Clinical next generation sequencing to identify actionable aberrations in a phase I program

Boland, Genevieve M.; Piha-Paul, Sarina A.; Subbiah, Vivek; Routbort, Mark J.; Herbrich, Shelley M.; Baggerly, Keith A.; Patel, Keyur P.; Brusco, Lauren; Horombe, Chacha; Naing, Aung; Fu, Siqing; Hong, David S.; Janků, Filip; Johnson, Amber; Broaddus, Russell R.; Luthra, Raja; Shaw, Kenna; Mendelsohn, John; Mills, Gordon B.; Meric‐Bernstam, Funda

doi:10.18632/oncotarget.4040

Cited by 48 publications

(49 citation statements)

References 21 publications

(20 reference statements)

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“…Massively parallel sequencing (MPS) offers several advantages over the single-gene approach (10)(11)(12)(13)(14)(15); most importantly, it offers a more sensitive and more comprehensive genomic profile that does not apply an a priori knowledge of alterations that may be more common in a specific tumor type. Several academic centers have demonstrated that large MPS panels can be employed in practice (11,16,17), with a number of groups reporting a high rate of "actionable" (informative or clinically relevant) gene alterations in clinical cancer cohorts (4,18,19).…”

Section: Introductionmentioning

confidence: 99%

Institutional implementation of clinical tumor profiling on an unselected cancer population

Sholl¹,

Khanh²,

Shivdasani³

et al. 2016

JCI Insight

349

314

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BACKGROUND.Comprehensive genomic profiling of a patient's cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprisewide, unselected cancer patient population has yet to be reported. METHODS.We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested.RESULTS. Our cohort consists of cancer patients unrestricted by disease site or stage. Across all consented patients, half had sufficient and available (>20% tumor) material for profiling; once specimens were received in the laboratory for pathology review, 73% were scored as adequate for genomic testing. When sufficient DNA was obtained, OncoPanel yielded a result in 96% of cases. 73% of patients harbored an actionable or informative alteration; only 19% of these represented a current standard of care for therapeutic stratification. The findings recapitulate those of previous studies of common cancers but also identify alterations, including in AXL and EGFR, associated with response to targeted therapies. In rare cancers, potentially actionable alterations suggest the utility of a "cancer-agnostic" approach in genomic profiling. Retrospective analyses uncovered contextual genomic features that may inform therapeutic response and examples where diagnoses revised by genomic profiling markedly changed clinical management. CONCLUSIONS.Broad sequencing-based testing deployed across an unselected cancer cohort is feasible. Genomic results may alter management in diverse scenarios; however, additional barriers must be overcome to enable precision cancer medicine on a large scale.

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Section: Introductionmentioning

confidence: 99%

Institutional implementation of clinical tumor profiling on an unselected cancer population

Sholl¹,

Khanh²,

Shivdasani³

et al. 2016

JCI Insight

349

314

View full text Add to dashboard Cite

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“…Between 29-72% of patients had potentially actionable targets after sequencing with multiplex panels in results from several large cohorts (123)(124)(125)(126). The number of actionable targets is highly variable depending on the available compounds for treatment at a center and the number of mutations assessed in each panel.…”

Section: Multigene Panelsmentioning

confidence: 99%

Current companion diagnostics in advanced colorectal cancer; getting a bigger and better piece of the pie

Loree

Kopetz

Raghav

2017

J. Gastrointest. Oncol.

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While the treatment of colorectal cancer continues to rely heavily on conventional cytotoxic therapy, an increasing number of targeted agents are under development. Many of these treatments require companion diagnostic tests in order to define an appropriate population that will derive benefit. In addition, a growing number of biomarkers provide prognostic information about a patient's malignancy. As we learn more about these biomarkers and their assays, selecting the appropriate companion diagnostic becomes increasingly important. In the case of many biomarkers, there are numerous assays which could provide the same information to a treating physician, however each assay has strengths and weaknesses. Institutions must balance cost, assay sensitivity, turn-around time, and labor resources when selecting which assay to offer. In this review we will discuss the current state of companion diagnostics available in metastatic colorectal cancer and explore emerging biomarkers and their assays. We will focus on KRAS, BRAF, HER2, and PIK3CA testing, as well as microsatellite stability assessment and multigene panels.

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“…Cependant, in fine, seulement 188 patients présentaient une mutation d'intérêt permettant de guider le traitement chez 38 % des patients, avec une importante variation entre types histologiques et localisations. Dans cette étude, une forte concordance était observée entre les anomalies observées dans la tumeur primaire et les métastases (seulement 2 cas sur les 64 testés qui présentaient des discordances (21). La présence de mutations de gènes codant pour des protéines actionnables est corrélée à l'obtention d'une réponse et un bénéfice pour le patient (22,23), notamment lorsque des combinaisons de thérapies ciblées sont envisagées.…”

Section: Un Bref Historique Des Programmes De Screening Moleculaireunclassified

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

Blay

Trédan

Pérol

2017

IJMS

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RESUMELa médecine moléculaire du cancer s'appuie sur l'identification d'anomalies génomique de l'ADN des cellules tumorales, permettant de guider le traitement des patients, en choisissant des inhibiteurs agissant sur les protéines mutées codées par les gènes mutés. Cependant, on assiste depuis 10 ans à l'émergence très rapide d'un nouveau corpus de connaissance décrivant les anomalies génomiques des cellules cancéreuses au sein des programmes internationaux comme ICGC ou TCGA, permettant de déboucher sur de nouvelles classifications nosologiques mais démontrant aussi l'extrême complexité et variabilité clonale des cellules cancéreuses chez le patient humain. Il s'agit désormais d'utiliser ces données nouvelles de manière efficace. Ceci requiert la constitution de plateformes de diagnostic explorant progressivement avec une plus grande profondeur les anomalies moléculaire de chaque patient individuel, et l'organisation de réunions de concertation pluridisciplinaires moléculaire permettant d'intégrer ces données au contexte clinique et global du patient, et requérant la contribution croissante des bio-informaticiens. Ce court article fait le point sur l'évolution de cette médecine moléculaire. ABSTRACTThe molecular medicine of cancer is based on the identification of genomic abnormalities in the DNA of tumor cells, guiding the treatment of patients, by choosing inhibitors acting on the mutated proteins encoded by the mutated genes. However, for the last 10 years, there has been a very rapid emergence of a new corpus of knowledge describing the genomic abnormalities of cancer cells in international programs such as ICGC or TCGA, leading to new nosological classifications, but also showing the extreme complexity and clonal variability of cancer cells in the human patient. The optimal use of this body of new data effectively. This requires 1) the construction of diagnostic platforms progressively exploring with greater depth the molecular anomalies of each individual patient and 2) the organization of multidisciplinary molecular consultation meetings to integrate these data into the clinical and global context of the patient. This evolution will also require a growing contribution of bio-informatics. This short article provides a short update on the evolution of this molecular medicine of cancer.

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Clinical next generation sequencing to identify actionable aberrations in a phase I program

Cited by 48 publications

References 21 publications

Institutional implementation of clinical tumor profiling on an unselected cancer population

Institutional implementation of clinical tumor profiling on an unselected cancer population

Current companion diagnostics in advanced colorectal cancer; getting a bigger and better piece of the pie

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

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