bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2021–08–29
nine papers selected by
Lara Paracchini, Humanitas Research
  1. Immune checkpoint inhibitors in ovarian cancer: where do we stand?
  2. Immune cells and signatures characterize tumor microenvironment and predict outcome in ovarian and endometrial cancers.
  3. TILs show early efficacy.
  4. Extracellular Vesicle-Derived DNA vs. CfDNA as a Biomarker for the Detection of Colon Cancer.
  5. Circulating TP53 mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX.
  6. Digital Pathology-based Study of Cell- and Tissue-level Morphologic Features in Serous Borderline Ovarian Tumor and High-grade Serous Ovarian Cancer.
  7. Clinical Utility of Liquid Biopsy-Based Actionable Mutations Detected via ddPCR.
  8. Clinical correlates of circulating cell-free DNA tumor fraction.
  9. MuA-based Molecular Indexing for Rare Mutation Detection by Next-Generation Sequencing.
  1. Ther Adv Med Oncol. 2021 ;13 17588359211039899
    Immune checkpoint inhibitors in ovarian cancer: where do we stand?
    Alexandra Leary, David Tan, Jonathan Ledermann.
      Numerous retrospective studies have demonstrated that the density of intra-tumoral immune cell infiltration is prognostic in epithelial ovarian cancer (OC). These observations together with reports of programmed death ligand-1 (PD-L1) expression in advanced OC provided the rationale for investigating the benefit of programmed death-1 (PD1) or PD-L1 inhibition in OC. Unfortunately clinical trials to date evaluating PD1/PD-L1 inhibition in patients with relapsed OC have been disappointing. In this review we will discuss early results from single agent PD1/PD-L1 inhibitors and the strategies to enhance benefit from immune-oncology agents in OC, including proposing anti-PD-L1 in combination with other agents (cytotoxics, anti-angiogenics, poly(ADP-ribose) polymerase. (PARP) inhibitors, targeted therapies or other immunotherapies), as well as evaluating these agents earlier in the disease course, or in biomarker selected patients.
    Keywords:  PARP inhibitors; anti-angiogenic; combinations; immune checkpoint inhibitors; ovarian cancer; predictive biomarkers
    DOI:  https://doi.org/10.1177/17588359211039899
  2. Immunotherapy. 2021 Aug 23.
    Immune cells and signatures characterize tumor microenvironment and predict outcome in ovarian and endometrial cancers.
    Ying Ni, Ahmed Soliman, Amy Joehlin-Price, Fadi Abdul-Karim, Peter G Rose, Haider Mahdi.
      Aims: We investigated immunogenomic signatures and correlated them with survival in ovarian cancer (OV) and endometrial cancer (EC). Materials & Method: We used whole transcriptome sequencing data from uterine serous cancer and The Cancer Genome Atlas data of OV and EC (n = 719). Gene expression score was calculated. Population abundance of immune cells were estimated. Results: TGF-β, myeloid cells, IFN-γ, T cells, B cells and endothelial cells predicted overall survival. Whereas CD47, neutrophils and endothelial cells predicted progression-free survival. In multivariate analyses, TGF-β, CD47 and monocytic cells predicted survival in high levels of microsatellite instability (MSI-H) EC whereas high IFN-γ trended toward improved survival in the MSI-S EC. High IFN-γ/low TGF-β and high IFN-γ/low CD47 signatures predicted longer overall survival. Low TGF-β/low CD47 signature predicted longer overall survival only in the MSI-H EC. Conclusion: Our data support the role of immune markers in predicting survival in OV/EC.
    Keywords:  CD47; MSI-H; T cells; TGF-β; immune cells; immune signatures; ovarian and endometrial cancers; survival; tumor-associated myeloid cells
    DOI:  https://doi.org/10.2217/imt-2021-0052
  3. Nat Rev Clin Oncol. 2021 Aug 27.
    TILs show early efficacy.
    Peter Sidaway.
      
    DOI:  https://doi.org/10.1038/s41571-021-00555-4
  4. Genes (Basel). 2021 Jul 29. pii: 1171. [Epub ahead of print]12(8):
    Extracellular Vesicle-Derived DNA vs. CfDNA as a Biomarker for the Detection of Colon Cancer.
    Kavita Thakur, Manu Smriti Singh, Sara Feldstein-Davydova, Victoria Hannes, Dov Hershkovitz, Shlomo Tsuriel.
      Liquid biopsy has emerged as a promising non-invasive way to diagnose tumor and monitor its progression. Different types of liquid biopsies have different advantages and limitations. In the present research, we compared the use of two types of liquid biopsy, extracellular vesicle-derived DNA (EV-DNA) and cell-free DNA (cfDNA) for identifying tumor mutations in patients with colon carcinoma.
    METHOD: DNA was extracted from the tumor tissue of 33 patients diagnosed with colon carcinoma. Targeted NGS panel, based on the hotspots panel, was used to identify tumor mutations. Pre-surgery serum and plasma were taken from the patients in which mutation was found in the tumor tissue. Extracellular vesicles were isolated from the serum followed by the extraction of EV-DNA. CfDNA was extracted from the plasma. The mutations found in the tumor were used to detect the circulating tumor DNA using ultra-deep sequencing. We compared the sensitivity of mutation detection and allele frequency obtained in EV-DNA and cfDNA.
    RESULTS: The sensitivity of mutation detection in EV-DNA and cfDNA was 61.90% and 66.67%, respectively. We obtained almost identical sensitivity of mutation detection in EV-DNA and cfDNA in each of the four stages of colon carcinoma. The total DNA concentration and number mutant copies were higher in cfDNA vs. EV-DNA (p value = 0.002 and 0.003, respectively).
    CONCLUSION: Both cfDNA and EV-DNA can serve as tumor biomarkers. The use of EV-DNA did not lead to improved sensitivity or better detection of tumor DNA in the circulation.
    Keywords:  EV-DNA; cfDNA; colon cancer; ctDNA; liquid biopsy
    DOI:  https://doi.org/10.3390/genes12081171
  5. Ther Adv Med Oncol. 2021 ;13 17588359211033704
    Circulating TP53 mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX.
    Fleur van der Sijde, Zakia Azmani, Marc G Besselink, Bert A Bonsing, Jan Willem B de Groot, Bas Groot Koerkamp, Brigitte C M Haberkorn, Marjolein Y V Homs, Wilfred F J van IJcken, Quisette P Janssen, Martijn P Lolkema, Saskia A C Luelmo, Leonie J M Mekenkamp, Dana A M Mustafa, Ron H N van Schaik, Johanna W Wilmink, Eveline E Vietsch, Casper H J van Eijck.
       Background: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS).
    Methods: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control (n = 30) or progressive disease (n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria.
    Results: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40-79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31-37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6-6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6-17.4 months).
    Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.
    Keywords:  FOLFIRINOX; TP53; circulating tumor DNA; pancreatic cancer; predictive biomarker
    DOI:  https://doi.org/10.1177/17588359211033704
  6. J Pathol Inform. 2021 ;12 24
    Digital Pathology-based Study of Cell- and Tissue-level Morphologic Features in Serous Borderline Ovarian Tumor and High-grade Serous Ovarian Cancer.
    Jun Jiang, Burak Tekin, Ruifeng Guo, Hongfang Liu, Yajue Huang, Chen Wang.
       Background: Serous borderline ovarian tumor (SBOT) and high-grade serous ovarian cancer (HGSOC) are two distinct subtypes of epithelial ovarian tumors, with markedly different biologic background, behavior, prognosis, and treatment. However, the histologic diagnosis of serous ovarian tumors can be subjectively variable and labor-intensive as multiple tumor slides/blocks need to be thoroughly examined to search for these features.
    Materials and Methods: We developed a novel informatics system to facilitate objective and scalable diagnosis screening for SBOT and HGSOC. The system was built upon Groovy scripts and QuPath to enable interactive annotation and data exchange.
    Results: The system was used to successfully detect cellular boundaries and extract an expanded set of cellular features representing cell- and tissue-level characteristics. The performance of cell-level classification for both tumor and stroma cells achieved >90% accuracy. The performance of differentiating HGSOC versus SBOT achieved 91%-95% accuracy for 6485 imaging patches which have sufficient tumor and stroma cells (minimum of ten each) and 97% accuracy for classifying patients when aggregating the results to whole-slide image based on consensus.
    Conclusions: Cellular features digitally extracted from pathological images can be used for cell classification and SBOT v. HGSOC differentiation. Introducing digital pathology into ovarian cancer research could be beneficial to discover potential clinical implications. A larger cohort is required to further evaluate the system.
    Keywords:  Digital pathology; high-grade serous ovarian cancer; serous borderline ovarian tumor
    DOI:  https://doi.org/10.4103/jpi.jpi_76_20
  7. Biomedicines. 2021 Jul 28. pii: 906. [Epub ahead of print]9(8):
    Clinical Utility of Liquid Biopsy-Based Actionable Mutations Detected via ddPCR.
    Irina Palacín-Aliana, Noemí García-Romero, Adrià Asensi-Puig, Josefa Carrión-Navarro, Víctor González-Rumayor, Ángel Ayuso-Sacido.
      Cancer is one of the leading causes of death worldwide and remains a major public health challenge. The introduction of more sensitive and powerful technologies has permitted the appearance of new tumor-specific molecular aberrations with a significant cancer management improvement. Therefore, molecular pathology profiling has become fundamental not only to guide tumor diagnosis and prognosis but also to assist with therapeutic decisions in daily practice. Although tumor biopsies continue to be mandatory in cancer diagnosis and classification, several studies have demonstrated that liquid biopsies could be used as a potential tool for the detection of cancer-specific biomarkers. One of the main advantages is that circulating free DNA (cfDNA) provides information about intra-tumoral heterogeneity, reflecting dynamic changes in tumor burden. This minimally invasive tool has become an accurate and reliable instrument for monitoring cancer genetics. However, implementing liquid biopsies across the clinical practice is still ongoing. The main challenge is to detect genomic alterations at low allele fractions. Droplet digital PCR (ddPCR) is a powerful approach that can overcome this issue due to its high sensitivity and specificity. Here we explore the real-world clinical utility of the liquid biopsy ddPCR assays in the most diagnosed cancer subtypes.
    Keywords:  breast cancer; cancer biomarkers; colorectal cancer; ddPCR; liquid biopsy; lung cancer; pancreatic cancer
    DOI:  https://doi.org/10.3390/biomedicines9080906
  8. PLoS One. 2021 ;16(8): e0256436
    Clinical correlates of circulating cell-free DNA tumor fraction.
    Joerg Bredno, Jafi Lipson, Oliver Venn, Alexander M Aravanis, Arash Jamshidi.
       BACKGROUND: Oncology applications of cell-free DNA analysis are often limited by the amount of circulating tumor DNA and the fraction of cell-free DNA derived from tumor cells in a blood sample. This circulating tumor fraction varies widely between individuals and cancer types. Clinical factors that influence tumor fraction have not been completely elucidated.
    METHODS AND FINDINGS: Circulating tumor fraction was determined for breast, lung, and colorectal cancer participant samples in the first substudy of the Circulating Cell-free Genome Atlas study (CCGA; NCT02889978; multi-cancer early detection test development) and was related to tumor and patient characteristics. Linear models were created to determine the influence of tumor size combined with mitotic or metabolic activity (as tumor mitotic volume or excessive lesion glycolysis, respectively), histologic type, histologic grade, and lymph node status on tumor fraction. For breast and lung cancer, tumor mitotic volume and excessive lesion glycolysis (primary lesion volume scaled by percentage positive for Ki-67 or PET standardized uptake value minus 1.0, respectively) were the only statistically significant covariates. For colorectal cancer, the surface area of tumors invading beyond the subserosa was the only significant covariate. The models were validated with cases from the second CCGA substudy and show that these clinical correlates of circulating tumor fraction can predict and explain the performance of a multi-cancer early detection test.
    CONCLUSIONS: Prognostic clinical variables, including mitotic or metabolic activity and depth of invasion, were identified as correlates of circulating tumor DNA by linear models that relate clinical covariates to tumor fraction. The identified correlates indicate that faster growing tumors have higher tumor fractions. Early cancer detection from assays that analyze cell-free DNA is determined by circulating tumor fraction. Results support that early detection is particularly sensitive for faster growing, aggressive tumors with high mortality, many of which have no available screening today.
    DOI:  https://doi.org/10.1371/journal.pone.0256436
  9. J Mol Biol. 2021 Aug 19. pii: S0022-2836(21)00442-3. [Epub ahead of print] 167209
    MuA-based Molecular Indexing for Rare Mutation Detection by Next-Generation Sequencing.
    Paulius Mielinis, Rasa Sukackaitė, Aistė Serapinaitė, Faustas Samoilovas, Gediminas Alzbutas, Karolis Matjošaitis, Arvydas Lubys.
      Detection of low-frequency mutations in cancer genomes or other heterogeneous cell populations requires high-fidelity sequencing. Molecular barcoding is one of the key technologies that enables the differentiation of true mutations from errors, which can be caused by sequencing or library preparation processes. However, current approaches where barcodes are introduced via primer extension or adaptor ligation do not utilize the full power of barcoding, due to complicated library preparation workflows and biases. Here we demonstrate the remarkable tolerance of MuA transposase to the presence of multiple replacements in transposon sequence, and explore this unique feature to engineer the MuA transposome complex with randomised nucleotides in 12 transposon positions, which can be introduced as a barcode into the target molecule after transposition event. We applied the approach of Unique MuA-based Molecular Indexing (UMAMI) to assess the power of rare mutation detection by shortgun sequencing on the Illumina platform. Our results show that UMAMI allows detection of rare mutations readily and reliably, and in this paper we report error rate values for the number of thermophilic DNA polymerases measured by using UMAMI.
    Keywords:  MuA transposase; UMI; library preparation; molecular barcodes; tagmentation
    DOI:  https://doi.org/10.1016/j.jmb.2021.167209
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