bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2021‒04‒04
ten papers selected by
Lara Paracchini
Humanitas Research

  1. Int J Mol Sci. 2021 Mar 06. pii: 2654. [Epub ahead of print]22(5):
      Liquid biopsies constitute a minimally invasive means of managing cancer patients, entailing early diagnosis, follow-up and prediction of response to therapy. Their use in the germ cell tumor field is invaluable since diagnostic tissue biopsies (which are invasive) are often not performed, and therefore only a presumptive diagnosis can be made, confirmed upon examination of the surgical specimen. Herein, we provide an overall review of the current liquid biopsy-based biomarkers of this disease, including the classical, routinely used serum tumor markers-the promising microRNAs rapidly approaching the introduction into clinical practice-but also cell-free DNA markers (including DNA methylation) and circulating tumor cells. Finally, and importantly, we also explore novel strategies and challenges for liquid biopsy markers and methodologies, providing a critical view of the future directions for liquid biopsy tests in this field, highlighting gaps and unanswered questions.
    Keywords:  DNA methylation; biomarkers; circulating tumor cells; diagnosis; follow-up; germ cell tumors; liquid biopsies; microRNAs; serum tumor markers
  2. Cancers (Basel). 2021 Mar 20. pii: 1420. [Epub ahead of print]13(6):
      Defective DNA damage response (DDR) pathways are enabling characteristics of cancers that not only can be exploited to specifically target cancer cells but also can predict chemotherapy response. Defective Homologous Recombination Repair (HRR) function, e.g., due to BRCA1/2 loss, is a determinant of response to platinum agents and PARP inhibitors in ovarian cancers. Most chemotherapies function by either inducing DNA damage or impacting on its repair but are generally used in the clinic unselectively. The significance of HRR and other DDR pathways in determining response to several other chemotherapy drugs is not well understood. In this study, the genomic, transcriptomic and functional analysis of DDR pathways in a panel of 14 ovarian cancer cell lines identified that defects in DDR pathways could determine response to several chemotherapy drugs. Carboplatin, rucaparib, and topotecan sensitivity were associated with functional loss of HRR (validated in 10 patient-derived primary cultures) and mismatch repair. Two DDR gene expression clusters correlating with treatment response were identified, with PARP10 identified as a novel marker of platinum response, which was confirmed in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Reduced non-homologous end-joining function correlated with increased sensitivity to doxorubicin, while cells with high intrinsic oxidative stress showed sensitivity to gemcitabine. In this era of personalised medicine, molecular/functional characterisation of DDR pathways could guide chemotherapy choices in the clinic allowing specific targeting of ovarian cancers.
    Keywords:  DNA damage repair; biomarker; chemotherapy; ovarian cancer
  3. Cancer Discov. 2021 Apr;11(4): 858-873
      Over the past 10 years, circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) have received enormous attention as new biomarkers and subjects of translational research. Although both biomarkers are already used in numerous clinical trials, their clinical utility is still under investigation with promising first results. Clinical applications include early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms. Here, we propose a conceptual framework of CTC and ctDNA assays and point out current challenges of CTC and ctDNA research, which might structure this dynamic field of translational cancer research. SIGNIFICANCE: The analysis of blood for CTCs or cell-free nucleic acids called "liquid biopsy" has opened new avenues for cancer diagnostics, including early detection of tumors, improved risk assessment and staging, as well as early detection of relapse and monitoring of tumor evolution in the context of cancer therapies.
  4. Diagnostics (Basel). 2021 Mar 07. pii: 465. [Epub ahead of print]11(3):
      Ovarian cancer is the eighth-most common cause of death among women worldwide. In the absence of distinctive symptoms in the early stages, the majority of women are diagnosed in advanced stages of the disease. Surgical debulking and systemic adjuvant chemotherapy remain the mainstays of treatment, with the development of chemoresistance in up to 75% of patients with subsequent poor treatment response and reduced survival. Therefore, there is a critical need to revisit existing, and identify potential biomarkers that could lead to the development of novel and more effective predictors for ovarian cancer diagnosis and prognosis. The capacity of these biomarkers to predict the existence, stages, and associated therapeutic efficacy of ovarian cancer would enable improvements in the early diagnosis and survival of ovarian cancer patients. This review not only highlights current evidence-based ovarian-cancer-specific prognostic and diagnostic biomarkers but also provides an update on various technologies and methods currently used to identify novel biomarkers of ovarian cancer.
    Keywords:  DNA repair pathways; biomarkers; cell-cycle-related genes; ovarian cancer; tumour mutation burden
  5. Cancer Discov. 2021 Apr 01.
      Synthetic lethality (SL) provides a conceptual framework for tackling targets that are not classically "druggable," including loss-of-function mutations in tumor suppressor genes required for carcinogenesis. Recent technological advances have led to an inflection point in our understanding of genetic interaction networks and ability to identify a wide array of novel SL drug targets. Here, we review concepts and lessons emerging from first-generation trials aimed at testing SL drugs, discuss how the nature of the targeted lesion can influence therapeutic outcomes, and highlight the need to develop clinical biomarkers distinct from those based on the paradigms developed to target activated oncogenes. SIGNIFICANCE: SL offers an approach for the targeting of loss of function of tumor suppressor and DNA repair genes, as well as of amplification and/or overexpression of genes that cannot be targeted directly. A next generation of tumor-specific alterations targetable through SL has emerged from high-throughput CRISPR technology, heralding not only new opportunities for drug development, but also important challenges in the development of optimal predictive biomarkers.
  6. Cancers (Basel). 2021 Mar 15. pii: 1298. [Epub ahead of print]13(6):
      Ovarian cancer treatment strategy is mainly based on three pillars: cytoreductive surgery, platinum-based chemotherapy, and targeted therapies. The latter in the last decade has provided a remarkable improvement in progression free patients and, hopefully, in overall survival. In particular, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit BRCA 1/2 mutations and DNA damage response deficiencies, which are believed to concern up to 50% of high grade epithelial ovarian cancer cases. While these agents have an established role in ovarian cancer treatment strategy in BRCA mutated and homologous recombination deficient patients, an appropriate predictive molecular test to select patients is lacking in clinical practice. At the same time, the impressive results of immunotherapy in other malignancies, have opened the space for the introduction of immune-stimulatory drugs in ovarian cancer. Despite immune checkpoint inhibitors as a monotherapy bringing only modest efficacy when assessed in pretreated ovarian cancer patients, the combination with chemotherapy, anti-angiogenetics, PARP inhibitors, and radiotherapy is believed to warrant further investigation. We reviewed literature evidence on PARP inhibitors and immunotherapy in ovarian cancer treatment.
    Keywords:  PARP inhibitors; immunotherapy; ovarian cancer; targeted therapy
  7. Cancer Med. 2021 Apr 03.
      BACKGROUND: In high grade serous ovarian cancer (HGSOC), there is a spectrum of sensitivity to first line platinum-based chemotherapy. This study molecularly characterizes HGSOC patients from two distinct groups of chemotherapy responders (good vs. poor).METHODS: Following primary debulking surgery and intravenous carboplatin/paclitaxel, women with stage III-IV HGSOC were grouped by response. Patients in the good response (GR) and poor response (PR) groups respectively had a progression-free intervals (PFI) of ≥12 and ≤6 months. Analysis of surgical specimens interrogated genomic and immunologic features using whole exome sequencing. RNA-sequencing detected gene expression outliers and inference of immune infiltrate, with validation by targeted NanoString arrays. PD-L1 expression was scored by immunohistochemistry (IHC).
    RESULTS: A total of 39 patient samples were analyzed (GR = 20; PR = 19). Median PFI for GR and PR patient cohorts was 32 and 3 months, respectively. GR tumors were enriched for loss-of-function BRCA2 mutations and had a significantly higher nonsynonymous mutation rate compared to PR tumors (p = 0.001). Samples from the PR cohort were characterized by mutations in MGA and RAD51B and trended towards a greater rate of amplification of PIK3CA, MECOM, and ATR in comparison to GR tumors. Gene expression analysis by NanoString correlated increased PARP4 with PR and increased PD-L1 and EMSY with GR. There was greater tumor immune cell infiltration and higher immune cell PD-L1 protein expression in the GR group.
    CONCLUSIONS: Our research demonstrates that tumors from HGSOC patients responding poorly to first line chemotherapy have a distinct molecular profile characterized by actionable drug targets including PARP4.
    Keywords:  genomic profiling; high grade serous; immune profiling; ovarian carcinoma; platinum resistance
  8. Cancers (Basel). 2021 Mar 27. pii: 1544. [Epub ahead of print]13(7):
      Epithelial ovarian cancer (EOC) remains the second most common cause of gynecological cancer deaths. To improve patients' outcomes, we still need reliable biomarkers of early relapse, of which external independent validation is a crucial process. Our previously established prognostic signature, MiROvaR, including 35 microRNAs (miRNA) able to stratify EOC patients for their risk of relapse, was challenged on a new independent cohort of 197 EOC patients included in the Pelvic Mass Study whose miRNA profile was made publically available, thus resulting in the only accessible database aside from the EOC TCGA collection. Following accurate data matrix adjustment to account for the use of different miRNA platforms, MiROvaR confirmed its ability to discriminate early relapsing patients. The model's original cutoff separated 156 (79.2%) high- and 41 (20.8%) low-risk patients with median progression free survival (PFS) of 16.3 months and not yet reached (NYR), respectively (hazard ratio (HR): 2.42-95% Confidence Interval (CI) 1.49-3.93; Log-rank p = 0.00024). The MiROvaR predictive accuracy (area under the curve (AUC) = 0.68; 95% Cl 0.57-0.79) confirms its prognostic value. This external validation in a totally independently collected, handled and profiled EOC cohort suggests that MiROvaR is a strong and reliable biomarker of EOC early relapse, warranting prospective validation.
    Keywords:  early relapse; epithelial ovarian cancer; independent validation; microRNA; molecular predictor
  9. Int J Mol Sci. 2021 Mar 26. pii: 3403. [Epub ahead of print]22(7):
      Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extracellular matrix breakdown, and development of support systems for tumors. Several studies have reported the direct involvement of MMPs with ovarian cancer, as well as their mechanisms of action in the tumor microenvironment. MMPs play a key role in upregulating transcription factors, as well as the breakdown of structural proteins like collagen. Proteolytic mechanisms have been shown to enhance the ability of ovarian cancer cells to migrate and adhere to secondary sites allowing for efficient metastasis. Furthermore, angiogenesis for tumor growth and development of metastatic implants is influenced by upregulation of certain proteases, including MMPs. While proteases are produced normally in vivo, they can be upregulated by cancer-associated mutations, tumor-microenvironment interaction, stress-induced catecholamine production, and age-related pathologies. This review outlines the important role of proteases throughout ovarian cancer progression and metastasis.
    Keywords:  extracellular matrix; matrix metalloproteinase; mesenchymal; mesothelial cells; ovarian cancer; peritoneum; proteases; proteolysis
  10. Mol Med. 2021 Apr 01. 27(1): 33
      Ovarian cancer is characterized by dysbiosis, referred to as oncobiosis in neoplastic diseases. In ovarian cancer, oncobiosis was identified in numerous compartments, including the tumor tissue itself, the upper and lower female genital tract, serum, peritoneum, and the intestines. Colonization was linked to Gram-negative bacteria with high inflammatory potential. Local inflammation probably participates in the initiation and continuation of carcinogenesis. Furthermore, local bacterial colonies in the peritoneum may facilitate metastasis formation in ovarian cancer. Vaginal infections (e.g. Neisseria gonorrhoeae or Chlamydia trachomatis) increase the risk of developing ovarian cancer. Bacterial metabolites, produced by the healthy eubiome or the oncobiome, may exert autocrine, paracrine, and hormone-like effects, as was evidenced in breast cancer or pancreas adenocarcinoma. We discuss the possible involvement of lipopolysaccharides, lysophosphatides and tryptophan metabolites, as well as, short-chain fatty acids, secondary bile acids and polyamines in the carcinogenesis of ovarian cancer. We discuss the applicability of nutrients, antibiotics, and probiotics to harness the microbiome and support ovarian cancer therapy. The oncobiome and the most likely bacterial metabolites play vital roles in mediating the effectiveness of chemotherapy. Finally, we discuss the potential of oncobiotic changes as biomarkers for the diagnosis of ovarian cancer and microbial metabolites as possible adjuvant agents in therapy.
    Keywords:  Antibiotic; EMT; Indole derivative; Lipopolysaccharide; Lysophosphatid; Microbial metabolite; Microbiome; Ovarian cancer; Probiotic