Molecular Testing of Solid Tumors

2011 ◽  
Vol 135 (1) ◽  
pp. 67-82 ◽  
Author(s):  
Anne Igbokwe ◽  
Dolores H. Lopez-Terrada
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Unknown Origin ◽  
Standard Of Care ◽  
Soft Tissue Tumors ◽  
Molecular Diagnostic ◽  
Original Research ◽  
Molecular Testing ◽  
Neoplastic Disease ◽  
Therapeutic Decisions

Abstract Context—Molecular testing of solid tumors is steadily becoming a vital component of the contemporary anatomic pathologist's armamentarium. These sensitive and specific ancillary tools are useful for confirming ambiguous diagnoses suspected by light microscopy and for guiding therapeutic decisions, assessing prognosis, and monitoring patients for residual neoplastic disease after therapy. Objective—To review current molecular biomarkers and tumor-specific assays most useful in solid tumor testing, specifically of breast, colon, lung, thyroid, and soft tissue tumors, malignant melanoma, and tumors of unknown origin. A few upcoming molecular diagnostic assays that may become standard of care in the near future will also be discussed. Data Sources—Original research articles, review articles, and the authors' personal practice experience. Conclusions—Molecular testing in anatomic pathology is firmly established and will continue to gain ground as the need for more specific diagnoses and new targeted therapies evolve. Knowledge of the more common and clinically relevant molecular tests available for solid tumor diagnosis and management, and their indications and limitations, is necessary if anatomic pathologists are to optimally use these tests and act as consultants for fellow clinicians directly involved in patient care.

Clinical Trial of NPI-0052 (2nd generation proteasome inhibitor) in Patients Having Advanced Malignancies with Expanded RP2D Cohorts in Lymphoma and CLL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4934-4934 ◽  
Author(s):  
Timothy Price ◽  
Peeter Padrik ◽  
Amanda Townsend ◽  
Paul Mainwaring ◽  
Lawrence Catley ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Proteasome Inhibitor ◽  
Standard Of Care ◽  
Proteasome Inhibition ◽  
Hematologic Malignancies ◽  
Preclinical Research ◽  
Novel Structure ◽  
Advanced Malignancies ◽  
Mantle Cell

Abstract Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of the 20S proteasome. NPI-0052 has a novel structure leading to a unique proteasome inhibition, toxicology and effect profile. Preclinical research suggests an improved therapeutic ratio and activity in hematologic and solid tumor malignancy models. Secondary to these findings, clinical trials are being conducted in patients with myeloma, lymphomas, leukemias and solid tumors. Materials and Methods: In this study patients with solid tumor, lymphoma or leukemia diagnoses were treated with NPI-0052 administered weekly, for 3 weeks in 4-week cycles in a 3+3 design dose escalation. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events (AE). In addition to regular safety monitoring, proteasome inhibition (PI) (baseline, D1 & D15) and pharmacokinetics PK (D1 & D15) were assayed in blood. Once a Recommended Phase 2 Dose (RP2D) is identified, RP2D cohorts of 10 patients in each lymphoma and CLL are enrolled. Results: 25 patients have been treated at doses ranging from 0.1 mg/m2 to 0.7 mg/m2. The AE profile has been very tolerable with fatigue, transient peri-infusion site discomfort and lymphopenia being commonly ascribed to NPI-0052. Whole blood pharmacokinetics were calculated for all patients on study. At the highest dose assessed PK parameters were (mean ± SD) AUCtot =215±129 ng/mL*min; Cmax =22.8 ±14 ng/mL; t1/2 =13.5 ± 9.2 mins; clearance= 7.8 ± 8.2 L/min and Vss = 132 ± 192 L. AUC and Cmax increased linearly with dose and the kinetics are apparently not dose dependant. PI has been assayed in blood, indicating a dose:response relationship with inhibition of chymotrypsin-like activity up to 100% observed and mean Day 1 inhibition of 78%. This level of proteasome inhibition is higher than that reported with standard doses of bortezomib, yet the profile of adverse drug reactions associated with bortezomib has not been observed. A total of 7 patients (33%) have had stable disease for at least 2 cycles (8 weeks; 2months), including one each with mantle cell lymphoma (4 cycles), Hodgkin’s lymphoma (4 cycles), follicular lymphoma (4 cycles) and sarcoma (5 cycles) and prostate adenocarcinoma, and two with melanoma (4 cycles). Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range while producing a toxicity profile that is tolerable and dissimilar to that of the standard of care proteasome inhibitor bortezomib. These data have supported additional studies being initiated in hematologic malignancies and solid tumors.

scholarly journals Oncotarget (ONCOALVO): A custom NGS panel for therapeutic decision in solid tumors refractory to conventional therapy.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 140-140
Author(s):  
Andre Marcio Murad
Keyword(s):  
Solid Tumors ◽  
Simultaneous Detection ◽  
Predictive Biomarkers ◽  
Copy Number Variations ◽  
Braf V600e ◽  
Molecular Testing ◽  
Precision Oncology ◽  
Cancer Genes ◽  
Brca1 And Brca2 ◽  
Therapeutic Decisions

140 Background: Next-generation sequencing (NGS) of tumor biopsies of solid tumors using commercially available platforms has broadly entered routine clinical practice to test for predictive biomarkers for patients with no available further standard therapies, as diagnostics rely on genomic testing of molecular alterations to enable effective cancer treatment. However, the high cost of large multigenic panels and especially the sequencing of the entire tumor exome is a concern, especially in a developing country such as Brazil. Methods: We report the clinical application of a panel of 57 genes that we call ONCOTARGET (ONCOALVO) which is based on the Thermo Fisher Oncomine Focus Assay, for the rapid and simultaneous detection of single nucleotide variants, short insertions and deletions, copy number variations, and gene rearrangements in 52 cancer genes with therapeutic relevance, but with the addition of 5 additional genes: the homologous recombination repair (HRR) genes BCRA1, BRCA2, ATM and CHEK2 that determine tumor sensitivity to inhibitors of the PARP enzyme and also KDR. 60 diagnostic samples of formalin-fixed, paraffin-embedded material submitted for molecular testing over a 2 year time period were analyzed so far. All patients had advanced solid tumors already refractory to conventional systemic therapy. Libraries were prepared from isolated nucleic acids and sequenced on the Ion Torrent S5 sequencer. Results: We found 40 potential therapy target pathogenic gene aberrations in 30 (50%) patients: KRAS - 10 (25%), BRCA1 - 8(20%), BRCA2 - 8(20%), PIK3CA - 4 (10%) mutations; and also 2 of each: ERBB2 (5%), BRAF-V600E (5%), KIT (5%), ALK (5%) mutations and one (2.5%) CCND1 amplification and one (2.5%) CDK4 mutacion. In 3 (7.5%) patients there were double mutations: BRCA1 and BRCA2 in 2 cases and BRCA2 and KRAS and one case. The Oncotarget workflow enabled a turnaround of 18½ days. Conclusions: ONCOTARGET was found to be a convenient tool for fast, reliable, broadly applicable and cost-effective targeted NGS of tumor samples in routine diagnostics and therapeutic decisions with a potential to become an important asset for precision oncology in Brazil.

Clinical prediction of bacteremia and early antibiotics therapy in patients with solid tumors

2021 ◽  
pp. 1-7
Author(s):  
Jonathan M. Hyak ◽  
Mayar Al Mohajer ◽  
Daniel M. Musher ◽  
Benjamin L. Musher
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Cardiopulmonary Arrest ◽  
Tertiary Care ◽  
Organ Transplant ◽  
Antibiotic Use ◽  
Care Hospital ◽  
Tumor Patients ◽  
Binomial Regression ◽  
Sirs Criteria

Abstract Objective: To investigate the relationship between the systemic inflammatory response syndrome (SIRS), early antibiotic use, and bacteremia in solid-tumor patients. Design, setting, and participants: We conducted a retrospective observational study of adults with solid tumors admitted to a tertiary-care hospital through the emergency department over a 2-year period. Patients with neutropenic fever, organ transplant, trauma, or cardiopulmonary arrest were excluded. Methods: Rates of SIRS, bacteremia, and early antibiotics (initiation within 8 hours of presentation) were compared using the χ2 and Student t tests. Binomial regression and receiver operator curves were analyzed to assess predictors of bacteremia and early antibiotics. Results: Early antibiotics were administered in 507 (37%) of 1,344 SIRS-positive cases and 492 (22%) of 2,236 SIRS-negative cases (P < .0001). Of SIRS-positive cases, 70% had blood cultures drawn within 48 hours and 19% were positive; among SIRS negative cases, 35% had cultures and 13% were positive (19% vs 13%; P = .003). Bacteremic cases were more often SIRS positive than nonbacteremic cases (60% vs 50%; P =.003), but they received early antibiotics at similar rates (50% vs 49%, P = .72). Three SIRS components predicted early antibiotics: temperature (OR, 1.7; 95% CI, 1.31–2.29; P = .0001), tachycardia (OR, 1.4; 95% CI, 1.10–1.69; P < .0001), and white blood-cell count (OR, 1.8; 95% CI, 1.56–2.14; P < .0001). Only temperature (OR, 1.6; 95% CI, 1.09–2.41; P = .01) and tachycardia (OR, 1.5; 95% CI, 1.09–2.06; P = .01) predicted bacteremia. SIRS criteria as a composite were poorly predictive of bacteremia (AUC, 0.57). Conclusions: SIRS criteria are frequently used to determine the need for early antibiotics, but they are poor predictors of bacteremia in solid-tumor patients. More reliable models are needed to guide judicious use of antibiotics in this population.

scholarly journals Randomized prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test

2021 ◽  
Author(s):  
Deanna G. Brockman ◽  
Christina A. Austin-Tse ◽  
Renée C. Pelletier ◽  
Caroline Harley ◽  
Candace Patterson ◽  
...  
Keyword(s):  
Diagnostic Test ◽  
Genome Sequencing ◽  
Standard Of Care ◽  
Molecular Diagnostic ◽  
Prospective Evaluation ◽  
Molecular Diagnostic Test

Trial in progress: Phase 1a/b study of PF-07284890 (brain-penetrant BRAF inhibitor) with/without binimetinib in patients with BRAF V600-mutant solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3152-TPS3152
Author(s):  
Vivek Subbiah ◽  
Martin Gutierrez ◽  
Carey K. Anders ◽  
George Ansstas ◽  
Taofeek K. Owonikoko ◽  
...  
Keyword(s):  
Disease Progression ◽  
Solid Tumors ◽  
Dose Level ◽  
Solid Tumor ◽  
Human Study ◽  
Tumor Type ◽  
Overall Response ◽  
Secondary Endpoints ◽  
Phase 1B ◽  
Brain Involvement

TPS3152 Background: BRAF inhibitors have transformed treatment (Tx) for patients (pts) with BRAF V600-mutant cancers, but long-term efficacy is limited by disease progression in the brain, due to poor brain penetration. PF-07284890 is a potent, selective, highly brain-penetrant, small-molecule inhibitor of BRAF V600 mutations. This first in human study will assess the PK, safety, and preliminary clinical activity of PF-07284890, as monotherapy and in combination with binimetinib (MEK inhibitor), in pts with BRAF V600-mutated advanced solid tumors with/without brain metastases. Methods: Phase 1a/1b open-label, multicenter, dose-finding study (NCT04543188). Pts will be ≥18 y with a histologically confirmed advanced/metastatic solid tumor including primary brain tumor (PBT), confirmed BRAF V600 mutation, and presence/absence of brain involvement. Pts will have disease progression despite prior Tx without alternative Tx options. Pts with brain metastasis/PBT > 4 cm and/or symptomatic brain disease will be excluded initially, but allowed based on emerging PK. Phase 1a is a dose escalation study of PF-07284890 (monotherapy and combination). ̃35 pts will be enrolled to determine maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of PF-07284890 (monotherapy and combination). Cohorts of 2-4 pts will be treated at each dose level of PF-07284890 until MTD/RDE determination (PF-07284890 starting dose: 50 mg QD; binimetinib 45 mg BID). Bayesian Logistic Regression Model will be used to inform dose level decisions. At least 6 pts each for monotherapy and combination will be treated at MTD/RDE. Phase 1a primary endpoints: Cycle 1 dose-limiting toxicities; MTD/RDE; AEs; lab abnormalities; and dose interruptions, modifications and discontinuations due to AEs. Secondary endpoints include PK parameters and overall response (RECIST; overall and intracranial; RANO for PBT). Phase 1b is a dose expansion and drug-drug interaction study to further evaluate PF-07284890 + binimetinib. Cohorts 1-4 (̃40 pts each) will enroll pts based on tumor type, brain involvement (asymptomatic/symptomatic), and prior Tx. Cohort 5 (̃20 pts) will include pts with any solid tumor including leptomeningeal metastases. Cohort 6 (̃10 pts) will assess the effect of PF-07284890 + binimetinib on CYP3A activity using midazolam as a substrate. Phase 1b primary endpoint: overall response (RECIST; overall and intracranial; RANO for PBT). Secondary endpoints: duration of response; progression-free survival; disease control rate; time to response; overall survival; AEs; lab abnormalities; and dose interruptions, modifications and discontinuations due to AEs; and PK parameters. For both Phase 1a and 1b, Tx will continue until disease progression, unacceptable toxicity or patient refusal. Study began enrolling pts in January 2021 and is ongoing. Clinical trial information: NCT04543188.

scholarly journals BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Ryan J. Sullivan ◽  
Keith T. Flaherty
Keyword(s):  
Standard Of Care ◽  
Diagnostic Techniques ◽  
Therapeutic Interventions ◽  
Molecular Testing ◽  
Braf Inhibitors ◽  
Testing Methods ◽  
Braf Mutations ◽  
Initial Discovery ◽  
Braf Mutant ◽  
Mutant Braf

Since the initial discovery that a subset of patients with cutaneous melanoma harbor BRAF mutations, substantial research has been focused on determining the pathologic consequences of BRAF mutations, optimizing diagnostic techniques to identify these mutations, and developing therapeutic interventions to inhibit the function of this target in mutation-bearing tumors. Recently, advances have been made which are revolutionizing the standard of care for patients with BRAF mutant melanoma. This paper provides an overview on the pathogenic ramifications of mutant BRAF signaling, the latest molecular testing methods to detect BRAF mutations, and the most recent clinical data of BRAF pathway inhibitors in patients with melanoma and BRAF mutations. Finally, emerging mechanisms of resistance to BRAF inhibitors and ways of overcoming this resistance are discussed.

scholarly journals Cell-free DNA From Pleural Effusion Samples: Is It Right for Molecular Testing in Lung Adenocarcinoma?

2021 ◽  
Vol 27 ◽  
Author(s):  
Attila Mokánszki ◽  
Emese Sarolta Bádon ◽  
Anikó Mónus ◽  
László Tóth ◽  
Nóra Bittner ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Lung Adenocarcinoma ◽  
Gene Mutations ◽  
Molecular Testing ◽  
Alternative Source ◽  
Cell Free Dna ◽  
Molecular Features ◽  
Free Dna ◽  
Mutational Status ◽  
Therapeutic Decisions

Pathogenic molecular features gained specific significance in therapeutic decisions in lung carcinoma in the past decade. Initial and follow up genetic testing requres appropriate amounts and quality of tumor derived DNA, but tumor sampling, especially for disease monitoring is generally limited. Further to the peripheral blood (PB), samples from pleural fluid, accumulating in diverse lung processes might serve as an alternative source for cell-free DNA (cfDNA) for genetic profiling. In our study, cfDNA isolated from the pleural effusion and from the PB, and genomic DNA (gDNA) obtained from tissue/cellular samples were analyzed and compared from altogether 65 patients with pulmonary disease, including 36 lung adenocarcinomas. The quantity of effusion cfDNA yield appeared to be significantly higher compared to that from simultaneously collected PB plasma (23.2 vs. 4.8 ng/μl, p &lt; 0.05). Gene mutations could be safely demonstrated from the effusion cfDNA fraction obtained from adenocarcinoma patients, 3/36 EGFR, 9/36 KRAS and 1/36 BRAF gene variants were detected. In this series, 9/13 samples showed an effusion+/plasma-mutational status, while only 1/13 samples presented with the opposite findings (effusion-/plasma+). gDNA analysis from sediment cell blocks from the identical effusion sample was surprisingly ineffective for lung adenocarcinoma profiling due to the low DNA yield. In conclusion, the cell free supernatant of pleural effusions appears to concentrate cancer derived cfDNA and seems to be particularly suitable for serial genotyping of pulmonary adenocarcinoma.

scholarly journals Flow Cytometry Immunophenotyping for Diagnostic Orientation and Classification of Pediatric Cancer Based on the EuroFlow Solid Tumor Orientation Tube (STOT)

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4945
Author(s):  
Cristiane de Sá de Sá Ferreira-Facio ◽  
Vitor Botafogo ◽  
Patrícia Mello Ferrão ◽  
Maria Clara Canellas ◽  
Cristiane B. Milito ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Pediatric Cancer ◽  
Diagnostic Procedures ◽  
Hematologic Malignancies ◽  
Multiparameter Flow Cytometry ◽  
Diagnostic Screening ◽  
Pediatric Solid Tumors

Early diagnosis of pediatric cancer is key for adequate patient management and improved outcome. Although multiparameter flow cytometry (MFC) has proven of great utility in the diagnosis and classification of hematologic malignancies, its application to non-hematopoietic pediatric tumors remains limited. Here we designed and prospectively validated a new single eight-color antibody combination—solid tumor orientation tube, STOT—for diagnostic screening of pediatric cancer by MFC. A total of 476 samples (139 tumor mass, 138 bone marrow, 86 lymph node, 58 peripheral blood, and 55 other body fluid samples) from 296 patients with diagnostic suspicion of pediatric cancer were analyzed by MFC vs. conventional diagnostic procedures. STOT was designed after several design–test–evaluate–redesign cycles based on a large panel of monoclonal antibody combinations tested on 301 samples. In its final version, STOT consists of a single 8-color/12-marker antibody combination (CD99-CD8/numyogenin/CD4-EpCAM/CD56/GD2/smCD3-CD19/cyCD3-CD271/CD45). Prospective validation of STOT in 149 samples showed concordant results with the patient WHO/ICCC-3 diagnosis in 138/149 cases (92.6%). These included: 63/63 (100%) reactive/disease-free samples, 43/44 (98%) malignant and 4/4 (100%) benign non-hematopoietic tumors together with 28/38 (74%) leukemia/lymphoma cases; the only exception was Hodgkin lymphoma that required additional markers to be stained. In addition, STOT allowed accurate discrimination among the four most common subtypes of malignant CD45− CD56++ non-hematopoietic solid tumors: 13/13 (GD2++ numyogenin− CD271−/+ nuMyoD1− CD99− EpCAM−) neuroblastoma samples, 5/5 (GD2− numyogenin++ CD271++ nuMyoD1++ CD99−/+ EpCAM−) rhabdomyosarcomas, 2/2 (GD2−/+ numyogenin− CD271+ nuMyoD1− CD99+ EpCAM−) Ewing sarcoma family of tumors, and 7/7 (GD2− numyogenin− CD271+ nuMyoD1− CD99− EpCAM+) Wilms tumors. In summary, here we designed and validated a new standardized antibody combination and MFC assay for diagnostic screening of pediatric solid tumors that might contribute to fast and accurate diagnostic orientation and classification of pediatric cancer in routine clinical practice.

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