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Glenn Heller - One of the best experts on this subject based on the ideXlab platform.

  • estimating the concordance Probability in a survival analysis with a discrete number of risk groups
    Lifetime Data Analysis, 2016
    Co-Authors: Glenn Heller
    Abstract:

    A clinical risk classification system is an important component of a treatment decision algorithm. A measure used to assess the strength of a risk classification system is discrimination, and when the outcome is survival time, the most commonly applied global measure of discrimination is the concordance Probability. The concordance Probability represents the pairwise Probability of lower patient risk given longer survival time. The c-index and the concordance Probability Estimate have been used to Estimate the concordance Probability when patient-specific risk scores are continuous. In the current paper, the concordance Probability Estimate and an inverse Probability censoring weighted c-index are modified to account for discrete risk scores. Simulations are generated to assess the finite sample properties of the concordance Probability Estimate and the weighted c-index. An application of these measures of discriminatory power to a metastatic prostate cancer risk classification system is examined.

  • analytic and clinical validation of a prostate cancer enhanced messenger rna detection assay in whole blood as a prognostic biomarker for survival
    European Urology, 2014
    Co-Authors: Glenn Heller, Daniel C Danila, Aseem Anand, Nikolaus Schultz, Mingliang Wan, Clifford C Sung, Charles Dai, Raya Khanin, Martin Fleisher
    Abstract:

    Abstract Background Biomarkers based on detecting prostate cancer (PCa)-specific transcripts in blood are associated with inferior outcomes, but their validation in a clinical context is lacking. Objective To determine whether detecting enhanced transcripts for PCa in whole blood using an analytically valid assay has prognostic significance relative to circulating tumor cell (CTC) enumeration. Design, setting, and participants The detection of KLK3, KLK2, HOXB13, GRHL2 , and FOXA1 in whole blood by reverse transcription polymerase chain reaction (RT-PCR) was studied in 97 men with metastatic castration-resistant PCa (mCRPC) as a prognostic factor for overall survival. Intervention The 2.5ml of blood was collected in PAXgene tubes for total RNA extraction and 7.5ml for CTC enumeration from patients with progressive mCRPC. Outcome measurements and statistical analysis PCa-enriched genes were detected using a sensitive RT-PCR assay in whole blood from patients with mCRPC. Analytical validity of the assay was established in a clinical laboratory environment. The frequency of detecting transcripts was compared to CTC enumeration using CellSearch in an independent data set and survival associations were explored by concordance Probability Estimate (CPE). Results and limitations Two or more genes were detected by PCR in 53% of patients (51 of 97; 95% confidence interval [CI], 43–63%), and unfavorable CTC counts (five of more cells) were seen in 46% (45 of 97; 95% CI, 36–56%). Importantly, transcripts were detectable in 11 of 52 patients with favorable CTC counts (21%; 95% CI, 8–35%). Transcript detection predicted overall survival in a proportional hazards model. Significantly, the predictive accuracy of RT-PCR detection in combination with CTC enumeration had a CPE of 0.752 (standard error: 0.038), although this was limited by the number of patients evaluated. Conclusions This validated RT-PCR assay detecting prostate-specific RNA in whole blood is prognostic for survival and may assess patient risk in tandem with CellSearch CTC enumeration. Its clinical utility is being prospectively explored.

  • circulating tumour cells as prognostic markers in progressive castration resistant prostate cancer a reanalysis of immc38 trial data
    Lancet Oncology, 2009
    Co-Authors: Martin Fleisher, Howard I Scher, Johann S De Bono, Kenneth J Pienta, Derek Raghavan, Glenn Heller
    Abstract:

    Summary Background Intermediate or surrogate endpoints for survival can shorten time lines for drug approval. We aimed to assess circulating tumour cell (CTC) count as a prognostic factor for survival in patients with progressive, metastatic, castration-resistant prostate cancer receiving first-line chemotherapy. Methods We identified patients with progressive metastatic castration-resistant prostate cancer starting first-line chemotherapy in the IMMC38 trial. CTCs were isolated by immunomagnetic capture from blood samples at baseline and after treatment. Baseline variables, including CTC count, titre of prostate-specific antigen (PSA), and concentration of lactate dehydrogenase (LDH), and post-treatment variables (change in CTCs and PSA) were tested for association with survival with Cox proportional hazards models. Concordance Probability Estimates were used to gauge discriminatory strength of the informative factors in identifying patients at low-risk and high-risk of survival. Findings Variables associated with high risk of death were high LDH concentration (hazard ratio 6·44, 95% CI 4·24–9·79), high CTC count (1·58, 1·41–1·77), and high PSA titre (1·26, 1·10–1·45), low albumin (0·10, 0·03–0·39), and low haemoglobin (0·72, 0·64–0·81) at baseline. At 4 weeks, 8 weeks, and 12 weeks after treatment, changes in CTC number were strongly associated with risk, whereas changes in PSA titre were weakly or not associated (p>0·04). The most predictive factors for survival were LDH concentration and CTC counts (concordance Probability Estimate 0·72–0·75). Interpretation CTC number, analysed as a continuous variable, can be used to monitor disease status and might be useful as an intermediate endpoint of survival in clinical trials. Prospective recording of CTC number as an intermediate endpoint of survival in randomised clinical trials is warranted. Funding The Prostate Cancer Foundation, Immunicon Corporation, Memorial Sloan-Kettering Cancer Center.

  • circulating tumor cell number and prognosis in progressive castration resistant prostate cancer
    Clinical Cancer Research, 2007
    Co-Authors: Daniel C Danila, Glenn Heller, Gretchen Gignac, Rita Gonzalezespinoza, Aseem Anand, Erika Tanaka, Hans Lilja, Lawrence H Schwartz, Steven M Larson, Martin Fleisher
    Abstract:

    PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We Estimated the Probability of survival over time by the Kaplan-Meier method. The concordance Probability Estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.

  • concordance Probability and discriminatory power in proportional hazards regression
    Biometrika, 2005
    Co-Authors: Mithat Gonen, Glenn Heller
    Abstract:

    The concordance Probability is used to evaluate the discriminatory power and the predictive accuracy of nonlinear statistical models. We derive an analytical expression for the concordance Probability in the Cox proportional hazards model. The proposed estimator is a function of the regression parameters and the covariate distribution only and does not use the observed event and censoring times. For this reason it is asymptotically unbiased, unlike Harrell's c-index based on informative pairs. The asymptotic distribution of the concordance Probability Estimate is derived using U-statistic theory and the methodology is applied to a predictive model in lung cancer. Copyright 2005, Oxford University Press.

Martin Fleisher - One of the best experts on this subject based on the ideXlab platform.

  • analytic and clinical validation of a prostate cancer enhanced messenger rna detection assay in whole blood as a prognostic biomarker for survival
    European Urology, 2014
    Co-Authors: Glenn Heller, Daniel C Danila, Aseem Anand, Nikolaus Schultz, Mingliang Wan, Clifford C Sung, Charles Dai, Raya Khanin, Martin Fleisher
    Abstract:

    Abstract Background Biomarkers based on detecting prostate cancer (PCa)-specific transcripts in blood are associated with inferior outcomes, but their validation in a clinical context is lacking. Objective To determine whether detecting enhanced transcripts for PCa in whole blood using an analytically valid assay has prognostic significance relative to circulating tumor cell (CTC) enumeration. Design, setting, and participants The detection of KLK3, KLK2, HOXB13, GRHL2 , and FOXA1 in whole blood by reverse transcription polymerase chain reaction (RT-PCR) was studied in 97 men with metastatic castration-resistant PCa (mCRPC) as a prognostic factor for overall survival. Intervention The 2.5ml of blood was collected in PAXgene tubes for total RNA extraction and 7.5ml for CTC enumeration from patients with progressive mCRPC. Outcome measurements and statistical analysis PCa-enriched genes were detected using a sensitive RT-PCR assay in whole blood from patients with mCRPC. Analytical validity of the assay was established in a clinical laboratory environment. The frequency of detecting transcripts was compared to CTC enumeration using CellSearch in an independent data set and survival associations were explored by concordance Probability Estimate (CPE). Results and limitations Two or more genes were detected by PCR in 53% of patients (51 of 97; 95% confidence interval [CI], 43–63%), and unfavorable CTC counts (five of more cells) were seen in 46% (45 of 97; 95% CI, 36–56%). Importantly, transcripts were detectable in 11 of 52 patients with favorable CTC counts (21%; 95% CI, 8–35%). Transcript detection predicted overall survival in a proportional hazards model. Significantly, the predictive accuracy of RT-PCR detection in combination with CTC enumeration had a CPE of 0.752 (standard error: 0.038), although this was limited by the number of patients evaluated. Conclusions This validated RT-PCR assay detecting prostate-specific RNA in whole blood is prognostic for survival and may assess patient risk in tandem with CellSearch CTC enumeration. Its clinical utility is being prospectively explored.

  • circulating tumour cells as prognostic markers in progressive castration resistant prostate cancer a reanalysis of immc38 trial data
    Lancet Oncology, 2009
    Co-Authors: Martin Fleisher, Howard I Scher, Johann S De Bono, Kenneth J Pienta, Derek Raghavan, Glenn Heller
    Abstract:

    Summary Background Intermediate or surrogate endpoints for survival can shorten time lines for drug approval. We aimed to assess circulating tumour cell (CTC) count as a prognostic factor for survival in patients with progressive, metastatic, castration-resistant prostate cancer receiving first-line chemotherapy. Methods We identified patients with progressive metastatic castration-resistant prostate cancer starting first-line chemotherapy in the IMMC38 trial. CTCs were isolated by immunomagnetic capture from blood samples at baseline and after treatment. Baseline variables, including CTC count, titre of prostate-specific antigen (PSA), and concentration of lactate dehydrogenase (LDH), and post-treatment variables (change in CTCs and PSA) were tested for association with survival with Cox proportional hazards models. Concordance Probability Estimates were used to gauge discriminatory strength of the informative factors in identifying patients at low-risk and high-risk of survival. Findings Variables associated with high risk of death were high LDH concentration (hazard ratio 6·44, 95% CI 4·24–9·79), high CTC count (1·58, 1·41–1·77), and high PSA titre (1·26, 1·10–1·45), low albumin (0·10, 0·03–0·39), and low haemoglobin (0·72, 0·64–0·81) at baseline. At 4 weeks, 8 weeks, and 12 weeks after treatment, changes in CTC number were strongly associated with risk, whereas changes in PSA titre were weakly or not associated (p>0·04). The most predictive factors for survival were LDH concentration and CTC counts (concordance Probability Estimate 0·72–0·75). Interpretation CTC number, analysed as a continuous variable, can be used to monitor disease status and might be useful as an intermediate endpoint of survival in clinical trials. Prospective recording of CTC number as an intermediate endpoint of survival in randomised clinical trials is warranted. Funding The Prostate Cancer Foundation, Immunicon Corporation, Memorial Sloan-Kettering Cancer Center.

  • circulating tumor cell number and prognosis in progressive castration resistant prostate cancer
    Clinical Cancer Research, 2007
    Co-Authors: Daniel C Danila, Glenn Heller, Gretchen Gignac, Rita Gonzalezespinoza, Aseem Anand, Erika Tanaka, Hans Lilja, Lawrence H Schwartz, Steven M Larson, Martin Fleisher
    Abstract:

    PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We Estimated the Probability of survival over time by the Kaplan-Meier method. The concordance Probability Estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.

Howard I Scher - One of the best experts on this subject based on the ideXlab platform.

  • circulating tumour cells as prognostic markers in progressive castration resistant prostate cancer a reanalysis of immc38 trial data
    Lancet Oncology, 2009
    Co-Authors: Martin Fleisher, Howard I Scher, Johann S De Bono, Kenneth J Pienta, Derek Raghavan, Glenn Heller
    Abstract:

    Summary Background Intermediate or surrogate endpoints for survival can shorten time lines for drug approval. We aimed to assess circulating tumour cell (CTC) count as a prognostic factor for survival in patients with progressive, metastatic, castration-resistant prostate cancer receiving first-line chemotherapy. Methods We identified patients with progressive metastatic castration-resistant prostate cancer starting first-line chemotherapy in the IMMC38 trial. CTCs were isolated by immunomagnetic capture from blood samples at baseline and after treatment. Baseline variables, including CTC count, titre of prostate-specific antigen (PSA), and concentration of lactate dehydrogenase (LDH), and post-treatment variables (change in CTCs and PSA) were tested for association with survival with Cox proportional hazards models. Concordance Probability Estimates were used to gauge discriminatory strength of the informative factors in identifying patients at low-risk and high-risk of survival. Findings Variables associated with high risk of death were high LDH concentration (hazard ratio 6·44, 95% CI 4·24–9·79), high CTC count (1·58, 1·41–1·77), and high PSA titre (1·26, 1·10–1·45), low albumin (0·10, 0·03–0·39), and low haemoglobin (0·72, 0·64–0·81) at baseline. At 4 weeks, 8 weeks, and 12 weeks after treatment, changes in CTC number were strongly associated with risk, whereas changes in PSA titre were weakly or not associated (p>0·04). The most predictive factors for survival were LDH concentration and CTC counts (concordance Probability Estimate 0·72–0·75). Interpretation CTC number, analysed as a continuous variable, can be used to monitor disease status and might be useful as an intermediate endpoint of survival in clinical trials. Prospective recording of CTC number as an intermediate endpoint of survival in randomised clinical trials is warranted. Funding The Prostate Cancer Foundation, Immunicon Corporation, Memorial Sloan-Kettering Cancer Center.

Daniel C Danila - One of the best experts on this subject based on the ideXlab platform.

  • analytic and clinical validation of a prostate cancer enhanced messenger rna detection assay in whole blood as a prognostic biomarker for survival
    European Urology, 2014
    Co-Authors: Glenn Heller, Daniel C Danila, Aseem Anand, Nikolaus Schultz, Mingliang Wan, Clifford C Sung, Charles Dai, Raya Khanin, Martin Fleisher
    Abstract:

    Abstract Background Biomarkers based on detecting prostate cancer (PCa)-specific transcripts in blood are associated with inferior outcomes, but their validation in a clinical context is lacking. Objective To determine whether detecting enhanced transcripts for PCa in whole blood using an analytically valid assay has prognostic significance relative to circulating tumor cell (CTC) enumeration. Design, setting, and participants The detection of KLK3, KLK2, HOXB13, GRHL2 , and FOXA1 in whole blood by reverse transcription polymerase chain reaction (RT-PCR) was studied in 97 men with metastatic castration-resistant PCa (mCRPC) as a prognostic factor for overall survival. Intervention The 2.5ml of blood was collected in PAXgene tubes for total RNA extraction and 7.5ml for CTC enumeration from patients with progressive mCRPC. Outcome measurements and statistical analysis PCa-enriched genes were detected using a sensitive RT-PCR assay in whole blood from patients with mCRPC. Analytical validity of the assay was established in a clinical laboratory environment. The frequency of detecting transcripts was compared to CTC enumeration using CellSearch in an independent data set and survival associations were explored by concordance Probability Estimate (CPE). Results and limitations Two or more genes were detected by PCR in 53% of patients (51 of 97; 95% confidence interval [CI], 43–63%), and unfavorable CTC counts (five of more cells) were seen in 46% (45 of 97; 95% CI, 36–56%). Importantly, transcripts were detectable in 11 of 52 patients with favorable CTC counts (21%; 95% CI, 8–35%). Transcript detection predicted overall survival in a proportional hazards model. Significantly, the predictive accuracy of RT-PCR detection in combination with CTC enumeration had a CPE of 0.752 (standard error: 0.038), although this was limited by the number of patients evaluated. Conclusions This validated RT-PCR assay detecting prostate-specific RNA in whole blood is prognostic for survival and may assess patient risk in tandem with CellSearch CTC enumeration. Its clinical utility is being prospectively explored.

  • circulating tumor cell number and prognosis in progressive castration resistant prostate cancer
    Clinical Cancer Research, 2007
    Co-Authors: Daniel C Danila, Glenn Heller, Gretchen Gignac, Rita Gonzalezespinoza, Aseem Anand, Erika Tanaka, Hans Lilja, Lawrence H Schwartz, Steven M Larson, Martin Fleisher
    Abstract:

    PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We Estimated the Probability of survival over time by the Kaplan-Meier method. The concordance Probability Estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.

Aseem Anand - One of the best experts on this subject based on the ideXlab platform.

  • analytic and clinical validation of a prostate cancer enhanced messenger rna detection assay in whole blood as a prognostic biomarker for survival
    European Urology, 2014
    Co-Authors: Glenn Heller, Daniel C Danila, Aseem Anand, Nikolaus Schultz, Mingliang Wan, Clifford C Sung, Charles Dai, Raya Khanin, Martin Fleisher
    Abstract:

    Abstract Background Biomarkers based on detecting prostate cancer (PCa)-specific transcripts in blood are associated with inferior outcomes, but their validation in a clinical context is lacking. Objective To determine whether detecting enhanced transcripts for PCa in whole blood using an analytically valid assay has prognostic significance relative to circulating tumor cell (CTC) enumeration. Design, setting, and participants The detection of KLK3, KLK2, HOXB13, GRHL2 , and FOXA1 in whole blood by reverse transcription polymerase chain reaction (RT-PCR) was studied in 97 men with metastatic castration-resistant PCa (mCRPC) as a prognostic factor for overall survival. Intervention The 2.5ml of blood was collected in PAXgene tubes for total RNA extraction and 7.5ml for CTC enumeration from patients with progressive mCRPC. Outcome measurements and statistical analysis PCa-enriched genes were detected using a sensitive RT-PCR assay in whole blood from patients with mCRPC. Analytical validity of the assay was established in a clinical laboratory environment. The frequency of detecting transcripts was compared to CTC enumeration using CellSearch in an independent data set and survival associations were explored by concordance Probability Estimate (CPE). Results and limitations Two or more genes were detected by PCR in 53% of patients (51 of 97; 95% confidence interval [CI], 43–63%), and unfavorable CTC counts (five of more cells) were seen in 46% (45 of 97; 95% CI, 36–56%). Importantly, transcripts were detectable in 11 of 52 patients with favorable CTC counts (21%; 95% CI, 8–35%). Transcript detection predicted overall survival in a proportional hazards model. Significantly, the predictive accuracy of RT-PCR detection in combination with CTC enumeration had a CPE of 0.752 (standard error: 0.038), although this was limited by the number of patients evaluated. Conclusions This validated RT-PCR assay detecting prostate-specific RNA in whole blood is prognostic for survival and may assess patient risk in tandem with CellSearch CTC enumeration. Its clinical utility is being prospectively explored.

  • circulating tumor cell number and prognosis in progressive castration resistant prostate cancer
    Clinical Cancer Research, 2007
    Co-Authors: Daniel C Danila, Glenn Heller, Gretchen Gignac, Rita Gonzalezespinoza, Aseem Anand, Erika Tanaka, Hans Lilja, Lawrence H Schwartz, Steven M Larson, Martin Fleisher
    Abstract:

    PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We Estimated the Probability of survival over time by the Kaplan-Meier method. The concordance Probability Estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.