Validation of the Labcorp Plasma Focus Test to Facilitate Precision Oncology Through Cell-Free DNA Genomic Profiling of Solid Tumors.

Genomic profiling is critical for precision oncology to guide treatment decisions. Liquid biopsy testing is a complementary approach to tissue testing, particularly when tissue is not readily available. The Labcorp Plasma Focus test is a circulating cell-free DNA genomic profiling test that identifies actionable variants in solid cancers, including non-small-cell lung, colorectal, melanoma, breast, esophageal, gastroesophageal junction, and gastric cancers. This study highlights the analytical validation of the test, including accuracy compared with orthogonal methods, as well as sensitivity, specificity, precision, reproducibility, and repeatability. Concordance with orthogonal methods showed percent positive agreement of 98.7%, 89.3%, and 96.2% for single nucleotide variants (SNVs), insertion/deletions (indels), and copy number amplifications (CNAs), respectively, and 100.0% for translocations and microsatellite instability (MSI). Analytical sensitivity revealed a median limit of detection of 0.7% and 0.6% for SNVs and indels, 1.4-fold for CNAs, 0.5% variant allele frequency for translocations, and 0.6% for MSI. Specificity was >99% for SNVs/indels and 100% for CNAs, translocations, and MSI. Average positive agreement from precision, reproducibility, and repeatability experiments was 97.5% and 88.9% for SNVs/indels and CNAs, and 100% for translocations and MSI. Taken together, these data show that the Labcorp Plasma Focus test is a highly accurate, sensitive, and specific approach for cell-free DNA genomic profiling to supplement tissue testing and inform treatment decisions.

The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA.

PURPOSE: Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon. EXPERIMENTAL DESIGN: Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases. RESULTS: Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months. CONCLUSION: We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy. IMPLICATIONS FOR PRACTICE: Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.

BRAF in Lung Cancers: Analysis of Patient Cases Reveals Recurrent BRAF Mutations, Fusions, Kinase Duplications, and Concurrent Alterations.

PURPOSE: Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor BRAF V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 BRAF alterations in lung cancer. PATIENTS AND METHODS: A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic BRAF base substitutions, short insertions and deletions, copy number changes, and rearrangements. RESULTS: Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. BRAF was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were BRAF V600E, 38% were BRAF non-V600E activating mutations, and 18% were BRAF inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and BRAF fusions (2.8%). The fusions involved three recurrent fusion partners: ARMC10, DOCK4, and TRIM24. BRAF V600E was associated with co-occurrence of SETD2 alterations, but other BRAF alterations were not and were instead associated with CDKN2A, TP53, and STK11 alterations (P < .05). Potential mechanisms of acquired resistance to BRAF V600E inhibition are demonstrated. CONCLUSION: This series characterized the frequent occurrence (4.4%) of BRAF alterations in lung cancers. Recurrent BRAF alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as ALK, and exceed that of ROS1 or RET. This work supports a broad profiling approach in lung cancers and suggests that non-V600E BRAF alterations represent a subgroup of lung cancers in which targeted therapy should be considered.

Leiomyosarcoma of the inferior vena cava: a case report and review of the literature.

A 68-year-old white female presented with two years of progressively worsening dyspnea. Echocardiography revealed a large right atrial mass and partial obstruction of the inferior vena cava. Further imaging revealed a cystic dense mass in the inferior vena cava and right atrium. Immunohistochemical stains were consistent with leiomyosarcoma. Intraoperatively, the tumor was noted to originate from the posterior aspect of the inferior vena cava. The patient underwent successful resection of the mass. Adjuvant radiation therapy was completed. The patient's dyspnea gradually improved and she continues to remain disease free five years post-resection.

Growth factors involved in prostate carcinogenesis.

Prostate cancer is the most common non-skin cancer affecting men in United States and the second leading cause of death after lung cancer. The clinical course of patients after given diagnosis of prostate cancer is highly variable and the underlying reasons for such variability remain elusive. To better understand the pathophysiology of prostate cancer, there has been a push to elucidate the molecular mechanisms that mediate the development and progression of prostate cancer. Recent literature has pointed that a complex interplay between various cytokines, growth factors, and androgen receptors regulate the growth and functions of the prostate gland. Amongst the currently implicated anomalous pathways involved in prostate oncogenesis, the IGF-IGFBP axis has been demonstrated to play a very important role, although the precise molecular events regulated by IGF remain to be elucidated. The tumor promoting functions of VEGF has been defined in tumor angiogenesis and currently remains the central focus of anti-angiogenesis therapy in prostate cancer. Another key cytokine, TGF-beta has tumor-suppressor functions in normal prostate gland, but its pleiotropic functions in prostate cancer are influenced by the hormonal state of the disease. In partnership with other deregulated growth factor signaling, the TGF-beta cascade has also been implicated in the spread of prostate cancer. Lastly, members of the EGFR family, particularly the HER2 receptor, have also been recognized as crucial elements of aberrant signal transduction pathways, which induce activation of downstream signaling, involved in cellular proliferation, cell survival, and angiogenesis. The abnormal function of a number of growth factors in prostate cancer biology explains the heterogeneity of its histologic grade, mode of presentation and disease prognosis. At the same time, continued research in this field allows for the potential development of drug therapies against a diverse pool of cancer causing targets.