bims-ovdlit 2022-11-13 papers

bims-ovdlit

Biomed News

on Ovarian cancer: early diagnosis, liquid biopsy and therapy

Issue of 2022–11–13
ten papers selected by
Lara Paracchini, Humanitas Research

Molecular monitoring in endometrial cancer - ready for prime time?
Profiling the immune landscape in mucinous ovarian carcinoma.
Resistance to Poly (ADP-Ribose) Polymerase Inhibitors (PARPi): Mechanisms and Potential to Reverse.
From the patient to the population: Use of genomics for population screening.
Integrative analysis of multi-omics data for liquid biopsy.
Spatial epigenomics in single cells.
Spatial genomics maps the structure, nature and evolution of cancer clones.
Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51.
Combination cancer immunotherapies: Emerging treatment strategies adapted to the tumor microenvironment.
Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Clin Cancer Res. 2022 Nov 10. pii: CCR-22-2781. [Epub ahead of print]

Molecular monitoring in endometrial cancer - ready for prime time?

Brooke M Grant, Trevor J Pugh, Amit M Oza.

Efforts are underway to define the role of minimally invasive strategies for molecular monitoring and risk stratification in endometrial cancer (EC). A recent publication aims to define the association between circulating tumour DNA (ctDNA) level and disease stage in newly diagnosed EC patients and determine whether sequencing of longitudinal cell-free DNA (cfDNA) samples can be used for disease monitoring and detection of progression or recurrence. These results accelerate the current knowledge of molecular follow up in EC.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2781
Gynecol Oncol. 2022 Nov 08. pii: S0090-8258(22)01899-6. [Epub ahead of print]168 23-31

Profiling the immune landscape in mucinous ovarian carcinoma.

Nicola S Meagher, Phineas Hamilton, Katy Milne, Shelby Thornton, Bronwyn Harris, Ashley Weir, Jennifer Alsop, Christiani Bisinoto, James D Brenton, Angela Brooks-Wilson, Derek S Chiu, Kara L Cushing-Haugen, Sian Fereday, Dale W Garsed, Simon A Gayther, Aleksandra Gentry-Maharaj, Blake Gilks, Mercedes Jimenez-Linan, Catherine J Kennedy, Nhu D Le, Anna M Piskorz, Marjorie J Riggan, Mitul Shah, Naveena Singh, Aline Talhouk, Martin Widschwendter, David D L Bowtell, Francisco J Candido Dos Reis, Linda S Cook, Renée T Fortner, María J García, Holly R Harris, David G Huntsman, Anthony N Karnezis, Martin Köbel, Usha Menon, Paul D P Pharoah, Jennifer A Doherty, Michael S Anglesio, Malcolm C Pike, Celeste Leigh Pearce, Michael L Friedlander, Anna DeFazio, Brad H Nelson, Susan J Ramus.

   OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients.
METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration.
RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates.
CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.

Keywords:  Immune infiltrate; Mucinous ovarian carcinoma; Rare histotype

DOI:  https://doi.org/10.1016/j.ygyno.2022.10.022
Curr Oncol Rep. 2022 Nov 08.

Resistance to Poly (ADP-Ribose) Polymerase Inhibitors (PARPi): Mechanisms and Potential to Reverse.

Christina R Washington, Kathleen N Moore.

   PURPOSE OF REVIEW: This review will focus on the most common mechanisms for poly (ADP-ribose) polymerase inhibitors' (PARPi) resistance and the main strategies for overcoming acquired or de novo PARPi resistance.
RECENT FINDINGS: Initial approvals for PARPi as part of treatment for advanced epithelial ovarian cancer (EOC) started in 2014 with patient with recurrent cancer characterized by BRCA mutations in the 3rd and 4th line and now have approvals for front-line maintenance in both the BRCA mutated and BRCAwt populations. As with all therapies, patients will eventually develop resistance to treatment. The most common mechanisms for PARPi resistance include reversion mutations, methylation events, and restoration of homologous recombination deficiency (HRD) through combinations and targeting replication stress. As more and more patients receive initial treatment (and potential retreatment with PARPi), we need to better understand the mechanisms in which tumors acquire PARPi resistance.

Keywords:  BRCA mutation; Epithelial ovarian cancer; Homologous recombination deficiency; Niraparib; Olaparib; PARP inhibitor resistance; PARP inhibitors; Restoration of homologous recombination proficiency; Rucaparib

DOI:  https://doi.org/10.1007/s11912-022-01337-6
Front Genet. 2022 ;13 893832

From the patient to the population: Use of genomics for population screening.

Chloe Mighton, Salma Shickh, Vernie Aguda, Suvetha Krishnapillai, Ella Adi-Wauran, Yvonne Bombard.

  Genomic medicine is expanding from a focus on diagnosis at the patient level to prevention at the population level given the ongoing under-ascertainment of high-risk and actionable genetic conditions using current strategies, particularly hereditary breast and ovarian cancer (HBOC), Lynch Syndrome (LS) and familial hypercholesterolemia (FH). The availability of large-scale next-generation sequencing strategies and preventive options for these conditions makes it increasingly feasible to screen pre-symptomatic individuals through public health-based approaches, rather than restricting testing to high-risk groups. This raises anew, and with urgency, questions about the limits of screening as well as the moral authority and capacity to screen for genetic conditions at a population level. We aimed to answer some of these critical questions by using the WHO Wilson and Jungner criteria to guide a synthesis of current evidence on population genomic screening for HBOC, LS, and FH.

Keywords:  familial hypercholestelemia; genetic testing; hereditary breast and ovarian cancer (HBOC); lynch syndrome; population screening; tier 1 conditions

DOI:  https://doi.org/10.3389/fgene.2022.893832
Br J Cancer. 2022 Nov 10.

Integrative analysis of multi-omics data for liquid biopsy.

Geng Chen, Jing Zhang, Qiaoting Fu, Valerie Taly, Fei Tan.

The innovation of liquid biopsy holds great potential to revolutionise cancer management through early diagnosis and timely treatment of cancer. Integrative analysis of different tumour-derived omics data (such as genomics, epigenetics, fragmentomics, and proteomics) from body fluids for cancer detection and monitoring could outperform the analysis of single modality data alone. In this review, we focussed on the discussion of early cancer detection and molecular residual disease surveillance based on multi-omics data of blood. We summarised diverse types of tumour-derived components, current popular platforms for profiling cancer-associated signals, machine learning approaches for joint analysis of liquid biopsy data, as well as multi-omics-based early detection of cancers, molecular residual disease monitoring, and treatment response surveillance. We also discussed the challenges and future directions of multi-omics-based liquid biopsy. With the development of both experimental protocols and computational methods dedicated to liquid biopsy, the implementation of multi-omics strategies into the clinical workflow will likely benefit the clinical management of cancers including decision-making guidance and patient outcome improvement.

DOI: https://doi.org/10.1038/s41416-022-02048-2
Nat Rev Genet. 2022 Nov 08.

Spatial epigenomics in single cells.

Linda Koch.

DOI: https://doi.org/10.1038/s41576-022-00552-y
Nature. 2022 Nov 09.

Spatial genomics maps the structure, nature and evolution of cancer clones.

Artem Lomakin, Jessica Svedlund, Carina Strell, Milana Gataric, Artem Shmatko, Gleb Rukhovich, Jun Sung Park, Young Seok Ju, Stefan Dentro, Vitalii Kleshchevnikov, Vasyl Vaskivskyi, Tong Li, Omer Ali Bayraktar, Sarah Pinder, Andrea L Richardson, Sandro Santagata, Peter J Campbell, Hege Russnes, Moritz Gerstung, Mats Nilsson, Lucy R Yates.

Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1-3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.

DOI: https://doi.org/10.1038/s41586-022-05425-2
Nat Commun. 2022 Nov 07. 13(1): 6722

Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51.

Anne Margriet Heijink, Colin Stok, David Porubsky, Eleni Maria Manolika, Jurrian K de Kanter, Yannick P Kok, Marieke Everts, H Rudolf de Boer, Anastasia Audrey, Femke J Bakker, Elles Wierenga, Marcel Tijsterman, Victor Guryev, Diana C J Spierings, Puck Knipscheer, Ruben van Boxtel, Arnab Ray Chaudhuri, Peter M Lansdorp, Marcel A T M van Vugt.

Sister chromatid exchanges (SCEs) are products of joint DNA molecule resolution, and are considered to form through homologous recombination (HR). Indeed, SCE induction upon irradiation requires the canonical HR factors BRCA1, BRCA2 and RAD51. In contrast, replication-blocking agents, including PARP inhibitors, induce SCEs independently of BRCA1, BRCA2 and RAD51. PARP inhibitor-induced SCEs are enriched at difficult-to-replicate genomic regions, including common fragile sites (CFSs). PARP inhibitor-induced replication lesions are transmitted into mitosis, suggesting that SCEs can originate from mitotic processing of under-replicated DNA. Proteomics analysis reveals mitotic recruitment of DNA polymerase theta (POLQ) to synthetic DNA ends. POLQ inactivation results in reduced SCE numbers and severe chromosome fragmentation upon PARP inhibition in HR-deficient cells. Accordingly, analysis of CFSs in cancer genomes reveals frequent allelic deletions, flanked by signatures of POLQ-mediated repair. Combined, we show PARP inhibition generates under-replicated DNA, which is processed into SCEs during mitosis, independently of canonical HR factors.

DOI: https://doi.org/10.1038/s41467-022-34519-8
Sci Transl Med. 2022 Nov 09. 14(670): eabo3605

Combination cancer immunotherapies: Emerging treatment strategies adapted to the tumor microenvironment.

Nicole Kirchhammer, Marcel P Trefny, Priska Auf der Maur, Heinz Läubli, Alfred Zippelius.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, resistance to ICB occurs frequently due to tumor-intrinsic alterations or extrinsic factors in the tumor microenvironment. This Viewpoint aims to give an update on recent developments in immunotherapy for solid tumors and highlights progress in translational research and clinical practice.

DOI: https://doi.org/10.1126/scitranslmed.abo3605
Nat Med. 2022 Nov 10.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Justin Jee, Emily S Lebow, Randy Yeh, Jeeban P Das, Azadeh Namakydoust, Paul K Paik, Jamie E Chaft, Gowtham Jayakumaran, A Rose Brannon, Ryma Benayed, Ahmet Zehir, Mark Donoghue, Nikolaus Schultz, Debyani Chakravarty, Ritika Kundra, Ramyasree Madupuri, Yonina R Murciano-Goroff, Hai-Yan Tu, Chong-Rui Xu, Andrés Martinez, Clare Wilhelm, Jesse Galle, Bobby Daly, Helena A Yu, Michael Offin, Matthew D Hellmann, Piro Lito, Kathryn C Arbour, Marjorie G Zauderer, Mark G Kris, Kenneth K Ng, Juliana Eng, Isabel Preeshagul, W Victoria Lai, John J Fiore, Afsheen Iqbal, Daniela Molena, Gaetano Rocco, Bernard J Park, Lee P Lim, Mark Li, Candace Tong-Li, Madhawa De Silva, David L Chan, Connie I Diakos, Malinda Itchins, Stephen Clarke, Nick Pavlakis, Adrian Lee, Natasha Rekhtman, Jason Chang, William D Travis, Gregory J Riely, David B Solit, Mithat Gonen, Valerie W Rusch, Andreas Rimner, Daniel Gomez, Alexander Drilon, Howard I Scher, Sohrab P Shah, Michael F Berger, Maria E Arcila, Marc Ladanyi, Ross L Levine, Ronglai Shen, Pedram Razavi, Jorge S Reis-Filho, David R Jones, Charles M Rudin, James M Isbell, Bob T Li.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

DOI: https://doi.org/10.1038/s41591-022-02047-z