bims-ovdlit 2021-11-07 papers

Issue of 2021–11–07
five papers selected by
Lara Paracchini, Humanitas Research

Front Oncol. 2021 ;11 675972

Homologous Recombination Deficiency Assays in Epithelial Ovarian Cancer: Current Status and Future Direction.

Ying-Cheng Chiang, Po-Han Lin, Wen-Fang Cheng.

Epithelial ovarian cancer (EOC) patients are generally diagnosed at an advanced stage, usually relapse after initial treatments, which include debulking surgery and adjuvant platinum-based chemotherapy, and eventually have poor 5-year survival of less than 50%. In recent years, promising survival benefits from maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) has changed the management of EOC in newly diagnosed and recurrent disease. Identification of BRCA mutations and/or homologous recombination deficiency (HRD) is critical for selecting patients for PARPi treatment. However, the currently available HRD assays are not perfect predictors of the clinical response to PARPis in EOC patients. In this review, we introduce the concept of synthetic lethality, the rationale of using PARPi when HRD is present in tumor cells, the clinical trials of PARPi incorporating the HRD assays for EOC, the current HRD assays, and other HRD assays in development.

Keywords: PARP inhibitor; RAD51 foci formation; epithelial ovarian cancer; genomic scar; homologous recombination deficiency; mutational signatures

DOI: https://doi.org/10.3389/fonc.2021.675972

Curr Oncol Rep. 2021 Nov 04. 23(12): 140

Circulating Tumour DNA and Colorectal Cancer: the Next Revolutionary Biomarker?

Mahendra Naidoo, Oliver Piercey, Jeanne Tie.

PURPOSE OF REVIEW: Improving outcomes for patients with colorectal cancer in both the adjuvant and metastatic setting has been challenging. Here, we review the current and future directions for using ctDNA in clinical practice.
RECENT FINDINGS: Circulating tumour DNA (ctDNA) with its ability to detect minimal residual disease is beginning to refine the way we assess recurrence risk in the adjuvant setting. We can potentially tailor treatments to reduce recurrence risk and minimize treatment toxicity. In the metastatic setting, ctDNA can provide a less invasive method of detecting clinically important genetic changes to guide molecularly targeted treatment and to identify mechanisms of molecular resistance. ctDNA can be a surrogate marker for treatment response and help guide the timing of anti-EGFR rechallenge. We await the results of the randomized clinical trials assessing clinical utility of ctDNA in both the adjuvant and metastatic setting before incorporating ctDNA into clinical practice.

Keywords: Adjuvant chemotherapy; Biomarker; Colorectal cancer; Metastatic; Minimal residual disease; Molecular resistance; ctDNA

DOI: https://doi.org/10.1007/s11912-021-01137-4

Front Genet. 2021 ;12 759832

Signatures Beyond Oncogenic Mutations in Cell-Free DNA Sequencing for Non-Invasive, Early Detection of Cancer.

Subhajyoti De.

Early detection of cancer saves lives, but an effective detection strategy in public health settings requires a delicate balance - periodic screening should neither miss rapidly progressing disease nor fail to detect rare tumors at unusual locations; on the other hand, even a modest false positive rate carries risks of over-diagnosis and over-treatment of relatively indolent non-malignant disease. Genomic profiling of cell-free DNA from liquid biopsy using massively parallel sequencing is emerging as an attractive, non-invasive screening platform for sensitive detection of multiple types of cancer in a single assay. Genomic data from cell-free DNA can not only identify oncogenic mutation status, but also additional molecular signatures related to potential tissue of origin, the extent of clonal growth, and malignant disease states. Utilization of the full potential of the molecular signatures from cfDNA sequencing data can guide clinical management strategies for targeted follow-ups using imaging or molecular marker-based diagnostic platforms and treatment options.

Keywords: cancer; cell-free DNA; early detection; non-invasive; sequencing

DOI: https://doi.org/10.3389/fgene.2021.759832

Mol Diagn Ther. 2021 Nov 01.

Commercial ctDNA Assays for Minimal Residual Disease Detection of Solid Tumors.

Kevin Chen, Misty D Shields, Pradeep S Chauhan, Ricardo J Ramirez, Peter K Harris, Melissa A Reimers, Jose P Zevallos, Andrew A Davis, Bruna Pellini, Aadel A Chaudhuri.

The detection of circulating tumor DNA via liquid biopsy has become an important diagnostic test for patients with cancer. While certain commercial liquid biopsy platforms designed to detect circulating tumor DNA have been approved to guide clinical decisions in advanced solid tumors, the clinical utility of these assays for detecting minimal residual disease after curative-intent treatment of nonmetastatic disease is currently limited. Predicting disease response and relapse has considerable potential for increasing the effective implementation of neoadjuvant and adjuvant therapies. As a result, many companies are rapidly investing in the development of liquid biopsy platforms to detect circulating tumor DNA in the minimal residual disease setting. In this review, we discuss the development and clinical implementation of commercial liquid biopsy platforms for circulating tumor DNA minimal residual disease detection of solid tumors. Here, we aim to highlight the technological features that enable highly sensitive detection of tumor-derived genomic alterations, the factors that differentiate these commercial platforms, and the ongoing trials that seek to increase clinical implementation of liquid biopsies using circulating tumor DNA-based minimal residual disease detection.

DOI: https://doi.org/10.1007/s40291-021-00559-x

Clin Chem. 2021 Oct 26. pii: hvab142. [Epub ahead of print]

Measurement Biases Distort Cell-Free DNA Fragmentation Profiles and Define the Sensitivity of Metagenomic Cell-Free DNA Sequencing Assays.

Adrienne Chang, Omary Mzava, Joan S Lenz, Alexandre P Cheng, Philip Burnham, S Timothy Motley, Crissa Bennett, John T Connelly, Darshana M Dadhania, Manikkam Suthanthiran, John R Lee, Amy Steadman, Iwijn De Vlaminck.

BACKGROUND: Metagenomic sequencing of microbial cell-free DNA (cfDNA) in blood and urine is increasingly used as a tool for unbiased infection screening. The sensitivity of metagenomic cfDNA sequencing assays is determined by the efficiency by which the assay recovers microbial cfDNA vs host-specific cfDNA. We hypothesized that the choice of methods used for DNA isolation, DNA sequencing library preparation, and sequencing would affect the sensitivity of metagenomic cfDNA sequencing.
METHODS: We characterized the fragment length biases inherent to select DNA isolation and library preparation procedures and developed a model to correct for these biases. We analyzed 305 cfDNA sequencing data sets, including publicly available data sets and 124 newly generated data sets, to evaluate the dependence of the sensitivity of metagenomic cfDNA sequencing on pre-analytical variables.
RESULTS: Length bias correction of fragment length distributions measured from different experimental procedures revealed the ultrashort (<100 bp) nature of microbial-, mitochondrial-, and host-specific urinary cfDNA. The sensitivity of metagenomic sequencing assays to detect the clinically reported microorganism differed by more than 5-fold depending on the combination of DNA isolation and library preparation used.
CONCLUSIONS: Substantial gains in the sensitivity of microbial and other short fragment recovery can be achieved by easy-to-implement changes in the sample preparation protocol, which highlights the need for standardization in the liquid biopsy field.

Keywords: cell-free DNA; liquid biopsy; pre-analytical

DOI: https://doi.org/10.1093/clinchem/hvab142