Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population

AbstractNeurotrophic tropomyosin receptor kinase (NTRK) gene fusions are rare oncogenic drivers in solid tumours. This study aimed to interrogate a large real-world database of comprehensive genomic profiling data to describe the genomic landscape and prevalence of NTRK gene fusions. NTRK fusion-positive tumours were identified from the FoundationCORE® database of >295,000 cancer patients. We investigated the prevalence and concomitant genomic landscape of NTRK fusions, predicted patient ancestry and compared the FoundationCORE cohort with entrectinib clinical trial cohorts (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]). Overall NTRK fusion-positive tumour prevalence was 0.30% among 45 cancers with 88 unique fusion partner pairs, of which 66% were previously unreported. Across all cases, prevalence was 0.28% and 1.34% in patients aged ≥18 and <18 years, respectively; prevalence was highest in patients <5 years (2.28%). The highest prevalence of NTRK fusions was observed in salivary gland tumours (2.62%). Presence of NTRK gene fusions did not correlate with other clinically actionable biomarkers; there was no co-occurrence with known oncogenic drivers in breast, or colorectal cancer (CRC). However, in CRC, NTRK fusion-positivity was associated with spontaneous microsatellite instability (MSI); in this MSI CRC subset, mutual exclusivity with BRAF mutations was observed. NTRK fusion-positive tumour types had similar frequencies in FoundationCORE and entrectinib clinical trials. NTRK gene fusion prevalence varied greatly by age, cancer type and histology. Interrogating large datasets drives better understanding of the characteristics of very rare molecular subgroups of cancer and allows identification of genomic patterns and previously unreported fusion partners not evident in smaller datasets.

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Real-world prevalence of homologous recombination repair gene (BRCA1/2 and ATM) mutations (HRRm) in patients (pts) with advanced prostate cancer (aPC) as detected by comprehensive genomic profiling (CGP) of circulating cell-free DNA (cfDNA).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.256 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 256-256

Author(s):

Nicolas Sayegh ◽

Umang Swami ◽

Pedro C. Barata ◽

Michael B. Lilly ◽

Roberto Nussenzveig ◽

...

Keyword(s):

Real World ◽

Tumor Tissue ◽

Parp Inhibitors ◽

World Population ◽

Chi Square ◽

Repair Gene ◽

Variants Of Unknown Significance ◽

Pathogenic Variants ◽

Comprehensive Genomic Profiling ◽

Chi Square Test

256 Background: PARP inhibitors, olaparib and rucaparib recently improved survival outcomes (in the Profound and Triton-2 trials) in pts with aPC harboring HRRm. Notably, ~35% of pts screened for the PROfound trial did not meet eligibility solely due to the lack of adequate quality/quantity of tumor tissue required for CGP (De Bono, NEJM, 2020). cfDNA analysis non-invasively assesses tumor-derived genomic alterations. We evaluated the prevalence of HRRm in a real-world aPC population, who had commercially available cfDNA assay results available. Methods: cfDNA based CGP (using a clinically-validated 73- to 74-gene panel i.e. Guardant360 or G360) from consecutive aPC pts between 11/2016–8/2020 were used for detection of HRRm. Frameshift and nonsense mutations were included as pathogenic. Variants of unknown significance were excluded. In this unmatched study, the prevalence of each HRRm was compared with those reported in literature using the chi square test. Results: cfDNA CGP from 7701 aPC pts were available for interrogation of BRCA1/BRCA2 mutations, & from 4671 aPC pts for ATM mutations. Prevalence of BRCA1 and 2 as detected by cfDNA was similar to historical CGP of primary tissue. Prevalence of BRCA1 was higher than historical CGP of metastatic tissue. Prevalence of ATM in cfDNA was higher than historic tumor tissue CGP but similar to prior reports from cfDNA testing (Table). Conclusions: In this large real-world population of pts with aPC undergoing routine cfDNA CGP by a CLIA certified lab, prevalence of HRRm was similar (or higher for BRCA1 and ATM) to what has been previously reported from the tumor tissue. These data provide the rationale for utilizing cfDNA CGP as a routine test for detection of HRRm in men with aPC to identify men who are candidates for PARPi. [Table: see text]

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Author Correction: Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population

npj Precision Oncology ◽

10.1038/s41698-021-00222-y ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

C. B. Westphalen ◽

M. G. Krebs ◽

C. Le Tourneau ◽

E. S. Sokol ◽

S. L. Maund ◽

...

Keyword(s):

Real World ◽

World Population ◽

Genomic Context

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FGFR2-altered gastroesophageal adenocarcinomas (GEA) are a rare clinicopathologic entity with a distinct genomic landscape.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.72 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 72-72

Author(s):

Samuel Jacob Klempner ◽

Russell Madison ◽

Jeffrey S. Ross ◽

Vincent A. Miller ◽

Siraj Mahamed Ali ◽

...

Keyword(s):

Tyrosine Kinases ◽

Tp53 Mutation ◽

Fusion Partner ◽

Wild Type ◽

Genomic Landscape ◽

Female Predominance ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Pre Treatment ◽

Tissue Specimens

72 Background: Therapies directed at receptor tyrosine kinases (RTKs) in GEA have met with limited success. The small molecule FGFR2 inhibitor AZD4547 failed in a phase II biomarker-selected trial, though activity has been seen with FGFR2-directed strategies, including monoclonal antibodies. Despite observed activity, very little is known about the genomic landscape of FGFR2-altered GEA. Using a large genomic database, we sought to examine the classes of FGFR2 alterations and frequency of co-occurring alterations in GEA. Methods: 6,667 tissue specimens from unique patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: We identified a total of 269 (4.0%) FGFR2-altered cases consisting of FGFR2 amplified (amp; 209, 78% of FGFR2-altered), FGFR2 mutated (mut; 40, 15%) and FGFR2 rearranged (re, 37, 14%). There was a female predominance in FGFR2-altered cases (M:F = 1.6:1) vs FGFR wild-type (WT) (2.8:1). Cases with FGFR2amp and FGFR2re were exclusively MS-stable. The most common fusion partner was TACC2 (22%). FGFR2amp GEA had higher rates of TP53 mutation versus either FGFR2re of FGFR2mut cases (p = 4.4E-6). Co-occurring alterations in the other GEA RTK targets including ERBB2 (10%) , EGFR (8%) and MET (3%) were observed in all types of FGFR2-altered GEA. Co-occurring downstream alterations in MYC (17%), KRAS (10%) and PIK3CA (5.6%) were observed frequently in each class of FGFR2-altered GEA. The median TMB for FGFR2-altered GEA was 3.6 mut/mb, which was not significantly different from a median of 4.3 mut/mb seen in FGFR2 WT samples (p = 0.53). Conclusions: FGFR2-altered GEA is a heterogenous subgroup with approximately 20% of FGFR2-altered samples harboring concurrent RTK alterations. Putative co-occurring modifiers of FGFR2 directed therapy including oncogenic MYC, KRAS, PIK3CA alterations were also frequent, suggesting that pre-treatment CGP and combination approaches may be needed to optimize patient selection.

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Real-world usage and outcomes for patients treated with immune checkpoint inhibitors across multiple treatment indications in the Veterans Affairs system.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15063 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15063-e15063

Author(s):

Jennifer La ◽

David Cheng ◽

Nhan Do ◽

Mary T. Brophy ◽

Nathanael Fillmore ◽

...

Keyword(s):

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Veterans Affairs ◽

World Population ◽

Cancer Type ◽

Multiple Treatment ◽

Treatment Indications ◽

Line Of Therapy

e15063 Background: Increasingly broad patient groups are being treated with immune checkpoint inhibitors (ICIs) in clinical practice, but few studies have assessed their usage and outcomes in large, comprehensive real-world cohorts. In this study, we identified patients who received ICI therapy through April 2019 in the Veterans Affairs (VA) system. We described patient characteristics and assessed survival outcomes for patients across multiple treatment indications based on the cancer type and line of therapy. Methods: We conducted a retrospective analysis using electronic health record data captured from VA facilities nationwide. Patients treated with ICI were identified based on pharmacy and orders records. The associated cancer type and line of therapy (first line 1L or later line 2L+) was ascertained based on data on patients’ treatment history, administrative codes, and VA cancer registry records. The distribution of time from ICI treatment initiation to death was separately assessed by treatment indication using Kaplan-Meier estimates. Results: We identified 13,276 patients treated with ICI. The mean age was 69 years old. A majority of patients were male (97.2%) and white (76.9%), and a substantial minority were African-American (16.9%). Among patients treated with ICI for an identifiable cancer type, the most common cancer types included non-small lung cancer (NSCLC; 47.2%), melanoma (22.2%), renal cell carcinoma (RCC; 6.7%), squamous cell carcinoma of the head and neck (SCCHN; 10.4%), and urothelial cancer (6.4%). For major treatment indications, VA patients generally exhibited lower rates of survival than those reported in many ICI clinical trials, but the results are more comparable to those in trials among a subgroup of non-frail patients. Conclusions: This study describes ICI utilization and outcomes across multiple tumor types in a real-world population at the VA. The results offer evidence on the utilization and performance of ICIs in a real-world population. In addition, this work establishes a platform for further analyses of ICI outcomes in real-world practice at the VA. [Table: see text]

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Sensor-controlled scalp cooling: a safe and effective method to prevent chemotherapy-induced alopecia in a real-world population of patients with breast or female genital tract cancer

10.26226/morressier.5770e29ed462b80290b4c52d ◽

2016 ◽

Author(s):

Christian Martin Kurbacher

Keyword(s):

Real World ◽

Genital Tract ◽

Female Genital Tract ◽

World Population ◽

Scalp Cooling ◽

Tract Cancer ◽

Female Genital

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Real World Performance Evaluation of Transcatheter Aortic Valve Implantation

Journal of Clinical Medicine ◽

10.3390/jcm10091890 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1890

Author(s):

Gabriele Pesarini ◽

Gabriele Venturi ◽

Domenico Tavella ◽

Leonardo Gottin ◽

Mattia Lunardi ◽

...

Keyword(s):

Aortic Valve ◽

Real World ◽

Baseline Risk ◽

Risk Scores ◽

World Population ◽

Control Analysis ◽

Transcatheter Aortic Valve ◽

Procedural Control ◽

Risk Patients ◽

Over Time

Background: The aim of this research is to describe the performance over time of transcatheter aortic valve implantations (TAVIs) in a high-volume center with a contemporary, real-world population. Methods: Patients referred for TAVIs at the University Hospital of Verona were prospectively enrolled. By cumulative sum failures analysis (CUSUM), procedural-control curves for standardized combined endpoints—as defined by the Valve Academic Research Consortium-2 (VARC-2)—were calculated and analyzed over time. Acceptable and unacceptable limits were derived from recent studies on TAVI in intermediate and low-risk patients to fit the higher required standards for current indications. Results: A total of 910 patients were included. Baseline risk scores significantly reduced over time. Complete procedural control was obtained after approximately 125 and 190 cases for device success and early safety standardized combined endpoints, respectively. High risk patients (STS ≥ 8) had poorer outcomes, especially in terms of VARC-2 clinical efficacy, and required a higher case load to maintain in-control and proficient procedures. Clinically relevant single endpoints were all influenced by operator’s experience as well. Conclusions: Quality-control analysis for contemporary TAVI interventions based on standardized endpoints suggests the need for relevant operator’s experience to achieve and maintain optimal clinical results, especially in higher-risk subjects.

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Clinical evaluation of type 2 disease status in a real‐world population of difficult to manage asthma using historic electronic healthcare records of blood eosinophil counts

Clinical & Experimental Allergy ◽

10.1111/cea.13841 ◽

2021 ◽

Author(s):

Adnan Azim ◽

Colin Newell ◽

Clair Barber ◽

Matthew Harvey ◽

Deborah Knight ◽

...

Keyword(s):

Clinical Evaluation ◽

Real World ◽

Disease Status ◽

Blood Eosinophil ◽

World Population ◽

Eosinophil Counts

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Glycemic Outcomes of Second-Line Diabetes Drug Choice in a Real-World Population

Mayo Clinic Proceedings Innovations Quality & Outcomes ◽

10.1016/j.mayocpiqo.2021.02.008 ◽

2021 ◽

Author(s):

Amisha Wallia ◽

Matthew J. O’Brien ◽

David T. Liss ◽

Raymond H. Kang ◽

Andrew J. Cooper ◽

...

Keyword(s):

Real World ◽

World Population ◽

Second Line ◽

Drug Choice ◽

Diabetes Drug ◽

Glycemic Outcomes

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Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

JCO Precision Oncology ◽

10.1200/po.19.00248 ◽

2020 ◽

pp. 972-987

Author(s):

Ramez N. Eskander ◽

Julia Elvin ◽

Laurie Gay ◽

Jeffrey S. Ross ◽

Vincent A. Miller ◽

...

Keyword(s):

Treatment Strategies ◽

Current Treatment ◽

High Grade ◽

Novel Treatment ◽

Sample Average ◽

Genomic Landscape ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Sample Range ◽

Novel Treatment Strategies

PURPOSE High-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape. PATIENTS AND METHODS Ninety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs. RESULTS The median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were PIK3CA (19.6% of cohort), MYC (15.5%), TP53 (15.5%), and PTEN (14.4%). RB1 GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors ( P < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with MSH2 alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in PIK3CA, MYC, PTEN, TP53, ARID1A, and RB1 alteration rates were found. CONCLUSION This large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.

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