bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2023–01–08
seventeen papers selected by
Sergio Marchini, Humanitas Research
  1. Prognostic relevance of HRDness gene expression signature in ovarian high-grade serous carcinoma; JGOG3025-TR2 study.
  2. PD-L1 is highly expressed in ovarian cancer and associated with cancer stem cells populations expressing CD44 and other stem cell markers.
  3. Imaging Mass Cytometry in Immuno-Oncology.
  4. cGAS in nucleus: The link between immune response and DNA damage repair.
  5. Targeting the DNA damage response for cancer therapy.
  6. Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial.
  7. Targeted therapy for mucinous ovarian carcinoma: evidence from clinical trials.
  8. Targeted DNA methylation from cell-free DNA using hybridization probe capture.
  9. Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis.
  10. Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy.
  11. Single-cell DNA methylation sequencing by combinatorial indexing and enzymatic DNA methylation conversion.
  12. Is Optimal Cytoreduction Post Neoadjuvant Chemotherapy the Only Prognostic Factor in Advanced Ovarian Cancer?
  13. Editorial: Targeting the PD-1/PD-L1 cancer immune evasion axis: Challenges and emerging strategies, Volume II.
  14. DNA methylation and cancer: transcriptional regulation, prognostic, and therapeutic perspective.
  15. Highlights from Recent Cancer Literature.
  16. Spatial PD-L1, immune-cell microenvironment, and genomic copy-number alteration patterns and drivers of invasive-disease transition in prospective oral precancer cohort.
  17. Survival in stage IV ovarian cancer with increased use of debulking surgery and bevacizumab.
  1. Br J Cancer. 2023 Jan 02.
    Prognostic relevance of HRDness gene expression signature in ovarian high-grade serous carcinoma; JGOG3025-TR2 study.
    Shiro Takamatsu, Kosuke Yoshihara, Tsukasa Baba, Muneaki Shimada, Hiroshi Yoshida, Hiroaki Kajiyama, Katsutoshi Oda, Masaki Mandai, Aikou Okamoto, Takayuki Enomoto, Noriomi Matsumura.
       BACKGROUND: This study aimed to evaluate the homologous recombination repair pathway deficiency (HRD) in ovarian high-grade serous carcinoma (HGSC).
    METHODS: In the ovarian cancer data from The Cancer Genome Atlas, we identified genes differentially expressed between tumours with and without HRD genomic scars and named these genes "HRDness signature". We performed SNP array, RNA sequencing, and methylation array analyses on 274 HGSC tumours for which targeted sequencing of 51 genes and clinical data were available to generate JGOG3025-TR2 dataset. The HRDness signature was tested on external datasets, including the JGOG3025-TR2 cohort, by computational scoring and machine-learning prediction.
    RESULTS: High scores and positive predictions of the HRDness signature were significantly associated with BRCA alterations, genomic scar scores, and better survival. On the other hand, among cases with high scores and/or positive predictions, those with BRCA1 methylation showed poorer survival. In the JGOG3025-TR2 cohort, HRD status was significantly associated with the use of olaparib after relapse and progression-free survival after its initiation.
    CONCLUSIONS: The HRDness gene expression signature is associated with a good prognosis, while BRCA1 methylation is associated with a poor prognosis. The newly generated JGOG3025-TR2 dataset will be useful in future HGSC studies.
    DOI:  https://doi.org/10.1038/s41416-022-02122-9
  2. BMC Cancer. 2023 Jan 05. 23(1): 13
    PD-L1 is highly expressed in ovarian cancer and associated with cancer stem cells populations expressing CD44 and other stem cell markers.
    Kholoud Alwosaibai, Salmah Aalmri, Miral Mashhour, Salim Ghandorah, Abdulraheem Alshangiti, Faisal Azam, Waleed Selwi, Lubna Gharaibeh, Yasser Alatawi, Zainab Alruwaii, Hashem O Alsaab.
       BACKGROUND: Immune checkpoint inhibitors, including PD-L1 (programmed death ligand-1) inhibitors have well documented anticancer therapeutic effect in most types of cancers but its use in the treatment of ovarian cancer is not yet proven. The aim of our study is to explore the predictive biomarkers in ovarian cancer and its association with the outcomes. We have investigated the role of PD-L1 expressions in the tumor microenvironment cells including immune cells and cancer stem cells in different types of ovarian cancer.
    METHODS: A total of 119 surgical archived ovarian cancer samples were collected from the pathology department at King Fahad Specialist Hospital, Dammam, Saudi Arabia that included serous carcinomas, clear cell carcinomas, mucinous carcinomas, endometrioid carcinomas, and granulosa cell tumors. Immunohistochemistry (IHC) staining was performed using (i) PD-L1 antibodies to detect PD-L1 expressions; (ii) CD8 and CD4 to detect Tumor Infiltrating Lymphocytes (TILs); and (iii) CD44, LGR5, and ALDH2 to detect stem cell markers. The clinicopathological data were collected from patients' medical record to investigate the association with PD-L1, TILs, and stem cells expressions.
    RESULTS: We report high PD-L1 expressions in 47.8% of ovarian cancer samples. PD-L1 expressions were detected in different types of epithelial ovarian cancer and were not associated with poor prognosis of ovarian cancer. However, determining the expression levels of TILs in the ovarian cancer tissues found that 81% (n = 97) of ovarian cancer samples have TILs that express both of CD8 and CD4 and significantly associated with high PD-L1 expressions. Interestingly, we have found that ovarian cancer tissues with high expressions of PD-L1 were associated with high expressions of stem cells expressing CD44 and LGR5.
    CONCLUSIONS: PD-L1 is highly expressed in the serous type of ovarian carcinomas and the overall expression of PD-L1 is not associated with poor survival rate. Furthermore, PD-L1 expressions are strongly associated with TILs and stem cell markers in ovarian cancer. Inhibiting the PD-L1 using immune checkpoint inhibitors might downregulate stem cell population that known to be associated with cancer recurrence.
    Keywords:  CD44; Immune-checkpoints markers; Immunotherapy; Ovarian cancer; PD-L1; Stem cell markers
    DOI:  https://doi.org/10.1186/s12885-022-10404-x
  3. Methods Mol Biol. 2023 ;2614 1-15
    Imaging Mass Cytometry in Immuno-Oncology.
    Tiziana Cotechini, Oliver Jones, Charles Colin Thomas Hindmarch.
      In situ profiling of the tumor-immune microenvironment (TiME) requires the ability to co-localize and detect multiple proteins simultaneously. Imaging mass cytometry (IMC), using the Hyperion™ imaging system is a novel multiplex imaging modality that currently enables detection of up to 50 markers on fixed tissues at subcellular resolution and thus has the potential to inform both pre-clinical and clinical research by providing investigators with spatially resolved information about the TiME. Here we provide an overview of the IMC workflow from sample fixation to analysis, with a focus on multiplex panel design and tissue staining.
    Keywords:  Hyperion™; Imaging mass cytometry; Immunology; In situ; Multiplex immunohistochemistry; Pathology; Spatial profiling; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-1-0716-2914-7_1
  4. Front Immunol. 2022 ;13 1076784
    cGAS in nucleus: The link between immune response and DNA damage repair.
    Jia-Xian Song, Deana Villagomes, Hongchang Zhao, Min Zhu.
      As the first barrier of host defense, innate immunity sets up the parclose to keep out external microbial or virus attacks. Depending on the type of pathogens, several cytoplasm pattern recognition receptors exist to sense the attacks from either foreign or host origins, triggering the immune response to battle with the infections. Among them, cGAS-STING is the major pathway that mainly responds to microbial DNA, DNA virus infections, or self-DNA, which mainly comes from genome instability by-product or released DNA from the mitochondria. cGAS was initially found functional in the cytoplasm, although intriguing evidence indicates that cGAS exists in the nucleus where it is involved in the DNA damage repair process. Because the close connection between DNA damage response and immune response and cGAS recognizes DNA in length-dependent but DNA sequence-independent manners, it is urgent to clear the function balance of cGAS in the nucleus versus cytoplasm and how it is shielded from recognizing the host origin DNA. Here, we outline the current conception of immune response and the regulation mechanism of cGAS in the nucleus. Furthermore, we will shed light on the potential mechanisms that are restricted to be taken away from self-DNA recognition, especially how post-translational modification regulates cGAS functions.
    Keywords:  DDR; cGAS; cancer therapy; innate immunity response; post-translational modification
    DOI:  https://doi.org/10.3389/fimmu.2022.1076784
  5. Biochem Soc Trans. 2023 Jan 06. pii: BST20220681. [Epub ahead of print]
    Targeting the DNA damage response for cancer therapy.
    Nicola J Curtin.
      The DNA damage response (DDR) is an elegant system, coordinating DNA repair with cell cycle checkpoints, that evolved to protect living organisms from the otherwise fatal levels of DNA damage inflicted by endogenous and environmental sources. Since many agents used to treat cancer; radiotherapy and cytotoxic chemotherapy, work by damaging DNA the DDR represents a mechanism of resistance. The original rational for the development of drugs to inhibit the DDR was to overcome this mechanism of resistance but clinical studies using this approach have not led to improvements in the therapeutic index. A more exciting approach is to exploit cancer-specific defects in the DDR, that represent vulnerabilities in the tumour and an opportunity to selectively target the tumour. PARP inhibitors (PARPi) selectively kill homologous recombination repair defective (HRD, e.g. through BRCA mutation) cells. This approach has proven successful clinically and there are now six PARPi approved for cancer therapy. Drugs targeting other aspects of the DDR are under pre-clinical and clinical evaluation as monotherapy agents and in combination studies. For this promising approach to cancer therapy to be fully realised reliable biomarkers are needed to identify tumours with the exploitable defect for monotherapy applications. The possibility that some combinations may result in toxicity to normal tissues also needs to be considered. A brief overview of the DDR, the development of inhibitors targeting the DDR and the current clinical status of such drugs is described here.
    Keywords:  ATM; ATR; CHK1; DNA damage response; DNA-PK; PARP
    DOI:  https://doi.org/10.1042/BST20220681
  6. Clin Cancer Res. 2023 Jan 03. pii: CCR-22-2032. [Epub ahead of print]
    Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial.
    Charles N Landen, Luciana Molinero, Habib Hamidi, Jalid Sehouli, Austin Miller, Kathleen N Moore, Cagatay Taskiran, Michael Bookman, Kristina Lindemann, Charles Anderson, Regina Berger, Tashanna Myers, Mario Beiner, Thomas Reid, Els Van Nieuwenhuysen, Andrew Green, Aikou Okamoto, Carol Aghajanian, Premal H Thaker, Stephanie V Blank, Victor K Khor, Ching-Wei Chang, Yvonne G Lin, Sandro Pignata.
       PURPOSE: To explore whether patients with BRCA1/2-mutated or homologous recombination-deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial.
    METHODS: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. PD-L1 status of tumor-infiltrating immune cells was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan-Meier estimates.
    RESULTS: Among biomarker-evaluable samples, 22% (234/1050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1024) had TMB ≥10 mut/Mb and 0.3% (3/1022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2-non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on immune cells) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors.
    CONCLUSIONS: Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2032
  7. Int J Gynecol Cancer. 2023 Jan 03. 33(1): 102-108
    Targeted therapy for mucinous ovarian carcinoma: evidence from clinical trials.
    Devindee Nugawela, Kylie L Gorringe.
      Mucinous ovarian carcinoma is a rare subtype of epithelial ovarian cancer. Despite being a chemoresistant tumour type, surgical resection and chemotherapy are still the current standard for management. This narrative review aims to explore the current evidence for targeted therapies in mucinous ovarian carcinoma. A review of the literature was performed to identify clinical trials and case reports of targeted therapy in patients with mucinous ovarian carcinoma. The databases and registers (PubMed, MEDLINE, Embase, Europe PMC, Cochrane Central Register of Clinical Trials, clinicaltrials.gov) were searched for articles published between January 2009 to June 2021 using keywords specific for mucinous ovarian carcinoma and targeted therapy. Records were screened and assessed for eligibility based on inclusion and exclusion criteria. From 684 records, 21 studies met the criteria to be included in the review. A total of 11 different targeted therapies were identified, each demonstrating varying degrees of clinical evidence supporting further investigation in patients with mucinous ovarian carcinoma. Targeted therapies identified in this review that warrant further investigations are bevacizumab, trastuzumab, nintedanib, AZD1775, sunitinib, cediranib and pazopanib. Many of the therapeutic agents may be investigated further in combination with other targeted therapies or chemotherapy. More clinical trials focusing on targeted therapy specifically in patients with mucinous ovarian cancer are required to inform clinical use. Multinational efforts are likely to be required to successfully conduct trials in this rare tumor type.
    Keywords:  cystadenocarcinoma, mucinous; medical oncology
    DOI:  https://doi.org/10.1136/ijgc-2022-003658
  8. NAR Genom Bioinform. 2022 Dec;4(4): lqac099
    Targeted DNA methylation from cell-free DNA using hybridization probe capture.
    David N Buckley, Gerald Gooden, Kuan Feng, Jacob Enk, Bodour Salhia.
      Cell-free (cf)DNA signatures are quickly becoming the target of choice for non-invasive screening, diagnosis, treatment and monitoring of human tumors. DNA methylation changes occur early in tumorigenesis and are widespread, making cfDNA methylation an attractive cancer biomarker. Already a proven technology for targeted genome sequencing, hybridization probe capture is emerging as a method for high-throughput targeted methylation profiling suitable to liquid biopsy samples. However, to date there are no reports describing the performance of this approach in terms of reproducibility, scalability, and accuracy. In the current study we performed hybridization probe capture using the myBaits® Custom Methyl-seq kit on 172 plasma samples and standards to evaluate its performance on cfDNA methylation analysis. The myBaits® assay showed high target recovery (>90%), demonstrated excellent reproducibility between captures (R 2 = 0.92 on average), and was unaffected by increasing the number of targets in a capture. Finally, myBaits® accurately replicated 'gold standard' beta values from WGBS (average R 2 = 0.79). The results of this study show that custom targeted methylation sequencing with myBaits® offers a cost-effective, reliable platform to profile DNA methylation at a set of discrete custom regions, with potential applicability to liquid biopsies for cancer monitoring.
    DOI:  https://doi.org/10.1093/nargab/lqac099
  9. Nat Commun. 2023 Jan 05. 14(1): 77
    Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis.
    Nicholas Light, Mehdi Layeghifard, Ayush Attery, Vallijah Subasri, Matthew Zatzman, Nathaniel D Anderson, Rupal Hatkar, Sasha Blay, David Chen, Ana Novokmet, Fabio Fuligni, James Tran, Richard de Borja, Himanshi Agarwal, Larissa Waldman, Lisa M Abegglen, Daniel Albertson, Jonathan L Finlay, Jordan R Hansford, Sam Behjati, Anita Villani, Moritz Gerstung, Ludmil B Alexandrov, Gino R Somers, Joshua D Schiffman, Varda Rotter, David Malkin, Adam Shlien.
      Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis.
    DOI:  https://doi.org/10.1038/s41467-022-35727-y
  10. Clin Cancer Res. 2023 Jan 04. pii: CCR-21-3750. [Epub ahead of print]
    Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy.
    Mary Helen Barcellos-Hoff, James L Gulley.
      Even though a cadre of agents that inhibit transforming growth factor β (TGFβ) is being tested in cancer patients, clinical benefit from TGFβ inhibition has not yet been achieved. The myriad mechanisms in which TGFβ is protumorigenic may be a key obstacle to its effective deployment; cancer cells frequently employ TGFβ-regulated programs that engender plasticity, enable a permissive tumor microenvironment, and profoundly suppress immune recognition, which is the target of most current early-phase trials of TGFβ inhibitors. Here we discuss the implications of a less well-recognized aspect of TGFβ biology regulating DNA repair that mediates responses to radiation and chemotherapy. In cancers that are TGFβ signaling-competent, TGFβ promotes effective DNA repair and suppresses error-prone repair, thus conferring resistance to genotoxic therapies and limiting tumor control. Cancers in which TGFβ signaling is intrinsically compromised are more responsive to standard genotoxic therapy. Recognition that TGFβ is a key moderator of both DNA repair and immunosuppression might be used to synergize combinations of genotoxic therapy and immunotherapy to benefit cancer patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-3750
  11. Cell Biosci. 2023 Jan 04. 13(1): 2
    Single-cell DNA methylation sequencing by combinatorial indexing and enzymatic DNA methylation conversion.
    Zac Chatterton, Praves Lamichhane, Diba Ahmadi Rastegar, Lauren Fitzpatrick, Hélène Lebhar, Christopher Marquis, Glenda Halliday, John B Kwok.
       BACKGROUND: DNA methylation is a critical molecular mark involved in cellular differentiation and cell-specific processes. Single-cell whole genome DNA methylation profiling methods hold great potential to resolve the DNA methylation profiles of individual cell-types. Here we present a method that couples single-cell combinatorial indexing (sci) with enzymatic conversion (sciEM) of unmethylated cytosines.
    RESULTS: The sciEM method facilitates DNA methylation profiling of single-cells that is highly correlated with single-cell bisulfite-based workflows (r2 > 0.99) whilst improving sequencing alignment rates, reducing adapter contamination and over-estimation of DNA methylation levels (CpG and non-CpG). As proof-of-concept we perform sciEM analysis of the temporal lobe, motor cortex, hippocampus and cerebellum of the human brain to resolve single-cell DNA methylation of all major cell-types.
    CONCLUSION: To our knowledge sciEM represents the first non-bisulfite single-cell DNA methylation sequencing approach with single-base resolution.
    Keywords:  APOBEC; Brain; DNA methylation; Epigenetics; Single-cell
    DOI:  https://doi.org/10.1186/s13578-022-00938-9
  12. South Asian J Cancer. 2022 Jul;11(3): 207-212
    Is Optimal Cytoreduction Post Neoadjuvant Chemotherapy the Only Prognostic Factor in Advanced Ovarian Cancer?
    Pravesh Dhiman, P P Bapsy, C N Patil, Renu Raghupathi.
      Pravesh Dhiman, DNB (Medical Oncology).Background  Epithelial ovarian cancer (EOC) is one of the leading causes of cancer-related death in women. Approximately 70% of patients with EOC are diagnosed in advanced stage [The International Federation of Gynecology and Obstetrics(FIGO stage III and IV)] with an expected 5-year survival rate of 30%. Numerous studies have shown that survival with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is noninferior to primary debulking surgery followed by chemotherapy. Materials and Methods  In this retroprospective observational study, 50 patients with advanced ovarian cancer, diagnosed from January 2012 to January 2015, were included and followed-up till January 2017. Correlation of NACT with patient profile, CA125 levels, clinicopathologic parameters, progression-free survival (PFS), and treatment response was studied. Statistical analysis was performed using log-rank test and Kaplan-Meir survival plots. Results  The extent of cytoreduction significantly correlated with PFS. The PFS was maximum in patients who had optimal cytoreduction (19 months) and 10 months in patients with suboptimal cytoreduction with p -value < 0.05. The survival was not significantly correlated with other parameters such as age, stage, preoperative CA125 levels, and ascites. Conclusions  The extent of cytoreduction following NACT in this study was associated with statistically significant PFS advantage in patients who were able to undergo optimal cytoreduction, but not significantly correlated to other factors such as age, stage, preoperative CA125 levels, and ascites. NACT followed by interval cytoreduction is an important modality affecting survival in advanced EOC. Further studies and longer follow-up are needed to demonstrate survival advantage over standard treatment.
    Keywords:  cytoreductive surgery; epithelial ovarian cancer; interval debulking surgery; neoadjuvant chemotherapy; progression-free survival
    DOI:  https://doi.org/10.1055/s-0042-1755291
  13. Front Pharmacol. 2022 ;13 1106129
    Editorial: Targeting the PD-1/PD-L1 cancer immune evasion axis: Challenges and emerging strategies, Volume II.
    Xiujing He, Jie Xu, Huan Meng, Hubing Shi.
      
    Keywords:  anti-cancer immunity; biomarker; combination therapy; immunotherapy; therapeutic toxicity
    DOI:  https://doi.org/10.3389/fphar.2022.1106129
  14. Med Oncol. 2023 Jan 05. 40(2): 71
    DNA methylation and cancer: transcriptional regulation, prognostic, and therapeutic perspective.
    Sannidhi Bhootra, Nandana Jill, Geetha Shanmugam, Sudeshna Rakshit, Koustav Sarkar.
      DNA methylation is one among the major grounds of cancer progression which is characterized by the addition of a methyl group to the promoter region of the gene thereby causing gene silencing or increasing the probability of mutations; however, in bacteria, methylation is used as a defense mechanism where DNA protection is by addition of methyl groups making restriction enzymes unable to cleave. Hypermethylation and hypomethylation both pose as leading causes of oncogenesis; the former being more frequent which occurs at the CpG islands present in the promoter region of the genes, whereas the latter occurs globally in various genomic sequences. Reviewing methylation profiles would help in the detection and treatment of cancers. Demethylation is defined as preventing methyl group addition to the cytosine DNA base which could cause cancers in case of global hypomethylation, however, upon further investigation; it could be used as a therapeutic tool as well as for drug design in cancer treatment. In this review, we have studied the molecules that induce and enzymes (DNMTs) that bring about methylation as well as comprehend the correlation between methylation with transcription factors and various signaling pathways. DNA methylation has also been reviewed in terms of how it could serve as a prognostic marker and the various therapeutic drugs that have come into the market for reversing methylation opening an avenue toward curing cancers.
    Keywords:  DNA methylation; DNA methyltransferase; Demethylation; Gene regulation; Prognostic marker; Therapeutic drugs
    DOI:  https://doi.org/10.1007/s12032-022-01943-1
  15. Cancer Res. 2023 Jan 04. 83(1): 1-2
    Highlights from Recent Cancer Literature.
      
    DOI:  https://doi.org/10.1158/0008-5472.CAN-83-1-BI
  16. Cancer. 2023 Jan 03.
    Spatial PD-L1, immune-cell microenvironment, and genomic copy-number alteration patterns and drivers of invasive-disease transition in prospective oral precancer cohort.
    William N William, Jianjun Zhang, Xin Zhao, Edwin R Parra, Naohiro Uraoka, Heather Y Lin, S Andrew Peng, Adel K El-Naggar, Jaime Rodriguez-Canales, Jaejoon Song, Ann M Gillenwater, Ignacio I Wistuba, Jeffrey N Myers, Kathryn A Gold, Renata Ferrarotto, Patrick Hwu, Teresa Davoli, J Jack Lee, John V Heymach, Vassiliki A Papadimitrakopoulou, Scott M Lippman.
       BACKGROUND: Studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent/metastatic head and neck squamous cell carcinoma therapy. This study investigated the timing, influence of somatic copy-number alterations (SCNAs), and clinical implications of PD-L1 and immune-cell patterns in oral precancer (OPC).
    METHODS: The authors evaluated spatial CD3, CD3/8, and CD68 density (cells/mm2 ) and PD-L1 (membranous expression in cytokeratin-positive intraepithelial neoplastic cells and CD68) patterns by multiplex immunofluorescence in a 188-patient prospective OPC cohort, characterized by clinical, histologic, and SCNA risk factors and protocol-specified primary end point of invasive cancer. The authors used Wilcoxon rank-sum and Fisher exact tests, linear mixed effect models, mediation, and Cox regression and recursive-partitioning analyses.
    RESULTS: Epithelial, but not CD68 immune-cell, PD-L1 expression was detected in 28% of OPCs, correlated with immune-cell infiltration, 9p21.3 loss of heterozygosity (LOH), and inferior oral cancer-free survival (OCFS), notably in OPCs with low CD3/8 cell density, dysplasia, and/or 9p21.3 LOH. High CD3/8 cell density in dysplastic lesions predicted better OCFS and eliminated the excess risk associated with prior oral cancer and dysplasia. PD-L1 and CD3/8 patterns revealed inferior OCFS in PD-L1 high intrinsic induction and dysplastic immune-cold subgroups.
    CONCLUSION: This report provides spatial insight into the immune landscape and drivers of OPCs, and a publicly available immunogenomic data set for future precancer interrogation. The data suggest that 9p21.3 LOH triggers an immune-hot inflammatory phenotype; whereas increased 9p deletion size encompassing CD274 at 9p24.1 may contribute to CD3/8 and PD-L1 depletion during invasive transition. The inferior OCFS in PD-L1-high, immune-cold OPCs support the development of T-cell recruitment strategies.
    Keywords:  HPV; PD-L1; T-cells; copy-number alterations; genomics; head and neck cancer; immune profiling; precancer; tumor microenvironment
    DOI:  https://doi.org/10.1002/cncr.34607
  17. Int J Gynecol Cancer. 2023 Jan 05. pii: ijgc-2022-003813. [Epub ahead of print]
    Survival in stage IV ovarian cancer with increased use of debulking surgery and bevacizumab.
    Leen Verleye, Diego Castanares-Zapatero, Carl Devos, Cindy De Gendt, Geert Silversmit, Nancy Van Damme, Frank Hulstaert, Nancy Thiry, Mattias Neyt.
       OBJECTIVES: Advanced ovarian cancer has a poor prognosis, with a 5 year survival probability of <30%. Attempts to improve survival have focused on debulking surgery and systemic therapy. We assessed the evolution of treatment patterns and survival of patients with advanced epithelial ovarian cancer with specific attention to changes in survival after introducing bevacizumab.
    METHODS: Population based data from the Belgian Cancer Registry were coupled with administrative reimbursement data from the compulsory health insurance organizations and the national database where date of death is registered, based on the patient's unique national number. Patients with epithelial ovarian cancer stage IV diagnosed in 2004-17 were included. The proportion of patients who underwent debulking surgery and received bevacizumab was calculated per incidence year. Survival was compared for the three incidence periods (2004-08, 2009-13, 2014-17) and before and after the introduction of bevacizumab.
    RESULTS: 2034 patients with stage IV epitheial ovarian cancer were included. From 2012 onwards, uptake of bevacizumab increased, with 50% of patients with stage IV ovarian cancer diagnosed in 2017 receiving bevacizumab. The proportion of stage IV patients who underwent debulking surgery also increased over time, from 21.1% in 2004-08 to 50.4% and 45.4% in 2009-13 and 2014-17, respectively. The 3 year observed survival probability fluctuated between 27% and 42% without a trend over time. The increase in debulking surgery was associated with improved survival (hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.79 to 0.98) but the introduction of bevacizumab was not (HR 0.94, 95% CI 0.85 to 1.03). For patients diagnosed in 2004, the mean cost per patient treated with oncological drugs was about €12 500, which doubled to about €25 000 for patients diagnosed in 2014 or later.
    CONCLUSIONS: Despite a rise in the use of debulking surgery and the introduction of bevacizumab into clinical practice, no improvement in 3 year survival probability was observed for patients with advanced ovarian cancer in Belgium.
    Keywords:  Medical Oncology; Ovarian Cancer; Surgery
    DOI:  https://doi.org/10.1136/ijgc-2022-003813
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