Showing papers in "Journal of the National Cancer Institute in 2019"

Stand-Alone Artificial Intelligence for Breast Cancer Detection in Mammography: Comparison With 101 Radiologists.

Abstract: Background Artificial intelligence (AI) systems performing at radiologist-like levels in the evaluation of digital mammography (DM) would improve breast cancer screening accuracy and efficiency. We aimed to compare the stand-alone performance of an AI system to that of radiologists in detecting breast cancer in DM. Methods Nine multi-reader, multi-case study datasets previously used for different research purposes in seven countries were collected. Each dataset consisted of DM exams acquired with systems from four different vendors, multiple radiologists' assessments per exam, and ground truth verified by histopathological analysis or follow-up, yielding a total of 2652 exams (653 malignant) and interpretations by 101 radiologists (28 296 independent interpretations). An AI system analyzed these exams yielding a level of suspicion of cancer present between 1 and 10. The detection performance between the radiologists and the AI system was compared using a noninferiority null hypothesis at a margin of 0.05. Results The performance of the AI system was statistically noninferior to that of the average of the 101 radiologists. The AI system had a 0.840 (95% confidence interval [CI] = 0.820 to 0.860) area under the ROC curve and the average of the radiologists was 0.814 (95% CI = 0.787 to 0.841) (difference 95% CI = -0.003 to 0.055). The AI system had an AUC higher than 61.4% of the radiologists. Conclusions The evaluated AI system achieved a cancer detection accuracy comparable to an average breast radiologist in this retrospective setting. Although promising, the performance and impact of such a system in a screening setting needs further investigation.

Invasive Epithelial Ovarian Cancer Survival by Histotype and Disease Stage.

Abstract: Background The understanding of ovarian cancer pathogenesis has recently shifted to recognize distinct changes in how ovarian cancer histotypes are defined. Using the 2014 World Health Organization (WHO) diagnostic guidelines, we classified ovarian cancer histotypes in Surveillance, Epidemiology, and End Results (SEER) cancer registry data and examined survival patterns by histotype and disease stage. Methods We extracted data on 28 118 incident epithelial ovarian cancer cases diagnosed in 2004-2014 from SEER and defined histotype using the 2014 WHO guidelines (high-grade serous, low-grade serous, endometrioid, clear cell, mucinous, carcinosarcoma, and malignant Brenner tumors). By histotype and disease stage, we estimated Kaplan-Meier survival curves and calculated age-adjusted overall and cause-specific survival estimates. Cox proportional hazards regression models were used to estimate histotype-specific hazard ratios (HRs) and 95% confidence intervals (CIs) by disease stage while adjusting for age at diagnosis, region, race/ethnicity, and receipt of surgery. Results Within two years after diagnosis, localized/regional-stage carcinosarcoma and distant-stage mucinous, clear cell, and carcinosarcoma had a higher risk of mortality compared with high-grade serous, with the most pronounced association for localized/regional carcinosarcoma (>1-2-year time period: HR = 3.81, 95% CI = 2.74 to 5.30) and distant-stage mucinous (0-1-year time period: HR = 3.87, 95% CI = 3.45 to 4.34). In the time period more than four to 10 years after diagnosis, hazard ratios for all histotypes relative to high-grade serous, irrespective of disease stage, were less than 1.00. Cumulatively, both localized/regional and distant-stage low-grade serous and endometrioid carcinomas had the most favorable outcomes. Conclusions Our large study, which is representative of the United States population and incorporates the most current knowledge of ovarian cancer pathogenesis, highlights the need to recognize ovarian cancer as a set of distinct diseases and not a single entity. Only then will we be able to effectively target the unique features of each histotype to reduce ovarian cancer mortality.

Systematic Review and Meta-Analysis of the Magnitude of Structural, Clinical, and Physician and Patient Barriers to Cancer Clinical Trial Participation.

Abstract: Background Barriers to cancer clinical trial participation have been the subject of frequent study, but the rate of trial participation has not changed substantially over time. Studies often emphasize patient-related barriers, but other types of barriers may have greater impact on trial participation. Our goal was to examine the magnitude of different domains of trial barriers by synthesizing prior research. Methods We conducted a systematic review and meta-analysis of studies that examined the trial decision-making pathway using a uniform framework to characterize and quantify structural (trial availability), clinical (eligibility), and patient/physician barrier domains. The systematic review utilized the PubMed, Google Scholar, Web of Science, and Ovid Medline search engines. We used random effects to estimate rates of different domains across studies, adjusting for academic vs community care settings. Results We identified 13 studies (nine in academic and four in community settings) with 8883 patients. A trial was unavailable for patients at their institution 55.6% of the time (95% confidence interval [CI] = 43.7% to 67.3%). Further, 21.5% (95% CI = 10.9% to 34.6%) of patients were ineligible for an available trial, 14.8% (95% CI = 9.0% to 21.7%) did not enroll, and 8.1% (95% CI = 6.3% to 10.0%) enrolled. Rates of trial enrollment in academic (15.9% [95% CI = 13.8% to 18.2%]) vs community (7.0% [95% CI = 5.1% to 9.1%]) settings differed, but not rates of trial unavailability, ineligibility, or non-enrollment. Conclusions These findings emphasize the enormous need to address structural and clinical barriers to trial participation, which combined make trial participation unachievable for more than three of four cancer patients.

An Observational Study of Deep Learning and Automated Evaluation of Cervical Images for Cancer Screening.

Abstract: Background Human papillomavirus vaccination and cervical screening are lacking in most lower resource settings, where approximately 80% of more than 500 000 cancer cases occur annually. Visual inspection of the cervix following acetic acid application is practical but not reproducible or accurate. The objective of this study was to develop a “deep learning”-based visual evaluation algorithm that automatically recognizes cervical precancer/cancer.

Antibody-Drug Conjugate-Based Therapeutics: State of the Science.

Abstract: Antibody-drug conjugates (ADCs) are complex engineered therapeutics consisting of monoclonal antibodies, directed toward tumor-associated antigens, to which highly potent cytotoxic agents are attached using chemical linkers. This targeted drug delivery strategy couples the precision of the antibody targeting moiety with the cytocidal activity of the payload, which is generally too toxic on its own to be systemically administered. In this manner, ADCs confer a means to reduce off-target toxicities in patients by limiting the exposure of normal tissues to the payload, thus broadening the potential therapeutic window compared with traditional chemotherapy. The pace of ADC development is accelerating, with the number of investigational agents in human trials having more than tripled over the past 5 years, underscoring the enthusiasm for this transformative approach to cancer treatment. Here, we review the key structural elements of ADC design (antibody, linker, and payload), highlighting critical aspects and technological advances that have affected the clinical effectiveness of this class of biopharmaceuticals. The ADC field continues to evolve, including ongoing efforts aimed at improving target selection, developing payloads with varied mechanisms of action and increased potency, designing innovative bioconjugation strategies, as well as maximizing efficacy and tolerability in patients. An overview of the current clinical trial landscape is provided, with emphasis on the clinical experience of the four ADCs to have received regulatory approval to date, as well as additional promising candidates currently in late-stage clinical development in both solid tumor and hematological malignancies.

Annual Report to the Nation on the Status of Cancer, Featuring Cancer in Men and Women Age 20-49 Years.

Abstract: BACKGROUND The American Cancer Society, Centers for Disease Control and Prevention, National Cancer Institute, and North American Association of Central Cancer Registries provide annual updates on cancer occurrence and trends by cancer type, sex, race, ethnicity, and age in the United States. This year's report highlights the cancer burden among men and women age 20-49 years. METHODS Incidence data for the years 1999 to 2015 from the Centers for Disease Control and Prevention- and National Cancer Institute-funded population-based cancer registry programs compiled by the North American Association of Central Cancer Registries and death data for the years 1999 to 2016 from the National Vital Statistics System were used. Trends in age-standardized incidence and death rates, estimated by joinpoint, were expressed as average annual percent change. RESULTS Overall cancer incidence rates (per 100 000) for all ages during 2011-2015 were 494.3 among male patients and 420.5 among female patients; during the same time period, incidence rates decreased 2.1% (95% confidence interval [CI] = -2.6% to -1.6%) per year in men and were stable in females. Overall cancer death rates (per 100 000) for all ages during 2012-2016 were 193.1 among male patients and 137.7 among female patients. During 2012-2016, overall cancer death rates for all ages decreased 1.8% (95% CI = -1.8% to -1.8%) per year in male patients and 1.4% (95% CI = -1.4% to -1.4%) per year in females. Important changes in trends were stabilization of thyroid cancer incidence rates in women and rapid declines in death rates for melanoma of the skin (both sexes). Among adults age 20-49 years, overall cancer incidence rates were substantially lower among men (115.3 per 100 000) than among women (203.3 per 100 000); cancers with the highest incidence rates (per 100 000) among men were colon and rectum (13.1), testis (10.7), and melanoma of the skin (9.8), and among women were breast (73.2), thyroid (28.4), and melanoma of the skin (14.1). During 2011 to 2015, the incidence of all invasive cancers combined among adults age 20-49 years decreased -0.7% (95% CI = -1.0% to -0.4%) among men and increased among women (1.3%, 95% CI = 0.7% to 1.9%). The death rate for (per 100 000) adults age 20-49 years for all cancer sites combined during 2012 to 2016 was 22.8 among men and 27.1 among women; during the same time period, death rates decreased 2.3% (95% CI = -2.4% to -2.2%) per year among men and 1.7% (95% CI = -1.8% to -1.6%) per year among women. CONCLUSIONS Among people of all ages and ages 20-49 years, favorable as well as unfavorable trends in site-specific cancer incidence were observed, whereas trends in death rates were generally favorable. Characterizing the cancer burden may inform research and cancer-control efforts.

Radiation Exposure From Pediatric CT Scans and Subsequent Cancer Risk in the Netherlands

Abstract: Background: Computed tomography (CT), a strong diagnostic tool, delivers higher radiation doses than most imaging modalities. As CT use has increased rapidly, radiation protection is important, particularly among children. We evaluate leukemia and brain tumor risk following exposure to low-dose ionizing radiation from CT scans in childhood. Methods: For a nationwide retrospective cohort of 168 394 children who received one or more CT scans in a Dutch hospital between 1979 and 2012 who were younger than age 18 years, we obtained cancer incidence, vital status, and confounder information by record linkage with external registries. Standardized incidence ratios were calculated using cancer incidence rates from the general Dutch population. Excess relative risks (ERRs) per 100 mGy organ dose were calculated with Poisson regression. All statistical tests were two-sided. Results: Standardized incidence ratios were elevated for all cancer sites. Mean cumulative bone marrow doses were 9.5 mGy at the end of follow-up, and leukemia risk (excluding myelodysplastic syndrome) was not associated with cumulative bone marrow dose (44 cases). Cumulative brain dose was on average 38.5 mGy and was statistically significantly associated with risk for malignant and nonmalignant brain tumors combined (ERR/100 mGy: 0.86, 95% confidence interval = 0.20 to 2.22, P = .002, 84 cases). Excluding tuberous sclerosis complex patients did not substantially change the risk. Conclusions: We found evidence that CT-related radiation exposure increases brain tumor risk. No association was observed for leukemia. Compared with the general population, incidence of brain tumors was higher in the cohort of children with CT scans, requiring cautious interpretation of the findings.

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis

Abstract: Background: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated. Methods: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III–IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method. Results: We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n ¼ 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] ¼ 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI ¼ 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patientlevel survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI ¼ 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI ¼ 14.5 to 21.5 months). Pooled event rates for grade III–IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI ¼ 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI ¼ 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI ¼ 8.1 to 14.2). No deaths were attributed to FOLFIRINOX. Conclusions: This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

Circulating Vitamin D and Colorectal Cancer Risk: An International Pooling Project of 17 Cohorts.

Abstract: BACKGROUND Experimental and epidemiological studies suggest a protective role for vitamin D in colorectal carcinogenesis, but evidence is inconclusive. Circulating 25-hydroxyvitamin D (25(OH)D) concentrations that minimize risk are unknown. Current Institute of Medicine (IOM) vitamin D guidance is based solely on bone health. METHODS We pooled participant-level data from 17 cohorts, comprising 5706 colorectal cancer case participants and 7107 control participants with a wide range of circulating 25(OH)D concentrations. For 30.1% of participants, 25(OH)D was newly measured. Previously measured 25(OH)D was calibrated to the same assay to permit estimating risk by absolute concentrations. Study-specific relative risks (RRs) for prediagnostic season-standardized 25(OH)D concentrations were calculated using conditional logistic regression and pooled using random effects models. RESULTS Compared with the lower range of sufficiency for bone health (50-<62.5 nmol/L), deficient 25(OH)D (<30 nmol/L) was associated with 31% higher colorectal cancer risk (RR = 1.31, 95% confidence interval [CI] = 1.05 to 1.62); 25(OH)D above sufficiency (75-<87.5 and 87.5-<100 nmol/L) was associated with 19% (RR = 0.81, 95% CI = 0.67 to 0.99) and 27% (RR = 0.73, 95% CI = 0.59 to 0.91) lower risk, respectively. At 25(OH)D of 100 nmol/L or greater, risk did not continue to decline and was not statistically significantly reduced (RR = 0.91, 95% CI = 0.67 to 1.24, 3.5% of control participants). Associations were minimally affected when adjusting for body mass index, physical activity, or other risk factors. For each 25 nmol/L increment in circulating 25(OH)D, colorectal cancer risk was 19% lower in women (RR = 0.81, 95% CI = 0.75 to 0.87) and 7% lower in men (RR = 0.93, 95% CI = 0.86 to 1.00) (two-sided Pheterogeneity by sex = .008). Associations were inverse in all subgroups, including colorectal subsite, geographic region, and season of blood collection. CONCLUSIONS Higher circulating 25(OH)D was related to a statistically significant, substantially lower colorectal cancer risk in women and non-statistically significant lower risk in men. Optimal 25(OH)D concentrations for colorectal cancer risk reduction, 75-100 nmol/L, appear higher than current IOM recommendations.

Developing a Quality of Cancer Survivorship Care Framework: Implications for Clinical Care, Research, and Policy.

Abstract: 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.

The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target

Abstract: BACKGROUND Immunotherapy has been less successful in treating prostate cancer than other solid tumors. We sought to better understand the immune landscape in prostate cancer and identify immune-related biomarkers and potential therapeutic targets. METHODS We analyzed gene expression data from 7826 prospectively collected prostatectomy samples (2013-2016), and 1567 retrospective samples with long-term clinical outcomes, for a total of 9393 samples, all profiled on the same commercial clinical platform in a CLIA-certified lab. The primary outcome was distant metastasis-free survival (DMFS). Secondary outcomes included biochemical recurrence-free survival (bRFS), prostate cancer-specific survival (PCSS), and overall survival (OS). All statistical tests were two-sided. RESULTS Unsupervised hierarchical clustering of hallmark pathways demonstrated an immune-related tumor cluster. Increased estimated immune content scores based on immune-specific genes from the literature were associated with worse bRFS (hazard ratio [HR] = 1.26 [95% confidence interval [CI] = 1.12 to 1.42]; P < .001), DMFS (HR = 1.34 [95% CI = 1.13 to 1.58]; P < .001), PCSS (HR = 1.53 [95% CI = 1.21 to 1.92]; P < .001), and OS (HR = 1.27 [95% CI = 1.07 to 1.50]; P = .006). Deconvolution using Cibersort revealed that mast cells, natural killer cells, and dendritic cells conferred improved DMFS, whereas macrophages and T-cells conferred worse DMFS. Interestingly, while PD-L1 was not prognostic, consistent with its low expression in prostate cancer, PD-L2 was expressed at statistically significantly higher levels (P < .001) and was associated with worse bRFS (HR = 1.17 [95% CI = 1.03 to 1.33]; P = .01), DMFS (HR = 1.25 [95% CI = 1.05 to 1.49]; P = .01), and PCSS (HR = 1.45 [95% CI = 1.13 to 1.86]; P = .003). PD-L2 was strongly associated with immune-related pathways on gene set enrichment analysis suggesting that it is playing an important role in immune modulation in clinical prostate cancer samples. Furthermore, PD-L2 was correlated with radiation response pathways, and also predicted response to postoperative radiation therapy (PORT) on multivariable interaction analysis (P = .03). CONCLUSION In the largest study of its kind to date, these results illustrate the complex relationship between the tumor-immune interaction, prognosis, and response to radiotherapy, and nominate PD-L2 as a potential novel therapeutic target in prostate cancer, potentially in combination with radiotherapy.

Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Abstract: Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5x10(-8)) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the d ...

Sex-Based Heterogeneity in Response to Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis.

Abstract: Background We previously showed that therapy with anti-checkpoints T-lymphocyte-associated protein 4 (anti-CTLA-4) or antiprogrammed cell death protein 1 (anti-PD-1) agents was more effective for men as compared with women. However, because the sex-dimorphism of the immune system is complex, involving multiple elements of immune responses, it is possible that women could derive larger benefit than men from strategies other than therapy with immune checkpoint inhibitors (ICIs) alone. Here we investigated whether women could derive larger benefit than men from the combination of chemotherapy and anti-PD-1 or anti-PD-L1. Methods We performed two meta-analyses. The first included all randomized controlled trials (RCTs) testing anti-PD1 and anti-PD-L1 plus chemotherapy vs chemotherapy to assess different efficacy between men and women. The second included all RCTs of first-line systemic treatment in advanced non-small cell lung cancer testing anti-PD-1/PD-L1 given either alone or combined with chemotherapy to assess the different efficacy of these two immunotherapeutic strategies according to patients' sex. For each RCT included in the two meta-analyses, first, a trial-specific ratio of hazard ratios (HRs) was calculated from the ratio of the reported hazard ratios in men and in women; second, these trial-specific ratios of hazard ratios were combined across trials using a random-effects model to obtain a pooled hazard ratios ratio. A pooled HRs ratio estimate lower than 1 indicates a greater treatment effect in men, and higher than 1 a greater effect in women. Results Eight RCTs were included in the first meta-analysis. The pooled overall survival hazard ratios (OS-HRs) comparing anti-PD-1/PD-L1 plus chemotherapy vs chemotherapy was 0.76 (95% confidence interval [CI] = 0.66 to 0.87) for men and 0.48 (95% CI = 0.35 to 0.67) for women. The pooled ratio of the overall survival hazard ratios reported in men vs women was 1.56 (95% CI = 1.21 to 2.01), indicating a statistically significant greater effect for women. Six RCTs were included in the second meta-analysis: three tested an anti-PD-1 alone, whereas three RCTs tested anti-PD-1/PD-L1 plus chemotherapy. The pooled overall survival hazard ratios were 0.78 (95% CI = 0.60 to 1.00) in men and 0.97 (95% CI = 0.79 to 1.19) in women for anti-PD-1 alone, compared with 0.76 (95% CI = 0.64 to 0.91) in men and 0.44 (95% CI = 0.25 to 0.76) in women for anti-PD-1/PD-L1 plus chemotherapy. The pooled ratio of overall survival hazard ratios was 0.83 (95% CI = 0.65 to 1.06) for anti-PD-1 alone, indicating a greater effect in men, and 1.70 (95% CI = 1.16 to 2.49) for anti-PD-1/PD-L1 plus chemotherapy, indicating a greater effect in women. Conclusion Women with advanced lung cancer derived a statistically significantly larger benefit from the addition of chemotherapy to anti-PD-1/PD-L1 as compared with men.

Methylation-Based Biological Age and Breast Cancer Risk.

Abstract: BACKGROUND Age is one of the strongest predictors of cancer, chronic disease, and mortality, but biological responses to aging differ among people. Epigenetic DNA modifications have been used to estimate "biological age," which may be a useful predictor of disease risk. We tested this hypothesis for breast cancer. METHODS Using a case-cohort approach, we measured baseline blood DNA methylation of 2764 women enrolled in the Sister Study, 1566 of whom subsequently developed breast cancer after an average of 6 years. Using three previously established methylation-based "clocks" (Hannum, Horvath, and Levine), we defined biological age acceleration for each woman by comparing her estimated biological age with her chronological age. Hazard ratios and 95% confidence intervals for breast cancer risk were estimated using Cox regression models. All statistical tests were two-sided. RESULTS Each of the three clocks showed that biological age acceleration was statistically significantly associated with increased risk of developing breast cancer (5-year age acceleration, Hannum's clock: hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.00 to 1.21, P = .04; Horvath's clock: HR = 1.08, 95% CI = 1.00 to 1.17, P = .04; Levine's clock: HR = 1.15, 95% CI = 1.07 to 1.23, P < .001). For Levine's clock, each 5-year acceleration in biological age corresponded with a 15% increase in breast cancer risk. Although biological age may accelerate with menopausal transition, age acceleration in premenopausal women independently predicted breast cancer. Case-only analysis suggested that, among women who develop breast cancer, increased age acceleration is associated with invasive cancer (odds ratio for invasive = 1.09, 95% CI = 0.98 to 1.22, P = .10). CONCLUSIONS DNA methylation-based measures of biological age may be important predictors of breast cancer risk.

CAR T-Cell Associated Neurotoxicity: Mechanisms, Clinicopathologic Correlates, and Future Directions.

Abstract: Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary new form of immunotherapy for the treatment of hematologic malignancies. The two primary toxicities associated with CAR T-cell therapy include cytokine-release syndrome and neurotoxicity. Cytokine-release syndrome is generally self-limited but high-grade toxicities like hypotension and hypoxemia can be managed with agents that block the effects of IL-6, like tocilizumab, and/or corticosteroids. Although CAR T-cell therapy-associated neurotoxicity is a well-described clinical phenomenon, its pathophysiology remains inadequately understood; treatments and preventive strategies remain elusive. Animal models and clinical trial experience suggest the centrality of monocytes, endothelial dysfunction, and the blood-brain barrier in the development of CAR T-cell-associated neurotoxicity. Here we report what is known from preclinical models, clinical trials, and histopathologic studies regarding the pathophysiology of neurotoxicity, predictors of its incidence, and potential targets for the treatment and prevention of neurotoxicity.

Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer.

Abstract: BACKGROUND Claudin18.2 (CLDN18.2), a gastric-specific membrane protein, has been regarded as a potential therapeutic target for gastric cancer and other cancer types. The aim of our study was to elucidate whether chimeric antigen receptor T (CAR T) cells redirected to CLDN18.2 have the potential to be used in the treatment of this deadly disease. METHODS CLDN18.2-specific humanized antibodies were developed using hybridoma and humanization technology. CLDN18.2-specific CAR T cells were prepared by lentiviral vector transduction. In vitro antitumor activities and cytokine production of the CAR T cells to gastric cancer cell lines were examined by cytotoxicity and ELISA assay. In vivo antitumor activities of CAR T cells were evaluated in mice bearing gastric cancer cell line and patient-derived tumor xenograft (PDX) models (n ≥ 6 mice per group). All statistical tests were two-sided. RESULTS Humanized CLDN18.2-specific hu8E5 and hu8E5-2I single-chain fragment variables (scFv) were successfully developed. CLDN18.2-specific CAR T cells were developed using hu8E5 or hu8E5-2I scFv as targeting moieties. Both hu8E5-28Z and hu8E5-2I-28Z CAR T cells comprising the CD28 costimulatory domain potently suppressed tumor growth in a cancer cell line xenograft mouse model (mean [SD] tumor volume: hu8E5-28Z = 118.0 [108.6] mm3 and hu8E5-2I-28Z group = 75.5 [118.7] mm3 vs untransduced T cell group = 731.8 [206.3] mm3 at day 29 after tumor inoculation, P < .001). Partial or complete tumor elimination was observed in CLDN18.2-positive gastric cancer PDX models treated with the hu8E5-2I-28Z CAR T cells (P < .001), which persist well in vivo and infiltrate efficiently into the tumor tissues. Although the CLDN18.2 CAR T cells could lyse target cells expressing murine CLDN18.2 (mCLDN18.2), no obvious deleterious effect on the normal organs including the gastric tissues was observed in the mice. CONCLUSIONS CLDN18.2-specific CAR T cells could be a promising treatment strategy for gastric cancer and potentially other CLDN18.2-positive tumors.

Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer: Mechanisms and Therapeutic Implications

Abstract: BACKGROUND Overcoming oxidative stress is a critical step for tumor progression; however, the underlying mechanisms in colorectal cancer (CRC) remain unclear. METHODS We investigated nicotinamide adenine dinucleotide (phosphate) (NAD(P))-dependent enzyme methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) expression, clinical relevance, redox modification, and molecular mechanisms using the CRC cells and tissues (n = 462 paired samples). The antitumor effects of MTHFD2 inhibitor LY345899 on CRC tumorigenesis and metastasis were evaluated in vitro and in vivo. Data analysis used Kaplan-Meier, Pearson's correlation, and Student t test where appropriate. All statistical tests were two-sided. RESULTS Here, we report that the patients with high expression of MTHFD2 have a shorter overall survival (HR = 1.62, 95% CI = 1.12 to 2.36, P = .01) and disease-free survival (HR = 1.55, 95% CI = 1.07 to 2.27, P = .02) than patients with low MTHFD2 expression. Suppression of MTHFD2 disturbs NADPH and redox homeostasis and accelerates cell death under oxidative stress, such as hypoxia or anchorage independence (P ≤ .01 for all). Also, genetic or pharmacological inhibition of MTHFD2 suppresses CRC cell growth and lung and peritoneal metastasis in cell-based xenografts (n = 5-8 mice per group). Importantly, LY345899 treatment statistically significantly suppresses tumor growth and decreases the tumor weight in CRC patient-derived xenograft models (n = 10 mice per group, mean [SD] tumor weight of the vehicle-treated group was 1.83 [0.19] mg vs 0.74 [0.30] mg for the LY345899-treated group, P < .001). CONCLUSIONS Our study presents evidence that MTHFD2 confers redox homeostasis and promotes CRC cell growth and metastasis. The folate analog LY345899 as MTHFD2 inhibitor displays therapeutic activity against CRC and warrants further clinical investigation for CRC treatment.

Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors

Abstract: Observational data have shown that some cancer survivors develop chronic conditions like frailty, sarcopenia, cardiac dysfunction, and mild cognitive impairment earlier and/or at a greater burden than similarly aged individuals never diagnosed with cancer or exposed to systemic or targeted cancer therapies. In aggregate, cancer- and treatment-related physical, cognitive, and psychosocial late- and long-term morbidities experienced by cancer survivors are hypothesized to represent accelerated or accentuated aging trajectories. However, conceptual, measurement, and methodological challenges have constrained efforts to identify, predict, and mitigate aging-related consequences of cancer and cancer treatment. In July 2018, the National Cancer Institute convened basic, clinical, and translational science experts for a think tank titled "Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors." Through the resulting deliberations, several research and resource needs were identified, including longitudinal studies to examine aging trajectories that include detailed data from before, during, and after cancer treatment; mechanistic studies to elucidate the pathways that lead to the emergence of aging phenotypes in cancer survivors; long-term clinical surveillance to monitor survivors for late-emerging effects; and tools to integrate multiple data sources to inform understanding of how cancer and its therapies contribute to the aging process. Addressing these needs will help expand the evidence base and inform strategies to optimize healthy aging of cancer survivors.

Advanced Intrahepatic Cholangiocarcinoma: Post Hoc Analysis of the ABC-01, -02, and -03 Clinical Trials.

Abstract: Background The incidence of intrahepatic cholangiocarcinoma (iCCA) is increasing. The aim of the study was to provide reference survival data for patients with advanced iCCA treated with first-line cisplatin-gemcitabine chemotherapy (current standard of care). Methods Individual data from patients with iCCA recruited into the prospective, random assignment Advanced Biliary Tract Cancer (ABC)-01, -02, and -03 studies were retrieved. The prevalence and survival of liver-only iCCA was also assessed. Survival analysis was performed using univariate and multivariable Cox regression. All statistical tests were two-sided. Results Of 534 patients recruited into the ABC-01, -02, and -03 studies, 109 (20.4%) had iCCA. Most patients (n = 86, 78.9%) had metastatic disease at the time of recruitment; 52 patients (47.7%) had liver-only disease. Following random assignment, 66 (60.6%) iCCA patients received cisplatin and gemcitabine. The median progression-free and overall survival (OS) were 8.4 months (95% confidence interval [CI] = 5.9 to 8.9 months) and 15.4 months (95% CI = 11.1 to 17.9 months), respectively. Of these 66 patients, 34 patients (51.5%) had liver-only disease. Following chemotherapy, 30 (45.5%) and 21 (31.8%) were progression-free at 3 and 6 months from chemotherapy commencement, respectively. The median OS for patients with liver-only iCCA at diagnosis and after 3 and 6 months of chemotherapy was 16.7 months (95% CI = 8.7 to 20.2 months), 17.9 months (95% CI = 11.7 to 20.9 months), and 18.9 months (95% CI = 16.7 to 25.9 months), respectively. Multivariable analysis confirmed that iCCA had a longer OS compared with other non-iCCA biliary tract cancers (hazard ratio = 0.58, 95% CI = 0.35 to 0.95, P value = .03); liver-only iCCA patients also showed longer OS even though findings did not reach statistical significance (hazard ratio = 0.65, 95% CI = 0.36 to 1.19, P value = .16). Conclusions Patients diagnosed with advanced iCCA have a better OS compared with other biliary tract cancers; a similar trend was identified for patients diagnosed with liver-only iCCA. These findings are to be considered for future clinical trial design.

Immunotherapy for Colorectal Cancer: A Review of Current and Novel Therapeutic Approaches

Abstract: 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.

Targeted Genomic Profiling of Acral Melanoma.

Abstract: Background Acral melanoma is a rare type of melanoma that affects world populations irrespective of skin color and has worse survival than other cutaneous melanomas. It has relatively few single nucleotide mutations without the UV signature of cutaneous melanomas, but instead has a genetic landscape characterized by structural rearrangements and amplifications. BRAF mutations are less common than in other cutaneous melanomas, and knowledge about alternative therapeutic targets is incomplete. Methods To identify alternative therapeutic targets, we performed targeted deep-sequencing on 122 acral melanomas. We confirmed the loss of the tumor suppressors p16 and NF1 by immunohistochemistry in select cases. Results In addition to BRAF (21.3%), NRAS (27.9%), and KIT (11.5%) mutations, we identified a broad array of MAPK pathway activating alterations, including fusions of BRAF (2.5%), NTRK3 (2.5%), ALK (0.8%), and PRKCA (0.8%), which can be targeted by available inhibitors. Inactivation of NF1 occurred in 18 cases (14.8%). Inactivation of the NF1 cooperating factor SPRED1 occurred in eight cases (6.6%) as an alternative mechanism of disrupting the negative regulation of RAS. Amplifications recurrently affected narrow loci containing PAK1 and GAB2 (n = 27, 22.1%), CDK4 (n = 27, 22.1%), CCND1 (n = 24, 19.7%), EP300 (n = 20, 16.4%), YAP1 (n = 15, 12.3%), MDM2 (n = 13, 10.7%), and TERT (n = 13, 10.7%) providing additional and possibly complementary therapeutic targets. Acral melanomas with BRAFV600E mutations harbored fewer genomic amplifications and were more common in patients with European ancestry. Conclusion Our findings support a new, molecularly based subclassification of acral melanoma with potential therapeutic implications: BRAFV600E mutant acral melanomas with characteristics similar to nonacral melanomas that could benefit from BRAF inhibitor therapy, and non-BRAFV600E mutant acral melanomas. Acral melanomas without BRAFV600E mutations harbor a broad array of therapeutically relevant alterations. Expanded molecular profiling would increase the detection of potentially targetable alterations for this subtype of acral melanoma.

A Prospective Study of Circulating Tumor DNA to Guide Matched Targeted Therapy in Lung Cancers

Abstract: BACKGROUND Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is commercially available and increasingly adopted in clinical practice despite a paucity of prospective data to support its use. METHODS Patients with advanced lung cancers who had no known oncogenic driver or developed resistance to current targeted therapy (n = 210) underwent plasma NGS, targeting 21 genes. A subset of patients had concurrent tissue NGS testing using a 468-gene panel (n = 106). Oncogenic driver detection, test turnaround time (TAT), concordance, and treatment response guided by plasma NGS were measured. All statistical tests were two-sided. RESULTS Somatic mutations were detected in 64.3% (135/210) of patients. ctDNA detection was lower in patients who were on systemic therapy at the time of plasma collection compared with those who were not (30/70, 42.9% vs 105/140, 75.0%; OR = 0.26, 95% CI = 0.1 to 0.5, P < .001). The median TAT of plasma NGS was shorter than tissue NGS (9 vs 20 days; P < .001). Overall concordance, defined as the proportion of patients for whom at least one identical genomic alteration was identified in both tissue and plasma, was 56.6% (60/106, 95% CI = 46.6% to 66.2%). Among patients who tested plasma NGS positive, 89.6% (60/67; 95% CI = 79.7% to 95.7%) were also concordant on tissue NGS and 60.6% (60/99; 95% CI = 50.3% to 70.3%) vice versa. Patients who tested plasma NGS positive for oncogenic drivers had tissue NGS concordance of 96.1% (49/51, 95% CI = 86.5% to 99.5%), and directly led to matched targeted therapy in 21.9% (46/210) with clinical response. CONCLUSIONS Plasma ctDNA NGS detected a variety of oncogenic drivers with a shorter TAT compared with tissue NGS and matched patients to targeted therapy with clinical response. Positive findings on plasma NGS were highly concordant with tissue NGS and can guide immediate therapy; however, a negative finding in plasma requires further testing. Our findings support the potential incorporation of plasma NGS into practice guidelines.

Acupuncture Versus Cognitive Behavioral Therapy for Insomnia in Cancer Survivors: A Randomized Clinical Trial.

Abstract: BACKGROUND Insomnia is a common and debilitating disorder experienced by cancer survivors. Although cancer survivors express a preference for using nonpharmacological treatment to manage insomnia, the comparative effectiveness between acupuncture and Cognitive Behavioral Therapy for Insomnia (CBT-I) for this disorder is unknown. METHODS This randomized trial compared 8 weeks of acupuncture (n = 80) and CBT-I (n = 80) in cancer survivors. Acupuncture involved stimulating specific points on the body with needles. CBT-I included sleep restriction, stimulus control, cognitive restructuring, relaxation training, and education. We measured insomnia severity (primary outcome), pain, fatigue, mood, and quality of life posttreatment (8 weeks) with follow-up until 20 weeks. We used linear mixed-effects models for analyses. All statistical tests were two-sided. RESULTS The mean age was 61.5 years and 56.9% were women. CBT-I was more effective than acupuncture posttreatment (P < .001); however, both acupuncture and CBT-I produced clinically meaningful reductions in insomnia severity (acupuncture: -8.31 points, 95% confidence interval = -9.36 to -7.26; CBT-I: -10.91 points, 95% confidence interval = -11.97 to -9.85) and maintained improvements up to 20 weeks. Acupuncture was more effective for pain at the end of treatment; both groups had similar improvements in fatigue, mood, and quality of life and reduced prescription hypnotic medication use. CBT-I was more effective for those who were male (P < .001), white (P = .003), highly educated (P < .001), and had no pain at baseline (P < .001). CONCLUSIONS Although both treatments produced meaningful and durable improvements, CBT-I was more effective and should be the first line of therapy. The relative differences in the comparative effectiveness between the two interventions for specific groups should be confirmed in future adequately powered trials to guide more tailored interventions for insomnia.

STAT3 Modulation of Regulatory T Cells in Response to Radiation Therapy in Head and Neck Cancer

Abstract: Background Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC. Methods We utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10 Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. Enzyme-linked immunosorbent assay was performed to assess secreted factors. For immune-modulating therapies, anti-PD-L1, anti-CTLA-4, and STAT3 antisense oligonucleotide (ASO) were used. All statistical tests were two-sided. Results Treatment with anti-CD25 and radiation led to tumor eradication (57.1%, n = 4 of 7 mice), enhanced T-cell cytotoxicity compared with RT alone (CD4 effector T cells [Teff]: RT group mean = 5.37 [ 0.58] vs RT + αCD25 group mean =10.71 [0.67], P = .005; CD8 Teff: RT group mean = 9.98 [0.81] vs RT + αCD25 group mean =16.88 [2.49], P = .01) and induced tumor antigen-specific memory response (100.0%, n = 4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n = 7 mice). STAT3 inhibition in combination with radiation, but not as a single agent, improved tumor growth delay, decreased Tregs, myeloid-derived suppressor cells, and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation. Conclusion We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation.

Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer During Follow-Up and Prognosis.

Abstract: BACKGROUND The prognostic relevance of circulating tumor cells (CTCs) at the time of primary diagnosis has been well established. However, little information is available regarding their prognostic relevance to follow-up care. METHODS The multicenter, open-label, phase III SUCCESS A trial compared two adjuvant chemotherapy regimens followed by 2 vs 5 years of zoledronate for early-stage, high-risk breast cancer patients. The presence of CTCs was assessed before and 2 years after chemotherapy using the FDA-approved CellSearch System. Overall survival (OS) and disease-free survival (DFS) were analyzed using univariate log-rank tests and multivariable Cox regressions. OS and DFS were measured starting from an assessment of CTCs 2 years after the completion of chemotherapy. All statistical tests were two-sided. RESULTS The sample included 1087 patients who participated in the translational research program of the SUCCESS A trial and for whom sufficient translational data were available regarding CTC status at baseline and at the 2-year follow-up visit. Two years after chemotherapy, 198 (18.2%) patients were CTC-positive. The median follow-up after this timepoint was 37 months. Cox regressions that included CTC status at baseline revealed that CTC status 2 years after chemotherapy had statistically significant and independent prognostic relevance for OS (hazard ratio [HR] = 3.91, 95% confidence interval [CI] = 2.04 to 7.52, P < .001) and DFS (HR = 2.31, 95% CI = 1.50 to 3.55, P < .001). CONCLUSION The presence of CTCs 2 years after chemotherapy was associated with decreased OS and DFS. Based on these results, active individualized surveillance strategies for breast cancer survivors based on biomarkers should be reconsidered.

Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ.

Abstract: BACKGROUND: A better definition of biomarkers and biological processes related to local recurrence and disease progression is highly warranted for ductal breast carcinoma in situ (DCIS). Stromal-epithelial interactions are likely of major importance for the biological, clinical, and pathological distinctions between high- and low-risk DCIS cases.METHODS: Stromal platelet derived growth factor receptor (PDGFR) was immunohistochemically assessed in two DCIS patient cohorts (n = 458 and n = 80). Cox proportional hazards models were used to calculate the hazard ratios of recurrence. The molecular mechanisms regulating stromal PDGFR expression were investigated in experimental in vitro co-culture systems of DCIS cells and fibroblasts and analyzed using immunoblot and quantitative real-time PCR. Knock-out of JAG1 in DCIS cells and NOTCH2 in fibroblasts was obtained through CRISPR/Cas9. Experimental data were validated by mammary fat pad injection of DCIS and DCIS-JAG1 knock-out cells (10 mice per group). All statistical tests were two-sided.RESULTS: PDGFRα(low)/PDGFRβ(high) fibroblasts were associated with increased risk for recurrence in DCIS (univariate hazard ratio = 1.59, 95% confidence interval [CI] = 1.02 to 2.46; P = .04 Wald test; multivariable hazard ratio = 1.78, 95% CI = 1.07 to 2.97; P = .03). Tissue culture and mouse model studies indicated that this fibroblast phenotype is induced by DCIS cells in a cell contact-dependent manner. Epithelial Jagged1 and fibroblast Notch2 were identified through loss-of-function studies as key juxtacrine signaling components driving the formation of the poor prognosis-associated fibroblast phenotype.CONCLUSIONS: A PDGFRα(low)/PDGFRβ(high) fibroblast subset was identified as a marker for high-risk DCIS. The Jagged-1/Notch2/PDGFR stroma-epithelial pathway was described as a novel signaling mechanism regulating this poor prognosis-associated fibroblast subset. In general terms, the study highlights epithelial-stromal crosstalk in DCIS and contributes to ongoing efforts to define clinically relevant fibroblast subsets and their etiology. (Less)

Contrasting Epidemiology and Clinicopathology of Female Breast Cancer in Asians vs the US Population.

Abstract: BACKGROUND The incidence of breast cancer among younger East Asian women has been increasing rapidly over recent decades. This international collaborative study systemically compared the differences in age-specific incidences and pathological characteristics of breast cancer in East Asian women and women of predominantly European ancestry. METHODS We excerpted analytic data from six national cancer registries (979 675 cases) and eight hospitals (18 008 cases) in East Asian countries and/or regions and, for comparisons, from the US Surveillance, Epidemiology, and End Results program database. Linear regression analyses of age-specific incidences of female breast cancer and logistic regression analyses of age-specific pathological characteristics of breast cancer were performed. All statistical tests were two-sided. RESULTS Unlike female colorectal cancer, the age-specific incidences of breast cancer among East Asian women aged 59 years and younger increased disproportionally over recent decades relative to rates in US contemporaries. For years 2010-2014, the estimated age-specific probability of estrogen receptor positivity increased with age in American patients, whereas that of triple-negative breast cancer (TNBC) declined with age. No similar trends were evident in East Asian patients; their probability of estrogen receptor positivity at age 40-49 years was statistically significantly higher (odd ratio [OR] = 1.50, 95% confidence interval [CI] = 1.36 to 1.67, P < .001) and of TNBC was statistically significantly lower (OR = 0.79, 95% CI = 0.71 to 0.88, P < .001), whereas the probability of ER positivity at age 50-59 years was statistically significantly lower (OR = 0.88, 95% CI = 0.828 to 0.95, P < .001). Subgroup analyses of US Surveillance, Epidemiology, and End Results data showed similarly distinct patterns between East Asian American and white American patients. CONCLUSIONS Contrasting age-specific incidences and pathological characteristics of breast cancer between East Asian and American women, as well as between East Asian Americans and white Americans, suggests racial differences in the biology.

Oral Leukoplakia and Risk of Progression to Oral Cancer: A Population-Based Cohort Study.

Abstract: Background The 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-a-vis progression, and histopathologic predictors of progression. Methods We conducted a retrospective cohort study (1996-2012) of patients with oral leukoplakia (n = 4886), identified using electronic medical records within Kaiser Permanente Northern California. Among patients with leukoplakia who received a biopsy (n = 1888), we conducted a case-cohort study to investigate histopathologic predictors of progression. Analyses included indirect standardization and unweighted or weighted Cox regression. Results Compared with the overall Kaiser Permanente Northern California population, oral cancer incidence was substantially elevated in oral leukoplakia patients (standardized incidence ratio = 40.8, 95% confidence interval [CI] = 34.8 to 47.6; n = 161 cancers over 22 582 person-years). Biopsied leukoplakias had a higher oral cancer risk compared with those that were not biopsied (adjusted hazard ratio = 2.38, 95% CI = 1.73 to 3.28). However, to identify a prevalent or incident oral cancer, the biopsy decision had low sensitivity (59.6%), low specificity (62.1%), and moderate positive-predictive value (5.1%). Risk of progression to oral cancer statistically significantly increased with the grade of dysplasia; 5-year competing risk-adjusted absolute risks were: leukoplakia overall = 3.3%, 95% CI = 2.7% to 3.9%; no dysplasia = 2.2%, 95% CI = 1.5% to 3.1%; mild-dysplasia = 11.9%, 95% CI = 7.1% to 18.1%; moderate-dysplasia = 8.7%, 95% CI = 3.2% to 17.9%; and severe dysplasia = 32.2%, 95% CI = 8.1%-60.0%. Yet 39.6% of cancers arose from biopsied leukoplakias without dysplasia. Conclusions The modest accuracy of the decision to biopsy a leukoplakia vis-a-vis presence or eventual development of oral cancer highlights the need for routine biopsy of all leukoplakias regardless of visual or clinical impression. Leukoplakia patients, particularly those with dysplasia, need to be closely monitored for signs of early cancer.

Transcriptome Characterization of Matched Primary Breast and Brain Metastatic Tumors to Detect Novel Actionable Targets.

Abstract: Background: Breast cancer brain metastases (BrMs) are defined by complex adaptations to both adjuvant treatment regimens and the brain microenvironment. Consequences of these alterations remain poorly understood, as does their potential for clinical targeting. We utilized genome-wide molecular profiling to identify therapeutic targets acquired in metastatic disease.Methods: Gene expression profiling of 21 patient-matched primary breast tumors and their associated brain metastases was performed by TrueSeq RNA-sequencing to determine clinically actionable BrM target genes. Identified targets were functionally validated using small molecule inhibitors in a cohort of resected BrM ex vivo explants (n = 4) and in a patient-derived xenograft (PDX) model of BrM. All statistical tests were two-sided.Results: Considerable shifts in breast cancer cell-specific gene expression profiles were observed (1314 genes upregulated in BrM; 1702 genes downregulated in BrM; DESeq; fold change > 1.5, Padj < .05). Subsequent bioinformatic analysis for readily druggable targets revealed recurrent gains in RET expression and human epidermal growth factor receptor 2 (HER2) signaling. Small molecule inhibition of RET and HER2 in ex vivo patient BrM models (n = 4) resulted in statistically significantly reduced proliferation (P < .001 in four of four models). Furthermore, RET and HER2 inhibition in a PDX model of BrM led to a statistically significant antitumor response vs control (n = 4, % tumor growth inhibition [mean difference; SD], anti-RET = 86.3% [1176; 258.3], P < .001; anti-HER2 = 91.2% [1114; 257.9], P < .01).Conclusions: RNA-seq profiling of longitudinally collected specimens uncovered recurrent gene expression acquisitions in metastatic tumors, distinct from matched primary tumors. Critically, we identify aberrations in key oncogenic pathways and provide functional evidence for their suitability as therapeutic targets. Altogether, this study establishes recurrent, acquired vulnerabilities in BrM that warrant immediate clinical investigation and suggests paired specimen expression profiling as a compelling and underutilized strategy to identify targetable dependencies in advanced cancers.

Cost-Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Pediatric Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Abstract: Background Chimeric antigen receptor T-cell (CAR-T) therapy is a promising new class of cancer therapy but has a high up-front cost. We evaluated the cost-effectiveness of CAR-T therapy among pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Methods We built a microsimulation model for pediatric patients with relapsed/refractory B-ALL receiving either CAR-T therapy or standard of care. Outcomes included costs, quality of life (health utility), complications, and survival. We measured cost-effectiveness with the incremental cost-effectiveness ratio (ICER), with ICERs under $100 000 per quality-adjusted life-year (QALY) considered cost effective. One-way and probabilistic sensitivity analyses were used to test model uncertainty. Results Compared to standard of care, CAR-T therapy increased overall cost by $528 200 and improved effectiveness by 8.18 QALYs, resulting in an ICER of $64 600/QALY. The model was sensitive to assumptions about long-term CAR-T survival, the complete remission rate of CAR-T patients, and the health utility of long-term survivors. The base model assumed a 76.0% one-year survival with CAR-T, although if this decreased to 57.8%, then CAR-T was no longer cost effective. If the complete remission rate of CAR-T recipients decreased from 81% to 56.2%, or if the health utility of disease-free survivors decreased from 0.94 to 0.66, then CAR-T was no longer cost effective. Probabilistic sensitivity analysis found that CAR-T was cost effective in 94.8% of iterations at a willingness to pay of $100 000/QALY. Conclusion CAR-T therapy may represent a cost-effective option for pediatric relapsed/refractory B-ALL, although longer follow-up of CAR-T survivors is required to confirm validity of these findings.