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OBJECTIVE: Alterations in DNA methylation are early events in endometrial cancer (EC) development and may have utility in EC detection via tampon-collected vaginal fluid. METHODS: For discovery, DNA from frozen EC, benign endometrium (BE), and benign cervicovaginal (BCV) tissues underwent reduced representation bisulfite sequencing (RRBS) to identify differentially methylated regions (DMRs). Candidate DMRs were selected based on receiver operating characteristic (ROC) discrimination, methylation level fold-change between cancers and controls, and absence of background CpG methylation. Methylated DNA marker (MDM) validation was performed using qMSP on DNA from independent EC and BE FFPE tissue sets. Women ≥45 years of age with abnormal uterine bleeding (AUB) or postmenopausal bleeding (PMB) or any age with biopsy-proven EC self-collected vaginal fluid using a tampon prior to clinically indicated endometrial sampling or hysterectomy. Vaginal fluid DNA was assayed by qMSP for EC-associated MDMs. Random forest modeling analysis was performed to generate predictive probability of underlying disease; results were 500-fold in-silico cross-validated. RESULTS: Thirty-three candidate MDMs met performance criteria in tissue. For the tampon pilot, 100 EC cases were frequency matched by menopausal status and tampon collection date to 92 BE controls. A 28-MDM panel highly discriminated between EC and BE (96% (95%CI 89-99%) specificity; 76% (66-84%) sensitivity (AUC 0.88). In PBS/EDTA tampon buffer, the panel yielded 96% (95% CI 87-99%) specificity and 82% (70-91%) sensitivity (AUC 0.91). CONCLUSION: Next generation methylome sequencing, stringent filtering criteria, and independent validation yielded excellent candidate MDMs for EC. EC-associated MDMs performed with promisingly high sensitivity and specificity in tampon-collected vaginal fluid; PBS-based tampon buffer with added EDTA improved sensitivity. Larger tampon-based EC MDM testing studies are warranted.
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Neoplasias Endometriales , Humanos , Femenino , Marcadores Genéticos , Ácido Edético/metabolismo , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Endometrio/metabolismo , ADN , Metilación de ADNRESUMEN
BACKGROUND AND AIMS: Variation in colorectal neoplasia detection limits the effectiveness of screening colonoscopy. By evaluating neoplasia detection rates of individual colonoscopists, we aimed to quantify the effects of pre-procedural knowledge of a positive (+) multi-target stool DNA (mt-sDNA) on colonoscopy quality metrics. METHODS: We retrospectively identified physicians who performed a high volume of + mt-sDNA colonoscopies; colorectal neoplasia at post-mt-sDNA colonoscopy was recorded. These colonoscopists were stratified into quartiles based on baseline adenoma detection rates. Baseline colonoscopy adenoma detection rates and sessile serrated lesion detection rates were compared to post-mt-sDNA colonoscopy neoplasia diagnosis rates among each quartile. Withdrawal times were measured from negative exams. RESULTS: During the study period (2014-17) the highest quartile of physicians by volume of post-mt-sDNA colonoscopies were evaluated. Among thirty-five gastroenterologists, their median screening colonoscopy adenoma detection rate was 32% (IQR, 28-39%) and serrated lesion detection rate was 13% (8-15%). After + mt-sDNA, adenoma diagnosis increased to 47% (36-56%) and serrated lesion diagnosis increased to 31% (17-42%) (both p < 0.0001). Median withdrawal time increased from 10 (7-13) to 12 (10-17) minutes (p < 0.0001) and was proportionate across quartiles. After + mt-sDNA, lower baseline detectors had disproportionately higher rates of adenoma diagnosis in female versus male patients (p = 0.048) and higher serrated neoplasia diagnosis rates among all patients (p = 0.0092). CONCLUSIONS: Knowledge of + mt-sDNA enriches neoplasia diagnosis compared to average risk screening exams. Adenomatous and serrated lesion diagnosis was magnified among those with lower adenoma detection rates. Awareness of the mt-sDNA result may increase physician attention during colonoscopy. Pre-procedure knowledge of a positive mt-sDNA test improves neoplasia diagnosis rates among colonoscopists with lower baseline adenoma detection rates, independent of withdrawal time.
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Adenoma , Neoplasias Colorrectales , Humanos , Masculino , Femenino , ADN de Neoplasias , Estudios Retrospectivos , Detección Precoz del Cáncer/métodos , Colonoscopía , Neoplasias Colorrectales/patología , Adenoma/patologíaRESUMEN
High-risk individuals (HRIs) with familial and genetic predisposition to pancreatic ductal adenocarcinoma (PDAC) are eligible for screening. There is no accurate biomarker for detecting early-stage PDAC. We previously demonstrated that a panel of methylated DNA markers (MDMs) accurately detect sporadic PDAC. In this study we compared the distribution of MDMs in DNA extracted from tissue of PDAC cases who carry germline mutations and non-carriers with family history, with control tissue and demonstrate high discrimination like that seen in sporadic PDAC. These results provide scientific rationale for examining plasma MDMs in HRIs with the goal of developing a minimally-invasive early detection test.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias PancreáticasRESUMEN
OBJECTIVE: Aberrant DNA methylation is an early event in carcinogenesis which could be leveraged to detect ovarian cancer (OC) in plasma. METHODS: DNA from frozen OC tissues, benign fallopian tube epithelium (FTE), and buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify OC MDMs. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent OC and FTE FFPE tissues. MDMs were tested using Target Enrichment Long-probe Quantitative Amplified Signal (TELQAS) assays in pre-treatment plasma from women newly diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. RESULTS: Thirty-three MDMs showed marked methylation fold changes (10 to >1000) across all OC subtypes vs FTE. Eleven MDMs (GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, RIPPLY3, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (73 (80%) high-grade serous (HGS)) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95% CI, 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86-0.96)). Among the 5 stage I/II HGS OCs included, all were correctly identified. CONCLUSIONS: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded candidate MDMs for OC that performed with high sensitivity and specificity in plasma. Larger plasma-based OC MDM studies, including testing of pre-diagnostic specimens, are warranted.
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Metilación de ADN , Neoplasias Ováricas , Biomarcadores de Tumor/genética , Proteínas CELF/genética , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/genética , Estudios de Factibilidad , Femenino , Marcadores Genéticos , Humanos , Proteínas del Tejido Nervioso/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Transaminasas/genéticaRESUMEN
OBJECTIVES: Multitarget stool DNA (MT-sDNA) testing has grown as a noninvasive screening modality for colorectal cancer (CRC), but real-world clinical data are limited in the post-FDA approval setting. The effect of previous colonoscopy on MT-sDNA performance is not known. We aimed to evaluate findings of colorectal neoplasia (CRN) at diagnostic colonoscopy in patients with positive MT-sDNA testing, stratified by patient exposure to previous colonoscopy. METHODS: We identified consecutive patients completing MT-sDNA testing over a 39-month period and reviewed the records of those with positive tests for neoplastic findings at diagnostic colonoscopy. MT-sDNA test positivity rate, adherence to diagnostic colonoscopy, and the positive predictive value (PPV) of MT-sDNA for any CRN and neoplastic subtypes were calculated. RESULTS: Of 16,469 MT-sDNA tests completed, testing returned positive in 2,326 (14.1%) patients. After exclusion of patients at increased risk for CRC, 1,801 patients remained, 1,558 (87%) of whom underwent diagnostic colonoscopy; 918 of 1,558 (59%) of these patients had undergone previous colonoscopy, whereas 640 (41%) had not. Any CRN was found in 1,046 of 1,558 patients (PPV = 67%). More neoplastic lesions were found in patients without previous colonoscopy (73%); however, the rates remained high among those who had undergone previous colonoscopy (63%, P < 0.0001). The large majority (79%) of patients had right-sided neoplasia. DISCUSSION: MT-sDNA has a high PPV for any CRN regardless of exposure to previous colonoscopy. Right-sided CRN was found at colonoscopy in most patients with positive MT-sDNA testing, representing a potential advantage over other currently available screening modalities for CRC.
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Colonoscopía , Neoplasias Colorrectales/diagnóstico , ADN de Neoplasias/análisis , Heces/química , Tamizaje Masivo/métodos , Anciano , Detección Precoz del Cáncer , Femenino , Humanos , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/diagnóstico , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
Early detection improves hepatocellular carcinoma (HCC) outcomes, but better noninvasive surveillance tools are needed. We aimed to identify and validate methylated DNA markers (MDMs) for HCC detection. Reduced representation bisulfite sequencing was performed on DNA extracted from 18 HCC and 35 control tissues. Candidate MDMs were confirmed by quantitative methylation-specific PCR in DNA from independent tissues (74 HCC, 29 controls). A phase I plasma pilot incorporated quantitative allele-specific real-time target and signal amplification assays on independent plasma-extracted DNA from 21 HCC cases and 30 controls with cirrhosis. A phase II plasma study was then performed in 95 HCC cases, 51 controls with cirrhosis, and 98 healthy controls using target enrichment long-probe quantitative amplified signal (TELQAS) assays. Recursive partitioning identified best MDM combinations. The entire MDM panel was statistically cross-validated by randomly splitting the data 2:1 for training and testing. Random forest (rForest) regression models performed on the training set predicted disease status in the testing set; median areas under the receiver operating characteristics curve (AUCs; and 95% confidence interval [CI]) were reported after 500 iterations. In phase II, a six-marker MDM panel (homeobox A1 [HOXA1], empty spiracles homeobox 1 [EMX1], AK055957, endothelin-converting enzyme 1 [ECE1], phosphofructokinase [PFKP], and C-type lectin domain containing 11A [CLEC11A]) normalized by beta-1,3-galactosyltransferase 6 (B3GALT6) level yielded a best-fit AUC of 0.96 (95% CI, 0.93-0.99) with HCC sensitivity of 95% (88%-98%) at specificity of 92% (86%-96%). The panel detected 3 of 4 (75%) stage 0, 39 of 42 (93%) stage A, 13 of 14 (93%) stage B, 28 of 28 (100%) stage C, and 7 of 7 (100%) stage D HCCs. The AUC value for alpha-fetoprotein (AFP) was 0.80 (0.74-0.87) compared to 0.94 (0.9-0.97) for the cross-validated MDM panel (P < 0.0001). Conclusion: MDMs identified in this study proved to accurately detect HCC by plasma testing. Further optimization and clinical testing of this promising approach are indicated.
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ADN de Neoplasias/sangre , Neoplasias Hepáticas/sangre , Carcinoma Hepatocelular , Metilación de ADN , ADN de Neoplasias/metabolismo , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Método Simple CiegoRESUMEN
BACKGROUND AND AIMS: Multitarget stool DNA (MT-sDNA) testing is now approved by the U.S. Food and Drug Administration for average-risk colorectal cancer screening. Trials leading to its approval used blinded colonoscopy as the reference standard. In the postapproval screen setting, the clinical performance and impact of MT-sDNA testing on unblinded colonoscopy has not been described. We measured the impact that knowledge of a positive MT-sDNA test result has on colonoscopy yield and quality. METHODS: The unblinded group comprised all patients with positive MT-sDNA results on screening from September 1, 2014 to September 30, 2015 at a single tertiary center. Off-label test patients were excluded. The blinded group included all MT-sDNA-positive participants in a preapproval screening study from the same center. Detailed colonoscopy findings and withdrawal times were recorded. RESULTS: There were 172 MT-sDNA-positive patients in the unblinded group and 72 in the blinded group. More total adenomatous/sessile serrated polyps (70% vs 53%, P = .013) and advanced neoplasms (28% vs 21%, P = .27) were detected in unblinded than in blinded groups. Median numbers of polyps detected were 2 (IQR, 1-4) and 1 (IQR, 0-2) in unblinded and blinded groups, respectively (P = .0007). Among polyps detected, flat or slightly raised lesions in the right side of the colon were proportionately more frequent with unblinded (40%) than with blinded examinations (9%) (P = .0017). Median withdrawal time was 19 minutes (IQR, 13-29) in the unblinded group compared with 13 minutes (IQR, 10-20) in the blinded group (P = .0001). CONCLUSIONS: Knowledge of a positive MT-sDNA result appears to have a beneficial impact on the diagnostic yield and quality of subsequent colonoscopy.
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Adenoma/diagnóstico , Carcinoma/diagnóstico , Pólipos del Colon/diagnóstico , Colonoscopía , Neoplasias Colorrectales/diagnóstico , ADN de Neoplasias/análisis , Heces/química , Adenoma/genética , Anciano , Carcinoma/genética , Pólipos del Colon/genética , Neoplasias Colorrectales/genética , ADN/análisis , Detección Precoz del Cáncer , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND/AIMS: The use of patient-reported outcomes in clinical trials is a focal point for research and policy. Non-compliance with planned questionnaires and missing data can threaten both internal validity and generalizability. This retrospective analysis was conducted to determine the extent of, and characteristics associated with, missing patient-reported outcomes. METHODS: Study characteristics, patient characteristics and adverse events, and reasons for non-compliance were compiled from 14 closed Alliance for Clinical Trials in Oncology, Mayo Clinic Cancer Center, or Mayo Clinic Cancer Research Consortium clinical trials. Compliance rates were calculated for each patient using the number of booklets completed while the patient was on trial divided by the number of booklets the patient was expected to complete. Frequency counts and summary statistics were compiled. Logistic regression techniques were employed. RESULTS: The 1640 included patients had a median age of 58 years and were mostly White (90.8%) and female (73.8%). Compliance rates per study ranged from 84.7% to 97.2%. The primary endpoint of overall compliance rate was 93.1%. A total of 1267 patients were compliant. Those non-compliant were slightly older (mean = 58.6 vs 57.5, p = 0.03) and had different types of cancers (p < 0.01). There were no differences in compliance according to tumor status (p = 0.66), clinical stage (p = 0.81), baseline quality of life (p = 0.42 for ≥8 vs <8 and p = 0.12 for ≥6 vs <6), or maximum adverse event grade incidence (p = 0.33 for grade 2+ incidence and p = 0.36 for grade 3+ incidence). Reasons for non-compliance included patient refusal (N = 136), booklet not administered to patient (N = 199), no clinic visit at the scheduled time for booklet completion (N = 40), and at-home-completed booklet not returned (N = 224). Logistic regression indicates gender (p < 0.01), race (p < 0.01), performance score (p = 0.02), dose delay status (p = 0.01), and incidence of grade 3 or higher adverse event (p = 0.03) were correlates of compliance. CONCLUSION: Patient-reported outcomes have successfully been implemented into Alliance and Mayo Clinic trials with high rates of patient compliance. Further improvement in compliance can be made with staff commitment and education. Patients are typically non-compliant only when the task at hand is burdensome, unclear, or logistically challenging. Existing tracking systems used for the other trial outcomes should be utilized to ensure successful capture of patient-reported outcomes.
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Ensayos Clínicos como Asunto , Neoplasias/terapia , Cooperación del Paciente , Medición de Resultados Informados por el Paciente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Calidad de Vida , Estudios Retrospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Regular screening for colorectal cancer (CRC) is critical for early detection and long-term survival. Despite the current screening options available and advancements in therapies there will be around 53,000 CRC related deaths this year. There is great interest in non-invasive alternatives such as plasma cell-free RNA (cfRNA) for diagnostic, prognostic, and predictive applications. In the current study, our aim was to identify and validate potential cfRNA candidates to improve early CRC diagnosis. In phase 1 (n = 49; 25 controls, 24 cancers), discovery total RNA sequencing was performed. Select exons underwent validation in phase 2 (n = 73; 35 controls, 29 cancers, 9 adenomas) using targeted capture sequencing (n = 10,371 probes). In phase 3 (n = 57; 30 controls, 27 cancers), RT-qPCR was performed on previously identified candidates (n = 99). There were 895 exons that were differentially expressed (325 upregulated, 570 downregulated) among cancers versus controls. In phases 2 and 3, fewer markers were validated than expected in independent sets of patients, most of which were from previously published literature (FGA, FGB, GPR107, CDH3, and RP23AP7). In summary, we optimized laboratory processes and data analysis strategies which can serve as methodological framework for future plasma RNA studies beyond just the scope of CRC detection. Additionally, further exploration is needed in order to determine if the few cfRNA candidates identified in this study have clinical utility for early CRC detection. Over time, advancements in technologies, data analysis, and RNA preservation methods at time of collection may improve the biological and technical reproducibility of cfRNA biomarkers and enhance the feasibility of RNA-based liquid biopsies.
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Biomarcadores de Tumor , Ácidos Nucleicos Libres de Células , Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/sangre , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Transcriptoma , Detección Precoz del Cáncer/métodos , Regulación Neoplásica de la Expresión Génica , Análisis de Secuencia de ARN/métodos , Estudios de Casos y ControlesRESUMEN
INTRODUCTION: Non-invasive assays are needed to better discriminate patients with prostate cancer (PCa) to avoid over-treatment of indolent disease. We analyzed 14 methylated DNA markers (MDMs) from urine samples of patients with biopsy-proven PCa relative to healthy controls and further studied discrimination of clinically significant PCa (csPCa) from healthy controls and Gleason 6 cancers. METHODS: To evaluate the panel, urine from 24 healthy male volunteers with no clinical suspicion for PCa and 24 men with biopsy-confirmed disease across all Gleason scores was collected. Blinded to clinical status, DNA from the supernatant was analyzed for methylation signal within specific DNA sequences across 14 genes (HES5, ZNF655, ITPRIPL1, MAX.chr3.6187, SLCO3A1, CHST11, SERPINB9, WNT3A, KCNB2, GAS6, AKR1B1, MAX.chr3.8028, GRASP, ST6GALNAC2) by target enrichment long-probe quantitative-amplified signal assays. RESULTS: Utilizing an overall specificity cut-off of 100% for discriminating normal controls from PCa cases across the MDM panel resulted in 71% sensitivity (95% CI: 49-87%) for PCa detection (4/7 Gleason 6, 8/12 Gleason 7, 5/5 Gleason 8+) and 76% (50-92%) for csPCa (Gleason ≥ 7). At 100% specificity for controls and Gleason 6 patients combined, MDM panel sensitivity was 59% (33-81%) for csPCa (5/12 Gleason 7, 5/5 Gleason 8+). CONCLUSIONS: MDMs assayed in urine offer high sensitivity and specificity for detection of clinically significant prostate cancer. Prospective evaluation is necessary to estimate discrimination of patients as first-line screening and as an adjunct to prostate-specific antigen (PSA) testing.
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PURPOSE: Patients undergoing treatment for cancer often report problems with their cognitive function, which is an essential component of health-related quality of life. Pursuant to this, a two-arm randomized, placebo-controlled, double-blind, phase III clinical trial was conducted to evaluate Ginkgo biloba (EGB 761) for the prevention of chemotherapy-related cognitive dysfunction in patients with breast cancer. METHODS: Previously chemotherapy naïve women about to receive adjuvant chemotherapy for breast cancer were randomized to receive 60 mg of EGB 761 or a matching placebo twice daily. The study agent was to begin before their second cycle of chemotherapy and to be taken throughout chemotherapy and 1 month beyond completion. The primary measure for cognitive function was the High Sensitivity Cognitive Screen (HSCS), with a secondary measure being the Trail Making Tests (TMT) A and B. Subjective assessment of cognitive function was evaluated by the cognitive subscale of the Perceived Health Scale (PHS) and the Profile of Mood States (POMS). Data were collected at baseline and at intervals throughout and after chemotherapy, up to 24 months after completion of adjuvant treatment. The primary statistical analysis included normalized area under the curve (AUC) comparisons of the HSCS, between the arms. Secondary analyses included evaluation of the other measures of cognition as well as correlational analyses between self-report and cognitive testing. RESULTS: One hundred and sixty-six women provided evaluable data. There were no significant differences in AUC up to 12 months on the HSCS between arms at the end of chemotherapy or at any other time point after adjuvant treatment. There were also no significant differences in TMT A or B at any data point. Perceived cognitive functions, as measured by the PHS and confusion/bewilderment subscale of the POMS, were not different between arms at the end of chemotherapy. There was also little correlation between self-reported cognition and cognitive testing. No differences were observed in toxicities per Common Terminology Criteria for Adverse Events (CTCAE) assessment between Ginkgo biloba and placebo throughout the study; however, after chemotherapy, the placebo group reported worse nausea (p = .05). CONCLUSION: This study did not provide any support for the notion that Ginkgo biloba, at a dose of 60 mg twice a day, can help prevent cognitive changes from chemotherapy. These analyses do provide data to further support the low associations between patients' self-report of cognition and cognitive performance, based on more formal testing.
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Neoplasias de la Mama/tratamiento farmacológico , Trastornos del Conocimiento/prevención & control , Ginkgo biloba , Fitoterapia , Quimioterapia Adyuvante/efectos adversos , Trastornos del Conocimiento/inducido químicamente , Femenino , Humanos , Persona de Mediana Edad , Autoinforme , Estados UnidosRESUMEN
BACKGROUND AND AIMS: Bariatric and metabolic surgery (BMS) may adversely affect noninvasive stool tests for colorectal cancer (CRC) screening through several mechanisms. Multitarget stool DNA (mt-sDNA) is approved for CRC screening; however, performance in post-BMS patients is unknown. As the rates of BMS are anticipated to increase with rising incidence of obesity, it is important to evaluate mt-sDNA test performance among these patients. METHODS: In a multisite academic and community-based practice, we obtained mt-sDNA results from 10/2014 to 12/2019 through electronic records and an institutional BMS registry. Average CRC risk patients with BMS prior to a positive mt-sDNA underwent a detailed chart review. Follow-up colonoscopy findings were compared to those among BMS patients screened with colonoscopy alone and a historical cohort of patients without BMS, screened by mt-sDNA. The primary study endpoint was the positive predictive value (PPV) for advanced colorectal neoplasia. RESULTS: Among 336 average-risk patients who had mt-sDNA after BMS, mt-sDNA was positive in 49 (14.6%), 47/49 (96%) underwent follow-up colonoscopy, and the PPV for advanced neoplasia was 12/47 (25.5%). This is similar to the PPV for advanced colorectal neoplasia (425/1542, 28%) in a historical cohort of persons without prior BMS, screened by mt-sDNA at our center (P = .86). Among those who had prior BMS, the rate of advanced neoplasia was higher after mt-sDNA compared to screening colonoscopy alone. CONCLUSION: Despite anatomic and physiologic mechanisms that could alter blood or DNA content in stool, BMS does not appear to adversely affect the PPV of mt-sDNA.
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Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgical prophylaxis.To validate a panel of methylated DNA markers (MDM) previously identified in sporadic colorectal cancer and endometrial cancer for discrimination of these cancers in LS.In a case-control design, previously identified MDMs for the detection of colorectal cancer and endometrial cancer were assayed by qMSP on tissue-extracted DNA. Results were normalized to ACTB values within each sample. Least absolute shrinkage and selection operator models to classify colorectal cancer and endometrial cancer were trained on sporadic cases and controls and then applied to classify colorectal cancer and endometrial cancer, in those with LS, and cross-validated.We identified colorectal cancer cases (23 with LS, 48 sporadic), colorectal controls (32 LS, 48 sporadic), endometrial cancer cases (30 LS, 48 sporadic), and endometrial controls (29 LS, 37 sporadic). A 3-MDM panel (LASS4, LRRC4, and PPP2R5C) classified LS-CRC from LS controls with an AUC of 0.92 (0.84-0.99); results were similar for sporadic colorectal cancer. A 6-MDM panel (SFMBT2, MPZ, CYTH2, DIDO1, chr10.4479, and EMX2OS) discriminated LS-EC from LS controls with an AUC of 0.92 (0.83-1.0); the AUC for sporadic endometrial cancer versus sporadic controls was nominally higher, 0.99 (0.96-1.0).MDMs previously identified in sporadic endometrial cancer and colorectal cancer discriminate between endometrial cancer and benign endometrium and colorectal cancer and benign colorectum in LS. This supports the inclusion of patients with LS within future prospective clinical trials evaluating endometrial cancer and colorectal cancer MDMs and may provide a new avenue for cancer screening or surveillance in this high-risk population. PREVENTION RELEVANCE: Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgery. Methylated DNA markers previously identified in sporadic endometrial cancer and colorectal cancer discriminate between benign and cancer tissue in LS.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Endometriales , Femenino , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Marcadores Genéticos , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Factores de Riesgo , Endometrio , Inestabilidad de MicrosatélitesRESUMEN
PURPOSE: Surveillance after primary melanoma treatment aims to detect early signs of low-volume systemic disease. The current standard of care, surveillance imaging, is costly and difficult to access. We therefore sought to develop methylated DNA markers (MDMs) as promising alternatives for disease surveillance. METHODS: We used reduced representation bisulfite sequencing (RRBS) to identify MDMs in DNA samples obtained from metastatic melanoma, benign nevi, and normal skin tissues. The identified MDMs underwent validation in an independent cohort of tissue and buffy coat DNA samples. Subsequently, we tested the validated MDMs in the plasma DNA of patients with metastatic melanoma undergoing surveillance with total body imaging and compared them with cancer-free controls. To estimate the overall predictive accuracy of the MDMs, we used random forest modeling with bootstrap cross-validation. RESULTS: Forty MDMs demonstrated discrimination between melanoma cases and controls consisting of benign nevi and normal skin. Nine MDMs passing biological validation in tissue were run on 77 plasma samples from individuals with a history of metastatic melanoma, 49 of whom had evidence of disease detected by imaging at the time of blood draw, and 100 cancer-free controls. The cross-validated sensitivity of the panel for imaging-positive disease was 80% with a specificity of 100% in cancer-free controls, resulting in an overall AUC of 0.88 (95% CI, 0.81 to 0.96). The survival estimates for patients with melanoma who tested positive for the panel at 6 months and 1 year were 67% and 56%, respectively, while those who tested negative had survival rates of 100% and 92%. CONCLUSION: MDMs identified by RRBS demonstrate a high degree of concordance with imaging results in the plasma of patients with metastatic melanoma. Further prospective studies in larger intended use cohorts are needed to confirm these findings.
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Melanoma , Nevo , Humanos , Marcadores Genéticos , Estudios Prospectivos , Melanoma/diagnóstico , Melanoma/genética , ADNRESUMEN
BACKGROUND: Radiographic surveillance of colorectal cancer (CRC) after curative-intent therapy is costly and unreliable. Methylated DNA markers (MDMs) detected primary CRC and metastatic recurrence with high sensitivity and specificity in cross-sectional studies. This study evaluated using serial MDMs to detect recurrence and monitor the treatment response to anti-cancer therapies. METHODS: A nested case-control study was drawn from a prospective cohort of patients with CRC who completed curative-intent therapy for CRC of all stages. Plasma MDMs were assayed vis target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, and analyzed in combination with serum carcinoembryonic antigen to yield an MDM score. Clinical information, including treatment and radiographic measurements of the tumor burden, were longitudinally collected. RESULTS: Of the 35 patients, 18 had recurrence and 17 had no evidence of disease during the study period. The MDM score was positive in 16 out of 18 patients who recurred and only 2 of the 17 patients without recurrence. The MDM score detected recurrence in 12 patients preceding clinical or radiographic detection of recurrent CRC by a median of 106 days (range 90-232 days). CONCLUSIONS: Plasma MDMs can detect recurrent CRC prior to radiographic detection; this tumor-agnostic liquid biopsy approach may assist cancer surveillance and monitoring.
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OBJECTIVE: Early identification of human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) is challenging and novel biomarkers are needed. We hypothesized that a panel of methylated DNA markers (MDMs) found in HPV(+) cervical squamous cell carcinoma (CSCC) will have similar discrimination in HPV(+)OPSCC tissues. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tissues were obtained from patients with primary HPV(+)OPSCC or HPV(+)CSCC; control tissues included normal oropharynx palatine tonsil (NOP) and cervix (NCS). Using a methylation-specific polymerase chain reaction, 21 previously validated cervical MDMs were evaluated on tissue-extracted DNA. Discrimination between case and control cervical and oropharynx tissue was assessed using area under the curve (AUC). RESULTS: 34 HPV(+)OPSCC, 36 HPV(+)CSCC, 26 NOP, and 24 NCS patients met inclusion criteria. Within HPV(+)CSCC, 18/21 (86%) of MDMs achieved an AUC ≥ 0.9 and all MDMs exhibited better than chance classifications relative to control cervical tissue (all p < 0.001). In contrast, within HPV(+)OPSCC only 5/21 (24%) MDMs achieved an AUC ≥ 0.90 but 19/21 (90%) exhibited better than chance classifications relative to control tonsil tissue (all p < 0.001). Overall, 13/21 MDMs had statistically significant lower AUCs in the oropharyngeal cohort compared to the cervical cohort, and only 1 MDM exhibited a statistically significant increase in AUC. CONCLUSIONS: Previously validated MDMs exhibited robust performance in independent HPV(+)CSCC patients. However, most of these MDMs exhibited higher discrimination for HPV(+)CSCC than for HPV(+)OPSCC. This suggests that each SCC subtype requires a unique set of MDMs for optimal discrimination. Future studies are necessary to establish an MDM panel for HPV(+)OPSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas/patología , Virus del Papiloma Humano , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/genética , Marcadores Genéticos , Metilación de ADN , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/genética , Papillomaviridae/genética , Neoplasias de Cabeza y Cuello/genéticaRESUMEN
BACKGROUND: Paclitaxel causes an acute pain syndrome (P-APS), occurring within days after each dose and usually abating within days. Paclitaxel also causes a more classic peripheral neuropathy, which steadily increases in severity with increasing paclitaxel total doses. Little detail is available regarding the natural history of these 2 syndromes, or any relationship between them, although a recent publication does provide natural history data about weekly paclitaxel, supporting an association between the severity of P-APS and eventual peripheral neuropathy symptoms. METHODS: Patients entering this study were about to receive paclitaxel and carboplatin every 3 weeks. Daily questionnaires were completed for the first week after every chemotherapy dose, and European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Chemotherapy-Induced Peripheral Neuropathy 20-item instruments were completed weekly. RESULTS: The P-APS severity peaked on day 4 after the initial chemotherapy dose, with 12%, 29%, 23%, and 36% of patients having maximal pain scores of 0, 1 to 4, 5 or 6, or 7 to 10 during the first week after the first dose of therapy, respectively. Patients with P-APS scores of 0 to 4 with the first dose of chemotherapy had less eventual sensory neuropathy than did patients with P-APS scores of 5 to 10 (P = 0.001). With regard to the more peripheral neuropathy, sensory neuropathy was more problematic than was either motor or autonomic neuropathy. Numbness and tingling were more common components of the sensory neuropathy than was pain. CONCLUSIONS: Patients with worse P-APS severities appear to have more eventual chemotherapy-induced peripheral neuropathy. This provides support for the concept that P-APS is a form of nerve pathology.
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Dolor Agudo/inducido químicamente , Antineoplásicos Fitogénicos/efectos adversos , Paclitaxel/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Dolor Agudo/etiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , SíndromeRESUMEN
BACKGROUND: There is little research on the quality of life (QOL) and spiritual well-being (SWB) of women diagnosed with ovarian cancer and their spouses. OBJECTIVE: We compared the SWB and QOL of these women and their spouses over a 3-year period. METHODS: This is a descriptive, longitudinal study involving 70 women with ovarian cancer and 26 spouses. Questionnaires were completed postoperatively and by mail 3, 7, 12, 18, 24, and 36 months later. All participants completed the Functional Assessment of Chronic Illness Therapy (FACIT)-Spiritual Well-Being-Expanded Version, Symptom Distress Scale, and open-ended questions about changes in their lives. Diagnosed women completed the FACIT-Ovarian and spouses the Caregiver Burden Interview and Linear Analog Self-Assessment scales. RESULTS: Women reported a high level of SWB over time. Spouses' SWB was significantly worse than the women's at 1 and 3 years (P ≤ .05). Insomnia, fatigue, and outlook/worry were problematic across time, with no significant differences between women and spouses except that women experienced more insomnia through 3 months (P = .02). Emotional well-being was compromised over time for the women but not their spouses until year 3. Physical and social well-being were compromised in spouses across time, while women's social well-being remained high and physical well-being was problematic only for the first year. LIMITATIONS: Limitations include a small spouse sample and, due to the disease process, attrition over time. CONCLUSIONS: Ovarian cancer has significant, but different, effects on women and spouses. Some effects are static, while others are not, which underscores the need for continual monitoring.
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Neoplasias Ováricas/psicología , Calidad de Vida , Espiritualidad , Esposos/psicología , Adaptación Psicológica , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Estudios Longitudinales , Masculino , Salud Mental , Persona de Mediana Edad , Factores Socioeconómicos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Historically, skin toxicity has been assessed in prospective clinical trials using the clinician-reported National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). The patient-reported Skindex-16 measures symptoms and perceptions of toxicity. This study was designed to compare information provided by these two measures. METHODS: Data were compiled from three placebo-controlled North Central Cancer Treatment Group studies (N06C4, N03CB, N05C4) having rash prevention as the primary objective. All used the Skindex-16 and CTCAE at baseline, weekly during treatment and during a minimum 2-week follow-up period. Statistical procedures, including Pearson correlations, were utilized to determine relationships between adverse event (AE) grades and Skindex-16 scores. RESULTS: Four hundred and twelve individual patients provided data (median age, 61; 134 male). Patients' Skindex-16 score results show a 0.9 overall mean (range 0-6 with 6 being worse symptoms), a 0.4 baseline mean (range, 0-4.3) and a 1.3 end-of-treatment mean (range, 0-5.9). Ninety-three, 142 and 177 patients experienced a grade 0, 1 and 2+ CTCAE skin toxicity, respectively. Baseline Skindex-16 scores had relatively low correlation with CTCAE grades. The correlation of rash grade with Skindex-16 scores ranged from r = 0.49 with the function subscale to r = 0.62 with the symptom subscale. The highest correlations of the maximum grade of any dermatological AE with the Skindex-16 were r = 0.48 for the total score and r = 0.55 for the symptom subscale. CONCLUSIONS: The data reported support the decision to include both measures in a clinical trial to assess the patient experience, as each measure may specifically target varying symptoms and intensities.
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Antineoplásicos/efectos adversos , Exantema/inducido químicamente , Exantema/clasificación , Neoplasias/complicaciones , Neoplasias/terapia , Radiodermatitis/clasificación , Índice de Severidad de la Enfermedad , Terminología como Asunto , Algoritmos , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/radioterapia , Cetuximab , Clorhidrato de Erlotinib , Femenino , Gefitinib , Humanos , Masculino , Persona de Mediana Edad , Furoato de Mometasona , Pregnadienodioles/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de la Síntesis de la Proteína/uso terapéutico , Quinazolinas/efectos adversos , Radiodermatitis/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Protectores Solares/uso terapéutico , Encuestas y Cuestionarios , Tetraciclina/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: Multitarget stool DNA (mt-sDNA) is approved for average-risk colorectal cancer screening; test performance in persons with prior radiation therapy (RT) has not been studied. RT can induce gastrointestinal bleeding and alter DNA methylation, which may affect mt-sDNA accuracy. Among patients previously treated with RT, we aimed to measure the positive predictive value (PPV) of mt-sDNA and compare these results to historical estimates of mt-sDNA PPV among average-risk patients. METHODS: After institutional review board approval, we conducted a retrospective cohort study of a multisite academic and community-based practice. Patients with RT and subsequent mt-sDNA use during the study period (2014-2016) were identified. The findings at diagnostic colonoscopy were compared with published reports among average-risk patients. Nominal P values were generated by 2-tailed Fisher's exact testing in comparisons of colorectal neoplasia (CRN) rates between groups. RESULTS: There were 220 patients who had RT before mt-sDNA testing. RT was delivered along the aerodigestive tract in 108 patients. Mt-sDNA tests were positive in 45 of 220 patients (20%), and colonoscopy findings were available for 42; 31 of 42 patients (74%) had CRN. PPV by mt-sDNA was similar when stratified by site of prior RT (along vs outside the aerodigestive tract; P = 1.00). Detection of advanced CRN (36%) was nominally higher than previously published retrospective (27%) and prospective (20%) studies. The median time from the start of RT to mt-sDNA use was 7 (interquartile range, 3-14) years. CONCLUSION: With a test positivity rate and PPV for CRN similar to reports among average-risk patients, prior RT does not appear to adversely affect mt-sDNA performance.