bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2021–05–23
thirteen papers selected by
Lara Paracchini, Humanitas Research
  1. The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?
  2. Homologous recombination deficiency: cancer predispositions and treatment implications.
  3. Methylated circulating tumor DNA as a biomarker for colorectal cancer diagnosis, prognosis, and prediction.
  4. Metronomic oral cyclophosphamide in relapsed ovarian cancer.
  5. BRCA mutated pancreatic cancer: A change is coming.
  6. The Detection of Cancer Epigenetic Traces in Cell-Free DNA.
  7. ChIP-Sequencing of TET Proteins.
  8. Distinct roles for RSC and SWI/SNF chromatin remodelers in genomic excision repair.
  9. Purification of TET Proteins.
  10. Endometrial Cancer, BRCA1, and BRCA2 in the UK Biobank Cohort.
  11. Gynecological sarcomas: literature review of 2020.
  12. The efficacy and safety of niraparib for ovarian cancer: a single-center observational study from China.
  13. Double drop-off droplet digital PCR (DDO-ddPCR): a novel, versatile tool for mutation screening and residual disease monitoring in acute myeloid leukemia using cellular or cell-free DNA.
  1. ESMO Open. 2021 May 17. pii: S2059-7029(21)00103-4. [Epub ahead of print]6(3): 100144
    The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?
    N Y L Ngoi, D S P Tan.
      The recognition of homologous recombination deficiency (HRD) as a frequent feature of high-grade serous ovarian cancer (HGSOC) has transformed treatment paradigms. Poly(ADP-ribose) polymerase inhibitors (PARPis), developed based on the rationale of synthetic lethality that predicates antitumor efficacy in tumors harboring underlying HRD, now represents an important class of therapy for HGSOC. Recent data have drawn attention to the assessment of homologous recombination DNA repair (HRR) as a prognostic and predictive biomarker in HGSOC, leading to increasing debate on the optimal means of defining and evaluating HRD, both genotypically and phenotypically. At present, clinical-grade assays such as myChoice CDx and FoundationOne CDx are approved companion diagnostics which can identify patients with HRD-positive HGSOC by diagnosing a 'genomic scar' reflecting underlying genomic instability. Yet despite the rapid maturation of this field, tumoral HRD status has been recognized to be dynamic over time and with treatment pressure. In practice, this means that restoration of HRR through mechanisms of platinum and PARPi resistance are not adequately represented by genomic scar assays, and contribute toward discordance with clinical PARPi response, or lack-thereof. It is thus critical that HRD testing is optimized to address the controversies of diverse HRD testing methodology, appropriate thresholds for HRD identification, and relevant timepoints for HRD testing, in order to realize the potential for PARPis to maximally benefit patients with HGSOC. Here, we discuss the premise of HRD testing in HGSOC, current methodologies for HRD identification and their performance in the clinic, highlight upcoming strategies, and discuss the challenges faced in moving this field forward.
    Keywords:  biomarkers; homologous recombination deficiency; ovarian cancer; poly(ADP-ribose) polymerase inhibitors
    DOI:  https://doi.org/10.1016/j.esmoop.2021.100144
  2. Oncologist. 2021 May 22.
    Homologous recombination deficiency: cancer predispositions and treatment implications.
    Ming Ren Toh, Joanne Ngeow.
      Homologous recombination (HR) is a highly accurate DNA repair mechanism. Several HR genes are established cancer susceptibility genes with clinically actionable pathogenic variants (PVs). Classically, BRCA1 and BRCA2 germline PVs are associated with significant breast and ovarian cancer risks. Patients with BRCA1/BRCA2 PVs display worse clinical outcomes but respond better to platinum-based chemotherapies and PARP inhibitors, a trait termed as "BRCAness". With the advent of whole-exome sequencing and multigene panels, PVs in other HR genes are increasingly identified among familial cancers. As such, several genes such as PALB2 are reclassified as cancer predisposition genes. But, evidence for cancer risks remains unclear for many others. In this review, we will discuss the cancer predispositions and treatment implications beyond BRCA1/BRCA2, with a focus on 24 HR genes: 53BP1, ATM, ATR, ATRIP, BARD1, BLM, BRIP1, DMC1, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RIF1, RMI1, RMI2, RPA1, TOP3A, TOPBP1, XRCC2, XRCC3. IMPLICATIONS FOR PRACTICE: Our review provides a quick and comprehensive read to both experts and amateurs to the topic. Interested readers are also directed to comprehensive reviews of specific topics discussed in the review (e.g. clinical trials on PARP inhibitors and other targeted inhibitors of HR proteins). Our table summarizes the risk estimates based on some of the largest and most recent studies, facilitating the reclassification of these HR genes as cancer predisposition genes. We have also highlighted several potential research questions in our review.
    DOI:  https://doi.org/10.1002/onco.13829
  3. Clin Epigenetics. 2021 May 17. 13(1): 111
    Methylated circulating tumor DNA as a biomarker for colorectal cancer diagnosis, prognosis, and prediction.
    Farah J Nassar, Zahraa S Msheik, Rihab R Nasr, Sally N Temraz.
      Worldwide, colorectal cancer (CRC) is a deadly disease whose death rate ranks second among cancers though its incidence ranks third. Early CRC detection is key and is associated with improved survival outcomes. However, existing tests for CRC diagnosis have several weaknesses thus rendering them inefficient. Moreover, reliable prognostic tests that can predict the overall cancer outcome and recurrence of the disease as well as predictive markers that can assess effectiveness of therapy are still lacking. Thus, shifting to noninvasive liquid biopsy or blood-based biomarkers is vital to improving CRC diagnosis, prognosis, and prediction. Methylated circulating tumor DNA (ctDNA) has gained increased attention as a type of liquid biopsy that is tumor-derived fragmented DNA with epigenetic alterations. Methylated ctDNA are more consistently present in blood of cancer patients as compared to mutated ctDNA. Hence, methylated ctDNA serves as a potential biomarker for CRC that is worth investigating. In this review, we explore what has been reported about methylated ctDNA as a biomarker for CRC diagnosis that can distinguish between CRC patients or those having adenoma and healthy controls as validated specifically through ROC curves. We also examine methylated ctDNA as a biomarker for CRC prognosis and prediction as confirmed through robust statistical analyses. Finally, we discuss the major technical challenges that limits the use of methylated ctDNA for clinical application and suggest possible recommendations to enhance its usage.
    Keywords:  Circulating biomarker; Colorectal cancer; Diagnosis; Methylation; Prognosis and prediction
    DOI:  https://doi.org/10.1186/s13148-021-01095-5
  4. Int J Gynecol Cancer. 2021 May 20. pii: ijgc-2021-002467. [Epub ahead of print]
    Metronomic oral cyclophosphamide in relapsed ovarian cancer.
    Pavlina Spiliopoulou, Samantha Hinsley, Iain A McNeish, Patricia Roxburgh, Ros Glasspool.
       OBJECTIVES: To describe the clinical activity of metronomic cyclophosphamide in a population of patients with recurrent ovarian cancer, and to identify predictors of clinical response.
    METHODS: We retrospectively reviewed all patients treated at our institution with oral metronomic cyclophosphamide for relapsed ovarian cancer between January 2012 and December 2016. These were identified from electronic chemotherapy prescription records. The primary endpoint was response rate by combined Gynecologic Cancer InterGroup (GCIG) criteria. Data on patient demographics, previous therapies, platinum resistance, germline BRCA1/2 (gBRCA1/2) status, disease response by radiological or cancer antigen 125 (CA125) criteria alone, adverse events secondary to metronomic cyclophosphamide treatment, progression-free survival, and overall survival were also evaluated.
    RESULTS: 50 out of 68 patients treated with oral metronomic cyclophosphamide were evaluable for disease response. By combination criteria (radiological plus CA125), complete response was 0%, partial response 32%, stable disease 16%, and progressive disease 52%. In the intention-to-treat population (n=68), progression-free survival and overall survival were 2.6 months and 6 months, respectively. Having a gBRCA1/2 mutation reduced the risk of disease progression by radiological criteria (OR 0.07, 95% CI 0.008 to 0.67, p=0.02), and patients with gBRCA1/2 mutations had improved progression-free survival (7.9 vs 2.5 months, HR 0.4, 95% CI 0.23 to 0.74, p=0.003) and overall survival (15.5 vs 6 months, HR 0.49, 95% CI 0.28 to 0.85, p=0.02) with metronomic cyclophosphamide when compared with patients without gBRCA1/2 mutations (or unknown gBRCA1/2 status).
    CONCLUSION: Oral metronomic cyclophosphamide showed a clinical benefit in 48% of patients with recurrent ovarian cancer. gBRCA1/2 status can be an independent predictor of response.
    Keywords:  BRCA1 protein; BRCA2 protein; ovarian cancer
    DOI:  https://doi.org/10.1136/ijgc-2021-002467
  5. World J Gastroenterol. 2021 May 07. 27(17): 1943-1958
    BRCA mutated pancreatic cancer: A change is coming.
    Michael N Rosen, Rachel A Goodwin, Michael M Vickers.
      Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease. Recently, patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors. Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8% of patients with sporadic pancreatic cancer. In patients with germline BRCA mutations, platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors are effective treatment options which may offer survival benefits. This review will focus on the molecular biology, epidemiology, and management of BRCA-mutated pancreatic cancer. Furthermore, we will discuss future directions for this area of research and promising active areas of research.
    Keywords:  BRCA; Deoxyribonucleic acid repair; Pancreatic cancer; Platinum chemotherapy; Poly (ADP-ribose) polymerase inhibitors; Systemic therapy
    DOI:  https://doi.org/10.3748/wjg.v27.i17.1943
  6. Front Oncol. 2021 ;11 662094
    The Detection of Cancer Epigenetic Traces in Cell-Free DNA.
    Anastasia P Koval, Konstantin A Blagodatskikh, Nikolay E Kushlinskii, Dmitry S Shcherbo.
      Nucleic acid fragments found in blood circulation originate mostly from dying cells and carry signs pointing to specific features of the parental cell types. Deciphering these clues may be transformative for numerous research and clinical applications but strongly depends on the development and implementation of robust analytical methods. Remarkable progress has been achieved in the reliable detection of sequence alterations in cell-free DNA while decoding epigenetic information from methylation and fragmentation patterns requires more sophisticated approaches. This review discusses the currently available strategies for detecting and analyzing the epigenetic marks in the liquid biopsies.
    Keywords:  biomarkers; cancer diagnostics and screening; cell-free DNA; epigenetics; liquid biopsy
    DOI:  https://doi.org/10.3389/fonc.2021.662094
  7. Methods Mol Biol. 2021 ;2272 251-262
    ChIP-Sequencing of TET Proteins.
    Kasper D Rasmussen, Kristian Helin.
      TET proteins are methylcytosine dioxygenases that interact directly with chromatin to shape the DNA methylation landscape. To increase the understanding of TET protein function in a specific cellular context, it is important to be able to map the interactions between TET proteins and DNA. This ChIP-seq protocol details our procedure to analyze TET2 bound DNA in disuccinimidyl glutarate (DSG) and formaldehyde-crosslinked chromatin but can also be adapted to study other TET enzymes.
    Keywords:  ChIP-seq; DNA methylation; DSG; TET1; TET2; TET3
    DOI:  https://doi.org/10.1007/978-1-0716-1294-1_15
  8. Genome Res. 2021 May 17.
    Distinct roles for RSC and SWI/SNF chromatin remodelers in genomic excision repair.
    Kaitlynne A Bohm, Amelia J Hodges, Wioletta Czaja, Kathiresan Selvam, Michael J Smerdon, Peng Mao, John J Wyrick.
      Nucleosomes are a significant barrier to the repair of UV damage because they impede damage recognition by nucleotide excision repair (NER). The RSC and SWI/SNF chromatin remodelers function in cells to promote DNA access by moving or evicting nucleosomes, and both have been linked to NER in yeast. Here, we report genome-wide repair maps of UV-induced cyclobutane pyrimidine dimers (CPDs) in yeast cells lacking RSC or SWI/SNF activity. Our data indicate that SWI/SNF is not generally required for NER but instead promotes repair of CPD lesions at specific yeast genes. In contrast, mutation or depletion of RSC subunits causes a general defect in NER across the yeast genome. Our data indicate that RSC is required for repair not only in nucleosomal DNA but also in neighboring linker DNA and nucleosome-free regions (NFRs). Although depletion of the RSC catalytic subunit also affects base excision repair (BER) of N-methylpurine (NMP) lesions, RSC activity is less important for BER in linker DNA and NFRs. Furthermore, our data indicate that RSC plays a direct role in transcription-coupled NER (TC-NER) of transcribed DNA. These findings help to define the specific genomic and chromatin contexts in which each chromatin remodeler functions in DNA repair, and indicate that RSC plays a unique function in facilitating repair by both NER subpathways.
    DOI:  https://doi.org/10.1101/gr.274373.120
  9. Methods Mol Biol. 2021 ;2272 225-237
    Purification of TET Proteins.
    Zhijun Huang, Jiyoung Yu, Jennifer Johnson, Seung-Gi Jin, Gerd P Pfeifer.
      The 5-methylcytosine (5mC) oxidation pathway mediated by TET proteins involves step-wise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5fC and 5caC can be removed from DNA by base excision repair and the completion of this pathway results in "demethylation" of 5mC by converting the modified base back into cytosine. In vitro studies with TET proteins aimed at analyzing their DNA substrate specificities and their activity within defined chromatin templates are relatively limited. Here we describe purification methods for mammalian TET proteins based on expression in insect cells or in 293T cells. We also briefly summarize a method that can be used to monitor 5-methylcytosine oxidase activity of the purified TET proteins in vitro.
    Keywords:  5-methylcytosine oxidation; DNA demethylation; Protein purification; TET proteins
    DOI:  https://doi.org/10.1007/978-1-0716-1294-1_13
  10. Am J Clin Oncol. 2021 May 19.
    Endometrial Cancer, BRCA1, and BRCA2 in the UK Biobank Cohort.
    Steven Lehrer, Peter H Rheinstein.
       OBJECTIVES: Endometrial cancer (EC) risk in BRCA1/2 mutation carriers has been uncertain. EC risk in women with germline BRCA1 or BRCA2 mutations was recently assessed in a multicenter cohort study. BRCA1/2 mutation carriers had a 2- to 3-fold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers. To further evaluate risk, we looked at EC and BRCA1/2 in the UK Biobank cohort.
    METHODS: EC diagnosis was ascertained using the 10th Revision of the International Classification of Diseases. We analyzed the single nucleotide polymorphisms (SNPs) rs799917 (BRCA1) and rs144848 (BRCA2). A case-control study found a possible association of rs799917 but not rs144848 with EC. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai.
    RESULTS: Percentage ECs within genotypes for SNPs rs799917 and rs144848 was 0.6%. The variability within SNP genotypes was insignificant (P=0.288 for rs799917, 2-tailed Fisher exact test; P=0.931 for rs144848). In comparison, an estimated 70,200 women who had been diagnosed with uterine cancer between 1991 and 2010 were alive in the UK at the end of 2010. A total of 21,892,000 UK residents were ages 50 to 92; approximately half were women. Therefore, prevalence of EC in these UK women was 0.6%, identical to percentage EC within 6 genotypes for SNPs rs799917 and rs144848.
    CONCLUSION: Although we cannot rule out an increase in several rare types of EC, our analysis suggests that the overall incidence or risk of EC does not appear to be increased by the presence of BRCA1 or BRCA2 mutations.
    DOI:  https://doi.org/10.1097/COC.0000000000000833
  11. Curr Opin Oncol. 2021 May 18.
    Gynecological sarcomas: literature review of 2020.
    Brunhilde Hanvic, Isabelle Ray-Coquard.
       PURPOSE OF REVIEW: This article, focus on recently published data of the last 18 months on the management of gynecologic sarcomas.
    RECENT FINDINGS: Different tools have been studied to identify the differences between benign from malignant uterine conjunctival tumor.Molecular biology impact more and more on the diagnosis of uterine sarcoma with new definitions of very specific groups. This will make it possible to better define the last group of endometrial sarcoma which has been defined as undifferentiated.In several articles, surgical approaches and fertility-sparing surgery were described including the role of surgery for recurrences.Some other articles have evaluated the potential benefice of adjuvant therapy for uterine sarcoma with early stages.Several new targeted therapies are in development. Notably deoxyribonucleic acid repair machinery in uterine leiomyosarcoma and also immune therapies, transforming growth factor beta pathway, mechanistic target of rapamycin inhibitor, anti angiogenics, etc.
    SUMMARY: This last year the potential interest for uterine sarcoma increased, demonstrated by the increasing number of publications in the literature compared to previous years. Despite this greater interest over time, the standard of care for uterine sarcoma does not change and we are always waiting for new innovative therapies able to change routine practice and survival of patients. Currently, the result of different clinical trials, which include new options as targeted molecular approach or immune checkpoint inhibitors are closed to be reported.
    DOI:  https://doi.org/10.1097/CCO.0000000000000753
  12. J Ovarian Res. 2021 May 17. 14(1): 68
    The efficacy and safety of niraparib for ovarian cancer: a single-center observational study from China.
    Jing Ni, Xianzhong Cheng, Qian Zhao, Zhiqin Dai, Xia Xu, Wenwen Guo, Hongyuan Gu, Rui Zhou, Yan Wang, Xiaoxiang Chen.
       BACKGROUND: Niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for first/second-line maintenance treatment of ovarian cancer patients with complete or partial response to platinum-based chemotherapy, and multi-line monotherapy in BRCAmt patients or platinum-sensitive recurrence patients with homologous recombination deficiency (HRD). We present real-world experience from a single center of China.
    METHODS: Patients treated with niraparib in Jiangsu Cancer Hospital between June 2019 to July 2020 were recruited. The initial dose was given according to individualization. Response and adverse events (AEs) were analyzed by Response Evaluation Criteria in Solid Tumors v1.1. and National Cancer Institute Common Terminology Criteria for Adverse Events v5.0, respectively. HRD testing (AmoyDx®) was detected in most patients. Treatment was given until unequivocal progression or intolerable toxicity.
    RESULTS: Twenty-two patients all received niraparib at a bolus of 200 mg/d. Fifty percent of patients with high-grade serous ovarian cancer are HRD-positive. Six patients underwent first-line maintenance therapy. Sixteen patients received exploratory therapy. Ultimately image evaluation revealed that two patients achieved partial response (PR) and one patient achieved stable disease (SD), yielding objective response rate (ORR) of 33.3% (95%CI = 0.060-0.759) and disease control rate (DCR) of 50% (95%CI = 0.140-0.861) in the exploratory multi-line monotherapy group. The most common AEs were nausea, thrombocytopenia, and anemia. Grade 3-4 thrombocytopenia were managed by dose reduction and interruption. Leg swelling was observed as a new adverse event.
    CONCLUSION: It is feasible that patients receiving a bolus of 200 mg/d in patients from Chinese population can acquire promising efficacy and tolerance. This is the first real-world data about niraparib in ovarian cancer patients with available HRD status from China.
    Keywords:  Efficacy; HRD; Niraparib; Ovarian cancer; Real world; Safety
    DOI:  https://doi.org/10.1186/s13048-021-00803-2
  13. J Mol Diagn. 2021 May 18. pii: S1525-1578(21)00122-7. [Epub ahead of print]
    Double drop-off droplet digital PCR (DDO-ddPCR): a novel, versatile tool for mutation screening and residual disease monitoring in acute myeloid leukemia using cellular or cell-free DNA.
    Christian Rausch, Maja Rothenberg-Thurley, Simon A Buerger, Sebastian Tschuri, Annika Dufour, Michaela Neusser, Stephanie Schneider, Karsten Spiekermann, Klaus H Metzeler, Frank Ziemann.
      In acute myeloid leukemia (AML), somatic gene mutations are important prognostic markers and increasingly constitute therapeutic targets. Therefore, robust, sensitive and fast diagnostic assays are needed. Current techniques for mutation screening and quantification, including next generation sequencing and quantitative PCR, each have weaknesses that leave a need for novel diagnostic tools. We established double drop-off digital droplet PCR (DDO-ddPCR) assays for gene mutations in NPM1, IDH2 and NRAS, which can detect and quantify diverse alterations at two nearby hotspot regions present in these genes. These assays can be used for mutation screening as well as quantification and sequential monitoring. We validated our assays against next-generation sequencing and existing ddPCR assays and achieved high concordance with an overall sensitivity comparable to conventional digital PCR. In addition, we studied the feasibility of detecting and monitoring genetic alterations in peripheral blood cell-free DNA of AML patients by DDO-ddPCR. Our analyses suggest that cfDNA analysis has similar sensitivity compared to qPCR-based analysis of peripheral blood. Finally, we studied the applicability of cell-free DNA-based digital PCR in several clinical scenarios and show that long-term monitoring of target-specific therapy, early response assessment during induction chemotherapy, and identification of mutations in patients with extramedullary disease are feasible using this approach. Thus, DDO-ddPCR based cfDNA analysis can complement existing genetic tools for diagnosis and disease monitoring in AML.
    DOI:  https://doi.org/10.1016/j.jmoldx.2021.05.001
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