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Plasma cell-free DNA (cfDNA) is emerging as an important diagnostic tool in cancer. However, cfDNA alterations may differ from those in tissue and sometimes may reflect processes unrelated to the cancer, including clonal hematopoiesis (CH). We examined plasma cfDNA, tested by next-generation sequencing (NGS), for characterized alterations (excluding variants of unknown significance) in 135 patients with invasive glioma. Overall, 21% (28/135) had ≥1 alteration; 17% (23/135) had CH-type cfDNA mutations. Temozolomide (a mutagenic alkylating agent) with concurrent radiation therapy prior to blood draw was significantly associated with an increase in CH-type mutations, even after age, race/ethnicity, and WHO-grade were considered as confounders (odds ratio [95% confidence interval, CI] 8.98 [1.13-71.46]; P = .04; multivariable analysis). Further, of 18 patients with invasive glioma who had both cfDNA and tissue DNA NGS and had ≥1 cfDNA alteration, 16 (89%) had ≥1 cfDNA alteration not found in their tissue DNA, including CH-type alterations in genes such as TP53 (most common), ATM, GNAS, and JAK2. Altogether, 87% of cfDNA alterations (20/23) observed in the 18 patients were implicated in CH. Finally, examining all 135 patients, CH-type cfDNA mutations were an independent prognostic factor for shorter survival (hazard ratio [95% CI] 3.28 [1.28-8.40]; P = .01). These findings emphasize that not all characterized cfDNA alterations detected in patients with solid tumors are cancer-related. Importantly, in patients with invasive gliomas who have had prior temozolomide and radiation, CH-related alterations in cfDNA are frequent and correlate with poor outcomes.

Predicting oncologic outcome is challenging due to the diversity of cancer histologies and the complex network of underlying biological factors. In this study, we determine whether machine learning (ML) can extract meaningful associations between oncologic outcome and clinical trial, drug-related biomarker and molecular profile information. We analyzed therapeutic clinical trials corresponding to 1102 oncologic outcomes from 104 758 cancer patients with advanced colorectal adenocarcinoma, pancreatic adenocarcinoma, melanoma and nonsmall-cell lung cancer. For each intervention arm, a dataset with the following attributes was curated: line of treatment, the number of cytotoxic chemotherapies, small-molecule inhibitors, or monoclonal antibody agents, drug class, molecular alteration status of the clinical arm's population, cancer type, probability of drug sensitivity (PDS) (integrating the status of genomic, transcriptomic and proteomic biomarkers in the population of interest) and outcome. A total of 467 progression-free survival (PFS) and 369 overall survival (OS) data points were used as training sets to build our ML (random forest) model. Cross-validation sets were used for PFS and OS, obtaining correlation coefficients (r) of 0.82 and 0.70, respectively (outcome vs model's parameters). A total of 156 PFS and 110 OS data points were used as test sets. The Spearman correlation (rs ) between predicted and actual outcomes was statistically significant (PFS: rs = 0.879, OS: rs = 0.878, P

EGFR exon 20 alterations are rare events seen mainly in non-small cell lung cancer (NSCLC). They include EGFR T790 and C797S mutations (associated with secondary resistance to classic EGFR tyrosine kinase inhibitors (TKIs)), and EGFR exon 20 in-frame insertions (associated with resistance to first- and second-generation EGFR TKIs). In silico modeling of structural changes in aberrant proteins has informed selection of compounds with potential clinical activity: poziotinib (whose smaller size permits access to the restricted kinase pocket created by EGFR and ERBB2 exon 20 insertions); cetuximab (an antibody that attenuates dimerization caused by EGFR exon 20 insertions), and TAK-788 (another EGFR/ERBB2 TKI). Other alterations, such as EGFR T790 M, are responsive to osimertinib, while the EGFR C797S alteration seen in osimertinib resistance demonstrates preclinical sensitivity to combined brigatinib and cetuximab. These observations indicate that clinical resistance can be overcome by utilizing advanced genomic interrogation coupled with computer modeling.

Anti-angiogenic therapies are an important class of anti-cancer treatment drugs. However, their efficacy is limited to certain tumors and would benefit from identifying a biomarker predictive of therapeutic response. TP53 (tumor protein p53) is a tumor suppressor gene frequently mutated in cancer and implicated in cell-cycle regulation, apoptosis, and angiogenesis. Data from 7,525 unique tumor samples (representing 30 tumor cohorts) were retrieved from the TCGA database to analyze the relationship between TP53-mutation status and VEGFA (vascular endothelial growth factor A) expression. Univariate analyses were done using a Mann-Whitney univariate test or Fisher's exact test. Parameters with a p-value (p)≤0.1 in univariate analysis were selected for follow-up multivariate analyses, including TP53-mutation status, cancer cohorts, cancer subtypes, and VEGFA expression. Our analysis demonstrates statistically significant increases in VEGFA mRNA tissue expression in TP53-mutated adenocarcinomas (but not in squamous cancers) compared to TP53 wild-type tumors. This association holds true in multivariate analyses and remains independent of HIF-1α and MDM2 overexpression. Our findings provide additional evidence that TP53 mutations are linked to the VEGF pathway, potentially offering insight into the mechanism behind increased sensitivity to anti-angiogenic therapies observed in some TP53-mutant tumors.

Tumor-associated neo-antigens are mutated peptides that allow the immune system to recognize the affected cell as foreign. Cells carrying excessive mutation load often develop mechanisms of tolerance. PD-L1/PD-1 checkpoint immunotherapy is a highly promising approach to overcome these protective signals and induce tumor shrinkage. Yet, the nature of the neo-antigens driving those beneficial responses remains unclear. Here, we show that APOBEC-related mutagenesis - a mechanism at the crossroads between anti-viral immunity and endogenous nucleic acid editing - increases neo-peptide hydrophobicity (a feature of immunogenicity), as demonstrated by in silico computation and in the TCGA pan-cancer cohort, where APOBEC-related mutagenesis was also strongly associated with immune marker expression. Moreover, APOBEC-related mutagenesis correlated with immunotherapy response in a cohort of 99 patients with diverse cancers, and this correlation was independent of the tumor mutation burden (TMB). Combining APOBEC-related mutagenesis estimate and TMB resulted in greater predictive ability than either parameter alone. Based on these results, further investigation of APOBEC-related mutagenesis as a marker of response to anti-cancer checkpoint blockade is warranted.

PurposeFusions that involve neurotrophic-tropomyosin receptor kinase (NTRK) genes are known drivers of oncogenesis. Therapies that target these ultra-rare, constitutionally active NTRK fusions have been remarkably effective. Herein, we analyze the prevalence of the full array of NTRK alterations-fusions, mutations, copy number alterations, and increased transcript expression-in diverse adult and pediatric tumor types to understand the landscape of NTRK aberrations in cancer.MethodsWe assessed 13,467 samples available from The Cancer Genome Atlas (adult tumors) and the St Jude PeCan database (pediatric tumors) for the prevalence of NTRK fusions, as well as associated genomic and transcriptomic co-aberrations in different tumor types.ResultsNTRK fusions were observed in 0.31% of adult tumors and in 0.34% of pediatric tumors. The most common gene partners were NTRK3 (0.16% of adult tumors) followed by NTRK1 (0.14% of pediatric tumors). NTRK fusions were found more commonly in pediatric melanoma (11.1% of samples), pediatric glioma (3.97%), and adult thyroid cancers (2.34%). Additional genomic and transcriptomic NTRK alterations- mutation, amplification, and mRNA overexpression-occurred in 14.2% of samples, whereas the frequency of alterations that implicated NTRK ligands and the NTRK co-receptor (p75NTR) ranged from 3.8% to 5.4%. Among 31 adult samples carrying NTRK fusions, co-alterations occurred often and usually involved the downstream phosphoinositide-3-kinase signaling pathway, cell-cycle machinery, other tyrosine-kinase receptors, and mitogen-activated protein kinase signals.ConclusionWhereas NTRK fusions are exceedingly rare, other NTRK abnormalities affect 14% of patients with cancer. Affecting these alterations has not yet been achievable in cancer. Genomic co-alterations occur frequently with NTRK fusions, but it is not known if co-targeting them can attenuate primary or secondary resistance to NTRK inhibitors.

Metastatic basal cell cancer (BCC) is an ultra-rare malignancy with no approved therapies beyond Hedgehog inhibitors. We characterized the genomics, tumor mutational burden (TMB), and anti-PD-1 therapy responses in patients with locally advanced or metastatic BCC. Overall, 2,039 diverse cancer samples that had undergone comprehensive genomic profiling (CGP) were reviewed. Eight patients with locally advanced/metastatic BCC were identified (two had two CGP analyses; total, 10 biopsies). Two tumors demonstrated PD-L1 amplification. Seven patients had >1 actionable alteration. The TMB (mutations/mb) (median (range)) was 90 (3-103) for the BCCs versus 4 (1-860) for 1637 cancers other than BCC (P < 0.0001). Median progression-free survival (PFS) for all four patients treated with PD-1 blockade was 10.7 months (range, 3.8 to 17.6+ months); three patients had an objective response. In conclusion, advanced/metastatic BCC often has biological features (high TMB; PD-L1 amplification) predictive of immunotherapy benefit, and patients frequently respond to PD-1 blockade.

Immunotherapy with checkpoint inhibitors, such as antibodies blocking the programmed cell-death receptor-1 (PD-1), has resulted in remarkable responses in patients having traditionally refractory cancers. Although response to PD-1 inhibitors correlates with PD-1 ligand (PD-L1 or PD-L2) expression, PD-1 ligand positivity represents only a part of the predictive model necessary for selecting patients predisposed to respond to immunotherapy. We used all genomic, transcriptomic, proteomic and phenotypic data related to 8,475 pan-cancer samples available in The Cancer Genome Atlas (TCGA) and conducted a logistic regression analysis based on a large set of variables, such as microsatellite instability (MSI-H), mismatch repair (MMR) alterations, polymerase δ (POLD1) and polymerase ε (POLE) mutations, activation-induced/apolipoprotein-B editing cytidine deaminases (AID/APOBEC) alterations, lymphocyte markers and mutation burden estimates to determine independent factors that associate with PD-1 ligand overexpression. PD-1 ligand overexpression was independently and significantly correlated with overexpression of and mutations in APOBEC3 paralogs. Additionally, while high tumor mutation burden and overexpression of PD-L1 have been previously correlated with each other, we demonstrate that the specific mutation pattern caused by APOBEC enzymes and called kataegis-rather than overall mutation burden, MSI-H or MMR alterations-correlates independently with PD-L1/PD-L2 expression. These observations suggest that APOBEC3 alterations, APOBEC3 overexpression and kataegis play an important role in the regulation of PD-1 ligand overexpression, and thus, their relationship with immune checkpoint inhibitor response warrants exploration.

Background: The incidence of thyroid cancer is increasing worldwide at an alarming rate. BRAF V600E mutation is described to be associated with a worse prognostic of thyroid carcinomas, as well as extrathyroidal invasion and increased mortality., Objective: To our knowledge, there are no reported studies neither from Morocco nor from other Maghreb countries regarding the prevalence of BRAF V600E mutation in thyroid carcinomas. Here we aim to evaluate the frequency of BRAF V600E oncogene in Moroccan thyroid carcinomas., Methods: In this Single-Institution retrospective study realized in the Anatomic Pathology and Histology Service in the Military Hospital of Instruction Mohammed V 'HMIMV' in Rabat, we report, using direct genomic sequencing, the assessment of BRAF V600E in 37 thyroid tumors., Results: We detected BRAF V600E mutation exclusively in Papillary Thyroid Carcinomas 'PTC' with a prevalence of 28% (8 PTC out 29 PTC). Like international trends, Papillary Thyroid Carcinomas 'PTC' is more frequent than Follicular Thyroid Carcinomas 'FTC' and Anaplastic Thyroid Carcinomas 'ATC' (29 PTC, 7 FTC and 1 ATC)., Conclusion: Our finding gives to the international community the first estimated incidence of this oncogene in Morocco showing that this prevalence falls within the range of international trends (30% to 90%) reported in distinct worldwide geographic regions., (© 2020 Kaabouch M et al.)