The actionable genomic mutational landscape in solid tumours.

Loddo, Marco; Hardisty, Keeda-Marie; Thatcher, Robert; Haddow, Tiffany Eira; Williams, Gareth

doi:10.1200/jco.2020.38.15_suppl.e13642

“…Actionable variants were identified in all glioblastoma patients tested and indeed the majority of patients harboured three or more actionable variants. This compares to our analysis of solid tumours overall where actionable variants were detected in 90% of patients with a median variant frequency of two (median 2, range 0-13) [27]. The genetic variants identified affect many key cancer-related regulatory networks including the PI3K/AKT/ MTOR, RAS/RAF/MEK/MAPK, JAK/STAT, PLC/PKC signalling pathways, DNA damage repair (DDR) pathways and cell cycle and immune checkpoints.…”

Section: Plos Onementioning

confidence: 60%

Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma

Williams¹,

Llewelyn²,

Thatcher³

et al. 2022

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The standard treatment for glioblastoma involves a combination of surgery, radiation and chemotherapy but have limited impact on survival. The exponential increase in targeted agents directed at pivotal oncogenic pathways now provide new therapeutic opportunities for this tumour type. However, lack of comprehensive precision oncology testing at diagnosis means such therapeutic opportunities are potentially overlooked. To investigate the role of semiconductor sequencing for detection of predictive biomarkers in routine glioblastoma samples we have undertaken analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture actionable genomic variants distributed across 505 genes. Analysis was performed across a cohort of 55 glioblastoma patients. Analysis of trending data has revealed a complex and rich actionable mutational landscape in which 166 actionable mutations were detected across 36 genes linked to 17 off label targeted therapy protocols and 111 clinical trials. The majority of patients harboured three or more actionable mutations affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signalling pathways, DNA-damage repair pathways and cell cycle checkpoints. Linkage with immunotherapy and PARP inhibitors was identified in 44% of glioblastoma patients as a consequence of alterations in DNA-damage repair genes. Taken together our data indicates that precision oncology testing utilising semiconductor sequencing can be used to identify a broad therapeutic armamentarium of targeted therapies and immunotherapies that can be potentially employed for the improved clinical management of glioblastoma patients.

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“…This platform enables detection of 867 druggable driver-partner oncogenic fusions via analysis of 51 driver and 349 partner genes, with linkage to 140 targeted therapy protocols. All variants detected are "actionable" and therefore treatable by targeted therapies either on-market FDA and EMA approved, carrying ESMO and NCCN guideline references or currently in clinical trials, phases I-IV, worldwide [18].…”

Section: Introductionmentioning

confidence: 99%

Utilisation of semiconductor sequencing for detection of actionable fusions in solid tumours

Loddo¹,

Hardisty²,

Llewelyn³

et al. 2022

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Oncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. However screening for fusions in routinely processed tissue samples is constrained due to degradation of nucleic acid as a result of formalin fixation., To investigate the clinical utility of semiconductor sequencing optimised for detection of actionable fusion transcripts in formalin fixed samples, we have undertaken an analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 867 of the most clinically relevant druggable driver-partner oncogenic fusions. Here we show across a real-life cohort of 1112 patients with solid tumours that actionable fusions occur at high frequency (7.4%) with linkage to a wide range of targeted therapy protocols including seven fusion-drug matches with FDA/EMA approval and/or NCCN/ESMO recommendations and 80 clinical trials. The more prevalent actionable fusions identified were independent of tumour type in keeping with signalling via evolutionary conserved RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT pathways. Taken together our data indicates that semiconductor sequencing for detection of actionable fusions can be integrated into routine diagnostic pathology workflows enabling the identification of personalised treatment options that have potential to improve clinical cancer management across many tumour types.

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“…This screen includes detection of 867 druggable driver-partner oncogenic fusions via analysis of driver and 349 partner genes, with linkage to 140 targeted therapy protocols. All variants detected are "actionable" and therefore treatable by targeted therapies either on-market FDA and EMA approved, carrying ESMO and NCCN guideline references or currently in clinical trials, phases I-IV, worldwide [18]. Here we have undertaken a retrospective analysis of test trending data to investigate the types and frequency of clinically relevant fusions in solid tumours.…”

mentioning

confidence: 99%

“…analysis of driver and 349 partner genes, with linkage to 140 targeted therapy protocols. All variants detected are "actionable" and therefore treatable by targeted therapies either on-market FDA and EMA approved, carrying ESMO and NCCN guideline references or currently in clinical trials, phases I-IV, worldwide [18].…”

mentioning

confidence: 99%

Utilisation of semiconductor sequencing for detection of actionable fusions in solid tumours

Loddo¹,

Hardisty²,

Haddow³

et al. 2021

Preprint

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0

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Oncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. However screening for fusions in routinely processed tissue samples is constrained due to degradation of nucleic acid as a result of formalin fixation., To investigate the clinical utility of semiconductor sequencing optimised for detection of actionable fusion transcripts in formalin fixed samples, we have undertaken an analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 867 of the most clinically relevant druggable driver-partner oncogenic fusions. Here we showacross a real-life cohort of 1112 patients with solid tumours that actionable fusions occur at high frequency (7.4%) with linkage to a wide range of targeted therapy protocols including seven fusion-drug matches with FDA/EMA approval and/or NCCN/ESMO recommendations and 80 clinical trials. The majority of actionable fusions identified were independent of tumour type in keeping with signalling via evolutionary conserved Wnt/β-catenin, RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT pathways. Taken together our data indicates that semiconductor sequencing for detection of actionable fusions can be integrated into routine diagnostic pathology workflows enabling the identification of personalised treatment options that have potential to improve clinical cancer management across many tumour types.Oncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. However screening for fusions in routinely processed tissue samples is constrained due to degradation of nucleic acid as a result of formalin fixation., To investigate the clinical utility of semiconductor sequencing optimised for detection of actionable fusion transcripts in formalin fixed samples, we have undertaken an analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 867 of the most clinically relevant druggable driver-partner oncogenic fusions. Here we showacross a real-life cohort of 1112 patients with solid tumours that actionable fusions occur at high frequency (7.4%) with linkage to a wide range of targeted therapy protocols including seven fusion-drug matches with FDA/EMA approval and/or NCCN/ESMO recommendations and 80 clinical trials. The majority of actionable fusions identified were independent of tumour type in keeping with signalling via evolutionary conserved Wnt/β-catenin, RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT pathways. Taken together our data indicates that semiconductor sequencing for detection of actionable fusions can be integrated into routine diagnostic pathology workflows enabling the identification of personalised treatment options that have potential to improve clinical cancer management across many tumour types.

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The actionable genomic mutational landscape in solid tumours.

Cited by 6 publications

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Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma

Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma

Utilisation of semiconductor sequencing for detection of actionable fusions in solid tumours

Utilisation of semiconductor sequencing for detection of actionable fusions in solid tumours

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