bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2021‒11‒28
seven papers selected by
Lara Paracchini
Humanitas Research

  1. Cancers (Basel). 2021 Nov 17. pii: 5756. [Epub ahead of print]13(22):
      Recent data have demonstrated substantial efficacy with poly (ADP-ribose) polymerase (PARP) inhibitors as treatment and/or maintenance therapy in patients with newly diagnosed advanced epithelial ovarian cancer (EOC). Here, we review efficacy and safety results from four recent Phase III trials in newly diagnosed EOC: SOLO1 (olaparib), PAOLA-1 (olaparib in combination with bevacizumab), PRIMA (niraparib), and VELIA (veliparib). The implications of these data for current clinical practice and areas for future research are discussed, including ongoing studies of targeted agents in the newly diagnosed setting. Data from SOLO1, PAOLA-1, PRIMA, and VELIA confirm the benefit of PARP inhibitors (olaparib, niraparib, veliparib) for women with newly diagnosed EOC. The greatest benefit was seen in patients with a BRCA1 and/or BRCA2 mutation or in the homologous recombination deficiency (HRD)-test positive subgroup. These four well-conducted studies have generated practice-changing data. However, deciding how to apply these results in clinical practice is challenging, and substantial differences in trial design impede cross-trial comparisons. Recent PARP inhibitor approvals (olaparib, niraparib) in the newly diagnosed EOC setting have provided new maintenance treatment options for a broader patient population. The results of these studies call for personalized medicine based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. Important areas for future research include appropriate use of both BRCA mutation and HRD testing to inform magnitude of PARP inhibitor benefit as well as exploring further options for patients who are HRD-test negative and for those who become PARP inhibitor resistant.
    Keywords:  BRCA mutation; PARP inhibitor; homologous recombination deficiency; ovarian cancer
  2. Cancers (Basel). 2021 Nov 10. pii: 5615. [Epub ahead of print]13(22):
      Cell-free DNA (cfDNA) analysis using liquid biopsies is a non-invasive method to gain insights into the biology, therapy response, mechanisms of acquired resistance and therapy escape of various tumors. While it is well established that individual cancer treatment options can be adjusted by panel next-generation sequencing (NGS)-based evaluation of driver mutations in cfDNA, emerging research additionally explores the value of deep characterization of tumor cfDNA genomics and fragmentomics as well as nucleosome modifications (chromatin structure), and methylation patterns (epigenomics) for comprehensive and multi-modal assessment of cfDNA. These tools have the potential to improve disease monitoring, increase the sensitivity of minimal residual disease identification, and detection of cancers at earlier stages. Recent progress in emerging technologies of cfDNA analysis is summarized, the added potential clinical value is highlighted, strengths and limitations are identified and compared with conventional targeted NGS analysis, and current challenges and future directions are discussed.
    Keywords:  DNA hydroxymethylation; DNA methylation; cell-free DNA; epigenomics; fragmentomics; histone modification; liquid biopsy; nucleosome positioning; precision medicine
  3. Cancers (Basel). 2021 Nov 14. pii: 5698. [Epub ahead of print]13(22):
      The ability to detect minimal residual disease (MRD) after a curative-intent surgery or treatment is of paramount importance, because it offers the possibility to help guide the clinical decisions related adjuvant therapy. Thus, the earlier MRD is detected, the earlier potentially beneficial treatment can be proposed to patients who might need it. Liquid biopsies, and in particular the next-generation sequencing of circulating tumor DNA (ctDNA) in the blood, have been the focus of an increasing amount of research in the past years. The ctDNA detection at advanced cancer stages is practicable for several solid tumors, and complements molecular information on acquired therapy resistance. In the context of MRD, it is by definition more challenging to detect ctDNA, but it is technically achievable and provides information on treatment response and probability of relapse significantly earlier than standard imaging methods. The clinical benefit of implementing this new technique in the routine is being tested in interventional clinical trials at the moment. We propose here an update of the current use of ctDNA detection by NGS as a tool to assess the presence of MRD and improve adjuvant treatment of solid tumors. We also discuss the main limitations and medium-term perspectives of this process in the clinic.
    Keywords:  adjuvant therapy; ctDNA; liquid biopsy; minimal residual disease
  4. Crit Rev Oncol Hematol. 2021 Nov 18. pii: S1040-8428(21)00329-2. [Epub ahead of print]168 103542
      Ovarian cancer (OC) is the most lethal gynecological malignancy and very little is known about the underlying tumorigenesis mechanisms. For other tumors, like colorectal cancer, a relationship between several opportunistic pathogens and cancer development and progression has been proven. Recent researches also underline a possible correlation between gut microbiota dysbiosis and cancer treatment efficacy and adverse effects. Several studies have also demonstrated a link between abdominal surgery and gut microbiota modifications. In this paper, we aim to review the available evidences of this issue in OC to understand if there is a relationship between gut microbiota modifications and efficacy and adverse effects of cancer therapies, either surgical and medical treatments. Well-designed clinical studies, with a robust translational component, are required to better understand the modulation of gut microbiota during OC treatment. The microbiota/microbiome composition analysis, in the near future, could represent a novel instrument to personalize anticancer therapies.
    Keywords:  Chemotherapy; Gut microbiota; Ovarian cancer; Radical surgery
  5. Cancers (Basel). 2021 Nov 09. pii: 5611. [Epub ahead of print]13(22):
      Cell-free DNA (cfDNA) methylation has emerged as a promising biomarker for early cancer detection, tumor type classification, and treatment response monitoring. Enrichment-based cfDNA methylation profiling methods such as cfMeDIP-seq have shown high accuracy in the classification of multiple cancer types. We have previously optimized another enrichment-based approach for ultra-low input cfDNA methylome profiling, termed cfMBD-seq. We reported that cfMBD-seq outperforms cfMeDIP-seq in the enrichment of high-CpG-density regions, such as CpG islands. However, the clinical feasibility of cfMBD-seq is unknown. In this study, we applied cfMBD-seq to profiling the cfDNA methylome using plasma samples from cancer patients and non-cancer controls. We identified 1759, 1783, and 1548 differentially hypermethylated CpG islands (DMCGIs) in lung, colorectal, and pancreatic cancer patients, respectively. Interestingly, the vast majority of DMCGIs were overlapped with aberrant methylation changes in corresponding tumor tissues, indicating that DMCGIs detected by cfMBD-seq were mainly driven by tumor-specific DNA methylation patterns. From the overlapping DMCGIs, we carried out machine learning analyses and identified a set of discriminating methylation signatures that had robust performance in cancer detection and classification. Overall, our study demonstrates that cfMBD-seq is a powerful tool for sensitive detection of tumor-derived epigenomic signals in cfDNA.
    Keywords:  cfDNA; cfMBD-seq; colorectal cancer; liquid biopsies; lung cancer; methylation; next-generation sequencing; pancreatic cancer
  6. Cancer Res. 2021 Nov 23. pii: canres.1718.2021. [Epub ahead of print]
      Testing peripheral blood for circulating tumor DNA (ctDNA) offers a minimally invasive opportunity to diagnose, characterize, and monitor the disease in individual cancer patients. ctDNA can reflect the actual tumor burden and specific genomic state of disease and thus might serve as a prognostic and predictive biomarker for immune checkpoint inhibitor (ICI) therapy. Recent studies in various cancer entities (e.g., melanoma, non-small cell lung cancer, colon cancer, and urothelial cancer) have shown that sequential ctDNA analyses allow for the identification of responders to ICI therapy with a significant lead time to imaging. ctDNA assessment may also help distinguish pseudo-progression under ICI therapy from real progression. Developing dynamic changes in ctDNA concentrations as a potential surrogate endpoint of clinical efficacy in patients undergoing adjuvant immunotherapy is ongoing. Besides overall ctDNA burden, further ctDNA characterization can help uncover tumor-specific determinants (e.g., tumor mutational burden, microsatellite instability) of responses or resistance to immunotherapy. In future studies, standardized ctDNA assessments need to be included in interventional clinical trials across cancer entities to demonstrate the clinical utility of ctDNA as a biomarker for personalized cancer immunotherapy.
  7. Ann Oncol. 2021 Nov 19. pii: S0923-7534(21)04785-2. [Epub ahead of print]
      BACKGROUND: Building on the success of targeted therapy in certain well-defined cancer genotypes, three platform studies - NCI-MATCH, LUNG-MAP and The National Lung Matrix Trial (NLMT) have attempted to discover new genotype-matched therapies for people with cancer.PATIENTS AND METHODS: We review the outputs from these platform studies. This review led us to propose a series of recommendations and considerations that we hope will inform future precision medicine programmes in cancer RESULTS: The three studies collectively screened over 13,000 patients. Across 37 genotype matched cohorts there have been 66/875 responders, an overall response rate of 7.5%. Targeting copy number gain yielded 5/199 responses across 9 biomarker:drug matched cohorts, a response rate of 2.5%.
    CONCLUSIONS: The majority of these studies used single-agent targeted therapies. Whilst pre-clinical data can suggest rational combination treatment to reverse adaptive resistance or block parallel activated pathways there is an essential need for accurate modelling of the toxicity:activity trade-off of combinations. Agent selection is often sub-optimal; dose expansion should only be performed with agents with clear clinical proof of mechanism and the high target selectivity. Targeting copy number change has been disappointing; it is crucial to define the drivers on shared amplicons that include the targeted aberration. Maximising outcomes with currently available targeted therapies requires moving towards a more contextualised stratified medicine acknowledging the criticality of the genomic, transcriptional and immunological context on which the targeted aberration is inscribed. Genomic complexity and instability is likely to be a leading cause of targeted therapy failure in genomically complex cancers. Pre-clinical models must be developed that more accurately capture the genomic complexity of human disease. The degree of attrition of studies performed after standard of care therapy suggest that serious efforts be made to develop a suite of precision medicine studies in the minimal residual disease setting.
    Keywords:  Targeted therapy; genotype-matching; platform trials; precision medicine