bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2021‒12‒19
twenty-one papers selected by
Sergio Marchini
Humanitas Research

  1. Methods Mol Biol. 2022 ;2424 3-10
      Ovarian cancer may arise from any of the histologic portions of the ovary including the epithelium, stroma, or germ cells. Of these, high-grade serous carcinoma arising from the epithelium of the ovary is the most common type. The clinical management and prognosis of ovarian cancer depend upon the stage of the cancer. Cancer stage is the extent to which the cancer has spread from its site of origin. For ovarian cancer, staging guidelines are determined by FIGO, the Fédération Internationale de Gynécologie et d'Obstétrique. The stage of ovarian cancer is determined by performing surgery to remove the ovaries and other gynecologic organs as well as lymph nodes and other tissues where the cancer may have spread. The histologic specimens from this surgery provide information from which the stage can be determined. In more advanced cases, this surgery may also include procedures to remove other areas of cancer. The stage of ovarian cancer guides treatment and is also the most important factor in ovarian cancer prognosis. Most epithelial ovarian cancers are diagnosed in advanced stages and are treated with surgery and chemotherapy. Despite aggressive treatment, the survival of patients with advanced stage epithelial ovarian cancer remains low, and more effective diagnostic and therapeutic approaches are needed.
    Keywords:  Epithelial ovarian cancer; International Federation of Gynecology and Obstetrics (FIGO); Ovarian cancer; Staging; Surgical staging
  2. Cancer J. 2021 Nov-Dec 01;27(6):27(6): 432-440
      ABSTRACT: The emergence of clinical trial data for poly(ADP-ribose) polymerase inhibitors (PARPi), in BRCA-associated ovarian cancer (epithelial ovarian cancer [EOC]) in 2009 (Lancet 2010;376:245-251) unleashed a rapid series of additional asset development and clinical trial activation across all lines of EOC treatment, ultimately leading to 8 new approvals of 3 different PARPi in EOC since 2014. Monotherapy iPARPi were approved as frontline maintenance treatment for all patients with EOC who respond to platinum-based chemotherapy irrespective of biomarker (niraparib) and for BRCA-associated cancers (olaparib) (; Combination of olaparib and bevacizumab was approved as maintenance for patients in response to platinum-based and bevacizumab containing frontline therapy whose tumor is characterized as homologous recombination deficient and as approved test by the Food and Drug Administration, inclusive of BRCA-associated cancers (N Engl J Med 2019;381:2416-2428). Niraparib, olaparib, and rucaparib were also approved as maintenance treatment following response to platinum-based therapy in the recurrent setting irrespective of biomarker (;; All 3 PARPi were also approved as treatment in lieu of chemotherapy for patients with BRCA-associated cancers in third line and beyond (; and platinum-sensitive homologous recombination deficient in the fourth line and beyond (, as well as the National Comprehensive Cancer Network listed in combination with bevacizumab for treatment of patients with platinum-sensitive recurrent disease ( Ongoing clinical trials in all lines of treatment are evaluating combinations of therapies to improve efficacy among biomarker negative tumors as well as overcome acquired PARPi resistance due to prior use.
  3. Front Pharmacol. 2021 ;12 743073
      Poly ADP-ribose polymerase inhibitor (PARPi) has become an important maintenance therapy for ovarian cancer after surgery and cytotoxic chemotherapy, which has changed the disease management model of ovarian cancer, greatly decreased the risk of recurrence, and made the prognosis of ovarian cancer better to certain extent. The three PARPis currently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of ovarian cancer are Olaparib, Niraparib and Rucaparib. With the incremental results from new clinical trials, the applicable population of PARPi for ovarian cancer have expanded to population with non-BRCA mutations. Although BRCA mutated population are still the main beneficiaries of PARPi, recent clinical trials indicated PARPis' therapeutic potential in non-BRCA mutated population, especially in homologous recombination repair deficiency (HRD) positive population. However, lack of unified HRD status detection method poses a challenge for the accurate selection of PARPi beneficiaries. The reversal of homologous recombination (HR) function during the treatment will not only cause resistance to PARPis, but also reduce the accuracy of the current method to determine HRD status. Therefore, the development of reliable HRD status detection methods to determine the beneficiary population, as well as rational combination treatment are warranted. This review mainly summarizes the latest clinical trial results and combination treatment of PARPis in ovarian cancer with non-BRCA mutations, and discusses the application prospects, including optimizing combination therapy against drug resistance, developing unified and accurate HRD status detection methods for patient selection and stratification. This review further poses an interesting topic: the efficacy and safety in patients retreated with PARPis after previous PARPi treatment---"PARPi after PARPi".
    Keywords:  HRD status detection; combination therapy; homologous recombination deficiency; ovarian cancer; poly ADP-ribose polymerase inhibitors
  4. Nature. 2021 Dec;600(7889): S35
    Keywords:  Cancer; Health care; Therapeutics
  5. Nature. 2021 Dec;600(7889): S40-S41
    Keywords:  Cancer; Microbiome
  6. Nature. 2021 Dec;600(7889): S39
    Keywords:  Cancer; Health care; Society
  7. EMBO J. 2021 Dec 17. e109221
      Within a tumor, cancer cells exist in different states that are associated with distinct tumor functions, including proliferation, differentiation, invasion, metastasis, and resistance to anti-cancer therapy. The identification of the gene regulatory networks underpinning each state is essential for better understanding functional tumor heterogeneity and revealing tumor vulnerabilities. Here, we review the different studies identifying tumor states by single-cell sequencing approaches and the mechanisms that promote and sustain these functional states and regulate their transitions. We also describe how different tumor states are spatially distributed and interact with the specific stromal cells that compose the tumor microenvironment. Finally, we discuss how the understanding of tumor plasticity and transition states can be used to develop new strategies to improve cancer therapy.
    Keywords:  EMT; cancer therapy; metastasis; single-cell; tumor heterogeneity
  8. Nature. 2021 Dec;600(7889): S42-S44
    Keywords:  Cancer; Health care
  9. Onco Targets Ther. 2021 ;14 5429-5434
      Ovarian clear cell carcinoma (OCCC) is a rare type of epithelial ovarian cancer characterized by a chemoresistant phenotype and high-grade tumor. Conventional therapies for OCCC include surgery and chemotherapy. However, these OCCC treatment approaches are characterized by a high risk of relapse and drug resistance resulting in poor prognosis. Therefore, alternative therapeutic approaches are required to achieve better outcomes. In this study, a PIK3CA p.R88Q mutation and PD-L1 expression with a tumor proportion score of 10% was explored in a patient who presented with rapid recurrence after surgery and unsuccessful postoperative chemotherapy. Based on the clinical condition and the patient preference, she was administered a novel combinatorial therapy comprising mTOR inhibitor everolimus, which is a well-known and potent inhibitor of the PI3K/AKT signaling pathway, and the anti-PD-1 antibody toripalimab. Treatment with this combinatorial therapy showed good prognosis, with more than eight months of disease control, and no severe adverse events were observed. The findings of this study provide a novel and effective strategy for OCCC patients. To the best of our knowledge, this is the first study to report a new combination regimen of immunotherapy (everolimus plus toripalimab) for solid tumors. Everolimus is not only an antitumor targeted drug but also an immunosuppressant; it's combination with immunotherapy is controversial. This is the first report to demonstrate that it has a synergistic effect.
    Keywords:  PIK3CA mutation; everolimus; high PD-L1 expression; ovarian clear cell carcinoma; toripalimab
  10. Nature. 2021 Dec;600(7889): S48-S49
    Keywords:  Cancer; Epidemiology
  11. Expert Rev Mol Diagn. 2021 Dec 16.
      INTRODUCTION: Carcinomas with defects in the homologous recombination (HR) pathway are sensitive to PARP inhibitors (PARPi). A robust method to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. Currently available DNA-based HRD tests either scan HR-related genes such as BRCA1 and BRCA2 for the presence of pathogenic variants or identify HRD-related genomic scars or mutational signatures by using whole-exome or whole-genome sequencing data. As an alternative to DNA-based tests, functional HRD tests have been developed that assess the actual ability of tumors to accumulate RAD51 protein at DNA double strand breaks as a proxy for HR proficiency.AREAS COVERED: This review presents an overview of currently available HRD tests and discuss the pros and cons of the different methodologies including their sensitivity for the identification of HRD tumors, their concordance with other HRD tests, and their capacity to predict therapy response.
    EXPERT OPINION: With the increasing use of PARP inhibitors in the treatment of several cancers there is an urgent need to implement HRD testing in routine clinical practice. To this end, calibration of HRD thresholds and clinical validation of both DNA-based and RAD51-based HRD tests should have top-priority in the coming years.
    Keywords:  BRCA1; BRCA2; RAD51; RAD51-FFPE test; RECAP test; genomic scars; homologous recombination deficiency; mutational signatures
  12. Curr Oncol. 2021 Nov 03. 28(6): 4446-4456
      BACKGROUND: High grade serous ovarian carcinoma (HGSOC) is the most lethal type of epithelial ovarian cancer, with a prevalence of germline BRCA1/2 mutations as high as 20%. Our objective is to determine whether the location of mutations in the different domains of the BRCA1/2 genes affects the clinical outcome of HGSOC patients.METHODS: A total of 51 women with BRCA1 or BRCA2 mutated ovarian cancer were identified. Progression-free survival (PFS) and overall survival (OS) were analyzed.
    RESULTS: In our study cohort, 35 patients were carriers of germline mutations in BRCA1 and 16 in BRCA2. The median PFS time following completion of the primary therapy was 23.8 months (95% CI 20.1-27.5) and the median OS was 92.9 months (95% CI 69.8-116.1) in all BRCA carriers. After multivariate analysis, no significant association among the location or type of BRCA1/2 mutation with PFS or OS was identified. Notably, significant differences in PFS between carriers of identical mutations in the same BRCA gene were detected.
    CONCLUSIONS: Among HGSOC patients, BRCA1/2 carriers with mutations in different locations of the genes show no significant difference in survival outcomes, in terms of PFS and OS, suggesting the potential effect of other genetic abnormalities and co-contributing risk factors.
    Keywords:  BRCA; germline mutations; ovarian cancer; survival
  13. Methods Mol Biol. 2022 ;2424 11-40
      Optimal use of human tissue for research requires an understanding of basic pathologic principles. Given that the physical assessment of tissue must occur as part of standard clinical examination, it cannot be handled directly by investigators unless they are also a part of the care team. The purpose of this chapter is to provide an overview of the clinical analytic process, from initial gross handling to histologic examination by light microscopy and the use of ancillary studies, in order to provide context for samples that are used in research and to highlight specific considerations that are relevant for obtaining appropriate tissue for experimental purposes. Given that they comprise >95% of ovarian malignancies, there is an emphasis on epithelial tumors.
    Keywords:  Ovarian cancer; Pathologic classification
  14. J Surg Oncol. 2022 Jan;125(1): 17-27
      Soft-tissue sarcomas are rare tumors arising from mesenchymal tissues. As a heterogeneous group comprising more than 50 types, the development of clinical trials remains challenging. Decision-making for neoadjuvant or adjuvant chemotherapy and radiation therapy is based on the available evidence of contemporary trials and multidisciplinary clinical judgment.
    Keywords:  chemotherapy; clinical trials; extremity sarcoma; immunotherapy; radiotherapy; retroperitoneal sarcoma
  15. Cancer Med. 2021 Dec 12.
      BACKGROUND: CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan-cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real-world clinical-grade sequencing.METHODS: This was a single-center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described.
    RESULTS: In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12-altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow-up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11-5.74). Ten patients with CDK12-altered tumors received at least one immune checkpoint inhibitor-containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression-free survival for patients who had metastatic disease and received a checkpoint inhibitor-containing regimen was 1.16 years (95% CI: 0.32-2.00).
    CONCLUSION: CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12-altered tumors.
    Keywords:  biomarkers; cancer genetics; clinical cancer research; genomics
  16. Cancer J. 2021 Nov-Dec 01;27(6):27(6): 511-520
      ABSTRACT: The use of poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitor therapies has seen substantial clinical success in oncology therapeutic development. Although multiple agents within these classes have achieved regulatory approval globally-in several malignancies in early and advanced stages-drug resistance remains an issue. Building on preclinical evidence, several early trials and late-phase studies are underway. This review explores the therapeutic potential of combination poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitor therapy in solid tumors, including the scientific and therapeutic rationale, available clinical evidence, and considerations for future trial and biomarker development across different malignancies using ovarian and other solid cancer subtypes as key examples.
  17. Cancer J. 2021 Nov-Dec 01;27(6):27(6): 501-505
      ABSTRACT: DNA damage response and repair (DDR) is responsible for ensuring genomic integrity. It is composed of intricate, complex pathways that detect various DNA insults and then activate pathways to restore DNA fidelity. Mutations in this network are implicated in many malignancies but can also be exploited for cancer therapies. The advent of inhibitors of poly(ADP-ribose) polymerase has led to the investigation of other DDR inhibitors and combinations to address high unmet needs in cancer therapeutics. Specifically, regimens, often in combination with chemotherapy, radiation, or other DDR inhibitors, are being investigated. This review will focus on 4 main DDR pathways-ATR/CHK1, ATM/CHK2, DNA-PKcs, and polymerase θ-and the current state of clinical research and use of the inhibitors of these pathways with other DDR inhibitors.
  18. Nature. 2021 Dec 15.
      The state and behaviour of a cell can be influenced by both genetic and environmental factors. In particular, tumour progression is determined by underlying genetic aberrations1-4 as well as the makeup of the tumour microenvironment5,6. Quantifying the contributions of these factors requires new technologies that can accurately measure the spatial location of genomic sequence together with phenotypic readouts. Here we developed slide-DNA-seq, a method for capturing spatially resolved DNA sequences from intact tissue sections. We demonstrate that this method accurately preserves local tumour architecture and enables the de novo discovery of distinct tumour clones and their copy number alterations. We then apply slide-DNA-seq to a mouse model of metastasis and a primary human cancer, revealing that clonal populations are confined to distinct spatial regions. Moreover, through integration with spatial transcriptomics, we uncover distinct sets of genes that are associated with clone-specific genetic aberrations, the local tumour microenvironment, or both. Together, this multi-modal spatial genomics approach provides a versatile platform for quantifying how cell-intrinsic and cell-extrinsic factors contribute to gene expression, protein abundance and other cellular phenotypes.
  19. Cancer Cell Int. 2021 Dec 11. 21(1): 663
      m6A (N6-methyladenosine) methylation, a well-known modification in tumour epigenetics, dynamically and reversibly fine tunes the entire process of RNA metabolism. Aberrant levels of m6A and its regulators, which can predict the survival and outcomes of cancer patients, are involved in tumorigenesis, metastasis and resistance. Ovarian cancer (OC) ranks first among gynaecological tumours in the causes of death. At first diagnosis, patients with OC are usually at advanced stages owing to a lack of early biomarkers and effective targets. After treatment, patients with OC often develop drug resistance. This article reviews the recent experimental advances in understanding the role of m6A modification in OC, raising the possibility to treat m6A modification and its regulators as promising diagnostic markers and therapeutic targets for OC.
    Keywords:  Demethylase; Methyltransferase; OC; RNA binding protein; m6A modification
  20. J Obstet Gynaecol. 2021 May 02. 1-7
      We compared the quality of life (QoL) of women with early versus advanced epithelial ovarian cancer and examined predicting factors for the poor QoL. We classified 157 participants into 108 with early disease (stage I-II) and 49 with advanced disease (stage III-IV). They completed two questionnaires: EORTC QLQ-C30 and Chiang Mai University (CMU) ovarian cancer QoL. For EORTC QLQ-C30, the study groups were comparable regarding global health status/QoL, functional scales, and summary scores. The advanced group had worse scores on symptom scales specifically appetite loss and constipation. For CMU Ovarian Cancer QoL, the advanced group had worse scores only in the gastrointestinal domain but not in urinary, lymphatic, and sexual/hormonal domains. These findings remained mostly unchanged after excluding those with recurrence. In multivariable analysis, currently receiving treatment was consistently associated with worse QoL scores. The advanced stage had more adverse impact only on the gastrointestinal domains of QoL, mainly during periods of receiving chemotherapy.IMPACT STATEMENTWhat is already known on this subject? Survival outcome for women with epithelial ovarian cancer varies depending mainly on stage. Those who survive advanced stage disease could expect long-term disease and treatment-related morbidities that significantly affected QoL. However, there has been very limited information regarding QoL of women who have the early disease in comparison to those with more advanced disease especially in the context of Asian culture.What do the results of this study add? Apart from the higher prevalence of gastrointestinal symptoms reported by the patients with advanced disease, the general well-being and other symptom-specific domains of QoL were comparable between women with early and advanced diseases. Receiving treatment is a consistent predictor for poor QoL.What are the implications of these findings for clinical practice and/or further research? In comparison to early-stage epithelial ovarian cancer, the advanced stage had more adverse impact only on the gastrointestinal domains of QoL, mainly during periods of receiving chemotherapy. This information will be useful for patient counselling. Future research should examine the underlying causes of this finding.
    Keywords:  Chemotherapy; oncology; ovarian cancer; quality of life
  21. Clin Epigenetics. 2021 Dec 13. 13(1): 219
      BACKGROUND: One of the fundamental assumptions of DNA methylation in clinical epigenetics is that DNA methylation status can change over time with or without interplay with environmental and clinical conditions. However, little is known about how DNA methylation status changes over time under ordinary environmental and clinical conditions. In this study, we revisited the high frequency longitudinal DNA methylation data of two Japanese males (24 time-points within three months) and characterized the longitudinal dynamics.RESULTS: The results showed that the majority of CpGs on Illumina HumanMethylation450 BeadChip probe set were longitudinally stable over the time period of three months. Focusing on dynamic and stable CpGs extracted from datasets, dynamic CpGs were more likely to be reported as epigenome-wide association study (EWAS) markers of various traits, especially those of immune- and inflammatory-related traits; meanwhile, the stable CpGs were enriched in metabolism-related genes and were less likely to be EWAS markers, indicating that the stable CpGs are stable both in the short-term within individuals and under various environmental and clinical conditions.
    CONCLUSIONS: This study indicates that CpGs with different stabilities are involved in different functions and traits, and thus, they are potential indicators that can be applied for clinical epigenetic studies to outline underlying mechanisms.
    Keywords:  Blood DNA methylation; EWAS marker likelihood; Illumina 450 K beadchip; Temporal stability