A Stepwise Integrated Approach to Personalized Risk Predictions in Stage III Colorectal Cancer

Salvucci, Manuela; Würstle, Maximilian L.; Morgan, Clare; Curry, Sarah; Cremona, Mattia; Lindner, Andreas U.; Bacon, Orna; Resler, Alexa J.; Murphy, Áine C.; O’Byrne, Robert; Flanagan, Lorna; Dasgupta, Sonali; Rice, Nadege; Pilati, Camilla; Zink, Elisabeth; Schöller, Lisa M.; Toomey, Sinéad; Lawler, Mark; Johnston, Patrick G.; Wilson, Richard H.; Camilleri-Broët, Sophie; Salto-Tellez, Manuel; McNamara, Deborah A.; Kay, Elaine W.; Laurent‐Puig, Pierre; Schaeybroeck, Sandra Van; Hennessy, Bryan T.; Longley, Daniel B.; Rehm, Markus; Prehn, Jochen H M

doi:10.1158/1078-0432.ccr-16-1084

Cited by 23 publications

(36 citation statements)

References 50 publications

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“…Amongst others, a 12‐gene expression recurrence score (RS) platform has been extensively evaluated both in retrospective series and as “prospectively designed retrospectively tested” analysis of large phase III adjuvant trials . The 12‐gene assay includes a reverse transcription polymerase chain reaction (RT‐PCR) quantification of key transcripts involved in cell cycle, stromal activation and genotoxic stress pathway .…”

Section: Discussionmentioning

confidence: 99%

Noninferiority of three months versus six months of oxaliplatin‐based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice?

Formica

Zaniboni

Loupakis

et al. 2018

Intl Journal of Cancer

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The eagerly awaited results of the multi-continental International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project have recently been presented at major oncological meetings. The 3-year disease-free survival (DFS) was presented for 12,834 Stage III colon cancer patients in a pooled analysis of 6 individual noninferiority phase III randomized trials, all investigating three versus six months of oxaliplatin-based adjuvant therapy. Noninferiority (NI) could not be demonstrated for the whole population as the DFS hazard ratio (HR) of 1.07 with its 95% CI of 1.00-1.15 crossed the postulated NI boundary of 1.12. However, there was an expected reduction in the incidence of specific side effects with the three months treatment. NI could be demonstrated for the T3N1 subgroup (∼60% of patients, HR for DFS 1.01, 95% CI 0.90-1.12). Moreover, NI was also declared for the subgroup treated with the CAPOX regimen (capecitabine plus oxaliplatin, ∼40% of patients), but the CAPOX choice was physician-based and not subject to randomization. Overall, the IDEA results indicate that three months of therapy might be adequate for most of Stage III tumors; however, a small subset of these patients still have high risk of recurrence and death with short treatment duration. Precise predictors of benefit need to be identified, nonetheless tumor-intrinsic factors, such as tumor stage, might currently be considered as useful tools to inform the decision-making process.

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Section: Discussionmentioning

confidence: 99%

Noninferiority of three months versus six months of oxaliplatin‐based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice?

Formica

Zaniboni

Loupakis

et al. 2018

Intl Journal of Cancer

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“…Stage III colorectal cancer patient data, including survival data and protein expression data were published previously [24]. All patients underwent 5-fluorouracil-based adjuvant chemotherapy and had clear resection margins (R0).…”

Section: Application Of the Model To Colorectal Cancer Patient Datamentioning

confidence: 99%

“…All patients underwent 5-fluorouracil-based adjuvant chemotherapy and had clear resection margins (R0). Raw data and processing scripts are downloadable from https:// doi.org/10.5281/zenodo.1162683 [24]. Concentrations of PC9, PC3, XIAP and SMAC were used as inputs alongside the median value of APAF1 measured previously in colorectal cancer cells of 0.123 μM [25].…”

Section: Application Of the Model To Colorectal Cancer Patient Datamentioning

confidence: 99%

“…Previously, we demonstrated that a simplified model of apoptosis execution was prognostic for disease free and overall survival in stage III colorectal cancer patients treated with chemotherapy [24]. We therefore aimed to discover if the molecular timer can contribute to correctly prognosticating patient outcome.…”

Section: Mathematical Modelling Prognosticates Treatment Response Andmentioning

confidence: 99%

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The apoptosome molecular timer synergises with XIAP to suppress apoptosis execution and contributes to prognosticating survival in colorectal cancer

Fullstone¹,

Bauer²,

Guttà³

et al. 2020

Cell Death Differ

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The execution phase of apoptosis is a critical process in programmed cell death in response to a multitude of cellular stresses. A crucial component of this pathway is the apoptosome, a platform for the activation of pro-caspase 9 (PC9). Recent findings have shown that autocleavage of PC9 to Caspase 9 (C9) p35/p12 not only permits XIAP-mediated C9 inhibition but also temporally shuts down apoptosome activity, forming a molecular timer. In order to delineate the combined contributions of XIAP and the apoptosome molecular timer to apoptosis execution we utilised a systems modelling approach. We demonstrate that cooperative recruitment of PC9 to the apoptosome, based on existing PC9-apoptosome interaction data, is important for efficient formation of PC9 homodimers, autocatalytic cleavage and dual regulation by XIAP and the molecular timer across biologically relevant PC9 and APAF1 concentrations. Screening physiologically relevant concentration ranges of apoptotic proteins, we discovered that the molecular timer can prevent apoptosis execution in specific scenarios after complete or partial mitochondrial outer membrane permeabilisation (MOMP). Furthermore, its ability to prevent apoptosis is intricately tied to a synergistic combination with XIAP. Finally, we demonstrate that simulations of these processes are prognostic of survival in stage III colorectal cancer and that the molecular timer may promote apoptosis resistance in a subset of patients. Based on our findings, we postulate that the physiological function of the molecular timer is to aid XIAP in the shutdown of caspase-mediated apoptosis execution. This shutdown potentially facilitates switching to pro-inflammatory caspase-independent responses subsequent to Bax/Bak pore formation.

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“… 6 However, systems approaches are not limited to the dynamical systems theory and differential equation models, 7 , 8 and current approaches often combine a range of statistical, mathematical and computational approaches in workflows to analyze and interpret data. 9 But also abstract models can challenge clinical practice, and are thus of direct relevance to medical practice. 10 While the classical bio-statistical analysis has a long history and its importance is widely accepted in evidence-based medicine, systems medicine requires a wider range of mathematical and computational techniques.…”

Section: Why ‘Systems’?mentioning

confidence: 99%

Whither systems medicine?

et al. 2018

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New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.

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A Stepwise Integrated Approach to Personalized Risk Predictions in Stage III Colorectal Cancer

Cited by 23 publications

References 50 publications

Noninferiority of three months versus six months of oxaliplatin‐based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice?

Noninferiority of three months versus six months of oxaliplatin‐based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice?

The apoptosome molecular timer synergises with XIAP to suppress apoptosis execution and contributes to prognosticating survival in colorectal cancer

Whither systems medicine?

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