Use of next-generation sequencing (NGS) to identify actionable genomic alterations (GA) in diverse solid tumor types: The Foundation Medicine (FMI) experience with 2,200+ clinical samples.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11020-11020 ◽  
Author(s):  
Vincent A. Miller ◽  
Jeffrey S. Ross ◽  
Kai Wang ◽  
Siraj M. Ali ◽  
Geoff Otto ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Drug Targets ◽  
Treatment Options ◽  
Additional Treatment ◽  
Clinical Samples ◽  
Tumor Type ◽  
Kinase Gene ◽  
Hybridization Capture ◽  
Small Indels ◽  
Tumor Types

11020 Background: ST oncology has been transformed by the linkage of GA with targeted therapeutics. Unfortunately, most STs still have no target detected by clinically available assays. More comprehensive testing platforms are needed to determine GA in ST and thus broaden treatment options. We developed a ST NGS diagnostic assay, optimized for routine clinical FFPE specimens including core and fine needle biopsies and malignant effusions, and analyzed > 2,200 patients’ tumors in a CLIA-certified lab (Foundation Medicine). Methods: Hybridization capture of 3,320 exons from 182 cancer-related genes and 37 introns of 14 genes commonly rearranged in cancer was applied to ≥ 50ng of DNA extracted from 2,200+ consecutive FFPE tumor specimens and sequenced to high unique coverage. GA (base substitutions, small indels, rearrangements, copy number alterations) were categorized as “actionable” if directly linked to a clinically available targeted treatment option or a mechanism-driven clinical trial. Results: 2,112/2,221 (95%) of specimens (most common 1° sites: lung 18%, breast 14%, colon 7%, other 34%) were successfully profiled (mean coverage 1134X). Alterations were reported in 155/182 (85%) of genes. Seventy-six percent of cases harbored ≥1 actionable GA, mean 1.6 (range 0-16); sixty-two percent harbored at least one actionable GA not assayed by available tumor-type specific tests or hotspot panels. This approach has led to novel insights into advanced cancer including: 13 novel, potentially druggable kinase gene fusions; alterations in known drug targets (e.g. ALK, EGFR, ERRB2, KIT, MET, PDGFR α and β, RAF1 and RET) in novel tumor types and new mechanisms of resistance to approved targeted therapies. Several patients demonstrated dramatic responses to treatment with targeted therapies directed against these alterations. Conclusions: Comprehensive NGS genomic profiling was successful in profiling >2,200 unselected clinical cases, identified actionable alterations in 76% of cases and provided additional treatment options for 62% of patients targeting alterations in genes not assayed by available hotspot panels.

Molecular profiling using the 92-gene assay for tumor classification of brain metastases.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13583-e13583
Author(s):  
Andrew Jacob Brenner ◽  
Raul Collazo ◽  
Catherine A. Schnabel ◽  
F Anthony Greco
Keyword(s):  
Brain Metastases ◽  
Targeted Therapies ◽  
Primary Tumor ◽  
Tumor Type ◽  
Federal Drug Administration ◽  
Gene Assay ◽  
Clinical Series ◽  
The Us ◽  
Tumor Types

e13583 Background: Nearly 200,000 patients are diagnosed with brain metastases in the US annually. Advances in targeted therapies make definitive diagnosis of the primary tumor type important but can be challenging in many patients. The 92-gene assay is a validated gene expression classifier of 50 tumor types/subtypes for patients with uncertain diagnoses. Results from a clinical series of brain biopsies and potential impact on treatment were evaluated. Methods: An IRB-approved, de-identified database of clinical and molecular information from biopsies (N = 24,486) submitted for testing with the 92-gene assay (CancerTYPE ID, Biotheranostics, Inc.) as part of routine care were reviewed. Descriptive analysis included patient demographics and molecular diagnoses. Results: Analysis included 464 brain biopsies. A molecular diagnosis was provided in 433 (93.3%) tested ( < 5% assay failure rate) with 24 different tumor types. Six primary tumor types made up the majority (67.4%) with almost one-third of the molecular predictions being Lung (31.2%), followed by Neuroendocrine (NET) (9.9%), Sarcoma (7.9%), Skin (6.4%), Gastroesophageal (6.2%), and Urinary bladder (5.8%). All of these 6 tumor types, for which activity in the CNS has been documented, have immune checkpoint inhibitors or other targeted therapies approved in selected cases by the US Federal Drug Administration (FDA) (Table). Conclusions: Molecular classification of brain metastases can identify distinct tumor types for which there are FDA approved targeted medications. Improving diagnostic precision with the 92-gene assay helps identify a subset of therapy-responsive metastatic brain tumors, thus improving therapy and possibly providing better outcomes and survival. [Table: see text]

The burden of illness in metastatic renal cell carcinoma (mRCC) patients after two targeted therapies: A review of the literature.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15043-e15043
Author(s):  
Giuseppe Di Lorenzo ◽  
John Coombs ◽  
Roman Casciano ◽  
Lee Stern
Keyword(s):  
Targeted Therapies ◽  
Negative Impact ◽  
Burden Of Illness ◽  
Data Extraction ◽  
Treatment Options ◽  
Unmet Need ◽  
Specific Treatment ◽  
Additional Treatment ◽  
Line Treatment ◽  
Medical Needs

e15043 Background: MRCC poses a substantial burden in terms of morbidity, mortality, impaired quality of life (QoL), and costs. Despite the emergence of targeted therapies (VEGF-TKIs and mTORs) in this setting, considerable unmet medical needs remain. Methods: A comprehensive literature search was performed to systematically review available data on the burden of mRCC. Included articles focused on the efficacy, toxicity, guidelines, therapy sequencing, and overall disease burden of mRCC patients who have failed multiple targeted therapies. Of the 933 articles mRCC articles identified, 83 met the criteria for data extraction. Results: An extensive amount of literature is published on targeted therapies in the treatment of patients with mRCC. Recently approved therapies report improved outcomes in 1st and 2nd line treatment; however, there are minimal data on the efficacy and safety of treatments following failure of 2 sequential targeted therapies. Specifically, two studies report OS in 2nd line failures: one prospective study of capecitabine as 3rd line treatment (OS: 7.2 months [CI: 4.6-8.8]) and one retrospective single arm study of 3rd line sorafenib use after failure of both VEGF-TKIs and mTORs (OS: 7 months [range: 6-10]). Consequently, of the six current practice guidelines, none recommend a specific treatment for patients who fail 2 targeted therapies. As highlighted in over 20 articles on therapy sequencing, the treatment population failing 2 targeted therapies represents an extremely heterogeneous group with a variety of prior therapies, for whom data are lacking. QoL and economic data focusing on patients in this setting were not identified. However, based upon evaluations in 1st and 2nd line patients, treatment toxicity and disease progression are expected to have a negative impact on QoL while increasing costs due to the associated need for additional treatment, hospitalizations, and other management. Conclusions: Despite significant advances in the treatment options for patients with mRCC, many patients inevitably progress and are left with few options. There is substantial unmet need for safe and effective 3rd line treatment options that can provide clinical benefit.

Genomic testing and treatment landscape in patients with advanced non-small cell lung cancer (aNSCLC) using real-world data from community oncology practices.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1585-1585 ◽  
Author(s):  
Hinco Jasper Gierman ◽  
Seth Goldfarb ◽  
Monica Labrador ◽  
Caroline M. Weipert ◽  
Bill Getty ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
P Value ◽  
Genomic Testing ◽  
Tumor Type ◽  
Real World Data ◽  
Nccn Guidelines ◽  
Community Oncology

1585 Background: While aNSCLC is a leading cause of US cancer deaths, targeted therapies and immune checkpoint inhibitors (ICPi) have emerged as important new treatment options for these pts NCCN guidelines recommend testing of eight genes in aNSCLC patients at diagnosis. Targetable alterations (TA) in four genes, EGFR, ALK, ROS1, and BRAF, are associated with FDA-approved therapies. The labels for ICPis indicate that pts with TAs in EGFR and ALK are not candidates for first line treatment with ICPi. Methods: The Integra Connect database, which includes electronic medical record (EMR) and claims data on approximately 600,000 cancer patients, was queried across five community oncology practices (289 oncologists) to identify aNSCLC patients (stage 3B or 4) treated since January 2017. Manual review of charts was done to abstract tumor type/stage, drug regimens, and evidence of somatic genetic testing. A Wilcoxon rank sum test was used to test difference in time to results (TTR) for blood- vs tissue-based tests. Results: A total of 1,203 aNSCLC patients were identified. Testing rates varied from 54% for EGFR to 22% for all 4 genes (table). 163 patients had a TA in EGFR, ALK, ROS1 or BRAF, and 55% of these pts did not receive targeted therapy. 84 pts with TA’s in EGFR or ALK had no evidence of progression on targeted therapy, yet 31 (37%) received an ICPi; 24% had the TA test result prior to ICPi use and 13% received the TA result after starting ICPi. Median TTR for blood-based somatic tests was shorter than tissue-based tests (4 vs 14 days, p-value= 3.5-e07). Conclusions: Our analysis in the community oncology setting for aNSCLC pts finds evidence of underutilization of genomic testing, underutilization of targeted therapies, and ICPi use outside of label. Further research is needed to identify strategies to increase testing in aNSCLC pts to provide physicians with the information needed to make optimal treatment decisions. [Table: see text]

Mutational burden of tumors with primary site unknown.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3039-3039 ◽  
Author(s):  
Laurie M. Gay ◽  
David Fabrizio ◽  
Garrett Michael Frampton ◽  
Caitlin F. Connelly ◽  
James Sun ◽  
...  
Keyword(s):  
Clinical Care ◽  
Treatment Options ◽  
Additional Treatment ◽  
Primary Site ◽  
Unknown Primary ◽  
Tumor Type ◽  
Coding Region ◽  
Tissue Samples ◽  
Primary Tumor Site ◽  
Mutational Burden

3039 Background: Higher levels of tumor mutational burden (TMB) can predict sensitivity to immunotherapies (IO), which are FDA approved to treat NSCLC, melanoma, and urothelial carcinoma (Ca). TMB may be a biomarker for sensitivity to IO, irrespective of tumor type. TMB has not been explored widely for tumors of unknown primary site, but may reveal additional treatment options. Methods: Comprehensive genomic profiling of DNA from FFPE tissue samples was performed using hybrid-capture, next-generation sequencing. TMB was calculated by counting all coding short variant alterations (base substitutions and indels), including synonymous alterations, and subtracting from this functionally oncogenic or germline alterations (per ExAC, dbSNPT, or internal algorithmic analysis). To calculate the TMB per Mb, the total number of relevant mutations is divided by the coding region of the bait set (0.8 Mb, 1.1 Mb, or 1.2 Mb). High, intermediate, and low TMB were defined as ≥20 mut/Mb, ≥6 and <20 mut/Mb, or <6 mut/Mb, respectively. Tumor types with >100 samples were analyzed. Results: From a database of 102,878 samples sequenced during routine clinical care, 6116 samples for which the primary tumor site was unclear at sequencing were identified. Table shows TMB metrics (mut/Mb) and median patient age for these cohorts. Conclusions: Significant numbers of patients with each tumor type have high TMB that may indicate benefit from IO, excepting GIST. As expected, urothelial tumors have higher than average TMB and more patients have high TMB. SCC tumors are commonly TMB high (23%), as are tumors difficult to define histologically (15%). For ACUP or CUP, the most common tumors, 8-11% have high TMB. Analysis of responses to treatment with IO are ongoing. [Table: see text]

Prioritizing targeted therapies in an evidence-based manner, integrating biological context and functional precision medicine.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14065-e14065
Author(s):  
Simina Boca ◽  
Krithika Bhuvaneshwar ◽  
Virneliz Fernandez-Vega ◽  
Jayaram Kancherla ◽  
Shruti Rao ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Targeted Therapies ◽  
Evidence Based ◽  
Tumor Type ◽  
Molecular Alterations ◽  
Her2 Breast Cancer ◽  
Evidence Level ◽  
Molecular Profiles ◽  
Tumor Types ◽  
Biological Context

e14065 Background: It is becoming increasingly common for cancer patients to undergo molecular profiling of their tumors in order to see whether there are any actionable DNA, gene expression, or protein expression signatures. For example, individuals with ER+ or HER2+ breast cancer or KRAS wild type (non-mutated) colorectal cancer are prescribed specific targeted therapies. When an individual’s molecular alterations do not match any currently-approved recommendations for their tumor type, their clinician may consider prescribing a therapy approved in a different tumor type. Unfortunately, tumors often eventually become resistant to the therapies they are exposed to, leading to a narrowing of options after each therapy line. Methods: We previously developed CDGnet, an evidence-based approach and web-based tool for prioritizing targeted therapies based on tumor molecular profiles based on known pathways which provide biological context. CDGnet considers approved therapies with biomarkers among the alterations for the individual’s tumor type and other tumor types as the first and second evidence level categories respectively. These are followed by therapies that target or have as biomarkers genes or proteins downstream of altered oncogenes, considering curated pathways for the individual’s tumor type and other tumor types as the third and fourth evidence level categories respectively. We are currently expanding CDGnet in order to include data from high-throughput screening (HTS) experiments of NCI oncologic drugs performed on patient-derived organoids. The concept of “functional precision medicine” consists of using functional drug efficacy determination directly on individual patients, in this case by considering drugs with low half maximal effective concentrations (EC50) which are tested on tissues derived from the actual patients. Results: We will present extensions to CDGnet that allow users to upload both the molecular profiles and the HTS data to see whether any drugs are predicted by both approaches or whether specific combinations appear promising for further testing. Preliminary results on a set of glioblastoma samples will be presented. Conclusions: We hope that extending CDGnet to also include HTS data will eventually allow a truly multi-factorial personalized oncology approach, whereby both molecular alterations at the DNA, RNA, and protein levels and patient-derived organoids will be considered in deciding on treatment plans for individuals.

scholarly journals OTHR-16. MOLECULAR PROFILING USING THE 92-GENE ASSAY FOR TUMOR CLASSIFICATION OF BRAIN METASTASES

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i21-i21
Author(s):  
Andrew Brenner ◽  
Raul Collazo ◽  
Catherine Schnabel ◽  
Anthony Greco
Keyword(s):  
Brain Metastases ◽  
Targeted Therapies ◽  
Primary Tumor ◽  
Tumor Type ◽  
Federal Drug Administration ◽  
Gene Assay ◽  
Clinical Series ◽  
The Us ◽  
Tumor Types

Abstract BACKGROUND: Nearly 200,000 patients are diagnosed with brain metastases in the US annually. Advances in targeted therapies make definitive diagnosis of the primary tumor type important but can be challenging in many patients. The 92-gene assay is a validated gene expression classifier of 50 tumor types for patients with uncertain tissue of origin diagnoses. Results from a clinical series of brain biopsies and potential impact on treatment were evaluated. METHODS: An IRB approved, de-identified database of clinical and molecular information from biopsies (N = 24,486) submitted for testing with the 92-gene assay (CancerTYPE ID, Biotheranostics, Inc.) as part of routine care were reviewed. Descriptive analysis included patient demographics and molecular diagnoses. RESULTS: Analysis included 464 brain biopsies. A molecular diagnosis was provided in 433 (93.3%) tested (&lt; 5% assay failure rate) with 24 different tumor types. Six primary tumor types made up the majority (67.4%) with almost one-third of the molecular predictions being Lung (31.2%), followed by Neuroendocrine (NET) (9.9%), Sarcoma (7.9%), Skin (6.4%), Gastroesophageal (6.2%), and Urinary bladder (5.8%). All of these 6 tumor types, for which activity in the CNS has been documented, have immune checkpoint inhibitors or other targeted therapies approved in selected cases by the US Federal Drug Administration (FDA). CONCLUSIONS: Molecular classification of brain metastases can identify distinct tumor types for which there are FDA approved targeted medications. Improving diagnostic precision with the 92-gene assay helps identify a subset of therapy-responsive metastatic brain tumors, thus improving therapy and possibly providing better outcomes and survival.

Conventional versus Mindfulness-based Interventions for Anxiety and Worry: A Review and Recommendations

2020 ◽  
Vol 16 (1) ◽  
pp. 60-67
Author(s):  
Deah Jo Abbott ◽  
Caleb Wayne Lack
Keyword(s):  
Treatment Options ◽  
Additional Treatment ◽  
Third Wave ◽  
Stage Model ◽  
Pharmacological Treatments ◽  
The Past ◽  
Behavioral Therapies ◽  
Cognitive Behavioral Therapies ◽  
Specific Disorders ◽  
Psychiatric Problems

Anxiety disorders are among the most prevalent and most functionally impairing psychiatric problems experienced by the population. Both pharmacological and psychological evidencebased treatments exist for a number of specific disorders, but may fail to fully relieve symptoms, pointing to the need for additional treatment options. Often considered to be part of the “third wave” of cognitive-behavioral therapies, treatments incorporating mindfulness have emerged in the past two decades as increasingly popular with clinicians and frequently sought out by consumers. The present article reviews the extant literature regarding the efficacy and effectiveness of mindfulnessbased treatments for anxiety, worry, and related problems. Although they have not attained the solid empirical status of CBT or certain pharmacological treatments, the extant research shows mindfulness- based interventions appear to be a promising and useful treatment for people suffering from anxiety and worry. Further work should be done, levels 3-5 of the NIH stage model to determine whether or not they should be further implemented.

scholarly journals 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

2021 ◽  
Vol 9 (4) ◽  
pp. 826
Author(s):  
Dorien Mabille ◽  
Camila Cardoso Santos ◽  
Rik Hendrickx ◽  
Mathieu Claes ◽  
Peter Takac ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Target ◽  
Drug Targets ◽  
De Novo ◽  
Treatment Options ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Purine Salvage ◽  
Interacting Protein ◽  
Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

scholarly journals Use of monoclonal antibody therapy for nosocomial SARS-CoV-2 infection in patients at high risk for severe COVID-19: experience from a tertiary-care hospital in Germany

Infection ◽  
2021 ◽  
Author(s):  
Johanna Koehler ◽  
Barbara Ritzer ◽  
Simon Weidlich ◽  
Friedemann Gebhardt ◽  
Chlodwig Kirchhoff ◽  
...  
Keyword(s):  
High Risk ◽  
Tertiary Care Hospital ◽  
Severe Disease ◽  
Treatment Options ◽  
Tertiary Care ◽  
Antibody Therapy ◽  
Additional Treatment ◽  
Care Hospital ◽  
Cross Sectional ◽  
Asymptomatic Patients

AbstractAdditional treatment options for coronavirus disease (COVID-19) are urgently needed, particularly for populations at high risk of severe disease. This cross-sectional, retrospective study characterized the outcomes of 43 patients with nosocomial severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection with and without treatment using monoclonal SARS-CoV-2 spike antibodies (bamlanivimab or casirivimab/imdevimab). Our results indicate that treatment with monoclonal antibodies results in a significant decrease in disease progression and mortality when used for asymptomatic patients with early SARS-CoV-2 infection.

282 Pan-tumor analysis of the association between PD-L1 combined positive score and response to pembrolizumab monotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A308-A308
Author(s):  
Lingkang Huang ◽  
Jared Lunceford ◽  
Junshui Ma ◽  
Kenneth Emancipator
Keyword(s):  
Tumor Cells ◽  
Immune Cells ◽  
Roc Analysis ◽  
Standard Of Care ◽  
Tumor Type ◽  
Operating Characteristics ◽  
Positive Score ◽  
Combined Positive Score ◽  
Line Of Therapy ◽  
Tumor Types

BackgroundPD-L1 is expressed on both tumor and immune cells; however, the mechanism by which PD-L1 modulates the adaptive immune response on tumor versus immune cells may differ. Additionally, the prevalence of PD-L1 expression and the partitioning between tumor and immune compartments varies by tumor type. While PD-L1 expression on tumor or immune cells can be scored separately, the PD-L1 combined positive score (CPS) captures both tumor and immune cell expression in one aggregate score. We performed a retrospective, exploratory analysis of the effectiveness of CPS as an enrichment biomarker across several studies of pembrolizumab monotherapy in patients with multiple tumor types.MethodsPD-L1 expression was assessed using PD-L1 IHC 22C3 pharmDx. Expression was measured using CPS (defined as the number of PD-L1–staining cells [tumor cells, lymphocytes, macrophages] divided by the total number of tumor cells, multiplied by 100) in tumor samples from single-arm (KEYNOTE-052 [UC], KEYNOTE-059 cohort 1 [G/GEJ], KEYNOTE-086 [TNBC], KEYNOTE-158 [cervical; SCLC], KEYNOTE-180 [EC], KEYNOTE-224 [HCC], KEYNOTE-427 [RCC]) and randomized (KEYNOTE-040 [HNSCC], KEYNOTE-045 [UC], KEYNOTE-061 [G/GEJ], KEYNOTE-119 [TNBC], KEYNOTE-240 [HCC]) pembrolizumab studies. Data were pooled across tumor types for pembrolizumab and for standard-of-care (in controlled studies), and then estimates of response rate, prevalence, and receiver operating characteristics (ROC) analysis were performed over various CPS cutpoints. CPS distribution by response, tumor type, and line of therapy were also assessed.ResultsThere were 3769 treated patients with available PD-L1 CPS (pembrolizumab, n=2678; standard-of-care, n=1091). The area under the ROC curve for ORR was 0.63 (95% CI, 0.61–0.66) for pembrolizumab and 0.48 (95% CI, 0.43–0.53) for standard-of-care when a positive association was evaluated between CPS and ORR (figure 1); individual cutpoints of 1, 10, 20, and 50 were examined (table 1). Figure 2 shows a boxplot of CPS distribution for response in pembrolizumab-treated patients.Abstract 282 Table 1Response Rates and Sensitivity at Individual CPS Cutpoints for Pembrolizumab-Treated PatientsAbstract 282 Figure 1ROC analysis of PD-L1 CPS for pembrolizumab versus standard-of-care therapyAbstract 282 Figure 2Boxplot of PD-L1 CPS distribution for responders versus nonresponders in pembrolizumab-treated patients by tumor type and line of therapy in order of descending median CPSConclusionsThis retrospective, exploratory pan-tumor analysis demonstrates that CPS is an effective scoring method for measuring PD-L1 expression and can be used as a predictive biomarker to identify patients likely to respond to pembrolizumab monotherapy. CPS demonstrated enrichment of response to pembrolizumab monotherapy across most, but not all, tumor types, including some tumor types for which efficacy favors pembrolizumab regardless of PD-L1 expression, and for which a companion diagnostic is therefore not needed. In the randomized studies, CPS did not show a consistent association with ORR for standard-of-care therapy.

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