bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2021–05–09
twelve papers selected by
Lara Paracchini, Humanitas Research
  1. Can Circulating Cell-Free DNA or Circulating Tumor DNA Be a Promising Marker in Ovarian Cancer?
  2. Detection of low-frequency DNA variants by targeted sequencing of the Watson and Crick strands.
  3. An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer.
  4. Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2).
  5. Hyperthermic Intraperitoneal Chemotherapy for Ovarian and Colorectal Cancer: A Review.
  6. The Silent Mutation.
  7. Speckle function for p53.
  8. Molecular visualization of cellular complexity.
  9. Chromatin context affects DNA repair pathway.
  10. Pioneering Heart Valve Approved for Patients With CHD.
  11. Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.
  12. Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes co-expressing CD39, CD103, and PD-1 in ovarian cancer.
  1. J Oncol. 2021 ;2021 6627241
    Can Circulating Cell-Free DNA or Circulating Tumor DNA Be a Promising Marker in Ovarian Cancer?
    Ming Yu, Yu Zhu, Lichen Teng, Jialin Cui, Yajuan Su.
      In recent years, the studies on ovarian cancer have made great progress, but the morbidity and mortality of patients with ovarian cancer are still very high. Due to the lack of effective early screening and detecting tools, 70% of ovarian cancer patients are diagnosed at an advanced stage. The overall survival rate of ovarian cancer patients treated with surgical combined with chemotherapy has not been significantly improved, and they usually relapse or resist chemotherapy. Therefore, a novel tumor marker is beneficial for the diagnosis and prognosis of patients with ovarian cancer. As the index of "liquid biopsy," circulating cell-free DNA/circulating tumor DNA (cfDNA/ctDNA) has attracted a lot of attention. It has more remarkable advantages than traditional methods and gives a wide range of clinical applications in kinds of solid tumors. This review attempts to illuminate the important value of cfDNA/ctDNA in ovarian cancer, including diagnosis, monitoring, and prognosis. Meanwhile, we will present future directions and challenges for detection of cfDNA/ctDNA.
    DOI:  https://doi.org/10.1155/2021/6627241
  2. Nat Biotechnol. 2021 May 03.
    Detection of low-frequency DNA variants by targeted sequencing of the Watson and Crick strands.
    Joshua D Cohen, Christopher Douville, Jonathan C Dudley, Brian J Mog, Maria Popoli, Janine Ptak, Lisa Dobbyn, Natalie Silliman, Joy Schaefer, Jeanne Tie, Peter Gibbs, Cristian Tomasetti, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein.
      Identification and quantification of low-frequency mutations remain challenging despite improvements in the baseline error rate of next-generation sequencing technologies. Here, we describe a method, termed SaferSeqS, that addresses these challenges by (1) efficiently introducing identical molecular barcodes in the Watson and Crick strands of template molecules and (2) enriching target sequences with strand-specific PCR. The method achieves high sensitivity and specificity and detects variants at frequencies below 1 in 100,000 DNA template molecules with a background mutation rate of <5 × 10-7 mutants per base pair (bp). We demonstrate that it can evaluate mutations in a single amplicon or simultaneously in multiple amplicons, assess limited quantities of cell-free DNA with high recovery of both strands and reduce the error rate of existing PCR-based molecular barcoding approaches by >100-fold.
    DOI:  https://doi.org/10.1038/s41587-021-00900-z
  3. Nat Med. 2021 May 03.
    An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer.
    Thomas Powles, Danielle Carroll, Simon Chowdhury, Gwenaelle Gravis, Florence Joly, Joan Carles, Aude Fléchon, Pablo Maroto, Daniel Petrylak, Frédéric Rolland, Natalie Cook, Arjun V Balar, Srikala S Sridhar, Matthew D Galsky, Petros Grivas, Alain Ravaud, Robert Jones, Jan Cosaert, Darren Hodgson, Iwanka Kozarewa, Richard Mather, Robert McEwen, Florence Mercier, Dónal Landers.
      Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC)1. AUC is characterized by several recurrent targetable genomic alterations2-5. This study ( NCT02546661 , BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway3-5.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9-36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC.
    DOI:  https://doi.org/10.1038/s41591-021-01317-6
  4. Nat Commun. 2021 05 03. 12(1): 2487
    Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2).
    Elizabeth M Swisher, Tanya T Kwan, Amit M Oza, Anna V Tinker, Isabelle Ray-Coquard, Ana Oaknin, Robert L Coleman, Carol Aghajanian, Gottfried E Konecny, David M O'Malley, Alexandra Leary, Diane Provencher, Stephen Welch, Lee-May Chen, Andrea E Wahner Hendrickson, Ling Ma, Prafull Ghatage, Rebecca S Kristeleit, Oliver Dorigo, Ashan Musafer, Scott H Kaufmann, Julia A Elvin, Douglas I Lin, Setsuko K Chambers, Erin Dominy, Lan-Thanh Vo, Sandra Goble, Lara Maloney, Heidi Giordano, Thomas Harding, Alexander Dobrovic, Clare L Scott, Kevin K Lin, Iain A McNeish.
      ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.
    DOI:  https://doi.org/10.1038/s41467-021-22582-6
  5. JAMA Oncol. 2021 May 06.
    Hyperthermic Intraperitoneal Chemotherapy for Ovarian and Colorectal Cancer: A Review.
    Ruby M van Stein, Arend G J Aalbers, Gabe S Sonke, Willemien J van Driel.
       Importance: The peritoneal surface is a common site of disease in ovarian and colorectal cancer. Peritoneal metastases carry a poor prognosis, despite maximal therapeutic efforts, including surgical removal of tumor deposits and intravenous chemotherapy. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a single intraoperative procedure that delivers chemotherapy directly into the abdominal cavity, leading to high intracellular drug concentration at the peritoneal surface. This review describes the current knowledge regarding the mechanism of action, safety, and efficacy of HIPEC in the treatment of peritoneal metastases from epithelial ovarian and colorectal cancers and explores current knowledge gaps.
    Observations: Toxic effects of HIPEC are limited. Evidence from a randomized trial shows improved recurrence-free and overall survival after HIPEC in patients with ovarian cancer who are ineligible for primary cytoreductive surgery (CRS). The effect of HIPEC for patients with ovarian cancer undergoing primary CRS or CRS for recurrent disease has not yet been determined, and results of ongoing trials must be awaited. A recent study in patients with peritoneal metastases from colorectal cancer did not show a benefit of HIPEC when added to perioperative chemotherapy.
    Conclusions and Relevance: Based on available evidence, various international guidelines include the option to add HIPEC to interval CRS for patients with stage III ovarian cancer. The role of HIPEC in colorectal cancer is less well defined. Future studies will need to tailor patient selection, timing, and optimal regimens of HIPEC to improve the effectiveness of this specialized treatment in ovarian, colorectal, and other tumor types.
    DOI:  https://doi.org/10.1001/jamaoncol.2021.0580
  6. JAMA. 2021 May 04. 325(17): 1721-1722
    The Silent Mutation.
    Margo A Peyton.
      
    DOI:  https://doi.org/10.1001/jama.2021.5484
  7. Nat Rev Mol Cell Biol. 2021 May 05.
    Speckle function for p53.
    Eytan Zlotorynski.
      
    DOI:  https://doi.org/10.1038/s41580-021-00379-1
  8. Nat Methods. 2021 May;18(5): 442-443
    Molecular visualization of cellular complexity.
    Michael R Wozny, Wanda Kukulski.
      
    DOI:  https://doi.org/10.1038/s41592-021-01131-5
  9. Nat Rev Genet. 2021 May 07.
    Chromatin context affects DNA repair pathway.
    Caroline Barranco.
      
    DOI:  https://doi.org/10.1038/s41576-021-00371-7
  10. JAMA. 2021 May 04. 325(17): 1713
    Pioneering Heart Valve Approved for Patients With CHD.
    Rebecca Voelker.
      
    DOI:  https://doi.org/10.1001/jama.2021.6103
  11. Cancer Med. 2021 May 07.
    Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.
    Robin L Jones, Thomas J Herzog, Shreyaskumar R Patel, Margaret von Mehren, Scott M Schuetze, Brian A Van Tine, Robert L Coleman, Roland Knoblauch, Spyros Triantos, Peter Hu, Waleed Shalaby, Tracy McGowan, Bradley J Monk, George D Demetri.
       BACKGROUND: As with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.
    METHODS: Patient data for multiple cardiac-related treatment-emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).
    RESULTS: Multivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24-2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12-2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75-4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16-3.05]; p = 0.010).
    CONCLUSIONS: For patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk. Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.
    Keywords:  anthracycline; cardiac toxicity; chemotherapy; patient outcomes; soft tissue sarcomas
    DOI:  https://doi.org/10.1002/cam4.3903
  12. Clin Cancer Res. 2021 May 07. pii: clincanres.4394.2020. [Epub ahead of print]
    Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes co-expressing CD39, CD103, and PD-1 in ovarian cancer.
    Céline M Laumont, Maartje C A Wouters, Julian Smazynski, Nicole S Gierc, Elizabeth A Chavez, Lauren C Chong, Shelby Thornton, Katy Milne, John R Webb, Christian Steidl, Brad H Nelson.
       PURPOSE: Tumor-infiltrating lymphocytes (TIL) are strongly associated with survival in most cancers; however, the tumor-reactive subset that drives this prognostic effect remains poorly defined. CD39, CD103, and PD-1 have been independently proposed as markers of tumor-reactive CD8+ TIL in various cancers. We evaluated the phenotype, clonality and prognostic significance of TIL expressing various combinations of these markers in high-grade serous ovarian cancer (HGSC), a malignancy in need of more effective immunotherapeutic approaches.
    EXPERIMENTAL DESIGN: Expression of CD39, CD103, PD-1, and other immune markers was assessed by high-dimensional flow cytometry, single-cell sequencing, and multiplex immunofluorescence of primary and matched pre/post-chemotherapy HGSC specimens.
    RESULTS: Co-expression of CD39, CD103, and PD-1 ("triple-positive" phenotype) demarcated subsets of CD8+ TIL and CD4+ regulatory T cells (Tregs) with a highly activated/exhausted phenotype. Triple-positive CD8+ TIL exhibited reduced TCR diversity and expressed genes involved in both cytolytic and humoral immunity. Triple-positive Tregs exhibited higher TCR diversity and a tumor-resident phenotype. Triple-positive TIL showed superior prognostic impact relative to TIL expressing other combinations of these markers. TIGIT was uniquely upregulated on triple-positive CD8+ effector cells relative to their CD4+ Treg counterparts.
    CONCLUSIONS: Co-expression of CD39, CD103, and PD-1 demarcates highly activated CD8+ and CD4+ TIL with inferred roles in cytolytic, humoral and regulatory immune functions. Triple-positive TIL demonstrate exceptional prognostic significance and express compelling targets for combination immunotherapy, including PD-1, CD39 and TIGIT.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-4394
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