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Cancer Insiders is your quickest access to important publications about cancer advances, which appear electronically even before they are seen by physicians in print. This is a service that is not available on most blog sites. We have aggregated material from the leading medical journals.
Breast Cancer Screening in the Precision Medicine Era: Risk-Based Screening in a Population-Based Trial - 2017-01-27
Ongoing controversy over the optimal approach to breast cancer screening has led to discordant professional society recommendations, particularly in women age 40 to 49 years. One potential solution is risk-based screening, where decisions around the starting age, stopping age, frequency, and modality of screening are based on individual risk to maximize the early detection of aggressive cancers and minimize the harms of screening through optimal resource utilization. We present a novel approach to risk-based screening that integrates clinical risk factors, breast density, a polygenic risk score representing the cumulative effects of genetic variants, and sequencing for moderate- and high-penetrance germline mutations. We demonstrate how thresholds of absolute risk estimates generated by our prediction tools can be used to stratify women into different screening strategies (biennial mammography, annual mammography, annual mammography with adjunctive magnetic resonance imaging, defer screening at this time) while informing the starting age of screening for women age 40 to 49 years. Our risk thresholds and corresponding screening strategies are based on current evidence but need to be tested in clinical trials. The Women Informed to Screen Depending On Measures of risk (WISDOM) Study, a pragmatic, preference-tolerant randomized controlled trial of annual vs personalized screening, will study our proposed approach. WISDOM will evaluate the efficacy, safety, and acceptability of risk-based screening beginning in the fall of 2016. The adaptive design of this trial allows continued refinement of our risk thresholds as the trial progresses, and we discuss areas where we anticipate emerging evidence will impact our approach.
Evaluation of Type Replacement Following HPV16/18 Vaccination: Pooled Analysis of Two Randomized Trials - 2017-01-27
Background: Current HPV vaccines do not protect against all oncogenic HPV types. Following vaccination, type replacement may occur, especially if different HPV types competitively interact during natural infection. Because of their common route of transmission, it is difficult to assess type interactions in observational studies. Our aim was to evaluate type replacement in the setting of HPV vaccine randomized controlled trials (RCTs).Methods: Data were pooled from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT001226810)—two large-scale, double-blind RCTs of the HPV-16/18 AS04-adjuvanted vaccine—to compare cumulative incidence of nonprotected HPV infections across trial arms after four years. Negative rate difference estimates (rate in control minus vaccine arm) were interpreted as evidence of replacement if the associated 95% confidence interval excluded zero. All statistical tests were two-sided.Results: After applying relevant exclusion criteria, 21 596 women were included in our analysis (HPV arm = 10 750; control arm = 10 846). Incidence rates (per 1000 infection-years) were lower in the HPV arm than in the control arm for grouped nonprotected oncogenic types (rate difference = 1.6, 95% confidence interval [CI] = 0.9 to 2.3) and oncogenic/nononcogenic types (rate difference = 0.2, 95% CI = −0.3 to 0.7). Focusing on individual HPV types separately, no deleterious effect was observed. In contrast, a statistically significant protective effect (positive rate difference and 95% CI excluded zero) was observed against oncogenic HPV types 35, 52, 58, and 68/73, as well as nononcogenic types 6 and 70.Conclusion: HPV type replacement does not occur among vaccinated individuals within four years and is unlikely to occur in vaccinated populations.
The Complexity of Achieving the Promise of Precision Breast Cancer Screening - 2017-01-27
Over 40 million women between the ages of 40 to 75 years (66% of women in this age group) will undergo screening mammography this year in the United States, at an estimated cost of $7.8 billion (1,2). Mammography is currently the most effective screening test for breast cancer, but it is imperfect. While rates of false-negative results are low, mammography has a statistically significant false-positive rate (3); one-third of healthy women receive an abnormal result that requires additional evaluation over a 10-year period (4). Estimates suggest that 2% to 12% of women are diagnosed with a breast cancer that would not have limited their life expectancy (5). Increasingly, we are realizing that breast cancer is not a single disease; tumors with different genetic “signatures” differ in prognosis (6), and they may differ in likelihood of early detection through screening (7). While there is early evidence that digital breast tomosynthesis may have modestly better cancer detection and lower rates of false-positive exams than digital mammography (8,9), this rapidly emerging technology is unlikely to resolve the plethora of issues around screening such as the ages when breast cancer screening should start and stop, how often women should be screened, and whether screening modalities should differ based on cancer risk or breast density.
Design and Validation of the GI-NEC Score to Prognosticate Overall Survival in Patients With High-Grade Gastrointestinal Neuroendocrine Carcinomas - 2017-01-27
Background: Prognostic markers for risk stratification of patients with gastrointestinal high-grade neuroendocrine carcinomas (GI-NECs) are lacking; we designed and validated a prognostic score for overall survival (OS).Methods: Consecutive patients diagnosed in five neuroendocrine specialist European centers were included. Patients were divided into three cohorts: a training cohort (TC), an external validation cohort (EVC), and a prospective validation cohort (PVC). Prognostic factors were identified by log-rank test, Cox-regression, and logistic regression analyses. The derived score was internally and externally validated. All statistical tests were two-sided.Results: Of 395 patients screened, 313 were eligible (TC = 109 patients, EVC = 184 patients, and PVC = 20 patients). The derived prognostic score included five variables: presence of liver metastases, alkaline phosphatase (ALK), lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group performance status (ECOG PS), and Ki67. In multivariable analysis, the score was prognostic for OS (hazard ratio [HR] = 1.86, 95% confidence interval [CI] = 1.47 to 2.35, P < .001) and had good discrimination (C-index = 0.76) and calibration (mean error = 0.021, 90th percentile = 0.037) in the TC. These results were validated in the EVC and PVC, in which our score was able to prognosticate for OS when adjusted for other prognostic variables in the multivariable analysis (HR = 1.85, 95% CI = 1.27 to 2.71, P = .001; and HR = 4.51, 95% CI = 1.87 to 10.87, P = .001, respectively). The score classified patients into two groups with incremental risk of death: group A (0–2 points, 181 patients [63.9%], median OS = 19.4 months, 95% CI = 16.1 to 25.1) and group B (3–6 points, 102 patients [36.1%], median OS = 5.2 months, 95% CI = 3.6 to 6.9).Conclusions: The GI-NEC score identifies two distinct patient cohorts; it provides a tool for clinicians when making treatment decisions and may be used as a stratification factor in future clinical trials.
The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion - 2017-01-28
Background: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion.Methods: Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided.Results: PD-L1 is expressed in 60% to 90% of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2% to 52.1% of pancreatic tumor–infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P = .03–.001) and when CTLs are neutralized (P = .03–<.001). H3K4 trimethylation (H3K4me3) is enriched in the cd274 promoter in pancreatic tumor cells. MLL1 directly binds to the cd274 promoter to catalyze H3K4me3 to activate PD-L1 transcription in tumor cells. Inhibition or silencing of MLL1 decreases the H3K4me3 level in the cd274 promoter and PD-L1 expression in tumor cells. Accordingly, inhibition of MLL1 in combination with anti-PD-L1 or anti-PD-1 antibody immunotherapy effectively suppresses pancreatic tumor growth in a FasL- and CTL-dependent manner.Conclusions: The Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 axis play contrasting roles in pancreatic cancer immune surveillance and evasion. Targeting the MLL1-H3K4me3 axis is an effective approach to enhance the efficacy of checkpoint immunotherapy against pancreatic cancer.
Proportion of Never-Smoker Non–Small Cell Lung Cancer Patients at Three Diverse Institutions - 2017-01-27
Background: Approximately 10% to 15% of lung cancer cases in the United States occur in never smokers, but there has been much debate about whether this rate is increasing. To determine whether the proportion of never smokers among lung cancer cases is increasing, we conducted a retrospective study using registries from The University of Texas Southwestern Medical Center, Parkland Hospital, and Vanderbilt University.Methods: Registries were queried for demographic information from 1990 to 2013 including sex, age, stage, and self-reported smoking history. Ten thousand five hundred ninety-three non–small cell lung cancer (NSCLC) case patients and 1510 small cell lung cancer (SCLC) case patients were captured, and logistic regression analysis was performed. All statistical tests were two-sided.Results: The proportion of never-smoker NSCLC patients increased from 8.0% in the years 1990 to 1995 to 14.9% in 2011 to 2013 (P < .001). This increase was also observed using multivariable logistic regression after controlling for sex, stage at diagnosis, and race/ethnicity. The percentage of never smokers among SCLC case patients (1.5% in 1990–1995 to 2.5% in 2011–2013, P = .36) or squamous cell NSCLC case patients did not statistically significantly change during this period.Conclusions: This study demonstrates an increasing proportion of NSCLC patients who have never smoked in a large, diverse patient population between 1990 and 2013. Given that this increase appears independent of sex, stage, and race/ethnicity and also occurred in our county hospital, this trend is unlikely due to changes in referral patterns and suggests that the actual incidence of lung cancer in never smokers is increasing.
PD-L1 Expression in Pancreatic Cancer - 2017-01-28
Pancreatic ductal adenocarcinoma (PDAC) has the most dismal prognosis among all major solid malignancies, with five-year survival of approximately 6% (1). PDAC is also highly resistant to chemotherapy and radiotherapy (2). Although there have been successful developments of targeted therapies for other cancers, little progression has been made finding new therapies for PDAC despite promising results from preclinical studies (3).
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