Kaiser Permanente Northern California since 2003. All statistical tests were two sided. Three-year risks following an HPV-negative result were lower than 3-year risks following a Pap-negative result (CIN3+ = 0.069% vs 0.19%, P < .0001; Cancer = 0.011% vs 0.020%, P < .0001) and 5-year risks following an HPV-negative/Pap-negative cotest (CIN3+ = 0.069% vs 0.11%, P < .0001; Cancer = 0.011% vs 0.014%, P = .21). These findings suggest that primary HPV testing merits consideration as another alternative for cervical screening.


Background

Recent concerns about potential overdiagnosis and overtreatment of ductal carcinoma in situ of the breast (DCIS) render evaluation of late effects of treatment, such as cardiovascular disease (CVD), of great importance. We studied cardiovascular morbidity and mortality in a large population-based cohort of DCIS patients.

Methods

Data on all incident DCIS case patients in the Netherlands between 1989 and 2004 who were diagnosed before the age of 75 years were obtained (n = 10468). CVD data was acquired through linkage with population-based registries. Standardized mortality ratios were calculated by comparing mortality in our cohort with that in the Dutch female population, taking into account person-years of observation. Within-cohort comparisons were based on multivariable competing-risk regression.

Results

Compared with the general population, 5-year survivors of DCIS had a similar risk of dying due to any cause (standardized mortality ratio [SMR] = 1.04; 95% confidence interval [CI] = 0.97 to 1.11) but a lower risk of dying of CVD (SMR = 0.77; 95% CI = 0.67 to 0.89). No difference in CVD risk was found when comparing 5-year survivors treated with radiotherapy with those treated with surgery only. Left-sided vs right-sided radiotherapy also did not increase this risk (hazard ratio [HR] = 0.94; 95% CI = 0.67 to 1.32). In a subgroup analysis of all DCIS patients diagnosed between 1997 and 2005, we were able to account for history of CVD and did not observe a risk difference between treatment groups (left-sided vs right-sided radiotherapy: HR = 0.94; 95% CI = 0.68 to 1.29).

Conclusions

After a median follow-up of 10 years, we did not find an increased risk for cardiovascular morbidity or mortality after radiotherapy for DCIS when comparing surgery and radiotherapy vs surgery only, nor when comparing radiotherapy for left-sided vs right-sided DCIS. Compared with the general population, DCIS patients have a decreased risk of cardiovascular death, independent of treatment.


Background

Screening mammography utilization in Vermont has declined since 2009 during a time of changing screening guidelines and increased interest in personalized screening regimens. This study evaluates whether the breast cancer risk distribution of the state’s screened population changed during the observed decline.

Methods

We examined the breast cancer risk distribution among screened women between 2001 and 2012 using data from the Vermont Breast Cancer Surveillance System. We estimated each screened woman’s 5-year risk of breast cancer using the Breast Cancer Surveillance Consortium risk calculator. Annual screening counts by risk group were normalized and age-adjusted to the Vermont female population by direct standardization.

Results

The normalized rate of low-risk (5-year breast cancer risk of <1%) women screened increased 8.3% per year (95% confidence interval [CI] = 4.8 to 11.9) between 2003 and 2008 and then declined by –5.4% per year (95% CI = –8.1 to –2.6) until 2012. When stratified by age group, the rate of low-risk women screened declined –4.4% per year (95% CI = –8.8 to 0.1; not statistically significant) for ages 40 to 49 years and declined a statistically significant –7.1% per year (95% CI = –12.1 to –2.0) for ages 50 to 74 years during 2008 to 2012. These declines represented the bulk of overall decreases in screening after 2008, with rates for women categorized in higher risk levels generally exhibiting small annual changes.

Conclusions

The observed decline in women screened in Vermont in recent years is largely attributable to reductions in screening visits by women who are at low risk of developing breast cancer.


Background

Newer approaches to mammography, including digital image acquisition and computer-aided detection (CAD), and adjunct imaging (e.g., magnetic resonance imaging [MRI]) have diffused into clinical practice. The impact of these technologies on screening-related cost and outcomes remains undefined, particularly among older women.

Methods

Using the Surveillance, Epidemiology, and End Results–Medicare linked database, we constructed two cohorts of women without a history of breast cancer and followed each cohort for 2 years. We compared the use and cost of screening mammography including digital mammography and CAD, adjunct procedures including breast ultrasound, MRI, and biopsy between the period of 2001 and 2002 and the period of 2008 and 2009 using 2 and t test. We also assessed the change in breast cancer stage and incidence rates using 2 and Poisson regression. All statistical tests were two-sided.

Results

There were 137150 women (mean age = 76.0 years) in the early cohort (2001–2002) and 133097 women (mean age = 77.3 years) in the later cohort (2008–2009). The use of digital image acquisition for screening mammography increased from 2.0% in 2001 and 2002 to 29.8% in 2008 and 2009 (P < .001). CAD use increased from 3.2% to 33.1% (P < .001). Average screening-related cost per capita increased from $76 to $112 (P < .001), with annual national fee-for-service Medicare spending increasing from $666 million to $962 million. There was no statistically significant change in detection rates of early-stage tumors (2.45 vs 2.57 per 1000 person-years; P = .41).

Conclusions

Although breast cancer screening–related costs increased substantially from 2001 through 2009 among Medicare beneficiaries, a clinically significant change in stage at diagnosis was not observed.


Background

Contralateral prophylactic mastectomy (CPM) rates have substantially increased in recent years and may reflect an exaggerated perceived benefit from the procedure. The objective of this study was to evaluate the magnitude of the survival benefit of CPM for women with unilateral breast cancer.

Methods

We developed a Markov model to simulate survival outcomes after CPM and no CPM among women with stage I or II breast cancer without a BRCA mutation. Probabilities for developing contralateral breast cancer (CBC), dying from CBC, dying from primary breast cancer, and age-specific mortality rates were estimated from published studies. We estimated life expectancy (LE) gain, 20-year overall survival, and disease-free survival with each intervention strategy among cohorts of women defined by age, estrogen receptor (ER) status, and stage of cancer.

Results

Predicted LE gain from CPM ranged from 0.13 to 0.59 years for women with stage I breast cancer and 0.08 to 0.29 years for those with stage II breast cancer. Absolute 20-year survival differences ranged from 0.56% to 0.94% for women with stage I breast cancer and 0.36% to 0.61% for women with stage II breast cancer. CPM was more beneficial among younger women, stage I, and ER-negative breast cancer. Sensitivity analyses yielded a maximum 20-year survival difference with CPM of only 1.45%.

Conclusions

The absolute 20-year survival benefit from CPM was less than 1% among all age, ER status, and cancer stage groups. Estimates of LE gains and survival differences derived from decision models may provide more realistic expectations of CPM.


Background

The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis.

Methods

An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided.

Results

miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P = .03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p–treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P = .03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P = .03, n = 9), with an associated decrease in infiltrating macrophages (R 2 = .303).

Conclusions

These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.


Background

A multi-institutional phase II trial was performed to assess a hypofractionated accelerated radiotherapy regimen for early stage non–small cell lung cancer (NSCLC) in an era when stereotactic body radiotherapy was not widely available.

Methods

Eighty patients with biopsy-proven, peripherally located, T1-3 N0 M0 NSCLC were enrolled. Eligible patients received 60 Gy in 15 fractions using a three-dimensional conformal technique without inhomogeneity correction. The gross tumour volume (GTV) was the primary tumor only, and the planning target volume (PTV) margin was 1.0 to 1.5cm. The primary endpoint was the 2-year primary tumor control rate. Toxicities were measured using the Common Terminology Criteria for Adverse Events version 3.0.

Results

The median follow-up of patients was 49 months (range = 21–63 months). The median age of patients was 75.9 years. The actuarial rate of primary tumor control was 87.4% (95% confidence interval [CI] = 76.2% to 93.5%) at 2 years. Overall survival was 68.7% (95% CI = 57.2% to 77.6%) at 2 years. The actuarial rates of developing regional and distant relapse at 2 years were 8.8% (95% CI = 4.1% to 18.7%) and 21.6% (95% CI = 13.5% to 33.5%), respectively. Tumor size greater than 3cm was associated with an increased risk of developing distant relapse (hazard ratio = 3.11; 95% CI = 1.30 to 7.42; two-sided log-rank test P = .007). The most common grade 3+ toxicities were fatigue (6.3%), cough (7.5%), dyspnea (13.8%), and pneumonitis (10.0%)

Conclusions

Conformal radiotherapy to a dose of 60 Gy in 15 fractions resulted in favorable primary tumor control and overall survival rates in patients with T1-3 N0 M0 NSCLC. Severe toxicities were uncommon with this relatively simple treatment technique.


Breast cancer is a heterogeneous disease, divisible into a variable number of clinical subtypes. A fundamental question is how many etiological classes underlie the clinical spectrum of breast cancer? An etiological subtype reflects a grouping with a common set of causes, whereas a clinical subtype represents a grouping with similar prognosis and/or prediction. Herein, we review the evidence for breast cancer etiological heterogeneity. We then evaluate the etiological evidence with mRNA profiling data. A bimodal age distribution at diagnosis with peak frequencies near ages 50 and 70 years is a fundamental characteristic of breast cancer for important tumor features, clinical characteristics, risk factor profiles, and molecular subtypes. The bimodal peak frequencies at diagnosis divide breast cancer overall into a "mixture" of two main components in varying proportions in different cancer populations. The first breast cancer tends to arise early in life with modal age-at-diagnosis near 50 years and generally behaves aggressively. The second breast cancer occurs later in life with modal age near 70 years and usually portends a more indolent clinical course. These epidemiological and molecular data are consistent with a two-component mixture model and compatible with a hierarchal view of breast cancers arising from two main cell types of origin. Notwithstanding the potential added value of more detailed categorizations for personalized breast cancer treatment, we suggest that the development of better criteria to identify the two proposed etiologic classes would advance breast cancer research and prevention.


Background

Adolescents and young adults (AYAs; aged 15–39 years) have inferior survival in comparison with younger (aged 0–14 years) cancer patients. Impact of care at specialized centers such as National Cancer Institute–designated Comprehensive Cancer Centers (NCICCC) for AYAs of all ages or the Children’s Oncology Group (COG) for AYAs aged 15 to 21 years with central nervous system (CNS) tumors remains unstudied.

Methods

We constructed a cohort of 560 children and 784 AYAs with CNS tumors reported to the Los Angeles cancer registry from 1998 to 2008. Cox and logistic regression models were used, with two-sided P values from Wald 2 tests.

Results

In Cox regression analysis restricted to World Health Organization (WHO) grade II tumors, patients of all ages saw worse outcome if not treated at NCICCC/COG sites (non-NCICCC/COG vs NCICCC/COG: hazard ratio [HR] =1.73; 95% confidence interval [CI] = 1.09 to 2.72). Furthermore, the worse outcome for AYAs compared with children (HR = 1.90; 95% CI = 1.21 to 2.98; P = .005) was abrogated (HR = 1.35; 95% CI = 0.79 to 2.29; P = .27) by care at NCICCC/COGs. Those less likely to receive care at NCICCC/COG sites included young AYAs (aged 15–21 years vs children: odds ratio [OR] = 0.23; 95% CI = 0.11 to 0.48; P < .001) and older AYAs (aged 22–39 years) with low socioeconomic status (OR = 0.39; 95% CI = 0.17 to 0.89; P = .02), public/no insurance (OR = 0.30; 95% CI = 0.12 to 0.71; P < .01), and distance to care greater than 5 miles (OR = 0.29; 95% CI = 0.15 to 0.57; P < .001).

Conclusions

Population-based data reveal that care at NCICCC/COG sites mitigates inferior outcome in AYAs with WHO grade II CNS tumors compared with children. Compared with children, AYAs are less likely to receive care at NCICCC/COGs. Insurance, socioeconomic status, and distance serve as barriers to care at NCICCCs for older AYAs.


Background

Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.

Methods

Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student’s t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni’s Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.

Results

High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.

Conclusions

Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.


This sixteenth biannual report of the Cochrane Haematological Malignancies Group highlights recently published randomized controlled trials (RCTs) in the field of hemato-oncology, with special focus on non-Hodgkin’s lymphoma. The report covers the publication period June 2012 to July 2013. Trials are selected regarding their methodology and implication for clinical practice. Studies were identified by electronic search of MEDLINE using a broad search filter that covers all topics in hemato-oncology combined with a highly sensitive search filter for randomized trials (Cochrane Handbook for Systematic Reviews of Interventions). Four RCTs are presented in detail, followed by two further RCTs of high importance in a short version. The report is finalized with an overview of new and updated Cochrane Reviews.





Myopericytoma (MPC) is a rare tumor with perivascular proliferation of pluripotent stem-cell–like pericytes. Although indolent, MPC may be locally aggressive with recurrent disease. The pathogenesis and diagnostic biomarkers of MPC are poorly understood. We discovered that 15% of benign MPCs (thyroid, skin; 3 of 20 samples) harbored BRAFWT/V600E; 33.3% (1 of 3 samples) of BRAFWT/V600E-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAFWT/V600E, were clonal and expressed pericytic-differentiation biomarkers crucial for its microenvironment. BRAFWT/V600E-positive thyroid MPC primary cells triggered in vitro (8.8-fold increase) and in vivo (3.6-fold increase) angiogenesis. Anti-BRAFV600E therapy with vemurafenib disrupted angiogenic and metabolic properties (~3-fold decrease) with down-regulation (~2.2-fold decrease) of some extracellular-matrix (ECM) factors and ECM-associated long non-coding RNA (LincRNA) expression, with no effects in BRAFWT-pericytes. Vemurafenib also inhibited (~3-fold decrease) cell viability in vitro and in BRAFWT/V600E-positive thyroid MPC patient-derived xenograft (PDX) mice (n = 5 mice per group). We established the first BRAFWT/V600E-dependent thyroid MPC cell culture. Our findings identify BRAFWT/V600E as a novel genetic aberration in MPC pathogenesis and MPC-associated biomarkers and imply that anti-BRAFV600E agents may be useful adjuvant therapy in BRAFWT/V600E-MPC patients. Patients with BRAFWT/V600E-MPC should be closely followed because of the risk for multifocality/recurrence.


Background

Gemcitabine is a potent nucleoside analogue against solid tumors, but development of drug resistance is a substantial problem. Removal of gemcitabine incorporated into DNA by repair mechanisms may contribute to resistance in chemo-refractory solid tumors. Human hepatocellular carcinoma (HCC) is usually very chemoresistant to gemcitabine.

Methods

We treated HCC in vitro and in vivo (orthotopic murine model with human Hep3B or HepG2 xenografts, 7–10 CB17SCID mice per group) with gemcitabine. The role of homologous recombination repair proteins in repairing stalled replication forks was evaluated with hyperthermia exposure and cell-cycle analysis. The Student t-test was used for two-sample comparisons. Multiple group data were analyzed using one-way analysis of variance. All statistical tests were two-sided.

Results

We demonstrated that Mre11-mediated homologous recombination repair of gemcitabine-stalled replication forks is crucial to survival of HCC cells. Furthermore, we demonstrated inhibition of Mre11 by an exonuclease inhibitor or concomitant hyperthermia. In orthotopic murine models of chemoresistant HCC, the Hep3B tumor mass with radiofrequency plus gemcitabine treatment (mean ± SD, 180±91mg) was statistically significantly smaller compared with gemcitabine alone (661±419mg, P = .0063).

Conclusions

This study provides mechanistic understanding of homologous recombination inhibiting-strategies, such as noninvasive radiofrequency field-induced hyperthermia, to overcome resistance to gemcitabine in refractory human solid tumors.


Background

In neural invasion (NI), cancer cells are classically assumed to actively invade nerves and to cause local recurrence and pain. However, the opposite possibility, that nerves may reach cancer cells even in their preinvasive stage and thereby promote cancer spread, has not yet been genuinely considered. The present study analyzes the reaction of Schwann cells of peripheral nerves to carcinogenesis in pancreatic cancer and colon cancer.

Methods

Two novel 3D migration and Schwann cell outgrowth assays were developed to monitor the timing and the specificity of Schwann cell migration and cancer invasion toward peripheral neurons through digital-time-lapse microscopy and after blockade of nerve growth factor (NGF) signalling via siRNA or a small-molecule inhibitor of the p75NTR receptor. The frequency and emergence of the Schwann cell markers Sox10, S100, ALDH1L1, and glial-fibrillary-acidic-protein (GFAP) around cancer precursor lesions were studied in human and conditional murine pancreatic and colon cancer specimens using multiple immunolabeling.

Results

Schwann cells migrated toward pancreatic and colon cancer cells, but not toward benign cells, before the onset of cancer migration toward peripheral neurons. This chemoattraction was inhibited after blockade of p75NTR-signaling on Schwann and pancreatic cancer cells. Schwann cells were specifically detected around murine and human pancreatic intraepithelial neoplasias (PanINs) (mean percent of murine PanINs surrounded by Schwann cells = 78.9%, 95% CI = 70.9 to 86.8%, and mean percent of human PanINs surrounded by Schwann cells = 52.5%, 95% CI = 14.7 to 90.4%; human: n = 44, murine: n = 14) and intestinal adenomas (mean percent of murine adenomas surrounded by Schwann cells = 64.2%, 95% CI = 28.6 to 99.8%, and mean percent of human adenomas surrounded by Schwann cells = 17.2%, 95% CI = -126.9 to 161.4; human: n = 36, murine: n = 12). The Schwann cell presence in this premalignant stage was associated with the frequency of NI in the malignant phase.

Conclusions

Schwann cells have particular and specific affinity to cancer cells. Emergence of Schwann cells in the premalignant phase of pancreatic and colon cancer implies that, in contrast with the traditional assumption, nerves—and not cancer cells—migrate first during NI.


Background

Data from animal and cell-line models suggest that vitamin D metabolism plays an important role in pancreatic tumor behavior. Although vitamin D deficiency has been implicated in numerous cancers, the vitamin D status of patients with advanced pancreatic cancer and the effect of baseline vitamin D levels on survival are unknown.

Methods

Participants in this correlative study (CALGB 151006) were enrolled in CALGB 80303, which was a randomized trial of patients with advanced pancreatic cancer that demonstrated no difference in overall survival (OS) among patients treated with gemcitabine plus placebo vs gemcitabine plus bevacizumab. We measured baseline serum 25-hydroxyvitamin D (25[OH]D) levels and examined associations between baseline 25(OH)D levels and progression-free survival and OS using the Cox rank score test. All statistical tests were two-sided.

Results

Of 256 patients with available serum, the median 25(OH)D level was 21.7ng/mL (range 4 to 77). 44.5% of patients were vitamin D deficient (25[OH]D <20ng/mL), and 32.4% were insufficient (25[OH]D ≥20 and <30ng/mL). 25(OH)D levels were lower in black patients compared with white patients, and patients of other/undisclosed race (10.7 vs 22.4 vs 20.9ng/mL, P < .001). Baseline 25(OH)D levels were not associated with PFS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .60) or OS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .95).

Conclusion

Vitamin D deficiency was highly prevalent among patients with a new diagnosis of advanced pancreatic cancer. Black patients had statistically significantly lower 25(OH)D levels than white patients. In this cohort of patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS.


Survivors of childhood cancer frequently experience cancer-related cognitive dysfunction, commonly months to years after treatment for pediatric brain tumors, acute lymphoblastic leukemia (ALL), or tumors involving the head and neck. Risk factors for cancer-related cognitive dysfunction include young age at diagnosis, treatment with cranial irradiation, use of parenteral or intrathecal methotrexate, female sex, and pre-existing comorbidities. Limiting use and reducing doses and volume of cranial irradiation while intensifying chemotherapy have improved survival and reduced the severity of cognitive dysfunction, especially in leukemia. Nonetheless, problems in core functional domains of attention, processing speed, working memory and visual-motor integration continue to compromise quality of life and performance. We review the epidemiology, pathophysiology and assessment of cancer-related cognitive dysfunction, the impact of treatment changes for prevention, and the broad strategies for educational and pharmacological interventions to remediate established cognitive dysfunction following childhood cancer. The increased years of life saved after childhood cancer warrants continued study toward the prevention and remediation of cancer-related cognitive dysfunction, using uniform assessments anchored in functional outcomes.











Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology.







The identification of oncogenic driver mutations in cancer has led to the rapid rise of genotype-directed treatments such as EGFR and BRAF kinase inhibitors. Standard tumor biopsy remains a cumbersome and morbid procedure for patients, leading to a growing interest in noninvasive plasma genotyping approaches. Circulating tumor cells are of interest; however, the processing of specimens is complicated and time consuming. By comparison, cell-free DNA (cfDNA) genotyping has the potential to be convenient and relatively simple to process in a short time period. Several technologies are under development for cfDNA analysis, such as allele-specific polymerase chain reaction (PCR), coamplification at Lower Denaturation temperatures (COLD) PCR, emulsion PCR, and massively parallel sequencing. Broad clinical validity will need to be established for different assays, and clinical utility will need to be evaluated within prospective trials to determine which assays will best predict the efficacy of therapy and patient outcomes. In addition, assay standardization will be critical prior to widespread use in routine clinical practice. The Cell Free DNA Working Group, under the sponsorship of Transgenomic, was convened to evaluate the molecular assays in development and provide recommendations for application and interpretation of these tests in the context of future clinical research. The consensus commentary of the Cell Free DNA Working Group for the use of cfDNA plasma genotyping assays is presented here, including future steps in the development of these technologies.