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Association of circulating tumor DNA from the cerebrospinal fluid with high-risk CNS involvement in patients with diffuse large B-cell lymphoma Dear Editor, Central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) patients correlates with dismal outcomes, and the detection sensitivity of conventional diagnosis of lymphoma is restricted.1-4 Circulating tumor DNA from cerebrospinal fluid (CSF-ctDNA) has played an important part in the application of liquid biopsy for patients with CNS cancers.5 In this study, we provided new insights into feasibility of CSF-derived biomarkers for CNS relapse diagnosis in DLBCL patients. Moreover, we compared alterations in five CSF-CNS genes from systemic tumor tissue of DLBCL patients in high-risk (HR) group with an additional dataset of 40 patients clinically diagnosed as low risk (LR) for CNS relapse. Five CSF-CNS genes in CSF was found to be associated with CNS risk in DLBCL patients, which deserve further investigation to determine their relevance among the diagnosis, treatment, and outcome. [Extracted from the article]

Ibrutinib‐based combination therapy with high‐dose methotrexate (HD‐MTX) has recently shown clinical activity against relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL). Herein, we report our real‐world experience of treating 11 newly diagnosed PCNSL patients with the ibrutinib/MTX combination. HD‐MTX was given at 3.5 g/m2 every 2‐week for eight doses. Ibrutinib was held upon HD‐MTX infusion until clearance and was administered daily post‐induction until disease progression, intolerable toxicity, or death. Nine out of 11 patients completed the induction phase and received ibrutinib as maintenance therapy. An objective response rate (ORR) of 82% (9/11) was observed including complete response (64%) and partial response (18%). The median progression‐free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The ibrutinib/MTX combination was well tolerated in these treatment‐naïve PCNSL patients with an acceptable safety profile. Moreover, the longitudinal analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) revealed that CSF ctDNA detection was closely associated with tumor response, and sustained tumor responses correlated with the clearance of ctDNA from the CSF. In sum, our data not only demonstrated the clinical benefit of the ibrutinib and HD‐MTX combination regimen in treating newly diagnosed PCNSL patients in a real‐world setting, but also highlighted the significance of liquid biopsy including CSF ctDNA in tracing tumor burden and assessing treatment response. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland, with a relatively high cure rate. Distant metastasis (DM) of PTC is uncommon, but when it occurs, it significantly decreases the survival of PTC patients. The molecular mechanisms of DM in PTC have not been systematically studied. We performed whole exome sequencing and GeneseeqPrime (425 genes) panel sequencing of the primary tumor, plasma and matched white blood cell samples from 20 PTC with DM and 46 PTC without DM. We identified somatic mutations, gene fusions and copy number alterations and analyzed their relationships with DM of PTC. BRAF‐V600E was identified in 73% of PTC, followed by RET fusions (14%) in a mutually exclusive manner (P < 0.0001). We found that gene fusions (RET, ALK or NTRK1) (P < 0.01) and chromosome 22q loss (P < 0.01) were independently associated with DM in both univariate and multivariate analyses. A nomogram model consisting of chromosome 22q loss, gene fusions and three clinical variables was built for predicting DM in PTC (C‐index = 0.89). The plasma circulating tumor DNA (ctDNA) detection rate in PTC was only 38.9%; however, it was significantly associated with the metastatic status (P = 0.04), tumor size (P = 0.001) and invasiveness (P = 0.01). In conclusion, gene fusions and chromosome 22q loss were independently associated with DM in PTC and could serve as molecular biomarkers for predicting DM. The ctDNA detection rate was low in non–DM PTC but significantly higher in PTC with DM. [ABSTRACT FROM AUTHOR]

Tumour‐induced osteomalacia (TIO) is a very rare paraneoplastic syndrome with bone pain, fractures and muscle weakness, which is mostly caused by phosphaturic mesenchymal tumours (PMTs). Cell‐free DNA (cfDNA) has been regarded as a non‐invasive liquid biopsy for many malignant tumours. However, it has not been studied in benign tumours, which prompted us to adopt the targeted next‐generation sequencing approach to compare cfDNAs of 4 TIO patients, four patients with bone metastasis (BM) and 10 healthy controls. The mutational landscapes of cfDNA in TIO and BM groups were similar in the spectrum of allele frequencies and mutation types. Markedly, deleterious missense mutations in FGFR1 and loss‐of‐function mutations in MED12 were found in 3/4 TIO patients but none of BM patients. The gene ontology analysis strongly supported that these mutated genes found in TIOs would play a potential role in PMTs' process. The genetic signatures and corresponding change in expression of FGFR1 and FGF23 were further validated in PMT tissues from a test cohort of another three TIO patients. In summary, we reported the first study of the mutational landscape and genetic signatures of cfDNA in TIO/PMTs. [ABSTRACT FROM AUTHOR]

Background: One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated the utility of ctDNA to reflect the efficacy of treatment and to monitor resistance mechanisms. Methods: Targeted next‐generation sequencing (NGS) of 416 cancer‐relevant genes was performed on 41 plasma biopsy samples of 19 HER2+ and 12 HER2‐ BC patients. Longitudinal ctDNA samples were analyzed in three BC patients over the treatment course for detecting acquired mutations. Results: In HER2+ BC patients, ERBB2 somatic copy numbers in ctDNA samples were significantly higher in patients progressed on HER2‐targeted therapy than those who were still responding to the treatment. Recurrent acquired mutations were detected in genes including ERBB2, TP53, EGFR, NF1, and SETD2, which may contribute to trastuzumab resistance. In longitudinal analyses, the observed mutation allele frequencies were tracked closely in concordance with treatment responses. A novel ERBB2 p.(Leu869Arg) mutation was acquired in one patient upon resistant to trastuzumab therapy, which was further validated as an oncogenic mutation in vitro and contributed to resistance. In HER2‐ BC patients with chemotherapy resistance, genetic alterations on TP53, PIK3CA, and DNA damage repair genes were frequently observed. Conclusions: In summary, ctDNA monitoring, particularly longitudinal analyses, provides valuable insights into the assessment of targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2‐ BC patients, respectively. [ABSTRACT FROM AUTHOR]