bims-ovdlit 2022-09-18 papers

Issue of 2022–09–18
five papers selected by
Lara Paracchini, Humanitas Research

Ann Oncol. 2022 Sep 08. pii: S0923-7534(22)04141-2. [Epub ahead of print]

The Clinical Landscape of Cell-Free DNA Alterations in 1,671 Patients with Advanced Biliary Tract Cancer.

BACKGROUND: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology.
PATIENTS AND METHODS: We analyzed next-generation sequencing data of 2,068 cfDNA samples from 1,671 patients with advanced BTC generated with Guardant360. We performed clinical annotation on a multi-institutional subset (n=225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes.
RESULTS: Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. FGFR2 fusions, IDH1 mutations, and BRAF V600E were clonal in majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%).
CONCLUSIONS: These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.

Keywords: Biliary tract cancer; Cell-free DNA; Cholangiocarcinoma; Liquid Biopsy

DOI: https://doi.org/10.1016/j.annonc.2022.09.150

J Hematol Oncol. 2022 Sep 12. 15(1): 131

Liquid biopsy: current technology and clinical applications.

Mina Nikanjam, Shumei Kato, Razelle Kurzrock.

Liquid biopsies are increasingly used for cancer molecular profiling that enables a precision oncology approach. Circulating extracellular nucleic acids (cell-free DNA; cfDNA), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs) can be isolated from the blood and other body fluids. This review will focus on current technologies and clinical applications for liquid biopsies. ctDNA/cfDNA has been isolated and analyzed using many techniques, e.g., droplet digital polymerase chain reaction, beads, emulsion, amplification, and magnetics (BEAMing), tagged-amplicon deep sequencing (TAm-Seq), cancer personalized profiling by deep sequencing (CAPP-Seq), whole genome bisulfite sequencing (WGBS-Seq), whole exome sequencing (WES), and whole genome sequencing (WGS). CTCs have been isolated using biomarker-based cell capture, and positive or negative enrichment based on biophysical and other properties. ctDNA/cfDNA and CTCs are being exploited in a variety of clinical applications: differentiating unique immune checkpoint blockade response patterns using serial samples; predicting immune checkpoint blockade response based on baseline liquid biopsy characteristics; predicting response and resistance to targeted therapy and chemotherapy as well as immunotherapy, including CAR-T cells, based on serial sampling; assessing shed DNA from multiple metastatic sites; assessing potentially actionable alterations; analyzing prognosis and tumor burden, including after surgery; interrogating difficult-to biopsy tumors; and detecting cancer at early stages. The latter can be limited by the small amounts of tumor-derived components shed into the circulation; furthermore, cfDNA assessment in all cancers can be confounded by clonal hematopoeisis of indeterminate potential, especially in the elderly. CTCs can be technically more difficult to isolate that cfDNA, but permit functional assays, as well as evaluation of CTC-derived DNA, RNA and proteins, including single-cell analysis. Blood biopsies are less invasive than tissue biopsies and hence amenable to serial collection, which can provide critical molecular information in real time. In conclusion, liquid biopsy is a powerful tool, and remarkable advances in this technology have impacted multiple aspects of precision oncology, from early diagnosis to management of refractory metastatic disease. Future research may focus on fluids beyond blood, such as ascites, effusions, urine, and cerebrospinal fluid, as well as methylation patterns and elements such as exosomes.

Keywords: CTC; Liquid biopsy; Precision medicine; cfDNA; ctDNA

DOI: https://doi.org/10.1186/s13045-022-01351-y

Nat Rev Cancer. 2022 Sep 15.

Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation.

Lana E Kandalaft, Denarda Dangaj Laniti, George Coukos.

Treatment of high-grade serous ovarian cancer (HGSOC) remains challenging. Although HGSOC can potentially be responsive to immunotherapy owing to endogenous immunity at the molecular or T cell level, immunotherapy for this disease has fallen short of expectations to date. This Review proposes a working classification for HGSOC based on the presence or absence of intraepithelial T cells, and elaborates the putative mechanisms that give rise to such immunophenotypes. These differences might explain the failures of existing immunotherapies, and suggest that rational therapeutic approaches tailored to each immunophenotype might meet with improved success. In T cell-inflamed tumours, treatment could focus on mobilizing pre-existing immunity and strengthening the activation of T cells embedded in intraepithelial tumour myeloid niches. Conversely, in immune-excluded and immune-desert tumours, treatment could focus on restoring inflammation by reprogramming myeloid cells, stromal cells and vascular epithelial cells. Poly(ADP-ribose) polymerase (PARP) inhibitors, low-dose radiotherapy, epigenetic drugs and anti-angiogenesis therapy are among the tools available to restore T cell infiltration in HGSOC tumours and could be implemented in combination with vaccines and redirected T cells.

DOI: https://doi.org/10.1038/s41568-022-00503-z

Gynecol Oncol. 2022 Sep 09. pii: S0090-8258(22)00480-2. [Epub ahead of print]

Blood-based DNA methylation profiling for the detection of ovarian cancer.

Ning Li, Xin Zhu, Weiqi Nian, Yifan Li, Yangchun Sun, Guangwen Yuan, Zhenjing Zhang, Wenqing Yang, Jiayue Xu, Analyn Lizaso, Bingsi Li, Zhihong Zhang, Lingying Wu, Yu Zhang.

OBJECTIVES: Ovarian cancer is a fatal gynecological cancer due to the lack of effective screening strategies at early stage. This study explored the utility of DNA methylation profiling of blood samples for the detection of ovarian cancer.
METHODS: Targeted bisulfite sequencing was performed on tissue (n = 152) and blood samples (n = 373) obtained from healthy women, women with benign ovarian tumors, or malignant epithelial ovarian tumors. Based on the tissue-derived differentially-methylated regions, a supervised machine learning algorithm was implemented and cross-validated using the blood-derived DNA methylation profiles of the training cohort (n = 178) to predict and classify each blood sample as malignant or non-malignant. The model was further evaluated using an independent test cohort (n = 184).
RESULTS: Comparison of the DNA methylation profiles of normal/benign and malignant tumor samples identified 1272 differentially-methylated regions, with 49.4% hypermethylated regions and 50.6% hypomethylated regions. Five-fold cross-validation of the model using the training dataset yielded an area under the curve of 0.94. Using the test dataset, the model accurately predicted non-malignancy in 96.2% of healthy women (n = 53) and 93.5% of women with benign tumors (n = 46). For patients with malignant tumors, the model accurately predicted malignancy in 44.4% of stage I-II (n = 9), 86.4% of stage III (n = 59), 100.0% of stage IV tumors (n = 6), and 81.8% of tumors with unknown stage (n = 11). Overall, the model yielded a predictive accuracy of 89.5%.
CONCLUSIONS: Our study demonstrates the potential clinical application of blood-based DNA methylation profiling for the detection of ovarian cancer.

Keywords: DNA methylation; Early detection; Ovarian cancer

DOI: https://doi.org/10.1016/j.ygyno.2022.07.008

Cancer Cell. 2022 Sep 12. pii: S1535-6108(22)00385-3. [Epub ahead of print]40(9): 895-900

Spatial transcriptomics.

Ana C Anderson, Itai Yanai, Lucy R Yates, Linghua Wang, Alexander Swarbrick, Peter Sorger, Sandro Santagata, Wolf H Fridman, Qiang Gao, Livnat Jerby, Benjamin Izar, Lulu Shang, Xiang Zhou.

Spatial transcriptomics, with other spatial technologies, has enabled scientists to dissect the organization and interaction of different cell types within the tumor microenvironment. We asked experts to discuss some aspects of this technology from revealing the tumor microenvironment and heterogeneity, to tracking tumor evolution, to guiding tumor therapy, to current technical challenges.

DOI: https://doi.org/10.1016/j.ccell.2022.08.021