Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers

Hirshfield, Kim M.; Tolkunov, Denis; Zhong, Judy; Ali, Siraj M.; Stein, Mark N.; Murphy, Susan; Vig, Hetal; Vázquez, Alexei; Glod, John; Moss, Rebecca A.; Белый, В. А.; Chan, Chang S.; Chen, Suzie; Goodell, Lauri; Foran, David J.; Yelensky, Roman; Palma, Norma Alonzo; Sun, James; Miller, Vincent A.; Stephens, Philip J.; Ross, Jeffrey S.; Kaufman, Howard L.; Poplin, Elizabeth; Mehnert, Janice M.; Tan, Antoinette R.; Bertino, Joseph R.; Aisner, Joseph; DiPaola, Robert S.; Rodrı́guez-Rodrı́guez, Lorna; Ganesan, Shridar

doi:10.1634/theoncologist.2016-0049

Cited by 67 publications

(66 citation statements)

References 52 publications

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“…The average number of genetic alterations considered actionable by the board was 1.9 (range, zero to six alterations). Genes recurrently altered across samples were similar to those reported from other series, 9–11 although the relative frequencies were influenced by the case mix seen by our tumor board (Fig 2). In terms of targetable pathways, the phosphatidylinositol-3 kinase (PI3K) pathway was most frequently altered (63 alterations), followed by the G 1 cell cycle checkpoint (61 alterations) and FGFR pathways (30 alterations).…”

Section: Resultssupporting

confidence: 83%

Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board

Dalton

Forde

Kang

et al. 2017

JCO Precision Oncology

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Purpose Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. Methods A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration–approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. Results One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months (95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43%(95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. Conclusion The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.

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Section: Resultssupporting

confidence: 83%

Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board

Dalton

Forde

Kang

et al. 2017

JCO Precision Oncology

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“…The authors concluded that broad implementation of multiplex hotspot testing is feasible but that only a small portion of the patients with cancer characterized by actionable alterations were actually enrolled onto genotype-matched trials. Other studies on smaller populations have provided support for the ability of comprehensive tumor genomic profiling to direct the point-of-care management of patients with cancer, (10,11) although the percentage of patients subsequently enrolled in genotype-matched clinical trials was similarly low (10).…”

Section: Current Approachesmentioning

confidence: 99%

“…To increase the number of feasible therapeutic options recommended for patients undergoing broad-based genomic sequencing, many center-wide efforts have been initiated (9)(10)(11)(12)(13). These often recommendations to the referring physician in a point-of-care manner, and subsequent follow up of patient outcomes.…”

Section: Current Approachesmentioning

confidence: 99%

“…These often recommendations to the referring physician in a point-of-care manner, and subsequent follow up of patient outcomes. In some cases, this process is conducted in the setting of a prospective, observational clinical trial approved by an institutional review board (9)(10)(11). The importance of carrying out these efforts at an academic medical center is highlighted by the depth of expertise required at every step along the way, including tumor tissue acquisition, assessment, and processing; genomic profiling and analysis; molecular tumor board review; clinical care and translational research performed by core personnel; data acquisition; and outcome assessment.…”

Section: Current Approachesmentioning

confidence: 99%

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Precision Medicine: Implications for Science and Practice

Ganesan

Rodrı́guez-Rodrı́guez

DiPaola

2016

Journal of the American College of Surgeons

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“…In this manuscript, we address this problem and introduce LOHGIC (LOH-germline Inference Calculator) to assess germline-versus-somatic status of mutations and predict presence of LOH in tumor-only deep-sequencing data. We evaluate LOHGIC using precision-oncology data collected at Rutgers Cancer Institute of New Jersey 25 , and validate our predictions using available genetic counseling reports.…”

Section: Introductionmentioning

confidence: 99%

Inference of Germline Mutational Status and Evaluation of Loss of Heterozygosity in High-Depth, Tumor-Only Sequencing Data

Khiabanian

Hirshfield

Goldfinger

et al. 2018

JCO Precision Oncology

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PURPOSE Inherited germline defects are implicated in up to 10% of human tumors, with particularly well-known roles in breast and ovarian cancers that harbor BRCA1/2-mutated genes. There is also increasing evidence for the role of germline alterations in other malignancies such as colon and pancreatic cancers. Mutations in familial cancer genes can be detected by high throughput sequencing (HTS), when applied to formalin-fixed paraffin-embedded (FFPE) tumor specimens. However, due to often lack of patient-matched control normal DNA and/or low tumor purity, there is limited ability to determine the genomic status of these alterations (germline versus somatic) and to assess the presence of loss of heterozygosity (LOH). These analyses, especially when applied to genes such as BRCA1/2, can have significant clinical implications for patient care. METHODS LOHGIC (LOH-Germline Inference Calculator) is a statistical model selection method to determine somatic-versus-germline status and predict LOH for mutations identified via clinical grade, high-depth, hybrid-capture tumor-only sequencing. LOHGIC incorporates statistical uncertainties inherent to HTS as well as specimen biases in tumor purity estimates, which we use to assess BRCA1/2 mutations in 1,636 specimens sequenced at Rutgers Cancer Institute of New Jersey. RESULTS Evaluation of LOHGIC with available germline sequencing from BRCA1/2 testing, demonstrates 93% accuracy, 100% precision, and 96% recall. This analysis highlights a differential tumor spectrum associated with BRCA1/2 mutations. CONCLUSION LOHGIC can assess LOH status for both germline and somatic mutations. It also can be applied to any gene with candidate, inherited mutations. This approach demonstrates the clinical utility of targeted sequencing in both identifying patients with potential germline alterations in tumor suppressor genes as well as estimating LOH occurrence in cancer cells, which may confer therapeutic relevance.

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Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers

Cited by 67 publications

References 52 publications

Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board

Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board

Precision Medicine: Implications for Science and Practice

Inference of Germline Mutational Status and Evaluation of Loss of Heterozygosity in High-Depth, Tumor-Only Sequencing Data

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